18 Diabetes by Urvi Trivedi

SECTION 18

Diabetes 158.

Unburdening the Burden of Diabetes V Seshiah, V Balaji, Madhuri S Balaji

739

159.

Diabetes: Ethical Issues Vitull K Gupta, Meghna Gupta, Sonia Arora

742

160.

Continuous Glucose Monitoring (CGM) Systems YP Munjal, Joydeep Chaudhuri, RK Singal

746

161.

Lipids and Diabetes Vijay Panikar, Tejas Kamat, Jimit Vadgama

751

162.

Appoach to Brittle Diabetes Seetha Raju

755

163.

Pancreatic Diabetes Sidhartha Das, SK Tripathy, BP Panda

757

164.

Diabetes Mellitus: A CV Risk Equivalent Kashinath Padhiary

762

165.

Statin Associated New Onset Diabetes Mellitus – Myth or Reality? VA Kothiwale, Deebanshu Gupta, R Ravikanth, Saurabh Gaur

764

166.

Alpha Cells, Glucagon and Type 2 Diabetes SP Sondhi, Amit Rastogi, Shaifali Nandwani

768

167.

Treating Diabetes - A Matter of Selectivity of Sulphonylureas AJ Asirvatham

770

168.

Type 2 Diabetes in Young Samar Banerjee

774

169.

Metformin Revisited – 2016 Rajinder Singh Gupta, Harbir Kaur Rao

778

170.

Hydroxychloroquine: A Therapeutic Choice in Diabetes Mellitus Narayan Deogaonkar

782

171.

Insulin Pumps in India NP Jain, Rishu Bhanot

785

172.

SGLT-2 Inhibitor: A Unique Antidiabetic in Type 2 Diabetes Mellitus AK Chauhan

788

173.

SGLT2 Inhibitors Vijay Negalur

791

174.

Clinical Impact of Newer Insulins for the Management of Type 2 Diabetes Marc Evans

796

175.

Prevention and Management of Diabetic Autonomic Neuropathy AK Mukherjee

803

176.

Management of Autonomic Neuropathy in Diabetes R Rajasekar

809

177.

Approach to Hypoglycemia Benny Negalur

814

178.

Prevention of Diabetes Mellitus Anupam Prakash, Yash Pal Munjal, Aparna Kansal, Ghan Shyam Pangtey

817

179.

Hyperglycemia in Pregnancy Sunil Gupta, Gurleen Wander

821

180.

Basal Insulin in Type 2 Diabetes Mellitus Parikshit Goswami

826

181.

Empagliflozin: Potential Mechanisms of Cardiovascular Benefits Aparna Kansal, Suman Kirti, YP Munjal

830

C H A P T E R

158

Unburdening the Burden of Diabetes

The prevalence of diabetes is increasing globally and India is no exception. The lifestyle modification and drug intervention are likely to delay or postpone the development of overt diabetes in persons diagnosed to have impaired glucose tolerance. This is a post primary prevention strategy. The primary prevention is more important as this effort is likely to reverse or halt the epidemic of disease. Women with Gestational Diabetes Mellitus (GDM) are an ideal group for the primary prevention of diabetes as they are at increased risk of future diabetes, predominantly type 2 diabetes, as are their children. Pima Indians have the highest prevalence of diabetes. This is attributed to the children exposed in utero to maternal diabetes. Hence as a policy to identify GDM and its consequences on the infant, a 75gm Oral Glucose Tolerance Test has been recommended to all Pima Indian women during the 3rd trimester of pregnancy. Ethnically Asian Indian women also have high prevalence of diabetes and the relative risk of developing Gestational Diabetes Mellitus in them is 11.3 times compared to White women. This necessitates universal screening for gestational diabetes during pregnancy in India. Probably the undiagnosed gestational diabetes that has been occurring in the past has resulted in the increased prevalence of diabetes in India. The timely action taken now in screening all pregnant women for glucose intolerance, achieving euglycemia in them and ensuring adequate nutrition may prevent in all possibility, India becoming the diabetes capital of the world. The prevalence of diabetes is increasing globally and India is no exception. The concern is that India would be having the highest population of diabetes by 2025.1 The increased prevalence is attributed to the aging population structure, urbanization, the obesity epidemic, and physical inactivity. While all these factors contribute to the epidemic of diabetes, early life exposures are emerging as potential risk factors. The ‘‘fetal origin of disease’’ hypothesis proposes that gestational programming may critically influence adult health and disease. Gestational programming is a process whereby stimuli or stresses that occur at critical or sensitive periods of development, permanently change structure, physiology, and metabolism, which predispose individuals to disease in adult life. Traditionally and convincingly, lifestyle modifications and drug interventions have proved to delay or postpone the development of overt diabetes in persons diagnosed to have impaired glucose tolerance. This is a post primary prevention strategy. The primary prevention of Type 2 DM at best would mean to keep genetically or otherwise susceptible individuals

V Seshiah, V Balaji, Madhuri S Balaji

normoglycemic and not only preventing Type 2 DM from developing. The primary prevention is more important than post primary prevention, as this effort is likely to reverse or halt the epidemic of disease. Women with Gestational Diabetes Mellitus (GDM) are an ideal group for the primary prevention of diabetes as they are at increased risk of developing diabetes predominantly Type 2 DM as are their children. Gestational Diabetes Mellitus is defined as carbohydrate intolerance of variable severity with onset or first recognition during the present pregnancy. Women with GDM have an increased lifetime risk of developing diabetes, at over 3 times compared to controls at 16 years after index pregnancy. By 17 years of age one third of children born to GDM mothers have had evidence of IGT or Type 2 DM. In our ongoing community based project sponsored by World Diabetes Foundation, 33% of the women who developed GDM had maternal history of diabetes. The familial predisposition to type 2 diabetes mellitus is mediated by both genetic and intrauterine environmental factors. The contribution of the genetic factor may be due to the major role played by maternal mitochondrial DNA in the transmission of disease. The ovum is well supplied with mitochondria but the sperm contains a few and even those few do not persist in the offspring. At fertilization, it is the nucleus of the spermatazoan that enters the ovum and thus all the cytoplasm, mitochondria and mitochondrial DNA are exclusively maternally inherited. Maternal inheritance is attributed to mutation in the gene(s) present on mitochondrial DNA and is transmitted invariably by an affected mother to her progeny. However studies have also shown, low genetic risk for diabetes, exposure to hyperglycemia in utero significantly increases the risk of diabetes in adult life. Yet another study revealed that children exposed in utero to maternal diabetes are at a higher risk of obesity and diabetes than their unexposed siblings, suggesting that the increased risk to the exposed offspring is not exclusively genetic. These observations clearly indicate the need to focus on the intra uterine environment. The maternal fuels glucose, amino acids and lipids (mixed nutrients) which are in excess in women with glucose intolerance due to decreased insulin secretion or action, cross the placenta and stress the fetal beta cells. The fetus responds to the mixed nutrients by secreting large quantities of insulin. This results in increasing adiposity and accrual of visceral fat that eventually causes decrease in fetal pancreatic reserve and the infant is at risk for developing

DIABETES

740

subsequent diabetes. On the other hand, intrauterine malnutrition causes intrauterine growth retardation and this under nutrition is associated with decreased pancreatic reserve. Thus both small for dates infants and large for dates infants are at risk for subsequent diabetes. In India, both under nutrition and over nutrition exist during pregnancy. There are two reported studies in India which are related to the size at birth to future risk of Type 2 diabetes. In Mysore, low birth weight did not increase the risk of diabetes but babies who were short and fat (higher body mass index, BMI) at birth were at increased risk.16 Fall et al speculate that the rise in Type 2 diabetes in Indian urban populations may have been triggered by mild obesity in mothers, leading to glucose intolerance during pregnancy, macrosomic changes in the fetus and insulin deficiency in adult life. Yet another study by Yajnik et al attributes high prevalence of Type 2 DM and IGT in Indian people may be linked to poor fetal growth.17 Same author also suggests that Type 2 DM in India may be programmed in fetal life, hence diabetes prevention will have to start in early life (in utero) and continue in later life. The importance is that the intrauterine millieur interieur, whether one of nutritional deprivation or one of nutritional plenty, results in changes in pancreatic development and peripheral response to insulin that may lead to adult onset GDM and Type 2 DM. The aim should be to help the pregnant women to have infants born with weight appropriate for gestational age (AGA) by adequate and appropriate nutrition and maintaining fasting plasma glucose < 90mg and peak plasma glucose < 120 mg. In Pima Indians, the population with the highest known rate of diabetes, a study found that the increased exposure to diabetes in utero and childhood obesity accounted for most of the increased prevalence of diabetes over the past 30 years. If the diabetic intrauterine environment is substantially contributing to the obesity and diabetes epidemics, populations that have a high prevalence of diabetes will continue to be disproportionately affected by these epidemics, resulting in a perpetual widening of health disparities between racial and ethnic groups. It is imperative to understand the trans generational epidemiology and etiology of diabetes and develop simple, economical, and effective prevention strategies. These observations call for the screening for the glucose intolerance during pregnancy and ensuring adequate nutrition for the developing fetus. The WHO criteria of 2h PPG > 140 mg/dl identifying a large number of cases may have a greater potential for prevention and is being followed in many parts of the world.The screening for glucose intolerance is usually performed around 24 – 28 weeks of gestation. But a statistically significant number of GDM mothers deliver big babies despite good glycemic control in the third trimester. This is due to the undetected glucose intolerance in them in the early weeks of gestation that influences the fetal growth. Fetal pancreatic islets of Langerhans differentiate during the 10th and 11th week

of development and begin to release insulin in response to nutrients as early as 11th – 15th weeks of gestation. The priming of the beta cell mass in early gestation may account for the persistent fetal hyperinsulinemia throughout pregnancy and the risk of accelerated growth, even when the mother enjoys good metabolic control in later pregnancy. Alterations of intrauterine environment in particular, the development of hyperinsulinemia is strongly associated with the development of obesity and IGT during childhood and puberty. ‘Early maternal metabolic imprint may affect the fetal growth’. This observation implies that screening is to be performed in the first trimester itself as the fetal beta cell recognizes and response to maternal glycemic level as early as 16 th week of gestation. The criteria recommended by WHO is simple and cost effective and is practiced in many centers. But the pregnant woman has to be in the fasting state. Asking a pregnant woman to come in the fasting state is impractical in many settings due to long distance of travel to reach the health centers for the test. Besides pregnant woman does not want to be in the fasting state for long hours as she believes that fasting is not good for her fetus. International association of diabetes in pregnancy study group (IADPSG), recommends that GDM can be diagnosis if any one value meet or exceed FPG 92mgs,1hr 180mgs and 2hr pg 153mgs with 75g of oral glucose load. This procedure also impractical as it is not cost effective and the pregnant women has to be in the fasting state. To overcome all this practical problems A single step procedure of diagnosing GDM with 2hr pg>/ 140mgs after oral administration of 75g glucose to a a pregnant women in the fasting or non-fasting state, irrespective of the last meal timing was introduced. This procedure has been validated by a number of studies and Diabetes and pregnancy study group in India has accepted this procedure .Ministry of health govt of India, WHO and International association of gynaecologists and obstetricians (FIGO) have also accepted this procedure for diagnosing GDM. Over the next 2 to 3 decades there will be 80 million reproductive age women with diabetes in the world. Of these 20 million will live in India alone creating a potential for extremely high rates of maternal and infant morbidity. Women who had GDM, develop overt diabetes at a young age, substantially increasing their lifetime risk of developing complications from diabetes. In conclusion, increasing maternal hyperglycemia is associated with increasing pregnancy morbidity and increased likelihood of subsequent diabetes in the mother. In addition, maternal hyperglycemia has a direct effect on the development of fetal pancreas and is associated with increased susceptibility to future diabetes in the infant an effect which is independent of genetic factors. Among ethnic groups in South Asian countries, Indian women have the highest frequency of GDM necessitating universal screening for glucose intolerance during pregnancy in India. Probably the undiagnosed glucose intolerance that has been occurring in the past

Lifestyle/pharmacologic intervention to delay/prevent the onset of overt diabetes.

Prevention of T2DM in the offspring starts in the uterus GDM

Intervention with MNT/insulin to maintain normal maternal plasma glucose

Newborn birth weight appropriate for gestational age Prevention of obesity and IGT in the offspring by MNT and lifestyle modification

Intervention with MNT + lifestyle + drugs to prevent GDM from progressing to T2DM

Fig. 1

Hence, an important public health priority is prevention of diabetes, starting with maternal health pre and post conception. Preventive measures against Type 2 DM should start during intra uterine period and continue throughout life from early childhood. The timely action taken now in screening all pregnant women for glucose intolerance, achieving euglycemia in them and ensuring adequate nutrition may prevent in all probability, the vicious cycle of transmitting glucose intolerance from one generation to another.

REFERENCES

Text book of Diabetes and Pregnancy Edited by Moshe Hod, Lois Jovanovic, Gain Carlo Di Renzo, Alberto, Oded Langer. Published by MD Martin Dunitz Taylor &Francis Group Plc 2003

741

CHAPTER 158

Postpartum care

has resulted in the increased prevalence of diabetes in India. Moreover, women who have GDM, because of their high diabetes risk and young age, are ideally suited to be targeted for lifestyle or pharmacologic interventions to delay or prevent the onset of overt diabete.

C H A P T E R

159 “Ethics” stands for a set of philosophical beliefs and practices concerned with the distinction between right and wrong or system of moral values or code of conduct relating to morals in human beings. Morals are mainly derived from religious practices and are not open to arguments or logic. Ethics on the other hand are intellectually derived by a particular profession (Medicine, law etc) for its specific needs and may / can be changed or modified as per needs of the society or community. Medical ethics refers chiefly to the rules of etiquette adopted by the medical profession to regulate professional conduct with each other, with individual patients, with society, including considerations of the motives behind that conduct. Over the centuries, Hippocratic Oath has been rewritten often to suit the values of different cultures. The oath was restructured in 1947 by International Doctors Association at the Declaration of Geneva and a new International Code of Medical Ethics was conceived. In India registration by MCI is necessary for practice and doctors have to submit a duly signed declaration instead of Hippocratic Oath. In modern era traditional medical ethics changed into an interdisciplinary field involving theologians, lawyers, philosophers, social scientists and historians, as well as physicians and other health professionals because of increasing impact of science and technology, public expectations from new medicines and surgical techniques, changes in the financing and delivery of health care. With more stakeholders, such as medical devices companies, pharmaceutical companies, diagnostic clinics, insurance companies, clinical trial organizations and other service providers entering the field, there was a need to expand the scope of the definition of ethics within the field of medicine. Now the terms “bio-medical ethics”, “bio-pharmaceutical ethics”, and “health care ethics” are gaining importance.

DIABETES: AN OVERVIEW

The worldwide prevalence of diabetes is estimated to increase from 4% in 1995 to 5.4% by 2025. The increase will be sharpest in developing countries, where the number of diabetics will almost triple from 84 million to 228 million. The developing world will be responsible for more than 75% of diabetics in 2025, up from 62% in 1995. Among developing countries, the highest increase in prevalence will be in China followed by India. However, the greatest increase in numbers will be seen in India, where the number of diabetics will rise from 19 million in 1995 to 57 million in 2025, heading the list of countries with the greatest numbers of diabetics.

Diabetes: Ethical Issues Vitull K Gupta, Meghna Gupta, Sonia Arora

DIABETES: ETHICAL ISSUES

An increase in the number of diabetics is likely to have a serious impact on our country’s health-care system raising many ethical and social issues related to diabetes. Performing research and preventing, diagnosing, and treating diabetes raises ethical, legal, social and policy issues. Issues raised by diabetes include understanding and addressing barriers to research, such as analyzing the impact of patents on genes related to diabetes or of statutes that restrict certain types of research; assessing the challenges of bringing new diabetes-related technologies through the government approval process; conflicts of interest in research and medicine; and understanding and protecting the rights of human subjects in diabetes research, including genetics based research on collected or stored tissue samples. Other topics include assuring people’s access to appropriate services and healthcare; preventing discrimination against people who have diabetes, a predisposition to diabetes, or family members with diabetes; and analyzing the effects of direct marketing to patients on diagnosis, prevention, and treatment.

Primary prevention strategies: Ethical Issues

The burden of diabetes in the next 25 years is likely to sharpen the ethical dilemma of access to primary care as opposed to technologically-intensive care for complications. There is an urgent need to consider public health interventions to reduce the burden of diabetes and to contain its economic and social costs. Without primary prevention strategies at the public health level, the number of undiagnosed and uncared for diabetics will increase, as will the number of complications requiring a higher technological input. This in turn will limit access to health care for large numbers of patients. Scientific evidence of efficacy must also be considered before the allocation of limited healthcare resources. Primary prevention strategies which limit or delay the onset of diabetes are likely to be most desirable and cost effective. The question of dividing funds between primary prevention and pure research is likely to cause intense political, social and ethical debates. In a society like ours, the fascination for technologically-intensive, hospital based care is likely to take precedence over more cost-effective measures. At present, bureaucratic controls, corruption and a lack of motivation are some factors responsible for the abysmal quality of primary health care in India compromising the primary prevention strategies for diabetes, sparking ethical debates.

Primary Prevention of T2DM by Lifestyle Intervention: Ethical Issues

All of the major efficacy studies of lifestyle for primary prevention of diabetes were restricted to persons with glucose intolerance or very high risk for T2DM. However, the effectiveness of lifestyle intervention for persons at lower risk for diabetes is unknown. Is it ethical to await results of a new, extensive series of randomized controlled trials to evaluate intervention efficacy in groups at lower risk for diabetes or is it acceptable to infer intervention efficacy in these groups?

Possible harm associated with health recommendations has recently received considerable attention initiating debate that do broad, population-based programs require less evidence of efficacy than do individual clinical interventions or even greater proof is necessary in population-wide health promotion than in clinical care. Evidence that health promotion aimed at the general public will improve health needs to be even stronger than evidence for treating sick patients. Implementation of lifestyle programs for primary prevention of diabetes without full consideration of the effect on resources needed for other proven, effective diabetes treatment programs could set back efforts to reduce the overall burden of diabetes and initiate an ethical debate. So health professionals must ensure that the ethical mandate of nonmalfeasance, primum non nocere—first, do no harm—applies to health promotion and disease prevention programs as well as to clinical medicine.

Self-management of diabetes: Ethical Issue

Patient self-management (SM) of chronic diseases like diabetes is an evolving movement. Potential benefits from proper preparation and maintenance of patient SM skills include quality care tailored to the patient’s preferences and life goals, and increase in skills in problem solving, confidence and success, generalizable to other parts of the patient’s life. Four ethical issues arise with SM. 1) insufficient patient/family access to preparation that will optimize their competence to SM without harm to themselves, 2) lack of acknowledgement that an ethos of patient empowerment can mask transfer of responsibility beyond patient/family competency to handle that responsibility, 3) prevailing assumptions that preparation for SM cannot result in harm and that its main purpose is to deliver physician instructions, and 4) lack of standards for patient selection, which has the potential to exclude individuals who could benefit from learning to SM. Addressing these ethical issues require more evidence

743

Market-driven research in Diabetes: Ethical Issues

As the number of diabetic patients’ increases, the private health sector will find new and lucrative market opportunities. Given the present government’s economic and social philosophy, the market is take precedence over the patient’s interests. Market-driven research can deprive patients of cost effective treatment modalities. For example, companies have stopped production of cheaper forms of insulin (Bovine and Pork) arguing that human insulin is more physiological. Now there is promotion of analogs as compared to human insulin. However, the cost difference is phenomenal. There is ample evidence that healthrelated strategies, including those in the development of newer drugs, tend to be driven by the market rather than by people’s needs. Traditional medicines can contribute significantly towards the development of cost effective treatment modalities, guided by evidencebased research. Currently, compartmentalisation within medical education and in the medical profession prevents scientific research in traditional medicines. Such issues of market influences generate ethical debates relating market influences of diabetes care.

Costly therapy and diabetic complications: Ethical Issue

Various scientific trials have shown the enhanced benefits of aggressive insulin therapy to control and delay the onset of complications in sever diabetes, but intensive therapy with insulin is costly. So ethical dilemma faced by doctors is whether to start costly, intensive therapy with expensive human insulin to prevent future complications or to continue traditional therapy which could lead to early complications. Medical practitioners are often faced with an ethical dilemma rooted in economics. For example, foot gangrene is one of the most dreaded complications of diabetes. It is often possible to salvage the foot, but only at great expense. The family must incur heavy debts for this high-technology treatment. The alternative to taking on this economic burden may be amputation. In young diabetics, the loss of a limb can be crippling, even affecting one’s employment. The difficult decision to amputate is often based on social and economic factors. Similarly, in the case of end stage renal disease, where renal transplant is not feasible and the patient has multisystem failure, the question is how long should hemodialysis be continued in view of increasing costs and an almost certain unfavorable outcome. Such dilemmas are likely to increase as the number of diabetics with complications increases and the resource crunch becomes severe leading to a wider debate on ethical, social and economic issues related to management of diabetic complications. One cost-effective strategy for the treatment of diabetic complications is to develop effective home care by a cadre of health workers. Another area which needs attention is the development of special footwear for diabetic patients. Today, despite the many patients with foot problems, cost effective and scientifically devised footwear is not available even in urban areas. This presents another ethical dilemma to the

CHAPTER 159

Despite high interest on the part of the public and media in lifestyle approaches and support from respected authorities, the public is becoming overburdened with health recommendations, many of which are unclear, inconsistent, and impractical. Disease prevention programs that do not work in the real world, even if grounded in science, may erode public confidence in lifestyle change as a worthy goal. This creates ethical implications of translating diabetes prevention by lifestyle intervention into clinical practice.

about feasibility of SM and to optimize the benefits of SM while assuring that potential harms are controlled.

744

practitioner who salvages a foot at great economic and social costs — only to see the patient’s feet damaged by the lack of effective footwear. The development of effective footwear is a low-tech labor-intensive industry. It is also probably not very profitable, and hence neglected.

DIABETES

Diabetes and Driving Safety: Ethical issues

Driving is a common yet highly complex task and requires multitasking incorporating visual, motor, and cognitive abilities. Safe operation of a vehicle has significant implications for the physical and financial well-being of both our patients and the general public and it becomes a medical, public health and ethical issues for health care professionals regarding risk of both acute and chronic effects of diabetes like proliferative and advanced nonproliferative retinopathy may cause significant loss of peripheral vision and visual acuity (particularly in dim light situations or night driving). Peripheral neuropathy may result in significant lower limb proprioceptive defects, interfering with safe use of the pedals. Acute complications like significant hypoglycemia and hyperglycemia may impair perceptual, motor, cognition, awareness, and judgment. In light of the legal and ethical issues surrounding these growing scientific findings, the American Diabetes Association released a Position Statement on diabetes and driving which states that people with diabetes should be assessed individually, taking into account each individual’s medical history as well as the potential related risks associated with driving. Health care professionals, have a responsibility to discuss driving safety with patients who may have compromised driving ability secondary to diabetes and counseling them on preventive measures.

Diabetic Clinical Trials: Ethical Issues

The Declaration of Helsinki, an international document that describes ethical principles to be used in clinical investigations, states that “In any medical study, every patient, including those of a control group, if any, should be assured of the best proven diagnostic and therapeutic method”. But many of the placebo-controlled trials currently being performed to assess new oral diabetic therapies do not meet this ethical standard. Comparing an experimental drug with a placebo is perfectly ethical when no proven effective therapy exists and when the risk-to-benefit ratio needs to be assessed. However, when effective therapy exists, the use of placebo control subjects does not meet the ethical standard because efficacy and safety of the experimental medication should be tested by blindly randomizing to an existing drug that has been shown as effective and safe and not to placebo. Another ethical issue is, how long can hyperglycemia be permitted to continue in diabetic subjects undergoing trial? Prolonged hyperglycemia or more than 6 months hyperglycemia has the potential to exacerbate macrovascular complications and will have an adverse effect on the quality of life creating an ethical dilemma.

Predictive Genetic Testing for Diabetes: Ethical Issues

T2DM is a prevalent, chronic condition associated with

extensive morbidity, decreased quality of life, and increased utilization of health services. The polygenic nature of T2DM has been a major challenge to identifying genes involved in the pathogenesis of this disease knowledge that could give rise to new treatments and tests. Several genetic and genomic studies have identified genetic variants associated with increased risk to diabetes. As a result, commercial testing is available to predict an individual’s genetic risk. Although the clinical benefits of testing have not yet been demonstrated, it is worth considering some of the ethical implications of testing for diabetes. As new predictive genetic tests for T2DM are developed and commercialized, it will be critical to consider the potential ethical implications they raise and steps to prevent or ameliorate harms. Genetic susceptibility testing services for T2DM is available but experts are not convinced of its current clinical validity and utility generating an ethical issue. The variability of the severity of T2DM poses difficulties for the ethical evaluation of susceptibility testing for the disease. From a precautionary perspective, it could be argued that T2DM should be viewed as a severe disease and require high levels of genetic counseling and psychological support or hardly causes any psychological harm or emotional impact at all. There may be discrepancies between the severity of a disease as perceived by medical professionals and the severity of the same disease as perceived by other publics. There are both therapeutic options and well-established preventive strategies available for diabetes for children as well as for adults, at the level of lifestyle improvements. Existence of preventive options for T2DM implies a potential for medical benefits to be obtained from susceptibility testing. As a consequence, if false reassurance occurs, it may lead to harm. Individuals who are found to be at decreased risk may wrongly feel assured that they will remain free from disease, regardless of their lifestyles. They may fail to understand that general health recommendations are relevant to the whole of the population, including low-risk subgroups. Low-risk individuals may ignore these recommendations and consequently put their health conditions at risk. In presence limited or moderate clinical validity burdensome or too strong preventive measures will definitely raise ethical issues, such as psychological harms: at-risk children who do not adhere to lifestyle recommendations and develop the disease later in life may blame themselves or be blamed by others. Such ‘victim-blaming’ or feelings of guilt will not always be justified in the context of a multifactorial disease for which susceptibility testing is of moderate predictive ability: some at-risk individuals may develop the disease even if they take appropriate measures, whereas other at-risk individuals may not fall ill despite their failing to take preventive action. There is currently insufficient evidence to support an offer of genetic susceptibility testing for T2DM to children or minors.

Type 1 DM Research with Children: Ethical Issues

HLA genotyping can be used to identify children at increased risk for type 1 diabetes mellitus (T1DM) and research studies to evaluate this testing strategy are currently being implemented. Research involving children raises significant questions, and families may need guidance in considering the risks and benefits of participation.

Embryonic stem cells: Ethical issue

Surgical treatment of T2DM: Ethical Issues

International conferences on bariatric surgery for T2DM have concluded that bariatric surgery is an effective treatment of T2DM in morbidly obese subjects (body-mass index (BMI) > 35 kg/m2) and recently bariatric surgery has been launched as an attractive treatment alternative for patients with T2DM and BMI < 35 kg/m2 generating ethical debate because of limited evidence on the effect and safety of bariatric surgery in persons with BMI < 35 kg/ m2 particularly in those with T2DM. Some critics argue that even with high quality evidence for morbidly obese persons, we cannot uncritically extrapolate results on T2DM from persons with BMI ≥ 35 kg/m2 to those with

745

REFERENCES

1. King H: Global burden of diabetes. Diabetes Care 1998; 21:1414-1431. 2. Arun Bal. Diabetes: ethical, social and economic aspects. The Indian Journal of Medical Ethics 2000; 8:3. 3. David F. Williamson, Frank Vinicor, Barbara A. Bowman. Primary Prevention of Type 2 Diabetes Mellitus by Lifestyle Intervention: Implications for Health Policy. Ann Intern Med 2004; 140:951-957. 4.

Redman BK. Responsibility for control; ethics of patient preparation for self-management of chronic disease. Bioethics 2007; 21:243-50.

5. Daniel J. Cox, Harsimran Singh, Daniel Lorber. Diabetes and Driving Safety: Science, Ethics, Legality & Practice. Am J Med Sci 2013; 345:263–265. 6. David S. H. Bell. Ethics in Diabetic Clinical Trials. Diabetes Care 2001; 24:606-606. 7. Susanne B. Haga. Ethical Issues of Predictive Genetic Testing for Diabetes. J Diabetes Sci Technol 2009; 3:781–788. 8. Eline M Bunnik, Maartje HN Schermer, A Cecile JW Janssens. The role of disease characteristics in the ethical debate on personal genome testing. BMC Medical Genomics 2012 9. Bjorn Hofmann, Joran Hjelmeaeth Torgeir Thorson Sovik. Moral challenges with surgical treatment of type 2 diabetes. 2013; 27:597–603.

CHAPTER 159

Stem cell research could provide a means of replacing damaged tissue in patients with diabetes and embryos are a potentially rich source of viable stem cells. Cloned embryos may one day allow the customized replacement of damaged tissues and organs. The ethical aspects of such a research are hotly debated. A philosophically coherent approach to embryo research would acknowledge the intrinsic value accorded by people to all human life. Society must find a way to reconcile these intuitive concerns with the utilitarian desire to maximize the benefits of stem cell research.

BMI < 35 kg/m2. A lack of high quality evidence on the effect of bariatric surgery for the treatment of T2DM in patients with BMI < 35/kg/m2 poses a wide variety of ethical challenges, which are important for decisions on the individual patient level, on the management level, and on the health policy making level. Other ethical dimension is that strong preferences among surgeons and patients may hamper high quality research.

C H A P T E R

160

Continuous Glucose Monitoring (CGM) Systems

INTRODUCTION

Continuous Glucose Monitoring (CGM) systems display the glucose level, the direction and magnitude of change of glucose levels, and can be used as a tool to predict impending glucose excursions (hypo- and hyperglycemia), and to assess glycaemic variability. In addition, reliable alarm signals of low or high glucose values warn the patient to take action. All this is being executed on a near-continuous basis, throughout the day, and this for several days, thereby facilitating pattern recognition, and helping the patient (and physician) to optimize therapy and improve metabolic control.1 Hyperglycemia, hypoglycemia, and glycemic variability have been associated with increased morbidity, mortality, length of stay, and cost in a variety of critical care and non–critical care patient populations in the hospital.2 Despite advances in insulin preparations, insulin delivery devices, and glucose monitoring technology, glycemic control in most T1DM patients is suboptimal. Published data from the T1D Exchange Clinical Registry (T1D Ex), which maintains health records on over 26,000 participants with T1DM from 68 clinics throughout the United States, reveals that the average glycated hemoglobin (HbA1c) among younger patients ranges from 8.3% to 8.7% (≤25 years); average HbA1c among older patients is only somewhat better at approximately 7.7%.3 The fact that increased glycemic variability (GV) is a strong predictor of hypoglycemia and is also correlated with poor glycemic control is probably the most compelling reason to identify and to work to minimize GV today. Glycemic variability, independent from other measures of glycemic control, is predictive of patient satisfaction with an intensive insulin regimen

THE EVOLUTION OF CGMS

Diabetes technology has progressed remarkably over the past 50 years-a progress that includes the development of markers for diabetes control, sophisticated monitoring techniques, mathematical models, assessment procedures, and control algorithms. Continuous glucose monitoring (CGM) was introduced in 1999 and has evolved from means for retroactive review of blood glucose profiles to versatile reliable devices, which monitor the course of glucose fluctuations in real time and provide interactive feedback to the patient.4 Depending on whether the CGM device penetrates/breaks the skin and/ or the sample is measured extracorporeally, these devices can be categorized as totally invasive, minimally invasive,

YP Munjal, Joydeep Chaudhuri, RK Singal

and noninvasive. In addition, CGM devices are further classified according to the transduction mechanisms used for glucose sensing (i.e., electrochemical, optical, and piezoelectric). CGM highlights different contributions of fasting and postprandial glucose values at different HbA1c levels in contrast to SMBG measurements, and can be used as a tool to assess the effect of a meal on postprandial glycemia. CGM can detect high postprandial glucose levels more reliably than SMBG. Indeed, the optimal timing of postprandial glucose measurement varies according to the composition of each meal, and single postprandial measurements can miss the highest peak values, which are only detectable with CGM1Many attempts to develop commercial devices for real-time noninvasive glucose measurements, such as those based on near infrared spectra, have been unsuccessful due to interference from other blood metabolites, inter- and intrapatient differences in tissue characteristics, and miniaturization of technology. Furthermore, either the poor accuracy or the short lifetimes of these devices have limited the amount of information on the alarm components of these devices. The GlucoWatch was the first commercial device that monitored glucose noninvasively and in real-time. Cygnus received the CE mark in 1999 and FDA clearance for the GlucoWatch in 2001, with an updated model approved in 2002. This device made use of reverse iontophoresis, a process by which an electric current brings interstitial glucose to the surface of the skin and then measures the amount of glucose via an electrochemical sensor. Although its noninvasive glucose monitoring was conceptually appealing, the GlucoWatch was plagued with high false alarm rates, an excessive warm up period of 2-3 hours, inability to operate under temperature changes and increased perspiration level, and the tendency to cause skin irritation in some patients. The GlucoWatch was discontinued on July 31, 2007. High sensor accuracy and alarm sensitivity has propelled the use of CGMs to warn of glycemic excursions. CGMs make use of small enzymatic sensors inserted beneath the skin to measure interstitial glucose. An oxidationreduction reaction produces a measureable current that is calibrated with a blood glucose measurement. The first commercial CGM, the MiniMed (Medtronic, Northridge, CA), was approved by the FDA in 1999, but alarms did not appear on commercial devices until the mid-2000s with the introduction of the Guardian (Medtronic, Northridge, CA) and the STS™ (DexCom, San Diego, CA) CGMs.5

THE CURRENT GAP- LACK OF STANDARDIZATION OF GLUCOSE REPORTING

Common definitions and metrics are needed in order to assess patient status, make more informed clinical decisions, and evaluate the performance of clinicians Some issues to be addressed include, 1.

Has the percentage of time patients are in good glycemic control improved?

Are patients in good control with fewer low, very low, and dangerously low glucose readings?

Standardization is a must as the clinical terms and metrics allows a more accurate assessment of individual patients and comparisons of progress from visit to visit.

Although CGM is called continuous, CGM devices actually sample interstitial fluid glucose intermittently, with a testing frequency ranging from every few seconds to several minutes between measurements. The measurements are averaged and presented as a single reading every few minutes to quarter hour. Software within the CGM devices can combine current levels with previous results to predict a future trend and direction of glucose change. CGM can thus display not only a single glucose result, but also the direction of glucose change (up, down, or stable), as well as the magnitude of change (the difference between glucose concentration per time interval). Because CGM presents current levels of glycemia along with trend information, this technology offers the potential to predict hypoglycemic events before they occur and describe patterns of glucose variability that may not be detectable from utilizing SMBG devices that intermittently sample blood only a few times per day.2 Glycemic variability (GV) - swings in blood glucose level, takes into account the intraday glycemic excursions including episodes of hyper and hypoglycemia. The postprandial hyperglycaemic excursions also contribute to GV. 3 Glucose variability has been identified as a predictor of hypoglycemia and has been found to be related to intensive care unit mortality. Other putative relations are between glucose variability and oxidative stress, as well as microvascular and macrovascular complications

747

UTILITY OF CGMS IN HOSPITALISED PATIENTS

A hospital CGMS will be routinely used by clinicians if it (1) decreases the amount of caregiver time and effort required for glucose monitoring and BG control, (2) is easy to set-up, calibrate, and use in a variety of hospital environments, (3) produces real-time glucose measurements with accuracy and reliability sufficient for dosing insulin (4) has a low incidence of false alarms for hyper and hypoglycaemia, (5) has a low incidence of device-related adverse events and no risk for a serious adverse event, and (6) has a cost/benefit ratio that justifies adding a new point-of-care technology for the critical care and general floors of the hospital

CGM devices are also categorised as 1) real time RT CGM (Personal CGM) and 2) Retrospective CGM (Professional CGM)

Professional CGM equipment (also sometimes referred to as retrospective CGM) is owned by the health care professional, clinic, or hospital, and is generally used for masked data collection. Patients remain unaware of monitoring results until they are downloaded and analyzed by the health care professional; this allows for an unbiased assessment of patients’ glucose control. Professional CGM is used in patients with type 1 diabetes mellitus (DM) or type 2 DM who are not at their hemoglobin A1c (HbA1c) target, who have recurrent hypoglycemia or hypoglycemia unawareness, or who are pregnant. Patients are typically asked to attend an office visit, receive instruction, wear a sensor for 3 to 7 days, keep a food and activity logbook, and then return to the office for interpretation. Professional CGM does not have alerts to indicate hyperglycemia or hypoglycemia. Patients are recommended to use professional CGM on an episodic basis. Since professional CGM requires minimal training and setup time, it may be easier for patients to use than personal CGM.8

Professional CGM devices includes Medtronic’s Ipro 2, Abbott’s Freestyle Libre Pro (Figure 1)

In contrast, a personal CGM device is owned by the patient. With personal CGM, glucose values are visible continuously; this allows for immediate therapeutic adjustments on the basis of “real-time” glucose results (personal CGM is also referred to as real-time CGM). Personal CGM is typically used by patients with type 1 DM who are not at their HbA1c target level and (a) have the ability to use and understand the information supplied; (b) have hypoglycemia or hypoglycemic unawareness; and/or (c) are pregnant. In addition, any patient who

CHAPTER 160

At present, there are three commercial CGM device manufacturers: DexCom, Medtronic, and Abbott with a software to download and analyze the CGM data and generate a report or series of reports. Despite similarities between the various software programs, there is no standardization regarding which statistics are reported or how the data are presented graphically nor is there common terminology for the various analyses presented. This represents a challenging “learning curve” that many clinicians never invest the time necessary to even start using CGM technology, let alone attempt to become proficient in its use. The sheer diversity and the options for the number of reporting have to be uniform and minimised. Focus on patient-friendly presentations of the data would also be of great benefit.

of diabetes. With regard to prediction of hypoglycemia, glucose variability has been shown predictive of severe hypoglycaemia in type 1diabetes and of non severe hypoglycaemia in type 2diabetes. With the development of the CGMS, a number of indicators, including the standard deviation of blood glucose (SD) and the mean amplitude of glucose excursion (MAGE), have been proposed to estimate glycemic variability. CGMS is now widely used to estimate glycemic variability in studies of diabetes and prediabetes.6,7

DIABETES

748

could benefit from the continuous feedback of glucose readings and/ or the hyperglycemia and hypoglycemia alarms in available personal CGM devices (such as patients with type 1 DM with HbA1c levels less than 7.0%) are potentially good candidates for this technology. Some personal CGM devices also have alarms that indicate a rapid rate of glucose change using trend markers or arrows, and some have “predictive alarms,” which calculate whether high or low glucose thresholds will be crossed, depending on rate of change and current glucose level (ie, they predict a low or high glucose level). The setup requirements for personal CGM are more intensive than for professional CGM and include programming customized glucose targets and alarm thresholds.9,10 Personal CGM devices include Guardian® REAL-Time CGMS, Dexcom G4TM PLATINUM (DG4P), Dexcom Seven Plus , Abbott’s FreeStyle Navigator® and Freestyle Navigator II , Abbott’s Flash glucose monitors (Figure 2).

New product category that rests somewhere between blood glucose meters and continuous glucose monitors (CGMs) - Flash glucose monitors

The disposable, water-resistant round sensor is the size of a silver dollar and the width of a finger, similar to a traditional CGM sensor. It can be worn up to 14 days on the back of the upper arm. No finger prick calibration is needed, since that functionality is all embedded into the core technology. Glucose readings can be taken as many times per day as needed or desired, with only a painless one-second scan. Results are transmitted to the receiver via wireless radio frequency tech. Scanning can take place while the sensor is under clothing, making testing more discreet and convenient. Each scan displays a real-

time glucose result, a historical trend and the direction the glucose is heading. The reader holds up to 90 days of data, providing a historical snapshot of glucose levels over time. The FreeStyleLibre System software enables the data to be presented in a user-friendly, visual chart for both healthcare professionals and patients, driving a more productive discussion around treatment and any necessary modification.11 The ambulatory glucose profile (AGP) provides a mean value across the day. All of the values from multiple days are shown on a single time scale from midnight to midnight. The average for each period is shown along with a standard deviation. Professional version of the flash glucose monitor has been launched recently in India. A round sensor—slightly larger than a Rs 10 coin. The physician can apply the water-resistant and disposable sensor on the back of the upper arm of a patient. The sensor is held in place with a self-adhesive pad and remains for 14 days, requiring no patient interaction with the sensor or finger-prick calibration. The system continuously measures glucose in interstitial fluid through a small filament that is inserted just under the skin. It records glucose levels every few minutes, capturing up to 1,340 glucose readings over the period, giving the treating physician comprehensive data for a complete glucose profile of their patient. After 14 days, the physician uses a reader to scan the sensor and download the glucose results stored in the sensor. However, scanning and downloading of data can be done intermittently by the physician every few days as and when required. Scanning can also be done while the sensor is under clothing.

Fig. 1: Free Style Libre Pro

749

CHAPTER 160

Fig. 2: Freestyle libre Pro- Flash glucose monitor new-onset T1DM 3.

Fig. 3: Glucose Categories & Related Clinical Diagnosis

GLUCOSE TARGET RANGES AND CATEGORIES

An appropriate patient selection, in order to choose those able to run the tool and motivated to use it, is necessary. Two approaches have been compared: patient-led and physician-driven prescription. Both modes of using CGM provide similar long-term metabolic improvement. However, physician-driven prescription is probably more cost-effective. The last key question is the education of patients by an experienced team. It can help them to translate the large amount of data from the monitor into effective self-management for optimalizing the CGM experience. However, elaboration of a validated algorithm is necessary to take full advantage of this device (Figure 3). The patients best suited for CGMS include,12,13 1.

The best suited - All T1DM, poor metabolic control, especially those treated with continuous subcutaneous insulin infusion (CSII), and compliant patients with HbA(1c) levels <7%. Less best suited - patients aged 8-18 years because they are reluctant to wear the sensors or those with

Deserving patients but with less evidence- patients aged <8 years, women during pregnancy, and those with HbA(1c) >10% and/or severe hypoglycaemia

Are all type 1 diabetes (T1DM) patients potential candidates for continuous glucose monitoring (CGM)? Clearly, some patients improve their metabolic control with this tool, such as adults with poor metabolic control, especially those treated with continuous subcutaneous insulin infusion (CSII), and compliant patients with HbA(1c) levels <7%. There are also less good candidates for CGM, such as patients aged 8-18 years because they are reluctant to wear the sensors or those with newonset T1DM. Other patient groups have not yet been evaluated, such as patients aged <8 years, women during pregnancy, and those with HbA(1c) >10% and/or severe hypoglycaemia. Beyond the indications, the mode of use of CGM is crucial. An appropriate patient selection, in order to choose those able to run the tool and motivated to use it, is necessary. How to prescribe the sensors is also an important question. Two approaches have been compared: patient-led and physician-driven prescription. Both modes of using CGM provide similar long-term metabolic improvement. However, physician-driven prescription is probably more cost-effective. The last key question is the education of patients by an experienced team. It can help them to translate the large amount of data from the monitor into effective self-management for optimalizing the CGM experience. However, elaboration of a validated algorithm is necessary to take full advantage of this device.

SUMMARY

Automation and standardization of the glucose measurement process have the potential to significantly improve BG control, clinical outcome, safety and cost. Given the demonstrated benefits of CGM in managing glycemia and reducing hypoglycemia, which can potentially lead to greater patient adherence and improved clinical outcomes, it is imperative that health care providers, clinical researchers, industry,

DIABETES

750

regulators, and payers work together to find ways to expand appropriate adoption of CGM use in clinical practice. Patient populations, diabetes medications, new technology, and systems of care can more effectively be assessed, thus facilitating efficient clinical decision making and appropriate design of clinic process and flow. Standardization also has the potential to make patient care and clinical research more efficient. While CGM has been shown to be valuable in several clinical settings, continued research is needed to define which individuals with T1DM or T2DM will benefit most from either realtime use of CGM or retrospective analysis of intermittent use of CGM It is anticipated that CGM devices will utilize constant feedback of analytical information from a glucose sensor to activate an insulin delivery pump, thereby ultimately realizing the concept of an artificial pancreas. The use of these technologies could be extended to current clinical care of type 2 diabetic patients especially for motivating them to accept earlier insulin treatments in case of ‘oral antidiabetic drug secondary failure’, and further for choosing the most appropriate insulin regimen.

REFERENCES

1. Christophe De Block, Begoña Manuel-y-Keenoy and Luc Van Gaal. A Review of Current Evidence with Continuous Glucose Monitoring in Patients with Diabetes. Journal of Diabetes Science and Technology 2008; 2:4. 2.

Joseph JI et al. J Diabetes Sci Technol 2015; 9:725-38.

3. Bergenstal

al;

Recommendations

for

standardizing glucose reporting and analysis to optimize clinical decision making in diabetes: the ambulatory glucose profile. J Diabetes Sci Technol 2013; 7:562-78. 4. Kovatchev BP. Diabetes technology: markers, monitoring, assessment, and control of blood glucose fluctuations in diabetes. Scientifica (Cairo) 2012; 2012:283821.

5. Howsmon D. J Diabetes Sci Technol. 2015 Apr

30;9(5):1126-37.Hypo- and Hyperglycemic Alarms: Devices and Algorithms

6. J. Hans DeVries. Glucose Variability: Where It Is Important and How to Measure It. Diabetes 2013; 62. 7.

Monnier L, Colette C, Owens D. Glycemic variability: the third component of the dysglycemia in diabetes. Is it important? How to measure it? J Diabetes Sci Technol 2008; 2:1094–1100.

8. Barry H. Ginsberg,The Current Environment of CGM Technologies. Journal of Diabetes Science and Technology Volume 1, Issue 1, January 2007. 9. Sandeep Kumar Vashist. Continuous Glucose Monitoring Systems: A Review. Diagnostics 2013; 3:385-412. 10. AACE Consensus Statement. Continuous monitoring. Endocr Pract 2010; 16 (No. 5) A.

glucose

11. h t t p s : / / w w w . a b b o t t d i a b e t e s c a r e . c o m / p r e s s room/2014/2014-e.html (accessed on 25/May/2015) 12. Riveline JP. Is continuous glucose monitoring (CGM) for everyone? To whom should CGM be prescribed and how? Diabetes Metab 2011; 37 Suppl4:S80-4. 13. Monnier L et al; Continuous glucose monitoring in patients with type 2 diabetes: Why? When? Whom? Diabetes Metab 2007; 33:247-52.

Lipids and Diabetes

C H A P T E R

161

Vijay Panikar, Tejas Kamat, Jimit Vadgama

INTRODUCTION

Type 2 Diabetes Mellitus (T2DM) remains a formidable public health issue and is associated with decreased survival predominantly due to cardiovascular disease (CVD). Evidence suggests T2DM and CVD are integrally related with regard to pathophysiologic processes and clinical outcomes. Diabetes is associated with a 2 to 4-fold increase in the risk of CVD compared with nondiabetic subjects. Approximately 80% of patients with T2DM will develop and possibly die of macrovascular disease. Coronary Artery Disease (CAD) and stroke are the top causes of death and disability in diabetes. Many diabetics possess other CVD risk factors, such as obesity, hypertension, and dyslipidemia. Whereas blood glucose control is fundamental to prevention of microvascular complications, controlling atherogenic cholesterol particle concentrations is fundamental to prevention of atherosclerotic CVD (ASCVD). To reduce the significant risk of ASCVD in T2DM patients, early intensive management of dyslipidemia is warranted. It has been reported that that the prevalence of dyslipidemia in Indian diabetic population is very high (90%). Studies in Indian subjects have also demonstrated that coronary artery disease in Indian diabetics develops earlier than general population, is more advanced at the time of diagnosis, more diffuse and progresses faster. Furthermore, results after interventions are inferior and hence carry a higher risk of mortality and morbidity.

Table 1: Diabetic dyslipidemia Elevated total TG Reduced HDL-C

LIPID ABNORMALITIES IN DIABETES

In uncontrolled T1DM the predominant abnormality is hypertriglyceridemia, secondary to absolute insulin deficiency. As expected, the level normalizes with adequate insulin therapy. The lipid profile in people with T2DM is characterized by elevated triglycerides (TG) and low levels of HDLcholesterol (HDL-C). LDL-cholesterol (LDL-C) levels in diabetic patients are not usually significantly increased compared with those in non diabetic patients. However, there are important differences in the types of LDL particles seen. Diabetics tend to have LDL particles that are small and dense compared with those in non diabetic individuals. This pattern, characterized by high TG, low HDL-C and small, dense LDL particles, referred to as diabetic dyslipidemia (Table 1), is a typical atherogenic lipid profile.

Pathogenesis of diabetic dyslipidemia

As a consequence of Insulin Resistance (IR) in T2DM the inhibitory effect of insulin on hormone-sensitive lipase is removed leading to increased lipolysis in the fat cells in adipose tissue, which leads to increased delivery of free fatty acids (FFAs) to the liver. Increased delivery of FFA to liver increases VLDL formation (insulin resistance also increase Apo-B formation in the Liver) due to which plasma VLDL and hence TG level is increased. VLDL exchanges its TGs with HDL via cholesterol ester transfer protein (VLDL gives away TG and accepts cholesterol ester from HDL). By the same mechanism it exchanges its TG for cholesterol esters from LDL as well. The TGs now acquired by HDL and LDL are digested by lipoprotein lipase and/or hepatic lipase. LDL thus gets converted to

LDL-C may be normal or slightly elevated  Small, dense LDL-C

Table 2: Lipid targets for patients with T2DM

 HDL 3 and  HDL1 and HDL 2

High risk patients: DM but no other major risks and/or age < 40

Very high risk patients: DM + ≥ 1 ASCVD risk factor (family history, HTN, low HDL-C, smoking) or established ASCVD

LDL-C

< 100

< 70

Non HDL-C

< 130

< 100

HDL-C

> 40 (men), > 50 (women)

< 150

Postprandial Hyperlipemia Fat cells

Liver

Kidney

FFA

CE VLDL

IR Insulin

TG ApoB VLDL

(CETP)

HDL

ApoA-I

CE (CETP) TG

LDL (Lipoprotein or hepatic lipase)

LDL

Fig. 1: Pathogenesis of diabetic dyslipidemia

752

Table 4: Drug therapy Drug class: Agents and daily doses MoA

Lipid/lipoprotein effects

Side effects

Contraindications

HMG-CoA reductase inhibitors (Statins): Atorvastatin (10-80 mg), Rosuvastatin (5-40 mg), Lovastatin (20-80 mg), Pravastatin (20-40 mg), Simvastatin (20-80 mg), Fluvastatin (20-80 mg), Cerivastatin (0.4-0.8 mg) Competitive inhibition of HMG-CoA reductase, the rate limiting enzyme in cholesterol biosynthesis.

LDL  20-55%

Myopathy,

HDL  5-15%

Increased liver

TG 10-30%

Enzymes

Absolute: Active or chronic liver disease Relative: Concomitant use of certain drugs*

DIABETES

Fibric acid derivatives: Fenofibrate (200 mg), Gemfibrozil (600 mg BID), Clofibrate (1000 mg BID) Activate PPAR-α in liver, muscle and adipose tissue: activates lipoprotein lipase,  release of fatty acids from adipose tissue

LDL  5-20% (may be increased in

Dyspepsia,

Severe renal disease,

patients with high TG)

Gallstones,

Severe hepatic

Myopathy,

Disease

HDL  10-20% TG  20-50%

Bile acid sequestrants: Cholestyramine (4-16 g), Colestipol (5-20 g), Colesevelam (2.6-3.8 g)  bile acid absorption,  hepatic conversion of CH to bile acids,  LDL receptors on hepatocytes

LDL  15-30%

Gastrointestinal

HDL  3-5%

distress

TG no change

Constipation

or increase

Decreased absorption of other drugs

Absolute: dysbetalipoproteinemia, TG >400 mg/dL Relative: TG >200 mg/dL

Nicotinic acid: Immediate release (crystalline) nicotinic acid (1.5-3 gm), extended release nicotinic acid (1-2 g), sustained release nicotinic acid (1-2 g)  production of VLDL,  lipolysis in adipocytes

LDL  5-25%

Flushing,

HDL  15-35%

Hyperglycaemia,

TG  20-50%

Hyperuricemia (or gout), Upper GI distress,

Absolute: Chronic liver disease, Severe gout Relative: Diabetes, Hyperuricemia, Peptic ulcer disease

Hepatotoxicity Ezetimibe (10 mg) Inhibits absorption of dietary cholesterol at intestinal brush border

 LDL 15-20%

Headache, diarrhoea

None

 TG 45%

Dyspepsia, gastritis

None

Saroglitazar (4 mg) Dual PPAR-α/γ agonist

* Cyclosporine, macrolide antibiotics, various anti-fungal agents, and cytochrome P-450 inhibitors (fibrates and niacin should be used with appropriate caution).

the more atherogenic small-dense LDL and HDL loses its Apo-A-1 which gets excreted through kidneys thereby lowering HDL levels (Figure 1). The atherogenic potential of diabetic dyslipidemia is conferred by the small, dense LDL particles as they readily enter subendothelial space and become oxidized.

How Indians are different

Indian dyslipidemia is different from its western counterparts in terms of lipid parameters. A study of Asian Indians living in the United States found that 54% of men had an HDL level below 40 mg/dL, and 68% of women had levels below 50 mg/dL. In the United States, 43% of Asian Indian males and 24% of Asian Indian females have TG levels that exceed 150 mg/dL. Lipoprotein(a) is still

considered an emerging risk factor in the US population at large, but appears to be a major risk factor in Asian Indians. A high level of Lp(a) is the most prevalent dyslipidemia in patients with premature CHD. Although Lp(a) levels above 30 mg/dL are generally considered the threshold at which high risk of premature CHD increases rapidly, levels below 20 mg/dL are considered optimal, particularly in Asian Indians. Studies of Asian Indians in North America found that 25-50% of sampled population had Lp(a) levels above 30 mg/dL.

SCREENING FOR DYSPIPIDEMIA

The 2015 the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) guidelines recommend screening of all

Table 5: Recommendations for statin treatment in diabetics 2013 ACC/AHA statin benefit groups

2014 NLA recommendations

Any clinical ASCVD

Moderate intensity statin if age > 75 or if not a candidate for statin therapy

Flowchart 1: Stepwise approach to treatment of dyslipidemia in diabetes No  Serum TG ≥ 500  Yes GOAL 1

Diabetes, age 40-75 y, no clinical ASCVD, LDL-C 70-189 mg/dl

Moderate intensity statin

TG lowering

- TLC

- Very low fat diet

- Statins, Fibrates, Ezetimibe

- Weight management and physical activity - Fibrates or nicotinic acid - When TG < 500 mg/dl, target LDL goal

High intensity statin if ASCVD risk ≥ 7.5%

Estimated 10-y ASCVD Moderate-to-high risk of 7.5%, age 40-75 y, intensity statin no clinical ASCVD, LDL-C 70-189 mg/dl

 GOAL 2

- Intensify TLC

Table 6: High-intensity and moderate-intensity statin therapy* Moderate-intensity statin therapy

High-intensity statin therapy

Lowers LDL cholesterol by 30 - <50%

Lowers LDL cholesterol by ≥ 50%

• Atorvastatin 10–20 mg

• Atorvastatin 40–80 mg

• Rosuvastatin 5–10 mg

• Rosuvastatin 20–40 mg

Achieve Non-HDL-C goal - Intensity therapy with LDL lowering drug - Add nicotinic acid or fibrate to lower VLDL 

GOAL 3

Achieve HDL-C goal

• Simvastatin 20–40 mg

- Glycemic control

• Pravastatin 40–80 mg

- Intensify TLC

• Lovastatin 40 mg

- Add Nicotinic acid or fibrates

• Fluvastatin XL 80 mg • Pitavastatin 2–4 mg adult diabetics with yearly fasting lipid profile: total cholesterol, TG, HDL-C, and LDL-C. If not at goal, lipid profiling should be repeated more frequently after initiation of treatment.

TARGET LIPID LEVELS IN DIABETES

The 2016 AACE/ACE consensus statement recognises that T2DM carries a high lifetime risk for developing ASCVD, stratifies risk for primary prevention as “high” or “very high” and recommends LDL-C targets of <100 mg/dL or <70 mg/dL and non-HDL-C targets of <130 mg/ dL or <100 mg/dL, respectively. Currently, HDL-C is not a target for therapy according to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) cholesterol treatment guidelines and the 2016 AACE/ACE consensus statement. However, the ADA considers levels of HDL-C > 40 mg/dL in men and > 50 mg/dL in women desirable (Table 2).

TREATMENT MODALITIES

The options available are glycemic control, lifestyle measures and specific lipid-modifying drugs (Table 4).

Therapeutic Lifestyle Changes

Strict glycemic control

Tight control of blood sugars can significantly reduces TG levels. HDL-C, being inversely related to TG, tends to rise with attainment of good glycemic control. LDL-C however is not altered by glycemic control.

Therapeutic Lifestyle changes •

Regular physical activity and weight reduction can reduce TG and raise HDL-C. LDL-C, however is not significantly altered by exercise.

•

Moderation of alcohol can also help to reduce TG levels

•

Smoking cessation is critical to reduce overall CV risk.

•

Medical nutrition therapy

Total carbohydrate to be reduced to 50-60% of calories

Total fat to be reduced to < 30% of total calories.

Saturated fat must reduced to < 7% of calories

MUFA and PUFA up to 10-15% of calories

Protein intake to be increased 10-20%% of calories.

CHAPTER 161

High intensity statin

Achieve LDL-C goal #

High intensity statin if ≤ 75 y LDL-C ≥ 190 mg/dl

753

754

•

Increased dietary fiber (soluble/viscous) to 10-25 g/ day e.g.-Soy protein, Fenugreek

•

Cholesterol < 200 mg/day

DIABETES

The Role of Statins in CHD risk reduction

Practically every clinical manifestation of atherosclerosis has been shown to be reduced by statin therapy, including fatal and nonfatal myocardial infarction, sudden cardiac death, episodes of unstable angina, revascularization procedures including percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG), stroke, symptoms of peripheral arterial disease, and total mortality. Importantly, statin therapy has not been associated with an increase in non-cardiovascular events. These data demonstrate that statins improve the quality of life (by reducing nonfatal events) and also prolong survival (by reducing total mortality). The 2013 ACC/AHA guidelines recommended treatment initiation with stains and initial dose based on individuals’ cardio-vascular risk, rather than LDL-C levels alone. The guidelines identified 4 Statin Benefit Groups (Table 5). In 2016, a comparison of the ACC/AHA guidelines with the 2014 National Lipid Association (NLA) recommendations provided guidance for treatment with moderate and high intensity statin therapy (Table 5, Table 6).

Approach to treatment of dyslipidemia

The scientific statement from the AHA and ADA recommends that the primary goal is to lower LDL-C followed by non-HDL-C lowering and HDL-C elevation (Flowchart 1).

CONCLUSIONS

Despite the steady decrease in mortality from CVD, the incremental CVD risks associated with T2DM persist. As a result, considerable work remains to be done to enhance our understanding of how to more effectively prevent CVD in patients with T2DM. The treatment goals for diabetic with or without CHD is stricter compared to those without diabetes. The primary goal is to lower LDL-C followed by non-HDL-C lowering and HDL-C elevation. Due to their proven benefits, statins remain the most commonly used drugs followed by fibrates.

REFERENCES

RM Parikh, Joshi SR, et al. Prevalence and pattern of diabetic dyslipidemia in Indian type 2 diabetic patients. Diabetes

& Metabolic Syndrome. Clinical Research & Reviews 2010; 4:10–12. 2.

Misra A, Luthra K, et al. Dyslipidemia in Asian Indians: Determinants and Significance. J Assoc Physicians India 2004; 52:137-42.

3. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106:3143421. 4. Fox CS, Golden SH, et al. Update on Prevention of Cardiovascular Disease in Adults with Type 2 Diabetes Mellitus in Light of Recent Evidence: A Scientific Statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2015; 38:1777–803. 5.

Stone NJ, Robinson JG, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129 (25 Suppl 2): S1-45.

6. Jacobson TA, Ito MK, et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1--full report. J Clin Lipidol 2015; 9:12969. 7. Adhyaru BB, Jacobson TA. New Cholesterol Guidelines for the Management of Atherosclerotic Cardiovascular Disease Risk: A Comparison of the 2013 American College of Cardiology/American Heart Association Cholesterol Guidelines with the 2014 National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia. Endocrinol Metab Clin North Am 2016; 45:1737. 8. Handelsman Y, Bloomgarden ZT, et al. American association of clinical endocrinologists and American college of endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan 2015. Endocr Pract 2015; 21(Suppl 1): 1-87 9.

Garber AJ, Abrahamson MJ, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2016 executive summary. Endocr Pract 2016; 22:84-113.

10. American Diabetes Association Standards of Medical Care in Diabetes 2016. Diabetes Care 2016; 39(Suppl. 1): S1–S112 11. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA 1999; 282:2340-2346.

C H A P T E R

162

Appoach to Brittle Diabetes

INTRODUCTION

Brittle diabetes is defined as severe instability of blood glucose levels with frequent and unpredictable episodes of hypoglycaemia or ketoacidosis that disrupts day to day life. Almost all diabetics experience swings of blood sugar which are less predictable and greater than in non diabetics. Brittle diabetes is uncommon (less than 1% of insulin taking population) and it causes a huge burden on the patient due to multiple hospital admissions. It is episodic and almost always related to stressful life situations. It affects 3/1000 insulin dependent diabetic patients mainly young women. Its prognosis is poor with lower quality of life scores, more microvascular and pregnancy complications and shortened life expectancy.

CAUSES OF BRITTLE DIABETES

Main causes includes •

Non physiologic matching of meals/exercise and insulin administration.

• Malabsorption •

Certain Drugs (alcohol, antipsycotics)

•

Defective insulin absorption or degradation

•

Defect of hyperglycaemic hormones especially glucocorticoid and glucagon.

•

Delayed gastric emptying as a result of autonomic neuropathy.

•

Psycosocial factors are very important and factitious brittleness may lead to a self perpetuating condition. This is because of patient centred behavioral issues. Some of these problems may be short lived and related to a stressful situation (unhappiness at school or home).

CLINICAL MANIFESTATIONS

Patients have wide swings of blood sugar levels and report differing blood sugar responses to the same dose and type of insulin. Most patients are in their twenties or thirties. Their glycated haemoglobin (HbA1c) are typically elevated (10-14%) and acute complications (DK and hypo) and chronic microvascular complications are commoner (67% versus 25%). Brittle diabetics also had a lower quality of life score. The age of death ranges from 27-45 years with a predominance in young women. Those who survived had resolution of brittleness, but suffered a significant complication burden. Frequent hypoglycaemia even if asymptomatic causes both defective glucose counter regulation and hypoglycaemia unawareness and thus a viscious cycle of recurrent hypoglycaemia.

Seetha Raju

CLINICAL ALGORITHM TO DETERMINE THE ETIOLOGY

The diagnostic algorithm was the glucose response to 0.1 unit / kg insulin administered subcutaneously and intravenously. If this response was ’’normal’’ then psycosocial evaluations were completed, including psycolinguistic and health psycological testing.Then other parameters affecting blood glucose concentration eg. gastric motility, counter regulatory hormones, coeliac disease, hypothyroidism, adrenal insufficiency, insulin autoantibodies and most importantly patients compliance with prescribed regimens were assessed. If the response were ‘’abnormal’’ the location of the insulin resistance was identified as being subcutaneous, intravascular or at the peripheral tissue.

EVALUATION AND DIAGNOSIS

A careful evaluation should be performed in patients with brittle diabetes. A detailed history as to the duration of diabetes, description of episodes of DK, severe hypos, presence of diabetic complications (particularly autonomic neuropathy) and prescribed insulin regimens should be taken. It should also be determined if there was a period of stable diabetes preceeding the brittleness and what happened in the patient’s life circumstances coincident with the onset of brittleness. Psycosocial factors need to be assessed. For patients with recurrent episodes of DK, a possible chronic cryptic infection (sinusitis, osteomyelitis, renal or perirenal abscess and lung abscess) should be excluded. For all patients a diabetic educational assessment is useful to evaluate whether the patients knows how to manage diabetes and rule out diabetes mismanagement (factitious brittle diabetes ). In this case a “in hospital” assessment and management of blood sugar is necessary. Iatrogenic hypoglycaemia is the result of the interplay of absolute or relative therapeutic insulin excess and compromised physiological and behavioural defences against falling plasma glucose concentrations in type 1 diabetes in type 1 diabetes mellitus (T1DM) and advanced type 2 diabetes mellitus (T2DM). Courtesy of Dr. Philip Cryer.

MANAGEMENT

Brittle diabetes is difficult to treat General principle •

Patients to be instructed how to match the insulin dose to the amount of carbohydrates ingested.

•

Insulin regimens must be individually tailored to reduce the risk of hypoglycaemia while matching

756

Table 1: Counterregulatory response to hypoglycaemia Condition

Glucose

Insulin

Glucagon

Epinephrine

Nondiabetic

Decreases

Increases

T1DM

No Decrease*

No Increase

Attenuated Increase*

T2DM

Decreases

Increases

Late(Absolute endogenous insulin deficient)

No Decrease*

No Increase

Attenuated Increase*

DIABETES

Early

glycaemic control. The use of insulin analogues with ultrafast or ultraslow action and use of subcutaneous insulin pumps are effective in brittle diabetes. •

SMBG is an excellent tool for the patients and a motivated patient can use this tool to manage his blood sugars.

•

CGM (Continuous glucose monitoring) may further facilitate the understanding of glycaemic variability.

•

Sensor augmented insulin pumps (an insulin pump with a CGM device) improves glycemic control without hypoglycaemia. Fully automated closed loop systems of insulin delivery based on CGM sensing (bionic pancreases) are available. This device also integrates glucagon delivery. Islet cell transplantation –an effective therapeutic option entailing good expected outcomes. The limiting factor is the effect of immunosuppressive therapy and recurrence of autoimmunity.

or clinician error in management, other causes being psycosocial, malabsorbtion, delayed gastric emptying, systemic insulin resistance. •

REFERENCES

David K McCullrch. M.D.David M.Nathan. M.D.Jean E Mulder M.D. - The adult patient win diabetes mellitus Up To Date June 2015.

Cartwright A, Wallymahmed M, Macfarlaane IA, et al. The outcome of brittle type 1 diabetes –a 20 year study QJM 2011; 104:575.

Vantyghem MC,press M.management strategies for brittle diabetes. Ann Endocrinol (Paris) 2006; 67:287.

Clar C, Barnard K, Cummins E, et al. Self – monitoring of blood glucose in type 2 diabetes; systematic review Health Technol Assess 2010; 14:1.

Polonsky WH, Fisher L, Schikman CH, et al. Structured self-monitoring of blood glucose significantly reduces A1C levels in poorly controlled, noninsulin-treated type 2 diabetes : results from the structured Testing Program study. Diabetes Care 2011; 34:262.

Gandhi GY, Kovalaske M, Kudva Y, et al. Effcacy of continuous glucose monitoring in improving glycemic control and reduceing hypoglycemia :a systematic review and meta – analysis of randomized trials. J Diabetes Sci Technol 2011; 5:952.

SPECIAL SITUATIONS

•

Hypoglycaemia unawareness A 2-3 Week period of scrupulous avoidance of hypoglycaemia is advisable since that often restores awareness (Table 1).

•

Gastroparesis – promotility agents improved gastric enptying and relieved the symptoms of gastroparesis but did not help with metabolic control.

•

Psycosocial – Psycotherapy may help in selected patients.

SUMMARY AND RECOMMENDATIONS

•

Brittle diabetes in defined as severe instability of blood glucose levels with frequent and unpredictable episodes of hypoglycaemia or ketoacidosis. The diagnosis is established when a patient with absolute insulin deficiency (type 1 or type 2) has frequent episodes of hyper or hypoglycaemia. The major cause of brittle diabetes is patient

The treatment includes diabetes education, intensive insulin therapy with frequent or continuous glucose monitoring and constant interaction between patient and the clinician. Psycotherapy is advocated in selected patients.

7. Szypowska A, Ramotowska A, Dzygalo K, Golocki D. Beneficial effect of real-time countious glucose monitoring system on gycemic control in type 1 diabetic patients: systemic review and meta-analysis of randomized trials. Eur J Endocrinol 2012; 166:567. 8. Yeh HC, Brown TT, Maruthur N, et al. Comparative effectiveness and safety of insulin delivery and glucose monitoring for diabetes mellitus : a systematic review and meta-analysis. Ann Intern Med 2012; 157:336. 9.

Juvenile Diabetes Research Foundation Continuous glucose monitoring study Group, Beck RW, Buckingham B, et al. Factors predictive of use and of benefit from continuous glucose monitoring in type 1 diabetes. Diabetescare 2009; 32:1947.

10. Ritholz MD, Atakov-Castillo A, Beste M, et al. Psychosocial factors associated with use of continuous glucose monitoring. Diabet Med 2010; 27:1060.

Pancreatic Diabetes

C H A P T E R

163 INTRODUCTION

Pancreatic or pancreatogenic diabetes is a form of secondary diabetes where pancreatic diseases with exocrine deficiency leads to endocrine dysfunction resulting in defective glucose homeostasis. Though it was felt over last few decades that patient’s suffering from diabetes mellitus who have pancreatic diseases like chronic pancreatitis, cystic fibrosis, post pancreatectomy states, pancreatic carcinoma etc. behave in a different manner from that of Type 1 & Type 2 diabetic patients1, only over last few years it was proved to be a distinct entity needing specific tailored approach. DM due to cystic fibrosis was recognized as a distinct clinical state because the patients have poor nutritional status, severe respiratory inflammatory symptoms, increased mortality rate from respiratory failure.2 They needed special care in evaluation and treatment. This type of secondary diabetes was called CFRD (cystic fibrosis related diabetes) where exocrine defect altered the pancreatic endocrine system. The march of events leading to recognition of pancreatic diabetes as a separate entity started with the observation of DM occurring in young population in the tropics where chronic pancreatitis was found to be the main reason. This was initially called Fibro Calculi Pancreatic Diabetes (FCPD). After years of confusion in nomenclature like Tropical diabetes/Malnutrition Related Diabetes (MRDM) it has been finally proven that this entity is a separate one

Table 1: Diagnostic criteria for Type 3C DM Major criteria (all must be fulfilled) : •

Presence of exocrine pancreatic insufficiency (according to monoclonal fecal elastase – 1 or direct function tests).

•

Pathological pancreatic imaging (by endoscopic ultrasound, MRI or CT).

•

Absence of Type 1 DM associated autoimmune markers.

Minor criteria : •

Impaired beta cell function (as measured by HOMA – B, C- peptide/ glucose ratio)

•

No excessive insulin resistance ( measured by HOMA- IR)

•

Impaired incretin (e.g, GIP) or pancreatic polypeptide secretion

•

Low serum levels of lipid soluble vitamins(A, D, E, K)

Adapted From Ewald and Bretzel4

Sidhartha Das, SK Tripathy, BP Panda

and is now called Pancreatic Diabetes or Type 3c Diabetes. There was a time when the cyanide containing cassava was thought to be the cause of chronic pancreatitis and diabetes. Epidemiological studies had shown that this type of diabetes was common in the countries of tropics where cassava consumption was high in the diet of countries like Brazil, Africa and South India particularly Kerala. Now a days various causes of chronic pancreatitis are incrimated in Pancreatic Diabetes.3 Later pancreatic diabetes due to other causes like chronic pancreatitis, pancreatic carcinoma etc. was given separate recognition by ADA & WHO as Type 3C diabetes, in the current classification & criteria for its diagnosis was laid down. (Table 1)

EPIDEMIOLOGY

In the general population prevalence of Type 2 DM is around 8%.5 As awareness regarding the pancreatic diabetes (Type 3C diabetes) as a separate clinical entity is increasing, western data reveals 10% of the newly diagnosed diabetes belong to Type 3.6 Though concrete data is not available in Asiatic population the prevalence is more. Chronic pancreatitis remains the main cause of pancreatic diabetes. Depending on the type of cohort study and duration of study, Type 3C diabetes occurrence varies from 26 to 80 % of chronic pancreatitis patient. In 80% Type 3C diabetes, chronic pancreatitis is the cause in 20% Adolescents and 40 to 55% adults of cystic fibrosis suffer from pancreatic diabetes.7,8,9,10 There is a high prevalence of calcific pancreatitis in Diabetes in tropics.3 It was reported that calcific pancreatitis is present in 8% of diabetics in Uganda, 8.9% in Nigeria, 7.5% in Congo and in one study it was seen to be present in 14.8% in Kerala (India).Chronic calcific pancreatitis leading to pancreatic diabetes is seen in 82.2% cases in Nigeria and 90% cases in India. The age of onset of pancreatic diabetes with Tropical Calcific Pancreatitis(TCP) was 12-25 years where as in alcohol induced chronic pancreatitis leading to pancreatic diabetes, the age of onset was 50-60 years.3

ETIOLOGY

In the etiology of pancreatic diabetes chronic pancreatitis tops the list. The other causes are listed below7-11 (Table 2)

PATHOGENESIS

Human Pancreas harbours around 1 million islets of 5-400 micron in diameter. Each islet has around 2000 insulin secreting beta cells, glucagon secreting alpha cells and somatostatin secreting delta cells.15 Pancreas

758

Table 2: Causes of Pancreatic Diabetes Acute pancreatitis

Table 3: Comparison of hormonal and metabolic aspects of pancreatic diabetes, Type-1 DM and Type-2 DM Pancreatic diabetes

Type-1 DM

Type-2 DM

Insulin secretion







Insulin sensitivity





Glucagon secretion



/

Plasma amino acids



/0

Ketosis prone







Glucose counter regulation



0/

lipids





Relapsing Pancreatitis Chronic Pancreatitis (Accounting for 80% of Pancreatic Diabetes) Haemochromatosis Pancreatic Carcinoma Pancreatectomy

DIABETES

Rarely Neonatal diabetes (Pancreatic Agenesis) As chronic pancreatitis is the major cause of pancreatic diabetes the different causes of chronic pancreatitis are given below Alcohol Gall stone Hypertriglyceridemia Congenital anomalies of pancreatic duct system – Pancreas divisum Ectopic pancreas Annular pancreas Hypertrophic sphincter of oddi Duct stone Autoimmune Pancreatitis Groove Pancreatitis7 Tropical calcific pancreatitis13 Hereditary Pancreatitis(PRSS1 Mitochondria) Genetic pancreatitis( SPINK 1 & Chromosome CFTR Mutation)14 Mutation of MCP -1 gene Drugs causing Pancreatitis Estrogen Corticosteroids Thiazides Incretin based anti diabetic Drugs Causes of pancreatic calcification Gall stone pancreatitis Familial Hyperlipoproteinemia Hyperparathyroidism Following pseudocyst of pancreas Rarely following – Mumps Miliary TB Progresive systemic sclerosis Blaunt trauma to abdomen Tropical calcific pancreatitis (TCP) Cystic fibrosis Schistosomiasis Hydatid disease

, Increased; 0, normal; , decreased; IDDM, insulin dependent diabetes mellitus; NIDDM, non – insulin dependent diabetes mellitus; Adapted from Nils Ewald, Philip D Hardt 37

also contains pancreatic polypeptide secreting pancreatic polypeptide cells. These islets are unevenly scattered throughout the pancreas along with the pancreatic acini. There is paracrine regulation of β-cell by the α-cell secretion. There is also a insulo-acinar axis where the functions of the acini is affected by the islet secretion. Pathogenesis of pancreatic diabetes mostly due to chronic pancreatitis, the tissue injury is thought to occur due to premature activation of pancreatic enzymes. This causes inflammation and auto digestion of the pancreatic tisse leading to tissue loss,replacement fibrosis, septa formation and calcification which leading to exocrine deficiency.16 The islets resist this auto digestive process to a much greater extent than the acinar cells. Later on the islet cell function decreases and islet atrophy ensues. So exocrine function loss predates endocrine deficiency leading to DM. The exocrine deficiency causes nutrient malabsorption resulting in impaired incretin secretion thereby decreasing the stimulus for insulin secretion. Due to accelerated gastric emptying post prandial rise in glucose level increases. Besides β-cell function loss glucagon secreting alpha cells are also affected but later in the course of the disease. This causes loss of glucagon response to hypoglycemia with wide excursion of glucose level making this type of DM brittle.17 In type 1 diabetes there is absolute insulin deficiency and in later stage insulin resistance. In Type 2 diabetes tissue sensitivity to insulin decreases whereas in Pancreatic DM tissue sensitivity to insulin is intact.18 (Table 3)

HISTOPATHOLOGY3,20,21

Histopathologic study of pancreas in pancreatic diabetes differs that of from Type 1 and 2 DM. In Type 1 DM auto immune Beta cell specific destruction is seen as insulitis, with infiltration of the lymphocytes in and around islets whereas in Type 2 diabetes islets and pancreas shows

759

Table 4: Clinical Characteristics for Common Forms of Diabetes T2DM

T3cDM

Autoimmunity

obesity

Chronic pancreatitis

Cystic fibrosis

Pancreatic resection

Median age of onset

2nd decade of life

6th decade of life

5th decade of life

3rd decade of life

Within 5 years of surgery

Pancreatic insufficiency

Yes

Pain Abdomen

Yes

Hepatic insulin sensitivity

Normal or decreased

Decreased

Normal or decreased

Peripheral insulin sensitivity

Normal or decreased

Decreased

Normal

Diabetic ketoacidosis

Yes

Hypoglycemia risk

Increased

Normal or increased

Pancreatic polypeptide response

Normal or decreased

Decreased or absent

Absent

Adapted from Gudipaty, Lalitha. Rickels36

amyloid deposition. In type 3C Pancreatic diabetes this amyloid deposition is not seen but in CFRD amyloid deposits are present.

CLINICAL FEATURES (TABLE 4)

Pancreatic diabetes patients usually have history of pancreatitis in past, pain abdomen, dyspepsia, steatorrhea and symptoms of malabsorption. Due to defect in fat soluble vitamins (A,D,E,K) absorption patients may show features of these vitamin deficiency states. Initially overt diabetes or hyperglycemia may not be present but only occurs during periods of stress, illness, surgery, high dose corticosteroids. As beta cell deficiency progress, these patients develop overt diabetes. Patients with chronic calcific pancreatitis may present with features of malabsorption and failure to thrive or with chronic abdominal pain of chronic pancreatitis or with osmotic features of DM. Very often they present with features of malabsorption and DM. In patients presenting with DM, the abdominal pain is less perceived due to autonomic neuropathy. Pancreatic diabetic patients do not develop DKA as the beta cell deficiency is seldom absolute and therefore were classified as ketosis resistant DM in the young in the older classification. Brittle Diabetes is another feature of Pancreatic Diabetes.22

Conventionally typing of diabetes is confirmed by presence of Type 1 associated autoantibodies and Type 2 diabetes by presence of insulin resistance. In Type 3C or pancreatic diabetes investigation for exocrine and endocrine deficiencies should be done. 1.

OGTT fasting blood glucose > 126 mg/dl and HbA1c > 6.5 % gives the diagnosis of pancreatic diabetes. If the FBG is between 100- 125 mg/dl or HbA1c 5.7- 6.5 %, this state is called IFG (impaired fasting glucose). If the 2 hr PPBG > 200 mg/dl, then it can be taken as diabetes and if it lies between 140200 mg/dl it is called as prediabetes.12

Exclusion of Type 1 diabetes is done by estimation of GAD antibodies, antibodies against islet cell antigen and insulin. Exclusion of Type 2 diabetes is done by estimation of fasting serum insulin which remains high in Type 2 diabetes reflecting insulin resistance.23

For exocrine deficiency in pancreatic diabetes, fecal elastase â&#x20AC;&#x201C; 1 estimation remains a conventional noninvasive measure.24 The PP (polypeptide) respone to 12 ounce of boost high protein supplemented with pancreatic enzymes is estimated23. In normal population the PP response increases 4 to 6 fold over the basal value whereas in pancreatic diabetes less than doubling over the basal value is the rule.25

Pancreatic imaging is a must in cases of pancreatic diabetes to establish the cause. Once evidence of calcification in the pancreatic duct is established in USG of abdomen,the above mentioned tests are inconsequences.

DIAGNOSIS

The diagnosis of pancreatic diabetes mellitus is entertained when 1.

Patients of diabetes mellitus have abdominal symptoms and features of malabsorption.

Wherever ambiguity regarding typing of diabetes mellitus as type 1 and type 2 arises, possibility of pancreatic diabetes mellitus should be thought of.

CHAPTER 163

T1DM Associated with

760

COMPLICATIONS

DIABETES

The complication of pancreatic diabetes follows the similar risk pattern as that of Type 2 diabetes mellitus with micro and macrovascular complications(e.g., CVD). These patients may show brittle diabetes with wide excursion of glucose level and frequent hypoglycemia. Nutritional deficiencies like decreased vitamin-D levels predispose them to osteoporosis.23 Diabetic ketoacidosis (DKA) is less in pancreatic diabetes.33-35 Another important aspect of pancreatic diabetes is that it is the harbinger of pancreatic carcinoma, hence Type 3C Diabetes is considered as a premalignant condition.26-28

MANAGEMENT

In the management of pancreatic DM the aim is to control the hyperglycemia (HbA1c <7%), care of exocrine deficiency like managing malnutrition and abdominal symptoms and sometimes giving special care to brittle diabetics. Management of pancreatic diabetes is problematic because of both carbohydrate and lipid malabsorption, irregular pattern of eating habits due to abdominal symptoms and loss of glucagon response to hypoglycemia. Till date no definite therapeutic guidelines have been established. So the consensus follows the treatment guidelines for Type 2 DM with modification when needed. In view of the pathological changes in exocrine as well as endocrine pancreas, insulin secretagogues or drugs enhancing innate insulin secretion have very little role to play. Similarly, the quantum of tissue insulin resistance being negligible, role of insulin sensitizers is also very limited. The mainstay of management is insulin therapy. Due to deficiency of exocrine pancreatic enzymes, supplementation with enzymes like lipase along with other nutritional supplements,fat soluble vitamin supplements like vit. A,D,E,K should be done in patients with FCPD. Lifestyle modifications like cessation of smoking, abstinence from alcohol and low fat diet is helpful. Surgical treatment is often given to patients of FCPD through the PEUSTOW’S procedure where the pancreatic duct is opened up longitudinally, then stones removed and pancreaticojejunostomy is performed. The residual β-cell and exocrine pancreatic mass is salvaged.Nesidioblastosis i.e regeneration of β-cell have occurred in some cases after surgical procedure. Endoscopic intervention can also be attempted in cases where there is primarily narrowing of the pancreatic duct in the head region. This procedure is performed with the help of ECLT ( Extra Corporeal Lithotripsy) which can pulverise the stone, especially in case of a large stone in head region of pancreatic duct. Total pancreatectomy with islet autotransplantation (TPIAT) is considered in pancreatic DM with pancreatic cancer.30

CONCLUSION

Pancreatic diabetes (Type 3C diabetes) is a separate entity for which diagnostic criteria and treatment modalities are different. 5 to 10% of the newly diagnosed diabetes are now Type 3 diabetes. Chronic pancreatitis remains the major cause of pancreatic diabetes. Exocrine deficiency often predates pancreatic diabetes. Defective pancreatic polypeptide response is the early marker of pancreatic diabetes.32 Some of the pancreatic diabetes patients are brittle. Chronic pancreatitis and pancreatic diabetes are considered to be premalignant condition for pancreatic carcinoma.

REFERENCES

Hart PA, Chari ST. Diabetes mellitus as a result of pancreatic cancer. Pancreapedia: Exocrine Panaceas Knowledge Base. DOI: 10.3998/panc.2015.34, 2015.

2. Moran A, Hardin D, Rodman D, Allen HF, Beall RJ, Borowitz D, et al. Diagnosis, screening and management of cystic fibrosis related diabetes mellitus: a consensus conference report. Diabetes Res Clin Pract 1999; 45:6173. PMID: 10499886. 3.

P.J. Gee Varghese, Annie Abraham. Calcific Pancreatitis And Diabetes In The Tropics, Second Edition, Published by Dr. P.J. Gee Varghese, Cochin, India, 1995

Ewald N, Bretzel RG. Diabetes mellitus secondary to pancreatic diseases (Type 3c) - Are we neglecting an important disease? Eur J Intern Med 2013; 24:203-206. PMID: 23375619.

Hardt PD, Brendel MD, Kloer HU, Bretzel RG. Is pancreatic diabetes (type 3c diabetes) underdiagnosed and misdiagnosed? Diabetes Care 2008; 31(Suppl 2):S165–S169.

Ewald N, Kaufmann C, Raspe A, Kloer HU, Bretzel RG, Hardt PD. Prevalence of diabetes mellitus secondary to pancreatic diseases (type 3c). Diabetes Metab Res Rev 2012; 28:338-342. PMID: 22121010.

Bertin C, Pelletier AL, Vullierme MP, Bienvenu T, Rebours V, Hentic O, et al. Pancreas Divisum Is Not a Cause of Pancreatitis by Itself But Acts as a Partner of Genetic Mutations. Am J Gastroenterol 2012; 107:311-317. PMID: 22158025.

8. Howes N, Lerch MM, Greenhalf W, Stocken DD, Ellis I, Simon P, et al. Clinical and genetic characteristics of hereditary pancreatitis in Europe.Clin Gastroenterol Hepatol 2004; 2:252-261. PMID: 15017610. 9. Malka D, Hammel P, Sauvanet A, Rufat P, O’Toole D, Bardet P, et al. Risk factors for diabetes mellitus in chronic pancreatitis. Gastroenterology 2000; 119:1324-1332. PMID: 11054391. 10. Rebours V, Boutron-Ruault MC, Schnee M, Ferec C, Le MC, Hentic O, et al. The natural history of hereditary pancreatitis: a national series. Gut 2009; 58:97-103. PMID: 18755888. 11. Wakasugi H, Funakoshi A, Iguchi H. Clinical assessment of pancreatic diabetes caused by chronic pancreatitis. J Gastroenterol 1998; 33:254-259. PMID: 9605958. 12. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2012; 35:S64-S71. PMID: 22187472. 13. Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, et al. Hereditary pancreatitis

is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996; 14:141-145. PMID: 8841182. 14. Schneider A, LaRusch J, Sun XM, Aloe A, Lamb J, Hawes R, et al. Combined Bicarbonate Conductance-Impairing Variants in CFTR and SPINK1 Variants Are Associated With Chronic Pancreatitis in Patients Without Cystic Fibrosis. Gastroenterology 2011; 140:162-171. PMID: 20977904. 15. Meier JJ, Butler PC. Insulin secretion. In: DeGroot LJ, Jameson JL, editors. Endocrinology, 5th ed. Philadelphia: Elsevier Saunders; 2005. pp. 961–973.

17. Larsen S, Hilsted J, Tronier B, Worning H. Pancreatic hormone secretion in chronic pancreatitis without residual beta-cell function. Acta Endocrinol (Copenh) 1988; 118:357364. PMID: 2899369. 18. Yasuda H, Harano Y, Ohgaku S, Kosugi K, Suzuki M, Hidaka H, et al. Insulin Sensitivity in Pancreatitis, Liver-Diseases, Steroid Treatment and Hyperthyroidism Assessed by Glucose, Insulin and Somatostatin Infusion. Horm Metab Res 1984; 16:3-6. PMID: 6141989 19. Gorelick F, Pandol SJ, Topazian M. Pancreatic physiology, pathophysiology, acute and chronic pancreatitis. Gastrointestinal Teaching Project, American Gastroenterological Association. 2003. 20. Gepts W. Pathologic Anatomy of Pancreas in Juvenile Diabetes Mellitus. Diabetes 1965; 14:619-&. PMID: 5318831. 21. Gepts W, Veld PAI. Islet Morphological-Changes. Diabetes Metab Rev 1987; 3:859-872. PMID: 3315523. 22. Nosadini R, Delprato S, Tiengo A, Duner E, Toffolo G, Cobelli C, et al. Insulin Sensitivity, Binding, and Kinetics in Pancreatogenic and Type-I Diabetes. Diabetes 1982; 31:346355. PMID: 6759250. 23. Rickels MR, Bellin M, Toledo FGS, Robertson RP, Andersen DK, Chari ST, et al. Detection, evaluation and treatment of diabetes mellitus in chronic pancreatitis:. Recommendations from Pancreas Fest 2012. Pancreatology 2013; 13:336342. PMID: 23890130. 24. Loser C, Mollgaard A, Folsch UR. Faecal elastase 1: a novel, highly sensitive, and specific tubeless pancreatic function test. Gut 1996; 39:580-586. PMID: 8944569. 25. Cui YF, Andersen DK. Pancreatogenic Diabetes: Special Considerations for Management. Pancreatology 2011; 11:279-294. PMID: 21757968.

761

27. Li D, Tang H, Hassan MM, et al. Diabetes and risk of pancreatic cancer: a pooled analysis of three large casecontrol studies. Cancer Causes Control 2011; 22:189–197. 28. Solanki NS, Barreto SG, Saccone GT. Acute pancreatitis due to diabetes: the role of hyperglycaemia and insulin resistance. Pancreatology 2012; 12:234–239. 29. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009; 32:193-203. PMID: 18945920. 30. Bellin MD, Freeman ML, Gelrud A, Slivka A, Clavel A, Humar A, et al. Total pancreatectomy and islet autotransplantation in chronic pancreatitis: Recommendations from PancreasFest. Pancreatology 2014; 14:27-35. PMID: 24555976. 31. Sikkens ECM, Cahen DL, Koch AD, Braat H, Poley JW, Kuipers EJ, et al. The prevalence of fat-soluble vitamin deficiencies and a decreased bone mass in patients with chronic pancreatitis. Pancreatology 2013; 13:238-242. PMID: 23719594. 32. Valenzuela JE, Taylor IL, Walsh JH. Pancreatic polypeptide response in patients with chronic pancreatitis. Dig Dis Sci 1979; 24:862-864. PMID: 520107. 33. Ebert R, Creutzfeldt W. Reversal of impaired GIP and insulin secretion in patients with pancreatogenic steatorrhea following enzyme substitution. Diabetologia 1980; 19:198– 204. [PubMed] 34. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; 26 Suppl 1:S5–S20.[PubMed] 35. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2011; 34 Suppl 1:S62–S69. [PMC free article] [PubMed] 36. Gudipaty, Lalitha. Rickels, Michael R. (2015). Pancreatogenic (Type 3c) Diabetes. Pancreapedia: Exocrine Pancreas Knowledge Base, DOI: 10.3998/panc.2015.35 37. Nils Ewald, Philip D Hardt. Diagnosis and treatment of diabetes mellitus in chronic pancreatitis. 2013; 19:7276– 7281. 38. Juris J. Meier; Arnd Giese. diabetes associated with pancreatic diseases. Curr Opin Gastroenterol 2015; 31:400406.

CHAPTER 163

16. Schrader H, Menge BA, Schneider S, et al. Reduced pancreatic volume and beta-cell area in patients with chronic pancreatitis. Gastroenterology 2009; 136:513–522.

26. Ben Q, Xu M, Ning X, et al. Diabetes mellitus and risk of pancreatic cancer: A meta-analysis of cohort studies. Eur J Cancer 2011; 47:1928–1937.

C H A P T E R

164

Diabetes Mellitus: A CV Risk Equivalent

At one time diabetes mellitus (DM) was considered as a major coronary risk factor along with smoking, hypertension and hypercholesterolemia. But the association of diabetes mellitus with coronary heart disease became so intimate that it is now being considered as the coronary equivalent. Once somebody develops diabetes he always carries the extra risk of various cardiovascular events. The CV risks might be in the – •

Blood vessels in heart causing ischaemic heart disease,

•

Renal vessels causing nephropathy,

•

Blood vessels in the eye ( retinopathy),

•

Blood vessels in the brain causing stroke.

•

Periphral arteries causing Peripheral vascular disease.

Excluding the involvement of major blood vessels in the heart microvascular involvement and involvement of the myocardial cells does occur; leading to systolic and diastolic heart failure. These later manifestations come under diabetic cardiomyopathy. Though the major problem in diabetes is hyperglycemia and the vascular damage is primarily mediated by hyperglycemia but many other factors do play a role. Even similar vascular damage do occur in those who have not yet developed diabetes mellitus; like the metabolic syndrome and prediabetic states( IGT and IFG).1

WHAT HAPPENS?

There occur changes in the large blood vessels, in small blood vessels, at the cellular level and at molecular levels.

MACROVASCULAR FACTORS

The main problem in the major blood vessels is atherosclerosis. Pathogenesis of atherosclerosis is same everywhere, but certain extra factors in DM operate so that atherosclerosis develops earlier and progresses faster. 97% of the diabetics have dyslipidemia.2 The lipid abnormality in diabetics is low HDL and high triglecerides. The LDL in these patients is small and dense, which helps them to enter into the endothelial cells more easily and forms stronger attachments with the arterial wall. Small LDL particles are more susceptible to oxidation. Once the LDL particles get oxidized they become immunogenic and attracts immune cells and initiates the process of inflammation. During the process various factors are released which helps atherogenesis. There occurs migration of smooth muscle cells, proliferation of endothelial cells and accumulation of leucocytes. LDL particles get glycated which increases its half life and it remains longer in the circulation and in the atheromatous plaque. At the same time glycation of

Kashinath Padhiary

HDL shortens its life span; there by reduces its beneficial effects. High triglyceride (often an essential component of diabetes or metabolic syndrome) level helps in production of small LDL and decreased HDL transport to liver encouraging high level of LDL and promoting the atherosclerotic process.3 Endothelial dysfunction also exists in diabetics. The net result of endothelial dysfunction is vasoconstriction which also contributes to atherosclerosis. Thus the lipid abnormality and the endothelial dysfunction are responsible for the macrovascular changes in diabetics and its consequences.

MICROVASCULAR FACTORS

Usually we mean retinopathy, nephropathy and neuropathy as the microvascular complications in diabetes mellitus, but such changes do occur all over the body. This small vessel disease is not related to atherosclerosis and not related to lipid abnormality. At physiological level microcirculation is maintained by local autonomic nerve supply and substances released by endothelium and metabolites released locally. Capillary permeability to different metabolites and the intactness of the junction between the endothelial cells are the most important factors in this regard. Normally the endothelium produces enough nitric oxide (NO) which acts as strong vasodilator. In diabetes all these undergo changes. Due to autonomic neuropathy local autoregulation of blood flow is not maintained. The thickness of the capillary basement membrane increases leading to inadequate exchange of materials (metabolic products and nutrients) between blood and tissues. Often this gives a sense of fatigue on exertion. However the junction between the endothelial cells becomes less efficient. There is alteration in charges at these points. This causes leakage of macromolecules like albumin. Hence micro-albuminuria is considered as the evidence of microangiopathy in DM.4 There is decreased release of NO and increased secretion of endothelin-1 which is a vasoconstrictor substance. The result is diffuse vasoconstriction almost in all the tissues leading loss of their vitality. These chemical changes have been noticed in both in DM as well as in metabolic syndrome. Decreased NO production is related to insulin deficiency and insulin resistance. One of the consequences of microvascular complication due to diabetic autonomic neuropathy (DAN) is sudden cardiac death and higher overall cardiac death.

CELLULAR FACTORS

The cells that are involved in vascular damage are inflammatory cells and the adipocytes. It has been observed by researchers that diabetes mellitus is a chronic

Adipocytes in diabetics are extremely active. They release different types of adipokines (Tumor necrosis factoralpha, interleukin-1beta, interleukin-6, plasminogen activator inhibitor-1).7 These are all proinflammatory markers. Level of all these increases as obesity increases. Adiponectin which is an anti-inflammatory marker is found to be reduced in obese individuals; hence contributing to the damaging effects of inflammatory markers. These changes are observed both in diabetics and prediabetics.

MOLECULAR FACTORS

Several molecules are involved in the process of vascular damage in diabetes mellitus. Of them the most important are the reactive oxygen species (ROS). These act as free radicals. Free radicals are molecules having unpaired electron in their outermost orbit. This makes them highly reactive. They are primarily released from mitochondria during the process of oxidative phosphorylation.8 They are also released during the process of inflammation by the leucocytes. This has been observed both in animal experiments and in studies in human. These reactive species react with various cell organelles as well as cell membrane causing damage to them. Free radicals in excess are also generated due to metabolism of glucose and free fatty acid in hyperglycemic states of DM. This exceeds the capacity of the cells to tackle the extra free radicals and thereby cell damage occurs. At molecular level there are four basic mechanism by which diabetes mellitus brings tissue damage. These are: •

Activation of the polyol pathway

•

Increased production of advanced glycosylation end products

•

Activation of protein kinase C

•

Activation of hexosamine pathway.

All these four mechanisms are initiated and propelled by ROS released by mitochondria. Hence oxidative stress is the important mechanism of diabetic organ damage.

OTHER FACTORS

The major vascular events in diabetics is thrombosis; either giving rise to myocardial infarction, cerebral infarction or blockage of peripheral arteries. Hence the final step is thrombosis. Here the platelet and the coagulation factors finish the total process of vascular damage. Changes

in them produce a state of hypercoagulability.9 It has been observed that platelet aggregation and adhesion is increased in DM. Activation of platelets releases so many factors like beta- thromboglobulin, platelet factor-4, thromboxane-B2. In some patients the platelet is so much activated that use of aspirin is not effective in these patients. This has been attributed as aspirin resistance. Similarly coagulation markers are also found to be elevated. Prothrombin activation fragments, thrombin anti-thrombin complexes are found to be elevated in diabetics. Some workers have also detected high level of fibrinogen, factor-VII, factor-VIII, Factor-XII, kallikrein and von Willebrand factor. It is also noticed that the fibrinolytic activity is reduced. This also encourages thrombotic process. In addition to the vascular changes causing several CV events, the myocardium is also directly damaged in diabetics. These patients present as heart failure. Both systolic and diastolic heart failure has been observed in the absence of any vascular events.10 It has been seen that for rise of Hb A1C by 1% there is 12% rise in heart failure in diabetic population. The factors that lead to heart failure, particularly diastolic heart failure are micro vascular disease, myocardial fibrosis, myocardial hypertrophy, DAN and failure of release of NO.

SUMMARY

The cardiovascular damage in diabetes mellitus is multifactorial. The process starts well before frank hyperglycemia develops either as prediabetic stage or metabolic syndrome. It is always better to remain free from these states by regular exercise and not developing obesity. CV changes are so vividly associated with DM that it deserves to be mentioned as CV risk equivalent.

REFERENCES

1. The DECODE study group: Glucose tolerance and mortality: comparision of WHO and American Diabetes association diagnostic criteria. Lancet 1999; 354:617-621. 2. Fagot-Campagna a, Rolka DB, Beckles GL,Greg EW, Narayan KM, Prevance of lipid abnormalities, awareness, and treatment in US adults with diabetes. Diabetes 49(suppl.1) 2000 A78. 3. Rosenson RS: Clinical role of LDL and HDL subclasses and apolipoprotein measurement. ACC Curr J Rev 2004; 33-37 4. Weir M: Microalbuminuria and cardiovascular disease. Clin J Am Soc Nephrol 2007; 2:581-590. 5. Kim J, Koh KK, Quon MJ: The union of vascular and metabolic actions of insulin in sickness and in health. Arteroscler Thromb Vasc Biol 2005; 46:1978-1985 6. Pickup JC, Mattock MB, Activation of the innate immune system as a predictor of cardiovascular mortality in type 2 diabetes mellitus. Diabetes Med 2003; 20:723-726. 7. Trayhurn P, Wood IS: signaling role of adipose tissue adipokines and inflammation in obesity. Biochem Soc Trans 2005; 33:1078-1081. 8. Nishikawa T, Araki E, Impact of mitochondrial ROS production in the pathogenesis of diabetes mellitus and its complications. Antiox Redox Sig 2007; 9:343-353. 9. Carr ME: Diabetes a hypercoagulable state. J Diabetes Comp 2001; 15:44-54. 10. Bell DS: Diabetic cardiomyopathy a unique entity or a complication of coronary artery disease? Diabetes Care 2003; 18:5708-5714.

763

CHAPTER 164

low grade inflammatory disorder.5 The inflammation is mostly confined to the vascular endothelium. The leucocytes involved in the inflammation release a lot of mediators and themselves are under influence of several chemicals like cytokines and chemokines. The inflammation preceds much befor frank diabetes mellitus; even prediabetic states. This inflammatory process is both responsible for the vascular damage as well as progression of diabetes mellitus. Hence this is the common source of both the processes. The effect of inflammation is decreased production of NO and increased production endothelin-1. The inflammatory mediators released cause enhanced capillary permeability, apoptosis and generation of reactive oxygen species. Certain workers have detected rise in sialic acid level persistently in majority of Type-2 diabetics.6

C H A P T E R

165

Statin Associated New Onset Diabetes Mellitus – Myth or Reality? VA Kothiwale, Deebanshu Gupta, R Ravikanth, Saurabh Gaur

cells: Another proposed mechanism involves the observation that patients with familial hypercholesterolemia (ie, elevated LDL-C) have low rates of DM. As intracellular cholesterol is believed to inhibit cellular function and survival. Statins upregulate LDL receptors to increase cholesterol transport. This activity occurs not only in the liver but other tissues, including the pancreas. So, pancreatic LDL receptor upregulation causes increased intracellular cholesterol levels and potentially toxic effects in β cells.

INTRODUCTION

As type 2 diabetes is accompanied by dyslipidaemia, statins provide a major role in preventing long term complications in diabetes and are also recommended in diabetics with normal LDL as well. During the Jupiter trial (Justification for the Use of Statins in Primary Prevention Trial) a small but significant link between new-onset diabetes mellitus (NOD) and statin therapy was noted with rosuvastatin users . From thereafter multiple analyses have confirmed this association. Results of recent observational studies strongly correlate NOD with statin use. Due to this the United States Food and Drug Administration released changes to statin safety label in 2012 with a warning that statins can lead to impaired fasting serum glucose levels and increase in glycosylated haemoglobin.

A definitive patho-physiological link between statins and glucose impairment is not there although various mechanisms have been proposed: 1.

Calcium channel blockade in beta cells: Insulin secretion from pancreatic cells is initiated by voltage gated calcium channels as intracellular calcium increases. Studies have shown that simvastatin leads to blockage of calcium channels, thereby causing diminished insulin secretion. Pravastatin has also been found to block calcium channels, but the doses required for this effect in higher for pravastatin. Decreased GLUT 4 expression & Decreased levels of coenzyme Q10: One of the co effects of bloackage of the HMG-CoA reductase enzyme by statins is that it also blocks the production of other substances in the cholesterol pathway, like isoprenoids - coenzyme Q10 etc. These byproducts up regulate GLUT4, which mediates peripheral glucose uptake. Treatment with clinical doses of atorvastatin cause decreased GLUT 4 expression resulting in the pathology. Other statins (simvastatin, lovastatin) have shown similar effects on GLUT4 expression. Interestingly, Ganesan and Ito demonstrated that simvastatin-induced insulin resistance was reversed by adding coenzyme Q10. The same in vitro study, on the other hand, demonstrated that pravastatin and ezetimibe (cholesterol blocker) do not reduce GLUT4 expression, suggesting that NOD is not just due to lowering of cholesterol. Diminished cholesterol uptake in pancreatic beta

Reduced adiponectin levels: A further proposed mechanism lies in the effect on the adiponectin metabolism. It is a hormone that modulates metabolic processes, including glucose regulation. It down regulates gluconeogenesis and increases glucose uptake; high levels of adiponectin have been associated with decrease in the risk of developing type 2 DM in a prospective study. Simvastatin has been reported to significantly reduce insulin sensitivity by virtue of decreasing adiponectin levels in hypercholesterolemic patients.

CLINICAL BENEFITS VERSUS DM RISK WITH STATINS

CV disease (CVD) is the leading cause of mortality and one of the most important causes of morbidity in the world. Statins have largely been shown in several landmark trials and meta-analyses to be beneficial in secondary prevention of CV events and primary prevention in patients belonging to high risk group. 1.

Sattar and colleagues estimated that statin treatment lead to 5.4 fewer deaths from coronary heart disease and cases of nonfatal myocardial infarction per 255 patients after 4 years of therapy, for each 1-mmol/L (39 mg/dL) reduction in LDL cholesterol compared with controls. In contrast, the risk of developing DM was one additional case for every 255 patients treated with statins.

In the meta-analysis by Preiss et al. ,6.5 CV events were prevented in the intensive-dose statin group per 1,000 patient-years; this in turn translates into a number needed to treat (NNT) of 155 for CV events and a number needed to harm (NNH) of 498 for new-onset DM. Considering secondary prevention, benefits of statin therapy outweigh DM risk.

Another important scenario not fully exploited in low-risk patients is primary prevention in patients with no history of previous CVD, for whom statin therapy is increasingly used for vascular prevention

Large and Short Randomised Control Trials

Meta-analysis by Taylor et al. found that statins in the primary prevention of CVD cause insignificant reduction in all-cause mortality; this meta-analysis showed that a mortality relative risk reduction (RRR) of 17 % was observed with statin treatment. However, they concluded that there is not enough evidence to recommend the use of statins in the primary prevention of heart disease. The authors of this meta-analysis came to conclusion that the absolute benefits were rather small—1,000 people have to be treated for 1 year to prevent one death. When used among people at low absolute risk the advantage of statin therapy may become insignificant, and a higher NNT is required to gain some benefit. So, it is still uncertain where exactly the point lies beyond which the protective and beneficial CV actions of statins start to outweigh the diabetogenic risk in primary prevention.

Jupiter Trial- Justification for Use of Statins in Prevention- An Intervention Trial Evaluating Rosuvastatin: Earlier to this trial there had been reports of impaired glucose tolerance and increased risk of diabetes associated with use of statins, the issue got attention after its publication in 2008, of results of (JUPITER), which was a large, randomized, placebo controlled, primary prevention trial.

Increased incidence of diabetes in persons taking rosuvastatin was reported in this trial, which included 17,802 men and women (average age 66 years) who were randomized into two groups: rosuvastatin (20 mg/day) or an inactive placebo drug. There was a 26% higher incidence of diabetes in the rosuvastatin group. The results of JUPITER started a wave of discussion regarding potential risks and benefits of statin therapy (Figure 2).

Prosper Trial: Investigators reported a 32% higher incidence of DM for those taking pravastatin (40 mg/day) compared with controls in the Prospective Study of Pravastatin in the Elderly at Risk trial.

Any assessment in role of statins in primary prevention should be made in light of patient CV risk and overall assessment

RATIONALE FOR TAILORED STATIN THERAPY

What is the rationale for individualized statin therapy? Different arguments are in favour of a more balanced tailored statin therapy based on clinical judgments, the patient’s cardiovascular and metabolic risk profile, and the dose of statin and its type used. A. B.

EVIDENCE FROM CLINICAL TRIALS

META ANALYTIC STUDIES - FURTHER EVIDENCE (TABLE 1)

In the background of varying and conflicting results of clinical trials, a few meta-analyses conducted in the past 5-6 years help to resolve the issue.

Have We Underestimated the Dimension of New Onset Diabetes In secondary prevention, the benefits of statin Mellitus with Statin Use therapy clearly outweigh the risks of DM.

In primary prevention of low-risk patients, the benefits of such a strategy is less clear and has to be balanced against the risk of ‘overmedicating’ the general population.

Ideal study- (Incremental Decrease in Endpoints through Aggressive Lipid Lowering). This study compared the incidence of new-onset DM to CV risk reduction among 15,056 patients with coronary heart disease or a history of myocardial infarction and non diabetics at baseline. Significant finding of this analysis was that the increase in risk of DM was largest in patients who were benefitted the most in terms of CV risk reduction with statin therapy. Pravastatin could be the right match for hyperlipidemic patients having low CV risk. But, despite its lower potential to lower LDL cholesterol, it seems to be the statin having least diabetogenic potential, currently available on the market. Although newer, more powerful, and more advertised statins are widely used, pravastatin could serve as a valuable alternative, especially for patients with a predisposition for DM. It is crucial to remember that statins cannot account for all new cases of DM diagnosed during hypolipidemic therapy and the hazard of developing new-onset DM is directly connected with already existing DM risk factors.

Two of the arguments called to put light upon this evidence can be cited: (i) the single studies were not designed and powered to primarily address DM as an endpoint and maximum follow-up did not exceed 5 years; (ii) the definition of DM varied among the trials, mostly derived from non-standardized criteria and screening of new onset DM was not regularly done. So, we may conclude that we may even have underestimated the dimension of the problem.

POPULATIONS WITH METABOLIC SYNDROME RISK FACTORS MORE PRONE TO NOD WITH STATIN USE

Certain populations, particularly those with various features of metabolic syndrome, may be more prone to developing NOD with statin use risk factors such as: Positive for hypertension, BMI >30, triglycerides >150 mg/ dL, Asian ethnicity, fasting blood glucose >100 mg/dL, women, older adults, those with a family history of DM, extended duration of statin use. Waters et al analyzed three large statin RCTs and concluded that in each fasting blood glucose, hypertension, BMI, and fasting triglycerides were independent risk factors for developing NOD with statin use. It was further determined that patients with two to four DM risk factors were more prone to developing NOD compared with those with zero to one risk factor.

765

CHAPTER 165

and in this scenario there has been controversy as to whether the absolute benefit of treatment outweighs the risk of developing DM.

766

IMPACT OF DIFFERENT TYPES AND DOSES OF STATIN – IS IT A CLASS EFFECT?

rosuvastatin or atorvastatin or any other powerful statin are highly recommended.

In recent years, the query remains as to whether or not the type of statin and the intensity of dose contribute to the conflicting results observed in RCTs and meta-analyses.

The potentially raised DM risk exceeding benefits should be particularly considered in individuals with low CV risk (0–1 risk factors).

A. Carter and colleagues recently conducted a population-based study, showing in a real-world setting that, compared with pravastatin, there was an increased risk of incident DM with atorvastatin, rosuvastatin and simvastatin .

Prior to initiation of statin therapy, screening for DM and metabolic syndrome risk factors may help identify patients at high risk of DM requiring closer monitoring. According to the recent evidence, pravastatin can be the statin of choice in such populations.

DIABETES

A published meta-analysis of five randomized trials (N = 32,752) found a higher incidence of new-onset DM in 1,449 (8.8 %) of the intensive-therapy group and 1,300 (8.0 %) of the moderate-therapy group. In contrast, incident CV disease occurred in 3,134 (19.1 %) of the intensive-therapy group and 3,550 (21.7 %) of the moderate-therapy group. Therefore, there was a 0.8 % absolute increase in DM cases on high-dose statins and a 2.6 % absolute reduction in adverse CV events.

Navarese and colleagues published the largest and most comprehensive meta-analysis so far, by comparing rates of new onset DM among different types and doses of statins. The main findings, derived from a population of 113,394 patients, were as follows:

There was a gradient in the risk for new-onset DM with different types and doses of statins

ii.

Pravastatin therapy was numerically associated with the lowest OR of new-onset DM compared with placebo; whereas treatment with rosuvastatin was numerically associated with a 25 % increased risk of DM compared with placebo

iii.

The cumulative probabilities indicated that highdose pravastatin had the highest probability of it being the safest treatment in terms of probability of causing new-onset DM, with simvastatin & rosuvastatin performing least well in this ranking

There is thus far a lack of conclusive evidence in favour of statin administration in low-risk patients for primary prevention.

CLINICALLY USEFUL CONCLUSIONS TO MINIMISE RISK OF NOD

FOLLOWING clinical considerations can be implemented to minimize the risk of statin-associated NOD: 1.

Screen patients to determine baseline glycemic values. This is especially important among those with risk factors for DM (eg, BMI >30 kg/ m2, hypertension, elevated triglycerides, fasting glucose 100–125 mg/dL, family history of DM, ethnic group [eg, Asians]). If baseline values are not established and glucose impairment is noted after statin initiation it may be naturally assumed that the elevation is statin related.

Avoid changes for patients with existing coronary heart disease and for high-risk primary prevention patients. The proven benefits of statin therapy surely outweigh the risk of glucose impairment in high-risk populations. Close monitoring of glycemic parameters for those on intensive statin therapy is important.

Understand that certain less-intensive statins appear to have minimal impact on glycemic indices. Practitioners may consider these for lowerrisk patients, those with risk factors for DM, or in individuals with risk factors for NOD. Studies have generally demonstrated that pravastatin, pitavastatin, lovastatin and fluvastatin have neutral to modest effects on glycemic markers; however, practitioners should be mindful of lovastatin due to its known drug interactions. The optimum moderate to maximum daily doses of these “moderate-intensity” statins ( fluvastatin 80 mg, pravastatin 40–80 mg, pitavastatin 2–4 mg, lovastatin 40 mg) achieve the 30% to 50% LDL-C reduction suggested by cholesterol guidelines.

Consider a nonstatin to achieve additional LDL-C reduction. Although they provide greater efficacy, higher statin doses generally demonstrate higher rates of NOD. As a result, practitioners may want to choose a less-intensive statin in certain patients, but are then faced with the dilemma of a diminished ability to reduce LDL-C. By adding a nonstatin option to the less-intensive statin may

iv. High-dose pravastatin when compared with placebo provided the most robust safety profile compared with the other high-dose statins; As an additional datum, by meta-regression analysis, the risk for developing DM did not get influenced by the different abilities of statins to reduce cholesterol. The benefits of statins outweigh the increased risk of DM in people with CVD or at moderate to high risk of CVD. In such patients, a powerful statin like rosuvastatin or atorvastatin should be recommended. 1.

Individuals with high CV risk (10-year risk >20 %, according to the Framingham risk score) or existing CVD should receive statin therapy as indicated.

Individuals with moderate CV risk (≥2 risk factors, 10-year risk ≤20 %) should also be prescribed a statin.

In high-risk subgroups such as following an acute coronary syndrome (ACS) episode, high doses of

help resolve this issue. Ezetimibe is glucose neutral and it causes modest but significant reductions in CV events when added to a statin. Bile acid resins effectively reduce HbA1c by approximately 0.5%. 5.

6. Choose concomitant antihypertensive agents wisely. As a co morbidity hypertension is a commonly associated with dyslipidemia. Older agents, such as β-blockers and also thiazide diuretics, increase NOD by 22% to 43%. On the other hand, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have demonstrated insulin-sensitizing properties and a reduced incidence of NOD, whereas calcium channel blockers are considered glucose neutral.

REFERENCES

Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated Creactive protein. N Engl J Med 2008; 359:2195-2207

Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001; 103:357-362.

Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative metaanalysis of randomised statin trials. Lancet 2010; 375:735-742.

Ridker PM, Pradhan A, MacFadyen JG, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012; 380:565-571.

5. Heart Protection Study Collaborative Group. MRC/ BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 highrisk individuals: a randomised placebo controlled trial. Lancet 2002; 360:7-22.

767

Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360:1623-1630.

8. Kostapanos MS, Milionis HJ, Agouridis AD, et al. Rosuvastatin treatment is associatedwith an increase in insulin resistance in hyperlipidaemic patients with impaired fasting glucose. Int J Clin Pract 2009; 63:1308-1313. 9.

Coleman CI, Reinhart K, Kluger J, et al. The effect of statins on the development of newonset type 2 diabetes: a metaanalysis of randomized controlled trials. Curr Med Res Opin 2008; 24:1359-1362.

10. Rajpathak SN, Kumbhani DJ, Crandall J, et al. Statin therapy and risk of developing type 2 diabetes: a metaanalysis. Diabetes Care 2009; 32:1924-1929. 11. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive dose compared with moderatedosestatin therapy: a metaanalysis. JAMA 2011; 305:2556-2564. 12. Navarese EP, Buffon A, Andreotti F, et al. Metaanalysis of impact of different types and doses of statins on newonset diabetes mellitus. Am J Cardiol 2013; 111:1123-1130. 13. Yada T, Nakata M, Shiraishi T, et al. Inhibition by simvastatin, but not pravastatin, of glucoseinduced cytosolic Ca2+ signalling and insulin secretion due to blockade of Ltype Ca2+ channels in rat islet betacells Br J Pharmacol 1999; 126:1205-1213. 14. Ganesan S, Ito MK. Coenzyme Q10 ameliorates the reduction in GLUT4 transporter expression induced by simvastatin in 3T3L1 adipocytes. Metab Syndr Relat Disord 2013; 11:251-255. 15. Nakata M, Nagasaka S, Kusaka I, et al. Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control. Diabetologia 2006; 49:1881-1892. 16. Besseling J, Kastelein JJ, Defesche JC, et al. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA 2015; 313:1029-1036. 17. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/ AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129:S1-S45.

CHAPTER 165

Proprotein convertase subtilisin kexin type 9 inhibitors are an approved medication class and their role has shown promising results in select high-risk populations, such as those with heterozygous familial hypercholesterolemia, to achieve further LDL-C reduction. Although it is undetermined at this time their future use in the general dyslipidemia population, available data up to this point have not shown an increased risk for NOD.

6. Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998; 339:1349-1357.

Alpha Cells, Glucagon and Type 2 Diabetes

C H A P T E R

166

SP Sondhi, Amit Rastogi, Shaifali Nandwani

HISTORY AND INTRODUCTION

Type 2 diabetes is one of the most prevalent disease in the world, about 44 crore people living with it in 2014, with a prevalence rate of 8.5% among the adults over 18 years of age. It is projected to grow in future and become the 7th leading cause of death in the year 2030. Last few decades have improved our understanding of diabetes, though we are far from the knowing it fully. It was in the year 1869 that a young 22 year old German pathologist Paul Langerhans noted islands of different looking cells in pancreas which were later called islet of Langerhans. It took another 20 years to link these cells to diabetes. These weigh only about 2 mg but majorly control the glucose metabolism in our body. An out of the job orthopaedic Dr Banting, while preparing for a lecture in physiology had the bright idea of isolating the chemical out of pancreas (later called insulin) by tying the exocrine duct in the dog pancreas. He was assisted by Best an intern chosen by the toss of a coin. This was a landmark discovery and after some purifications done by Collip, insulin was tried in type 1 diabetic boy Leonard Thompsons in 1921 with miraculous results. Medical world almost believed that it had discovered the cause and treatment of diabetes. In 1923 just two years later Murlin et al suggested the existence of glucagon and in 1948 Sutherland et al talked about the alha cells and its association with glucose metabolism. In 1950 its amino acid sequence was deciphered, but it was forgotten for the next 50 years because of a large shadow of B cells and insulin. There is renewed interest in alpha cell in causation of diabetes and its treatment for the last 2 decades.

ROLE OF ALPHA CELLS IN HEALTH (TABLE 1)

The alpha cells are as much involved in glucose metabolism as B cells. In a fasting state when there is

Table 1: α-Cell Function regulation Stimulatory Factors ( Glucagon)

Inhibitory Factors ( Glucagon)

Hypoglycaemia

Glucose

Protein meal

Carbohydrate meal

Amino acids

Ketones

Stress; adrenaline (epinephrine)

Insulin

Sympathetic/ parasympathetic nerves

GLP-1

GIP

Somatostatin

deficiency of glucose in the blood, the alpha cells produce more glucagon. Glucagon is produced from proglucagon in the alpha cells. It is carried in the portal blood to liver where it affects hepatocytes through glucagon receptors. It orders liver to produce glucose by glycogenolysis and neoglucogenesis, thus bringing up the blood glucose levels. In experiments done to stop glucagon secretion by giving somatostatin and maintaining constant insulin levels it was proven that glucagon is responsible for 75% of hepatic glucose output. It also causes ketogenesis and has a very short half-life (like insulin) of 5 minutes. Alpha cells have insulin receptors and glucagon secretion is controlled by insulin level. Insulin inhibits proglucagon gene transcription and thus decrease glucagon secretion. The flow of blood in pancreas is from b cells to alpha cells thus promoting this paracrine relationship. There are other stimulants to glucagon secretions than low insulin levels eg. hypoglycaemia, stress through hypothalamus, protein meal and catecholamines. In the post prandial state, exactly the opposite happens. Availability of carbohydrates in food stimulates insulin secretion from beta cells, which in turn brings down the glucagon secretion from alpha cells. Glucagon levels must come down in post prandial state otherwise hepatic glucose output won’t come down and blood glucose levels will remain unduly high. In a post prandial state hepatic glucose output is suppressed 50% by increasing insulin secretion and 50% by lowering of glucagon levels. Other factors which inhibit glucagon secretion are carbohydrate meal directly, somatostatin and GLP.

GLUCAGON IN TYPE 2 DIABETES

Lets’ review what happens in type 2 diabetes. There is a marked reduction in beta cells with amyloid deposition in pancreas. Unfortunately alpha cells population is not reduced as much. With the result that not only there is deficiency of insulin but also excess of glucagon. In fasting state glucagon levels are inappropriately high (50% more than in normal) which results in fasting hyperglycaemia. Similarly alpha cells are non-responsive to higher blood glucose in a post prandial state and continue to secrete high levels of glucagon. Does this happen only because of a paracrine effect of low insulin availability? This was thought true for a long time but some recent discoveries have questioned this hypothesis that inappropriate high levels of glucagon found in type 2 diabetes are secondary to low insulin levels only. The glucagon receptor null mice are those mice who have no receptors through which glucagon can work on their hepatocytes to increase blood

glucose. These mice do not develop diabetes even when all the beta cells are destroyed in them. GLP1 analogues decrease blood glucose through decreasing glucagon levels even in c peptide deficient type 1 diabetes. The interpretation of these two facts is that alpha cells dysregulation and its treatment may be independent of beta cell function.

IMPILCATIONS IN THE TREATMENT OF TYPE 2 DIABETES

There is a clear role of alpha cells and glucagon in causation of type 2 diabetes. A.

There was undue focus on insulin resistance and insulin deficiency.

The methods to assess glucagon were not easy and reliable.

The techniques to isolate the role of glucagon through the use of somatostatin were not refined

This defect needs to be addressed in management of type 2 diabetes. We have finally got some drugs which can correct this defect. These are 1. Drugs working through GLP axis eg. GLP1 analogues and DPP4 Inhibitors. 2. Amylin agonist eg. Pramilintide. Another thing to keep in mind is its role in hypoglycaemia. The first response to hypoglycaemia in an individual is to stop the production of insulin which in turn stimulates glucagon. Glucagon is the main hormone to correct the blood glucose through increased hepatic glucose output. In those individual who are severely insulinopenic (long duration type 2 diabetics) there is no insulin to

769

FUTURE

Considering the role of glucagon in type 2 diabetes, there is a scope for glucagon receptor blockers in treatment. Many pharmaceutical companies are doing trials in these experimental drugs. We are likely to hear more about these drugs in near future. These drugs result in alpha cells hypertrophy, hyperglucagonimia and in experimental animals this has resulted in increased evidence of pancreatic tumours. The alpha cells and glucagon are finally being acknowledged as one of the pathophysiological defects in type 2 diabetes. Increased glucagon levels and non-responsiveness of alpha cells to blood glucose levels are as much responsible for hyperglycaemia as insulin defects. There are some evidences that this is independent of paracrine effects of low insulin levels. The drugs likely to counter this defect are in different phase of development and may hit the market in near future.

REFERENCES

MU J , Jiang G, Brady E, Dallas Yang Q, Liu F, Woods J et al. Chronic Treatment with a Glucagon Receptor Antagonist Lowers Glucose and Modestly Raises Circulating Glucagon and Glucagon like Peptide 1 without Alpha Cell Hypertrophy in Diet Induced Obese Mice, Diabetologia 2011; 54:2381-91.

2. AmĂŠlio F Godoy-Matos, The role of glucagon on type 2 diabetes at a Glance, Godoy-Matos Diabetology & Metabolic Syndrome 2014, 6:91, 2-5.

CHAPTER 166

This was being neglected for three reasons in the past

be decreased in event of hypoglycaemia due to which there is no robust secretion of glucagon and they suffer prolonged hypo.

Treating Diabetes - A Matter of Selectivity of Sulphonylureas

C H A P T E R

167

AJ Asirvatham

INTRODUCTION

Diabetes is gaining the status of a potential epidemic in India at a faster rate with more than 62 million individuals currently diagnosed with the disease. According to 2000 statistics, India (31.7 million) topped the world with the highest number of people with diabetes mellitus, followed by China (20.8 million) and United States (17.7 million). Numerous antidiabetic drugs with different mechanisms are currently available for treatment of type 2 diabetes mellitus (T2DM). Sulphonylureas (SUs) are commonly used in the treatment of T2DM. SUs stimulate insulin secretion by closing ATP sensitive K+ (KATP) channels in pancreatic beta-cells by binding to the SU receptor SUR1. Unlike other SUs, gliclazide, a second generation SU oral hypoglycaemic agent (OHA) used in the treatment of T2DM, is unique in that it is specific for beta-cell K+ channel and does not activate Epac2 (Figure 1).

EPIDEMIOLOGY OF DIABETES

Incidence of diabetes in India shows patterns that are related to the geographical distribution of diabetes in India. Preliminary results from a large community study conducted by the Indian Council of Medical research (ICMR) revealed that a higher proportion of the population is affected in Maharashtra (9.2 million) and Tamil Nadu (4.8 million) compared to the states of Northern India (Chandigarh 0.12 million, Jharkhand 0.96 million). It is estimated that by the year 2030, diabetes mellitus may KATP channel

Other sulfonylurea

Gliclazide

afflict up to 79.4 million individuals in India, 42.3 million in China and 30.3 million in the United States.

EXISTING TREATMENT OPTIONS

T2DM is a major health problem that requires multiple pharmacotherapy. The current available glucose-lowering interventions include: • Metformin • Sulphonylureas • Glinides •

α-glucosidase inhibitors

•

Thiazolidinediones (TZDs or Glitazones)

• Insulin

PLACE OF SUs AMONGST OTHER AGENTS

SUs, after their introduction in clinical practice in 1950’s, have remained the mainstay of pharmacotherapy in the management of T2DM.The South Asian Federation of Endocrine Societies (SAFES) aims to encourage the rational, safe and smart prescription of SUs and recommends appropriate medication counseling by diabetes care professionals in South Asia. A careful choice of SUs, appropriate dosage, timing of administration and adequate personcentered care, will ensure that deserving patients are not deprived of the advantages of this well-established class of antidiabetic agents. Furthermore, the role of modern SUs in managing patients with Sulphonylurea moiety

Ca2+

Azabicyclooctyl ring

O β-cell

Insulin granule exocytosis

Fig. 1: Mechanism of action of gliclazide on pancreatic betacells (SUR: Sulphonylurea receptor; Epac2: Exchange protein directly activated by cAMP 2).

Aromatic ring

Fig. 2: The chemical structure of gliclazide. Gliclazide has three main structural features, an aromatic ring, a SU group and an aminoazabicyclo-octyl ring.

771

Table 1: Place of SUs in diabetes therapy Approach

Indication

Initial therapy

Monotherapy

Contraindication to metformin Intolerance to metformin

Combination therapy with metformin

High blood glucose levels at presentation

2 line therapy

Add on therapy

Inadequate glycemic control with metformin

Subsequent add on therapy

Add on to combination

Inadequate glycemic control with existing oral therapy

Special consideration

Biological factors

Age > 60

Renal impairment Neonatal diabetes MODY-3 Psychosocial factors Glucophenotype

Ramadan* Fasting hyperglycemia Postprandial hyperglycemia

*Preferred SUs include modern SUs like glipizide MR, gliclazide, gliclazide MR, glimepiride. MR: Modified release, SUs: Sulfonylureas, MODY: Maturity-onset diabetes of the young.

diabetes is supported by a large body of evidence. Thus, considering their efficacy, safety, pleiotropic benefits and low cost of therapy, SUs should be considered as a drug of choice for the treatment of diabetes in South Asia. SUs should be preferred as initial therapy in patients with newly or previously diagnosed (<5 years) with functional beta-cell mass, contraindication or intolerance to metformin, high HbA1c levels, suspected Maturity Onset Diabetes of the Young (MODY) and willingness to follow a regular dietary and exercise plan (Table 1).

CLASSIFICATION OF SUS BASED ON SAFES NEW GUIDELINES

Prescription patterns of antidiabetic drugs have changed in recent years with the introduction of newer classes of medications. OHAs still dominate the prescribing pattern in South Asia, either as monotherapy or in combination as majority of the population is treated with OHAs. As ambiguity exists regarding the most commonly prescribed OHAs, an attempt was made to classify them as conventional and modern SUs based on hierarchy of development and according to duration of action.

CLASSIFICATION OF SULPHONYLUREAS

Hierarchy of development • Conventional: glipizide •

Tolbutamide,

glibenclamide,

Modern: Glimepiride, gliclazide modified release (MR), glipizide MR, gliclazide

Duration of action •

Short-acting: Tolbutamide

•

Intermediate -acting: Glipizide, gliclazide

•

Long-acting: Glibenclamide, glimepiride, gliclazide MR, glipizide MR

SELECTION OF SU BASED ON THE NEED OF THE PATIENTS

For patients with T2DM, a patient-centered approach should be used to guide the choice of pharmacological agents. Efficacy, cost, potential side effects, weight, comorbidities, hypoglycaemia risk and patient preferences should be considered. Few implications for SUs are as follows: •

SUs are an effective, safe, well tolerated, affordable and convenient therapeutic option in the management of T2DM.

•

Modern SUs like gliclazide MR and glimepiride should be preferred over conventional SUs in T2DM patients at increased risk of hypoglycaemia.

•

SUs with a lower risk of hypoglycemia such as gliclazide MR and glimepiride are recommended in elderly patients.

•

Reduction of dose and longer intervals between dose adjustments for SUs are recommended in patients with mild/moderate hepatic impairment.

GLICLAZIDE STRUCTURAL DIFFERENCE

Gliclazide is a powerful free radical scavenger. This unique scavenging effect of gliclazide is due to the aminoazabicyclo-octyl ring that is grafted onto the SU group, which is absent in other SUs (glibenclamide, glimepiride) (Figure 2).

MOLECULAR β-CELL ACTION

It has been found that Gliclazide has intermittent β-cell stimulation rather than a continuous one. Hence the chances of hypoglycemic is much less when compared to other sulphonylureas.

MOLECULAR PERIPHERAL ACTION

Glimipride acts on the peripheral cells having insulin mimetic action Figure 3. The drugs acts on the peripheral cell caveolain the DIG area stimulating the insulin receptor

CHAPTER 167

Placement

772

oxidative stress in T2DM patients by improving plasma antioxidant status. It also has a positive antioxidant effects on beta-cells. Intermittent high levels of glucose leads to increased apoptosis of beta-cells. Gliclazide has been shown to have the unique property to reduce betacell apoptosis.

substrate 1 through non RTK pathway producing the effects of insulin, however it cannot happen in the absence of insulin.

GLICLAZIDE IN HYPOGLYCAEMIA

DIABETES

Hypoglycaemia is the foremost clinical concern when augmenting antidiabetic treatment. Hypoglycaemia induced due to SU with or without the need of external assistance occurs in about 1 in every 100 persons per year. A recent review has shown that patients treated with gliclazide experienced lower rates of severe hypoglycaemia.

RENAL AND CARDIOPROTIVE PROPERTY OF GLICLAZIDE

Renal Protection

Diabetic nephropathy is the most frequent complication for type 2 diabetic patients, increasing the risk of premature death and affecting the quality of life of the patients. Approximately, 24.9% of patients develop microalbuminuria, 5-20% develop macroalbuminuria, and 20%, a renal functional impairment.

The GlUcose control in type 2 diabetes: Diamicron MR vs. glimEpiride (GUIDE) study was the first study to show that gliclazide MR significantly lowers rates of confirmed hypoglycaemia as compared to glimepiride.

According to Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, patients receiving gliclazide MR showed 21% decrease in new or worsening nephropathy and 30% decrease in macroalbuminuria development.

Ramadan Trial

Hypoglycaemia is also witnessed frequently in Muslims during the month of Ramadan. In patients with diabetes, fasting can induce hypoglycaemia. According to South Asian guidelines modern SU like gliclazide MR is recommended as effective and economical option during Ramadan. A study in well controlled Asian T2DM patients showed that monotherapy with gliclazide MR in the evening can safely maintain glycaemic control with fewer hypoglycaemic episodes during the Ramadan fast.

Cardiovascular Protection

Studies have reported that gliclazide plays a cardioprotective role as it does not interfere with ischaemic preconditioning. ADVANCE trial demonstrated that intensive gliclazide MR treatment led to reduction in cardiovascular death by 12% (Figure 4).

BETA-CELL PRESERVATION

SUs are the mainstream of pharmacotherapy in the management of patients with T2DM. Their glycaemic

Gliclazide have been found to play a role in reducing

How Amaryl Works

non-DIG area Ins uli n Synthesis

ras raf

Ama n ryl

Grb 2

R T K

PKB IRS -1 p85 ppII5 SYP

SHC

Grb 2

MEK MAP K c-jun

n non RTK o

MEKKSOS

G P I p DIGs rP G o P t I e Caveolin i P n L s C

PI-3K p pp90 PHAS-1

Translation Transcription

Lipid

GSK-3

110 G L U T

Î˛

4 Translocation

Fig. 3: The metabolic and cardiovascular effects of glimepiride

773

Reduced apoptosis

Pancreas

Reduced oxidative stress Reduced endoplasmic reticulum stress

Reduced oxidative stress

Heart

Improved ischemic preconditioning

Gliclazide MR

Increased endothelial progenitors

Vessels

Improved endothelial mediated vasodilation

Reduced albuminuria

Better CVD Outcome

Reduced LDL oxidation

Fig. 4: The metabolic and cardiovascular effects of gliclazide efficacy, safety and tolerability support make their use as an integral part of diabetes treatment. Considering these factors SUs should be continued to be used as a frontline agent in the treatment of T2DM. Gliclazide has been found effective in the treatment of the metabolic defects. These actions along with its good general tolerability and low incidence of hypoglycaemia have allowed gliclazide to be well placed within the array of OHAs.

CONCLUSION

This even today a family of drugs discovered more than five decades ago is still alive and available for day to day usage. The developments and discoveries in this family has been the key facts in sustaining this group of drugs. Molecules like gliclazide and Glimipride have been the refined ones and proven beyond doubt that it is useful and safe yet much cheaper for the benefit of the people of countries like ours.

REFERENCES

Kalra S, Aamir AH, Raza A, Das AK, Khan AKA, Shrestha D, MdQureshi F, MdFariduddin, et al. Place of sulfonylureas in the management of type 2 diabetes mellitus in South Asia: A consensus statement. Indian J Endocrinol Metab 2015; 19:577-596.

Seino S, Takahashi H , Takahashi T, Shibasaki T. Treating diabetes today: a matter of selectivity of sulphonylureas. Diabetes Obes Metab 2012; 14:9-13.

Avogaro A. Treating diabetes today with gliclazide MR: a matter of numbers. Diabetes Obes Metab 2012; 14:14-9. doi: 10.1111/j.1463-1326.2011.01508.x.

4. Sarkar A, Tiwari A, Bhasin PS and Mitra M.

Pharmacological and Pharmaceutical Profile of Gliclazide: A Review. Journal of Applied Pharmaceutical Science 2011; 01:11-19.

Kim JY, Lim DM, Park HS, Moon CI, Choi KJ, Lee SK, et al. Exendin-4 protects against sulfonylurea-induced Î˛-cell apoptosis. J Pharmacol Sci 2012; 118:65-74. Epub 2011 Dec 21.

Piya MK, Tahrani AA, Barnett AH. Emerging treatment options for type 2 diabetes. Br J Clin Pharmacol 2010; 70:63144. doi: 10.1111/j.1365-2125.2010.03711.x.

Kaveeshwar SA, Cornwall J. The current state of diabetes mellitus in India. Australas Med J 2014;7:45-8. doi: 10.4066/ AMJ.2013.1979. eCollection 2014.

Ruiz M. Diamicron (gliclazide) MR the secretagogue with clinical benefits beyond insulin secretion. Medicographia 2013Íž 35:81-89.

9. Heller SR.A Summary of the ADVANCE Trial. Diabetes Care 2009; 32:S357-S361. 10. Mikov M, Al-Salami, Golocorbin-Kon S. Potentials and Limitations of Bile Acids and Probiotics in Diabetes Mellitus. In: Liu C-P, Ed. Type 1 Diabetes - Complications, Pathogenesis, and Alternative Treatments. Publisher: InTech, 2011; 365-401.

CHAPTER 167

Kidney

Glycemic control

C H A P T E R

168 ABSTRACT

Type 2 diabetes mellitus (T2DM) is a disease normally seen to appear after the 40 years of age. But now it is emerging in young adults at the level of global epidemic because of the increasing burden of obesity. It is also evident that this young diabetic population is an aggressive phenotype and is leading to the premature development of complications. This condition not only have impact on the quality of life but also unfavourably influences the long term outcome, raising the possibility of a serious public health challenge.

INTRODUCTION

The age of onset of T2DM is falling and this condition is now not uncommon among children, adolescents and young adults even at the age of ten. The National Institute for Health and Clinical Excellence (NICE) defines earlyonset T2DM as those subjects with current age below 40 years. This has been reported in many countries with different ethnic and cultural backgrounds with increasing prevalence of the sedentary lifestyle and obesity. These T2DM in young (T2DMY) are at high risk of developing premature microvascular complications (nephropathy, retinopathy and neuropathy) and macrovascular or cardiovascular diseases due to the adverse atherogenic risk factors and poor diabetes control. The clinical management is challenging as there no clinical trial evidence in this population. Future research strategies should explore its natural history and the development of complications, and outcomes studies pertaining to structured patient education, screening for diabetes in at risk groups, intensive treatment of glucose control and associated cardiovascular risk factors.

EPIDEMIOLOGY

The global burden of T2DM is significant and rising in any age group, but there is strong evidence that it is becoming more common among young adults particularly as reported from USA and Japan. Newly diagnosed T2DM is evident in up to 45% of certain groups of young children in the USA and this is clustered in certain ethnic groups such as Pima Indians, Hispanics, Asians and Afro-Carribeans. In Japan, the prevalence of T2DM among junior high school children has become double between 1976-1980 and 1991-1995. In Japan the prevalence of T2DM was approximately 50% and 75% respectively between 10-19 and 20-29 year. Early-onset T2DM has also been reported in China, Mexico, India and Australia. Bhatia, et al. from India found that, T2DMY accounted for 12% of cases (total 160 cases) of diabetes mellitus in

Type 2 Diabetes in Young Samar Banerjee

children below 18 years of age. The national survey of England in 2009 identified 328 youths under the age of 18 years with T2DM, representing 1.5% of the total diabetic population in this age group with peak prevalence in 10-14 year-olds. In the last 2 decades, obesity has increased by 70% in adults aged 30-39 years making young adults the fastest growing group for both obesity and T2DM.

PATHOPHYSIOLOGY OF T2DMY

The pathophysiology of early-onset T2DM subjects is similar to those above 40 years and is characterised by pancreatic β cell impairment and obesity-induced insulin resistance. Gungor et al showed that T2DMY subjects had pathophysiological features of β cell dysfunction, insulin resistance with reduced adiponectin levels and hepatic insulin resistance resulting in elevated hepatic glucose production. Compared with obese nondiabetic subjects, the insulin secretory defect and reduction in insulin sensitivity in obese diabetic patients were approximately 50-75% and 50% lower. This decline in β cell function is more rapid (15% per year) compared with the older T2DM cohort (6% per year) and as such these subjects were 80% more likely to require insulin therapy than the older subjects.

CLINICAL PRESENTATION AND DIAGNOSTIC CHALLENGES

The features of insulin resistance, often present in T2DMY are abdominal obesity, hypertension, dyslipidaemia, acanthosis nigricans, polycystic ovarian syndrome and non-alcoholic fatty liver. These features may be a forerunner of future T2DM. In contrast, younger subjects with Type I diabetes mellitus (TIDM) present with minimal features of insulin resistance and the onset of clinical presentation may be more rapid with a short history of polyuria, polydipsia and weight loss, and may have ketosis or ketoacidosis in more severe cases. But keep in mind that up to 30% of patients with T2DM can present with ketosis or ketoacidosis. Ketosis-prone T2DM occurs in a group of subjects with obesity, who presents with ketosis or ketoacidosis and subsequently enter a period of near normoglycaemic remission. At presentation, the β cell function is often severely impaired but improves after a few months of treatment with insulin, often allowing its discontinuation and responding to oral agents. Monogenic diabetes with a prevalence between 1-2%, formerly known as maturity-onset diabetes in the young (MODY), is a diagnosis that should be also considered

as a differential diagnosis of T2DMY. It is an inherited condition arising from a seven different mutation in a single gene which regulates β cell function. This diagnosis is based on four clinical scenarios; a.

diabetes diagnosed before 6 months of age irrespective of the current age;

patients with mild, stable fasting hyperglycaemia between 5.5-8.0 mmol/L;

familial, young onset diabetes that does not fit with either T1DM or T2DM

The diagnosis of monogenic diabetes is confirmed by genetic testing. One should be cautious to make the diagnosis of T2DM in a younger person. A case misdiagnosed as T2DM, when they actually have TIDM and requires insulin rather than oral antidiabetic treatment, can be life-threatening due to diabetic ketoacidosis. Similarly, misdiagnosing a patient as T1DM whilst they have T2DM can have a substantial negative impact on the quality of life as they are unnecessarily subjected to life-long multiple insulin injections and numerous blood glucose tests. Likewise making the correct diagnosis of monogenic diabetes can result in a significant impact on the type of treatment and quality of life. The salient distinguishing features of TIDM, T2DM and monogenic diabetes are shown in Table 1.

DIABETES COMPLICATIONS

Nephropathy

The renal complications occur earlier and are common. The prevalence of microalbuminuria is 7-22%, 28-42% and 60% at diagnosis, 5 and 10 years after diagnosis respectively. The diabetes duration, poor glycaemic control and hypertension are the conditions associated with progression. The nephropathy is more prevalent and its progression more rapid in T2DMY compared to same

775

Retinopathy

Like nephropathy, retinopathy can be present at diagnosis and can cause blindness at a younger age. In Japan out of 1065 subjects of T2DMY, 12.7% developed proliferative retinopathy before the age of 35 years and 24% of them were blind by a mean age of 32 years. Progression of retinopathy was determined by longer diabetes duration, poor diabetes control and hypertension. But when compared with TIDM, retinopathy appeared to be less common in T2DMY.

Neuropathy

The neuropathic complications can occur early among subjects with early-onset T2DM, perhaps to a greater degree than those with T1DM. A study from the UK showed 57% of T2DMY subjects had peripheral neuropathy while none of those with TIDM had this complication. Another study showed 40% subjects with T2DMY had evidence of peripheral neuropathy, six of whom had foot ulceration.

Macrovascular Disease

The T2DMY leads to adverse cardiovascular risk. A Canadian study with T2DM (n = 69, follow up 9 years), showed that the mortality during this period was 9% and among the survivors, 35% developed microalbuminuria, 45% were hypertensive and 6% were on dialysis in the background of poor glycaemic control. In a Japanese study, 1.3% of T2DMY subjects, diagnosed before the age of 30 years, developed atherosclerotic vascular disease at the mean age of 36 years. T2DMY subjects manifest higher aortic pulse wave pressure and increased vascular stiffness of similar degree, greater carotid intima media thickness and carotid artery stiffness. The “Patho-biological Determinants of Atherosclerosis in Youth (PDAY)” study showed that the process of atherosclerosis began in childhood or early

Table 1: Showing the main distinguishing features of TIDM, T2DM and monogenic diabetes Frequency

>90%

<10%

1-2%

Clinical Picture

Acute onset; symptomatic with weight loss, polyuria, polydipsia

Often asymptomatic

Variable, can be incidental finding

Obesity

Population frequency

Increased frequency

Population frequency

Parents with Diabetes

2-4%

80%

90%

Ketosis

Present

Usually absent

Common in neonatal forms, rare in others

Diabetes related Antibodies

Positive

Negative

Therapy

Insulin

Oral hypoglycaemics

Variable depending on subtypes

Associated autoimmune diseases

Yes

CHAPTER 168

d. young onset diabetes with extra-pancreatic involvement such as renal disease and deafness.

age group of T1DM patients. Yoo et al found persistent microalbuminuria and macroalbuminuria were seen in 18.2% and 4.5% among T2DM cohort respectively compared to 11.3% and 2.8% of those with TlDM despite having similar glycaemic control.

DIABETES

776

adulthood and its rate of progression was determined by the same risk factors (such as obesity, hypertension, dyslipidaemia, glucose intolerance and smoking) as in older individuals with cardiovascular disease.

young person with type 2 diabetes who is overweight or obese, advise them and their family members about the benefits of physical activity and weight loss, and provide support towards achieving this.

The T2DMY subjects also appear to be more resistant to the metabolic benefits of physical activities and raise the notion that this population may be non-responders to exercise.

Till date, metformin is the only oral hypoglycemic agent approved for T2DMY by FDA, older than 10 years. Metformin should be initiated as 500 mg orally daily or twice daily with meals and slowly titrated to 1000 mg orally twice daily over 3 - 4 weeks. There is limited experience with other oral agents (which may be beneficial in youth with type 2 diabetes) and hence not approved by FDA. Above the age of 16 any drug as per guidelines can be used.

Mohan et al noted that over 40% of the children with T2DM had two or more cardiovascular risk factors, e.g. central obesity, dyslipidemia or hypertension, compared to 13.6% among T1DM subjects of similar age.

CHALLENGES IN CLINICAL MANAGEMENT

The important goal in diabetes management is to prevent the development or reduce the progression of micro- and macrovascular complications and allow healthy growth and acceptable active life. A study by Song et al showed that early-onset T2DM subjects developed significant diabetes-related complications up to 20 years earlier, particularly for microvascular disease, compared to the later-onset cohort. Cardiovascular disease is the major cause of morbidity and mortality in T2DM. Due to the lack of definitive clinical evidence,there is suboptimal administration of cardio-protective treatment, particularly in relation to primary prevention of cardiovascular disease. One study has shown that only 23.9% and 39.6% of early-onset subjects received statin and antihypertensive treatment respectively and this is in contrast to the later-onset subjects where 67% and 75.8% received statin and antihypertensive treatment respectively, although the two groups had similar numbers of co-existing cardiovascular risk factors. Another study from Japan showed approximately 60% ofT2DM subjects aged between 10-19 years failed to attend regular clinic follow-up for up to 2 years. The irregular patients had higher obesity and blood pressure, a more adverse glycaemic and lipid profile and were less likely to have regular exercise or a proper diet. The periodic discontinuation of medications are common in T2DMY.

MANAGEMENT

Explain to the children and young people with type 2 diabetes and their family members that an HbA1c target level of 6.5% (48 mmol/mol ) or lower is ideal to minimise the risk of long-term complications. Treatment is based on lifestyle interventions and metformin as the first-line drug. Offer to the children and young people with type 2 diabetes, dietetic support to optimise body weight and blood glucose control. Encourage children and young people with type 2 diabetes to eat at least 5 portions of fruit and vegetables each day. At each clinic visit for children and young people with type 2 diabetes measure height and weight and plot on an appropriate growth chart, calculate BMI and decide the diet plan. At each contact with a child or

Initial treatment of youth with T2D should include metformin and/or insulin alone or in combination. Insulin should be initiated in youth with type 2 diabetes and metabolic decompensation or in cases of difficult controls with oral agents. The decision for the initial treatment modality is determined by symptoms, severity of hyperglycemia, and presence or absence of ketosis/ketoacidosis. If the patient is metabolically stable (HbA1c<9 and no symptoms), metformin monotherapy is the treatment of choice. If the patient is not metabolically stable, insulin will be required at least initially. A variety of insulin regimens are effective, but once a day NPH or basal insulin (0.25â&#x20AC;&#x201C; 0.5 units/kg starting dose) is often effective in attaining metabolic control.

FUTURE RESEARCH DIRECTIONS

There are important gaps in the understanding of the natural history in the evolution and progression of T2DMY including the development of diabetes-related complications among children, adolescents and young adults. Because of the epidemic of obesity affecting this population, there is a need for cost-effective screening strategies designed for the younger population to detect undiagnosed T2DM and to identify those at risk of T2DM to ensure they are effectively managed.

CONCLUSION

The condition of T2DMY raises both clinical and social problems. These group of affected persons have longer disease duration and exposure to the adverse diabetic state leading to higher risk of premature development of complications with significant morbidity and mortality occurring at much unexpected early age. As a result the young and productive workforce,who actually is the future of the society may be lost or become less effective together with the financial cost of treating these complications and daily man power loss. In absence of definite worldwide accepted guideline based on large prospective multi-centric trials, there is also hesitancy or therapeutic inertia as a consequence of cliniciansâ&#x20AC;&#x2122; uncertainty in treating these young individuals appropriately add to the problem. We need early diagnosis and preventive measures particularly in terms of obesity. The awareness should

be created amongst the primary care physicians, people at large, school teachers and should be started from the school level. Every school and college must have compulsory playground and play/exercise intervals, teaching about healthy food habit and its canteen should not vendor unhealthy fast foods.

REFERENCES

National Institute for Health and Clinical Excellence. Type 2 diabetes. The management of type 2 diabetes. NICE clinical guideline. London: NICE, 2008. Bhatia V; IAP National task force for childhood prevention of adult diseases. Insulin resistance and type 2 diabetes mellitus in childhood. Indian Pediatr 2004; 41:443-57.

3. Hillier TA, Pedula KL. Characteristics of an adult population with newly diagnosed type 2 diabetes: the relation of obesity and age of onset. Diabetes Care 2001; 24:1522-1527. 4.

Mokdad AH, Ford ES, Bowman BA et al. Diabetes trends in the US: 1990-98. Diabetes Care 2000; 23:1278-1283

Gungor N, Bacha F, Saad R et aI. Youth type 2 diabetes: insulin resistance, l3-cell failure or both ? Diabetes Care 2005; 28:638-644.

Eppens MC, Craig ME, Cusumano J et aI. Prevalence of diabetes complications in adolescents with type 2 compared with type I diabetes. Diabetes Care 2006; 29:1300-1306.

Yoo EG, Choi IK, Kim DH. Prevalence of microalbuminuria in young patients with type I and type 2 diabetes mellitus. J Pediatr Endocrinol Metab 2004; 17:1423-1427.

Yokoy ama 1-1, Okudaira M, Otani T et al. Existence of early-onset NIDDM Japanese demonstrating severe diabeti c complications. Diabetes Care 1997;20:844-847.

9. Paisey RB, Paisey RM,ThomsonMPet al. Protect ion from clinic al peripheral sensory neuropathy in Alstrom syndrome in contrast to early-on set type 2 diabetes. Diabetes Care 2009; 32:462 -464. 10. Dean H, Flett B. Natural history of type 2 diabetes diagnosed in childhood: long term follow-up in young adult years. Diabetes 2002; 51:A24. 11. Strong JP, Malcolm GT, McMahan CA et al. Prevalence and extent of atherosclerosis in adolescents and young adults: implications for prevent ion from the Pathological Determinants of Atherosclerosis in Youth Study. JAMA 1999; 281:727-735. 12. Mohan V, Jaydip R, Deepa R. Type 2 diabetes in Asian Indian youth. Pediatric Diabetes 2007; 8:28-34. 13. Song SH, Hardisty CA. Cardiovascular risk profile of early and later onset type 2 diabetes. Practical Diabetes Int 2007; 24:20-24. 14. Goland R, Lindgren C, Vargas I et al. Enhanced risk for premature vascular disease in adolescent-onset type 2 diabetes. Diabetes 2003;52:1749-P.

777

CHAPTER 168

We need better understanding of the factors involved in the development of T2DMY and its complications. This effort should be coupled with the implementation of public health initiatives to control and avert future increases in obesity to prevent this impending devastating disease of the society.

Metformin Revisited – 2016

C H A P T E R

169

Rajinder Singh Gupta, Harbir Kaur Rao

Diabetes mellitus (DM) is a metabolic disease characterized by high plasma glucose, which if not controlled effectively in time, will result in multiple micro-and macrovascular complications. The prevalence of diabetes is increasing world wild affecting 382 million people in 2013 and is expected to rise to 592 million by 2035. Diabetes is now recognized as the 8th leading cause of death and in 2012 and 2013, diabetes had resulted in 1.5 to 5.1 million deaths. Also, if not treated effectively in time, it is now recognized as the leading cause of end-stage kidney disease (ESRD), non-traumatic lower-limb amputations, blindness, and a major cause of cardio vascular disease and strokes in the individuals. With the availability of various oral drugs and insulin, DM can be treated and its complications can be minimized through appropriate glycemia control. For every 1% drop in HbA1C, there is a 40% reduction in the risk of microvascular complication (e.g. retinopathy, nephropathy, and neuropathy). Metformin, a biguanide, is well known treatment for type 2 diabetes mellitus that has diverse mechanism of actions. Various studies have elucidated the role of this drug in different pathologies. Data has been conclusive that Metformin also has beneficial role in lipid disorders as it improves the markers of metabolic syndrome. Evidence is accumulating that metformin also improves the fertility in females with polycystic ovarian syndrome (PCOS). It also delays aging and is effective in aging-related disorders and is equally effective inflammation-related disorders atleast in different rodent studies. Researchers are working to reveal more benefits of this magic drug, but it remains an unexplored territory for the medical community. Metformin was clinically developed in 1957 by the French physician Jean Sterne, who gave it its first trade name, glucophage (“Glucose eater”). Phenformin was quite popular in the 1960s, but was withdrawn in the early 1970s due to the emergence of frequent lactic acidosis and increased cardiac mortality. Metformin, a less lipophilic biguanide, proved safer and has replaced phenformin. Metformin ↓Liver Glucose Production ↓Muscle Glucose uptake ↑Adipose fat glucose uptake

Diabetes mellitus Polycystic Ovary Syndrome

HIV-related metabolic Abnormalities Steatohpatitis

Cardiovascular Protective effect Cancer

Fig. 1: Clinical Effects of Metformin

After 20 years of use in Europe, metformin was approved for use in the USA in 1995. In 2002, metformin became available as a generic medication, making it one of the least expensive diabetes treatments.

PHARMACOKINETICS OF METFORMIN

After oral administration, metformin is slowly absorbed from the proximal small intestine and absorption is apparently complete within 6 hours of ingestion. Metformin is rapidly distributed following absorption and does not bind to plasma proteins. The mean plasma elimination half-life after oral administration is between 4.0 and 8.7 hours. The clearance of metformin is dependent on renal elimination as metformin does not undergo relevant biotransformation in the liver or biliary excretion.

Factors how Metformin Scores over other Oral Hypoglycemic Agents (OHAs) •

Weight loss: favorable weight profile

•

Glycemic durability higher

•

Antihyperglycemic hypoglycemia

•

Submaximal dosing for therapeutic effects

•

“Vascular drug”: favorable cardiovascular effects, microvascular and macrovascular benefits

•

Lipid friendly: favorable modulation of deranged lipid parameters

•

Equivalent benfits demonstrated in obese and nonobese diabetics

•

Gestational DM: Trials underway show therapeutic role

effect:

freedom

CLINICAL EFFECTS OF METFORMIN (FIGURE 1)

from

Metformin, a biguanide, has been available for the treatment of type 2 diabetes mellitus for nearly 20 years. Its mechanism of action involves the suppression of endogenous glucose production, primarily by the liver. Because insulin levels decline with the metformin use, it has been termed an ‘insulin sensitizer’. Metformin has also been shown to have several beneficial effects on cardio vascular risk factors and it is the only oral Antihyperglycemic agent thus far associated with decreased macrovascular outcomes in patients with diabetes. It has potential role for a variety of insulin resistant and pre diabetic states, including impaired glucose tolerance, obesity, polycystic ovary syndrome and

Cardioprotective Effects of Metformin

Animal and in vitro studies proposed a protective action of metformin against several cardiovascular diseases linked to T2D, including myocardial infarction, hypertrophy, and diabetic cardiomyopathy, which lead to cardiac dysfunction that could evolve to heart failure. The molecular mechanisms involved in this protection are multifaceted, targeting endothelial, cardiomyocyte, and fibroblast dysfunctions.

Metformin’s and Cancer

Metformin’s anticancer mechanisms of action focus on both the systemic effects of the drug and the direct effects on cancer cells. Systemically, insulin and insulin-like growth factors (IGF) stimulate cancer cell proliferation through activation of PI3K-AKT signaling, leading to tumor growth by improving peripheral insulin sensitivity and increasing insulin growth factor-binding proteins (IGFBP), metformin treatment results in a net reduction in systemic glucose, insulin and IGFs, ultimately leading to inhibition of tumor growth. The current hypothesis for metformin’s direct action in cancer cells points to AMPK activation as primarily mediating metformin’s effects. In addition, reports indicate that metformin inhibits mitochondrial glycerophosphate dehydrogenase, a redox shuttle enzyme that reduces the conversion of lactate and glycerol to glucose and impairs hepatic gluconeogensis. Metformin also has novel anticancer effects that are independent of its impact on metabolism. Metformin may protect against cancer through modulation of small non-coding RNA segments (miRNA) that inhibit gene expression at the post-translational level. Evidence currently available suggests Metformin therapy is associated with estimated 29% reduction in lung cancer and 15% in cancer of the respiratory system. Metformin therapy was associated with significantly lower risks of cancers of the lung and respiratory system.

Metformin: Pancreatic Cancer in Patients with Type 2 Diabetes Mellitus

Recent epidemiological studies indicated that use of metformin might decrease the risk of various cancers among patients with type 2 diabetes mellitus (T2DM). The analysis included 11 articles (13 studies) comprising 10 cohort studies and 3 case-control studies. Use of metformin was associated with a significant lower risk of pancreatic cancer. Metformin associated with a 37%

reduction of pancreatic cancer risk compared with other treatments for diabetes.

779

Metformin and Insulin Resistance

Insulin resistance and beta-cell dysfunction, especially loss of first-phase insulin secretion, the early events in the pathogenesis of type 2 diabetes, also occur in firstdegree relatives of type 2 diabetic patients. Metformin reduces hepatic glucose output, partly via reduced gluconeogenesis, ameliorates insulin resistance, particularly in liver and muscle, and may inhibit glucose absorption. Numerous studies have shown that metformin improves glycemia by suppressing hepatic glucose production and enhancing insulin-mediated glucose uptake, often accompanied by reduced insulin levels.

Metformin in Polycystic Ovary Syndrome

The benefits of metformin on insulin sensitivity have been demonstrated in non-DM women with POCS. The use of metfomin is associated with increased menstrual cyclicity, improved ovulation, and a reduction in circulating androgen levels. Metabolic benefits are enhanced in the presence of weight loss, and weight loss itself may be enhanced in the presence of metformin. •

Women who lose even 5-10% of their total body weight can reduce central fat upto 30%, improve insulin sensitivity, and restore ovulation. Lifestyle intervention should be the cornerstone of therapy.

•

The initiation of metformin may be considered in women with PCOS who exhibit abnormal results on the 75g load oral glucose tolerance test (OGTT), but do not meet the criteria for DM.

•

In a subset of patients with oligomenorrheic PCOS, the initiation of metformin will instigate regular menstrual cycles.

Metformin and Gestational Diabetes Mellitus

Type 2 diabetes and gestational diabetes mellitus (GDM) are closely related disorders characterized by increased insulin resistance. Merformin, a biguanide compound, exerts its clinical effect by both reducing hepatic glucose output and by increasing insulin sensitivity. The result in a decreased glucose level without an associated high risk of either hypoglycemia or weight gain. These characteristics have established metformin as an ideal first-line treatment for people with type 2 diabetes; and hypothetically, a particularly attractive drug for use in pregnancy. However, metformin is known to cross the placenta, and its use in pregnancy has been limited by concerns regarding potential adverse effects on both the mother and the fetus. In women with established T2DM, insulin usually replaces oral agents during pregnancy; however, metformin has been continued during the pregnancy in some cases. In women with PCOS, metformin may initially be used to facilitate ovulation and promote conception and is then continued throughout the pregnancy. Metformin is currently listed as a category B drug for using pregnancy.

CHAPTER 169

the metabolic abnormalities associated with HIV disease. Metformin is transported into hepatocytes mainly through organic cation transporters (OCTs). OCT1 and partially inhibits mitochondrial respiratory- chain complex 1, resulting in reduced adenosine triphosphate (ATP) levels and accumulation of adenosine monophosphate (AMP). Gluconeogenesis is reduce as a result of ATP deficit limiting glucose synthesis. Inhibition of mitochondrial glycerol phosphate dehydrogenase (mGPD) contributes to altered redox state and reduce conversion of glycerol to glucose. Metformin-induced change in AMP/ATP ratio also activates AMPK, which suppresses lipid synthesis and exerts insulin-sensitizing effects.

DIABETES

780

Table 1: Improved cardiovascular outcomes with metformin in T2DM Study

Main Findings

UKPDS34

Reduced risk of macrovascular diabetic complications

Kooy, et al.

Reduced risk of composite of macrovascular events

PRESTO

Reduced risk of any clinical outcome, MI, Death

Johnson, et al.

40% reduction in risk of death. Reduced risk of mortality, Hospitalization, cardiovascular death

Eurich, et al.

30% reduction in risk of death, 70% reduction in risk of death or Hospitalization

Evans, et al.

3.7-fold lower risk of cardiovascular mortality

The metformin in Gestational Diabetes (MIG) trial demonstrated that there were no differences in neonatal outcomes when metformin was compared to subcutaneous insulin therapy for the management of GDM. A recent systematic review and meta-analysis by Dhuklotia et al. concluded that there were no differences in glycemia control of pregnancy outcomes when oral hypoglycemic agents were compared with insulin.

Effects on Thyorid Function

Metformin decreases serum levels of thyrotropin (TSH) to subnormal levels in hypothyroid patients that use levothyroxine (L-T4) on a regular basis. A significant decrease in TSH (P<0.001) without reciprocal changes in any thyroid function parameter in diabetic patients had also been reported but only in hypothyroid subjects, not in euthyoprid ones. The mechanism of the drop in TSH is unclear at this time.

Metformin Use in Renal Dysfunction (Chronic Kidney Disease)

NICE guidelines state the review of clinical circumstance when serum creatinine exceeds 130mmol/L (1.5mg/dl) or eGFR falls below 45ml/min per 1.73m2. Discontinue if serum creatinine exceeds 150mmol/L (1.7mg/dL0 or eGFR is below 30ml/min per 1.73 m2). The Canadian Diabetes Association practice guidelines based solely on eGFR, caution with eGFR <60ml/min per 1.73m2. Contraindication with eGFR <30 ml/min per 1.73 m2. The Australian Diabetes Society practice guidelines recommend against metformin with eGFR <30 ml/min per 1.73 m2. Caution with eGFR 30-45 ml/min per 1.73 m2.

Metformin and Cardiovascular Outcomes

Management of diabetic patients with heart failure is a complex endeavor. The initial reluctance to use metformin in these patients has given way to a broader acceptance after clinical trials and meta-analyses have revealed that some of the insulin-sensitizing agents lead to adverse cardiovascular events (Table 1).

Metformin has been reported to improve endothelial dysfunction, and to have antiinflammatory properties and reduced oxidative stress, processes that contribute to the disease process in congestive heart failure (CHF). Treatment with metformin is not associated with an increased risk of lactic acidosis among patients with type 2 diabetes mellitus who have no cardiac, renal or liver failure.

Effects on the Inflammatory Pathway

The benefits of metformin on macrovascular complications of diabetes, separate from its conventional hypoglycemic effects, may be partially explained by actions beyond glycemic control, particularly by action associated with inflammatory and atherothrombotic processes. Metformin can act as an inhibitor of pro-inflammatory responses through direct inhibition of NF-kB by blocking the PI3K-Akt pathway. This effect may partially explain the apparent clinical reduction of cardiovascular events not fully attributable to metforminâ&#x20AC;&#x2122;s antihyperglycemic action. There is some evidence that metformin also has a beneficial effect on some components of the antioxidant defense system. It can unregulate uncoupled proteins 2 (UCP2) in adipose tissue and can also cause an increase in reduced glutathione.

Effects on Body Weight

Metformin may have a neutral effect on body weight of patients with T2DM when compared to diet or may limit or decrease the weight gain experienced with sulfonylurea, TDZ, insulin, HAART, and antipsychotics drugs. Modest weight loss with metformin has been observed in subjects with IGT. However, a meta-analysis of overweight and obese. Non-diabetic subjects, found no significant weight loss as either a primary or as secondary outcome. However, metformin is widely recognized by endocrinologists and dibetologists as a weight reducing agent in clinical practice. Results have found an average weight loss of 5.8 kg (5.6%) under treatment with metformin for 6 months in over weight and obese mostly insulin resistant patients. Metformin is and effective drug to reduce weight in a naturalistic outpatient setting in insulin sensitive and insulin-resistant over weight and obese patients. Metformin may also have a positive effect on metabolic parameters such as waist circumference, fasting insulin and glucose levels and triglycerides.

Effect on Lipid Profile

Metformin is associated with improvements in lipoprotein metabolism, including decreases in LDL-C, fasting and postprandial TGs, and free fatty acids.

Effects on Blood Pressure

The hypertension associated with diabetes has an unclear pathogenesis that may involve insulin resistance. Insulin resistance is related to hypertension in both diabetic and non diabetic individuals and may contribute to hypertension by increasing sympathetic activity,

peripheral vascular resistance, renal sodium retention, and the vascular smooth muscle tone and proliferation. Data of the effects of metformin on BP are variable, with neutral effects or small decreases in SBP and DBP.

Metformin’s Contraindications

Metformin in the Management of Adult Diabetic Patients

Current guidelines form the American Diabetes Association /European Association for the Study of Diabetes (ADS/ EASD) and the American Association of Clinical Endocrinologists/ American College of Endocrinology (AACE/ACE) recommend early initiation of metformin as a first-line drug for monotherapy and combination therapy for patients with T2DM.This recommendation is based primarily on metformin’s glucose-lowering effects, relatively, low cost, and generally low level of side effects, including the absence of weight gain. Metformin’s first-line position was strengthened by the United Kingdom Prospective Diabetes Study (UKPDS) observation that the metformin-treated group had risk reduction of 32% (p=0.002) for any diabetes-related endpoint, 42% for diabetes-related death and 36% for allcause mortality compared with the control group. The UKPDS demonstrated that metformin is as effective as sulfonylurea in controlling blood glucose levels of obese patients with type 2 diabetes mellitus. Metformin has also been shown to be effective in normal weight patients.

781

1. Centers of Disease Control and Prevention. National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention 2011.Available 2.

Mahmood K, Naeem M, Rajimanjjad NA. Metformin: The hidden chronicles of a magic drug. Eur J Intern Med 2013; 24:20-6

DAS, A.K Metformin: The molecule of the Decade? Progress in Medicine 2015; 29:113-131.

4. Fortez m, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: From mechanisms of action to therapies. Cell Metab 2014; 20:953-66. 5.

Chan JC, Deerochanawong C, Shera AS, Yoon KH, Adam JM, Ta VB, et al. Role of metformin in the initiation of pharmacotherapy for type 2 diabetes: an Asian-pacific perspective. Diabetes Res Clin Pract 2007; 75:255-66.

Mathur R, Alexander CJ, Yano J, Trivax B, Azziz R. Use of metformin in polycystic ovary syndrome. AM J Obstet Gynecol 2008; 199:596-609.

Feig DS, Moses RG. Metformin therapy during pregnancy: good for the goose and good for the gosling too? Diabetes Care 2011; 34:2329-30.

Gandhi P, Bustani R, Madhuvrata P, Farrell. T. introduction of metformin for gestational diabetes mellitus in clinical practice; Has it had an impact? Eur J Obstet Gynecol Repord Biol 2012; 160:147-50.

9. Isoda K, Young J, Zirlik A. Metformin inhibits proinflammatory Responses and Nuclear Factor kβ in Human Vascular Wall Cells. Arterioscler Thromb Vase Biol 2006; 26:611-7. 10. Anedda A, Rial E, Gonzalez Barroso. Metformin induces oxidative stress in whi8te adipocytes and raises uncoupling protein levels. J Endrocrinol 2008; 199:33-40. 11. Wang Z, Lai ST, Xie L, Zhao JD, Ma NY, Zhu J, et al. Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Res Clin Pract 2014; 106:19-26.

CHAPTER 169

The most common contraindications to metformin use in people with type 2 diabetes are renal insufficiency, congestive heart failure, and advanced age (>80 years) Using metformin either in patients of advanced age (>80 years) or in a patient who has reduced renal function, requires one to consider the potential for decreased elimination ability.

REFERENCES

C H A P T E R

170

Hydroxychloroquine: A Therapeutic Choice in Diabetes Mellitus

INTRODUCTION

Type 2 Diabetes Mellitus (T2DM) is a heterogeneous disease with diverse pathophysiological processes. Association between hyperglycemia, chronic inflammation and vascular complications in diabetes is now well established. Chronic inflammation plays an important role in the development and progression of diabetes and its complications. Better understanding of the inflammatory basis for diabetes may provide improved modalities for diabetes prevention and treatment. HCQ was first approved in 1955 as an antimalarial agent. Large scale prospective as well as retrospective studies have shown that the use of HCQ was associated with a reduced incidence of T2DM. Use of HCQ for >4 years reduced the risk of diabetes by 77% in a prospective observational study conducted in 4905 RA patients. A renewed interest has been generated in the last decade due to research focused on T2DM, lipid lowering action, antiplatelet action, antithrombotic action and CV protective effects.

HCQ: NOVEL ANTIDIABETIC ACTION

Inhibition of Insulin Degradation

Insulin has a short plasma half-life of 4–6 minutes due to its rapid uptake and degradation in the cells by insulin-degrading enzymes (IDE). Chloroquine, akin to HCQ, is an acidotrophic drug. At a pH of <6, IDE has little proteolytic activity which may result in inhibition of endosomal degradation of insulin and intracellular insulin accumulation. HCQ significantly elevated blood insulin concentration and reduced glucose levels in an experimental study.

Reduction in Inflammation

Inflammation plays a crucial intermediary role in the mediating the progression from obesity to T2DM. It also influence all processes of atherogenesis. Insulin resistance is attributed to activation and release of various inflammatory markers such as IL-6, C-reactive protein (CRP), TNF-α etc. HCQ was shown to inhibit production of TNF-α, IL-1, IL-6 and interferon-γ (IFN-γ) and other inflammatory markers in chronic inflammatory states. An improvement in CRP levels was also seen in RA patients. It also inhibits prostaglandin synthesis and leukocyte activation and migration.

Preservation of β-Cells

Prediabetes reflects failing beta-cell compensation for an underlying state of insulin resistance. Progressive

Narayan Deogaonkar

pancreatic beta-cell defect that drives the deterioration of metabolic control over time begins early and may be present before the diagnosis of diabetes. Administration of HCQ in diabetic animals preserved islets of langerhans structure. Lowering of pancreatic levels of inflammatory mediators such as IL-1β, IL-6, TNF-α and Transforming growth factor-β1 also occurred. There was a significant increase in the β-cell area with a corresponding decrease in α-cell area along with suppression of β-cell apoptosis with HCQ.

Improvement in Insulin Sensitivity

A 6 weeks course with HCQ 6.5 mg/kg was demonstrated to improve insulin sensitivity in 13 obese non-diabetic individuals. HCQ significantly improved insulin sensitivity index from 4.5 to 8.9 and decreased HOMA-IR from 2.1 to 1.8. An improvement in insulin sensitivity and β-cell function was induced by treatment with HCQ 400 mg daily for 13 weeks in 17 obese individuals who had risk factors for insulin resistance. Significant increase in insulin sensitivity (20.0%), β-cell function (45.4%) and plasma adiponectin level (18.7%) occurred with treatment with HCQ. Actions of adiponectin include improvement in insulin sensitivity, protection from β-cell dysfunction and additional antiinflammatory and antiatherogenic properties.

TREATMENT OF T2DM

Add on to Sulfonylureas: Comparison to Placebo

Addition of HCQ improved the glycemic control in sulfonylurea-refractory T2DM patients. Sixty nine patients received HCQ 300-600 mg daily while 65 patients received placebo in addition to glyburide 10 mg twice daily. Addition of HCQ decreased HbA1c by an absolute amount of 1.02% more than placebo at 6 months.41 HCQ was shown to exert a positive glycemic effect in decompensated, sulfonylurea refractory diabetics. Sixteen patients on glibenclamide therapy (15 mg/day) were randomized to receive either HCQ (600 mg/day) or placebo for six months. A reduction in glucose profile was evident within 10-14 days after initiation of HCQ therapy. There was a significant reduction in glucose profile (-10.8 mmol/L) and HbA1c level (-3.3%) in patients who received glibenclamide and HCQ.

Add on to Insulin: Comparison to Placebo

HCQ was shown to decrease the daily insulin requirements

Glycemic parameters

Mean decrease at week 24 HCQ

Pioglitazone P value

total hip arthroplasty reported a significant reduction in fatal and non-fatal emboli. In the multiethnic LUMINA study use of HCQ was associated with a significant decrease in the risk of thrombotic events (hazard ratio: 0.54). These effects may be due to the inhibition of platelet aggregation and adhesion, decrease in lipid levels and inhibition of antiphospholipid antibody production.64

HbA1c (%)

0.87

0.90

0.909

Nephroprotection

FBG (mmol/L)

0.79

1.02

0.648

PPG (mmol/L)

1.77

1.36

0.415

Table 1: Mean decrease in HbA1c, FBG and PPG in HCQ and pioglitazone groups at week 24 compared to baseline. P value: Intergroup comparison between HCQ and pioglitazone groups

Add on to Metformin And Sulfonylurea: Comparison to Pioglitazone

The favorable glycemic effects of HCQ in Indian T2DM patients was established by Pareek A et al. T2DM patients uncontrolled (HbA1c: 7.5-11.5%) on a combination of metformin 1000 mg/day and glimepiride 4 mg/day or gliclazide 160 mg/day were randomized to receive either HCQ 400 mg/day (n=135) or pioglitazone 15 mg/day (n=132) for 24 weeks. There was a significant reduction in the mean HbA1c, FBG and PPG from baseline at week 24 in both the groups (Table 1). A marginal weight reduction of 1.08 kg was also reported with HCQ.6

PLEIOTROPIC EFFECTS

Lipid Lowering Effects

Studies spanning over the last three decades by various researchers have reported beneficial lipid lowering effects (TC, LDL-C, TC/HDL-C, LDL-C/HDL-C, VLDL-C and TG) with HCQ. The latest in this series of studies was a study conducted by Pareek A et al who showed the beneficial effects of fixed dose combination of hydroxychloroquine with atorvastatin in the treatment of dyslipidemia. There was a significantly greater percentage reduction in LDL-C, non-HDL-C and TC in patients treated with combination therapy than atorvastatin alone at 24 weeks. Atorvastatin increased the HbA1c level by 0.24% while the combination decreased HbA1c level by 0.18% with an intergroup difference of 0.42% (p=0.002). Fewer patients with prediabetes developed diabetes in combination group.

Antiplatelet Effects

Achuthan S et al (2014) showed that the reduction in platelet aggregation was by 11% with HCQ and 31.2% on combining it with aspirin. There was also a significant decrease in fibrinogen and erythrocyte sedimentation rate values.

Antithrombotic Effects

A study conducted in 2144 patients receiving HCQ before

REDUCTION IN CV DISEASE RISK AND EVENTS

The proven lipid lowering, antiplatelet, antithrombotic and nephroprotective effects offer an edge over other oral hypoglycemic agents and maybe beneficial in improving survival in diabetic patients. A retrospective cohort study among RA patients showed that HCQ treatment (400 mg/ day) had a significant protective effect against CV events such as MI, stroke, TIA and venous events. The dose of 200 mg/day demonstrated a significant protective effect against MI. A retrospective cohort study showed that use of HCQ was associated with a 72% CV disease risk reduction in RA patients. During the observation period 3 CV disease events occurred among 547 HCQ users and 99 occurred among 719 nonusers. The hazard ratio was 0.28 (p=0.002) for CV disease events and 0.30 (p=0.004) for composite CAD, stroke, and transient ischemic attack for hydroxychloroquine users versus nonusers respectively.

SAFETY AND TOLERABILITY

The lower toxicity of HCQ makes it more popular for use in conditions where relatively high drug dosages are required over long periods. It has been prescribed since 60 years in RA and >20 year long term studies are available in RA and >8 years long term studies are available in Lupus patients. Anorexia, abdominal pain, nausea, diarrhea and vomiting are the common adverse effects. Uncommon and reversible effects are pigmentary changes in skin and mucous membranes, bleaching of hair and alopecia. The frequency of hypoglycemia with HCQ is not known. The incidence of hypoglycemia was 0% in the HCQ group while it was 1.5% in the pioglitazone group in the RCT conducted in Indian diabetic patients. HCQ differs from chloroquine by the presence of a hydroxyl group which decreases the crossing through the blood retinal barrier. A large series of rheumatology patients showed only 1 case of clear toxicity among 1207 HCQ users. A cohort of 526 patients showed 0% incidence of retinopathy in first 6 years and 0.5% incidence after 8.7 years. Retinopathy is very uncommon if the recommended daily dose is not exceeded. American Academy of Ophthalmology in 2011 recommended a baseline retinal examination for patients starting HCQ

CHAPTER 170

by 30% in T2DM patients. 22 insulin-treated (70-110 units/ day) diabetic patients were allocated randomly to receive either insulin along with placebo (n=11) or insulin and HCQ (600 mg/day; n=11) for six months. There was a significant reduction in glucose profile (-11.7 mmol/L) and HbA1c level (-3.3%) in patients who received insulin and HCQ along with a significant reduction in daily insulin dose by 24 units.

Use of HCQ protects from renal damage in patients with lupus nephritis. HCQ takers exhibited a lower frequency of WHO Class IV glomerulonephritis, lower disease activity and received lower glucocorticoid doses than non-takers in a study.

783

784

to serve as a reference point and annual screening after 5 years of use. It is contraindicated in patients with preexisting retinopathy.

DIABETES

CONCLUSION

HCQ has a novel mechanism of action i.e. post receptor inhibition of insulin degradation for reducing blood glucose levels. Reduction in FBG, PPG and HbA1C (0.873.3%) is established in various settings. Considering the anti-hyperglycemic potential, anti-inflammatory activity and pleiotropic effects such as lipid lowering action, antiplatelet action, antithrombotic action and nephroprotective action, HCQ may emerge as a cost-

effective therapeutic option for uncontrolled diabetes patients. None of the newer drugs act on the core pathophysiologic process of beta cell dysfunction in diabetes. HCQ has shown promising results in improving beta cell function and has shown CV risk reduction in the settings of RA & lupus. The relevance of inflammatory mediators in pathogenesis of prediabetes, T2DM and diabetic complications has recently attracted considerable interest. Antidiabetic, anti-inflammatory and CV friendly benefits of HCQ makes it a therapeutic choice in various diabetic subgroups as an add on drug to OHAs as well as insulin.

Insulin Pumps in India

C H A P T E R

171 ABSTRACT

It has almost been five decades since the first insulin pump was launched in 1960. The first model was so big that it had to be worn on the back. In 2006, Medtronic MiniMed (Northridge, CA), recognized as pioneers in insulin pump therapy, introduced real-time insulin pumps where the glucose sensor and the pump were combined. The introduction of real-time insulin pumps was a major breakthrough toward ‘‘closing the loop’’ of insulin delivery, very near to the dream of inventing fully automatic devices. At present in India variety of insulin pumps are available. Although there are multiple benefits of CSII, its use has been limited in our Indian set up. Education barrier and affordability issues curtail its usage.

INTRODUCTION

Diabetes is fast gaining the status of a potential epidemic in India with more than 62 million diabetic individuals currently diagnosed with the disease.1 In 2030 estimated number of diabetics would reach upto 79 million if measures are not taken promptly.13 Insulin is the mainstay of treatment for patients with T1DM and long-standing T2DM to achieve good glycemic control. Intensive insulin therapy (IIT) (using multiple daily injections [MDI] or continuous subcutaneous insulin infusion [CSII]) has been shown to reduce the long-term micro- and macrovascular complications in patients with T1DM and T2DM.14 However, IIT increases the risk for severe hypoglycemia by threefold15. Although insulin pumps have been around for almost three decades but are becoming common usage only recently. The reasons for low usage of insulin pumps has been high cost, lack of knowledge and availability .

ARTIFICIAL PANCREAS

The artificial pancreas (AP), known as closed-loop control of blood glucose in diabetes, is a system combining a glucose sensor, a control algorithm, and an insulin infusion device. Artificial pancreas (AP) systems will automate blood-sugar management, dramatically reducing T1D-related risks and improving lives of people who have the disease. These systems will monitor glucose levels around the clock and automatically provide the right amount of insulin, and potentially other blood-sugar stabilizing hormones, at the right time. The heart of the system—sophisticated computer algorithms that live on a smartphone or similar device—will link to a continuous glucose monitor sensor and insulin pump to determine blood sugar trends and control insulin delivery.4 As AP technology advances, these systems will become

NP Jain, Rishu Bhanot

better and better at predicting blood-sugar changes and providing tightly controlled insulin dosing that virtually eliminates hyperglycemic and hypoglycemic episodes. AP systems are on the road to becoming the most revolutionary advance in diabetes care since the discovery of insulin. However, there are some major limitations associated with the closed loop system such as delay and inaccuracy in both glucose sensing and insulin delivery. They are being worked upon.Bionic Pancreas is one such AP project undergoing clinical trials.” Bionic Pancreas” is the name given to the dual chambered device that comprises two separate pumps for delivering both insulin and glucagon, a CGM, and a control algorithm built into a smart phone.

What is an Insulin Pump ?

An insulin pump (also known as continuous subcutaneous insulin infusion therapy; CSII) is a medical device used for the administration of insulin in the treatment of diabetes mellitus. A traditional pump includes: •

Pump (including controls, processing module, and batteries)

•

Disposable reservoir for insulin (inside the pump)

•

Disposable infusion set, including a cannula for subcutaneous insertion (under the skin) and a tubing system to interface the insulin reservoir to the cannula.

It is an alternative delivery mechanism for administration of insulin and is found to be superior to ordinary syringes and insulin pens.2 The device delivers insulin in two ways: 1.

Basal (sometimes called background) - delivering small amounts of insulin continuously in order to maintain cell function (replacing the need for long acting insulin)

Bolus - delivering a dose of insulin on demand to account for the carbohydrates in meals or to correct high BGLs.

An insulin pump is worn 24 hours a day but can be removed for up to two hours when required, e.g. for swimming, contact sport or showering. The advantages of the insulin pump (consistency of basal delivery, adjustable basal rates, and low insulin depots allowing the reduction of glycemic variability) have

(AADE) published their guidelines, which were as follows:11

786

•

Patients whose hemoglobin A1c (HbA1c) level is greater than 7%, accompanied by frequent severe hypoglycemia (< 55 mg/dL)

•

Patients who have hypoglycemic events that require third-party assistance or that interfere with work, school, or family obligations

• Patients with frequent and unpredictable fluctuations in blood glucose levels.

DIABETES

•

Fig. 1: Insulin Pump contributed to its reported superiority compared with multiple daily injections (MDI).3 However, insulin pump therapy is now challenged by new MDI regimens based on long-acting insulin analogues that could replace the use of CSII. As a consequence, health professionals now have to determine which patients are likely to benefit the most from CSII.5 Since that time randomized and non-randomized studies have shown the efficacy of CSII across all age groups. Continuous glucose sensors are now changing the way that CSII therapy can improve control by decreasing glycemic excursions and manipulate insulin delivery to avoid otherwise asymptomatic hypoglycemia detected by these sensors.6

HISTORY

In 1960 Dr. Arnold Kadish designed the first insulin pump to be worn as a backpack. Unfortunately, little attention was given to Kadish’s device due to its impracticality for daily use. A more wearable version was later devised by Dean Kamen in 1976.7 Keen and Pickup in 1970’s from Guy’s Hospital, London reported successful and practical use of a portable insulin pump device for CSII in patients with T1DM.8 One of the first commercial insulin pumps marketed in 1978 was the Autosyringe, also named ‘Big Blue Brick’.9

TYPES

Patients who perceive that diabetes management impedes the pursuit of personal or professional goals

In 2010, the American Association of Clinical Endocrinologists (AACE) published their findings about the suitable candidates for insulin pump, which are as follows:12

Class 1

Patients are classified as class 1 if they have type 1 diabetes mellitus (DM) and do not reach glycemic goals despite adherence to a maximum multiple daily injection (MDI) and are on a non-CSII program (≥4 insulin injections and ≥4 self-monitored blood glucose measurements daily), especially if they have the following: •

Very labile DM (erratic and wide glycemic excursions, including recurrent diabetic ketoacidosis [DKA])

• Frequent severe hypoglycemia hypoglycemia unawareness

and/or

•

Significant “dawn phenomenon” (increase in blood glucose levels, usually from 2 am to 8 am, resulting from increased secretion of counter-regulatory hormones, particularly growth hormone)

•

Extreme insulin sensitivity

• Special circumstance (eg, preconception, pregnancy, children, adolescents with eating problems, competitive athletes)

Class 2

The pumps currently available in India are manufactured by Medtronic and the various models are 722, 640G and 75410 as shown in Figure 1.

Patients are classified as class 2 if they have type 1 DM and are on a maximized basal-bolus MDI insulin regimen, defined as more than 3 daily injections, regardless of their level of glycemic control and who, after investigation and careful consideration, feel that CSII would be helpful or more suitable for lifestyle reasons.

Indications

Class 3

There are various companies, which manufacture and market various pumps in India.

Despite the increasing popularity of insulin pump therapy, there is no official guideline for the initiation of insulin pump use. There is an agreement of the fact that patient selection is the key since the patient needs to have the thorough knowledge about the functioning and insulin requirement. In 2009 the American Association of Diabetes Educators

Patients are classified as class 3 if they have insulinrequiring type 2 DM and satisfy any or all of the following: •

Positive C-peptide results but with suboptimal control on a maximal program of basal/bolus injections

•

Substantial “dawn phenomenon”

•

Erratic lifestyle (eg, frequent long-distance travel,

shift work, unpredictable schedules that disrupt maintaining timing of meals) •

Severe insulin resistance, candidate for U500 insulin via CSII (eg, type A and type B insulin resistance syndrome, congenital and acquired generalized lipodystrophy, hyperandrogenism– insulin resistance–acanthosis-nigricans [HAIRAN], Rabson-Mendenhall syndrome)

•

Selected patients with other DM types (eg, DM due to pancreatectomy)

Kaveeshwar SA, Cornwall J. The current state of diabetes mellitus in India. Australas Med J 2014; 7:45–8.

2. Kesavadev J, Das AK, Unnikrishnan R, 1st, Joshi SR, Ramachandran A, Shamsudeen J, et al. Use of insulin pumps in India: Suggested guidelines based on experience and cultural differences. Diabetes Technol Ther 2010; 12:823– 31. 3.

Didangelos T, Iliadis F. Insulin pump therapy in adults. Diabetes Res Clin Pract 2011; 93 Suppl 1:S109-13.

Cobelli C, Renard E, Kovatchev B. Artificial Pancreas: Past, Present, Future. Diabetes 2011; 60:2672-2682.

Hanaire, H. et al. Treatment of diabetes mellitus using an external insulin pump: the state of the art. Diabetes Metab 2008; 34:401–423.

•

Lack of motivation

•

Unrealistic expecatations

•

Lifestyle problems such as contact sports and sexual activity

•

Unable or unwilling to perform multiple daily insulin injections (≥3 daily), frequent blood glucose monitoring (≥4 daily), or carbohydrate counting

J Sherr, WV Tamborlane. Past, present, and future of insulin pump therapy: better shot at diabetes control. Mount Sinai Journal of Medicine 2008; 75:352–361.

•

Psychiatric illness

Pfeiffer E, Thum C, Clemens A. The artificial beta cell--a continuous control of blood sugar by external regulation of insulin infusion (glucose controlled insulin infusion system). Hormone and Metabolic Research 1974; 6:339–342.

Pickup JC, Keen H, Parsons JA, Alberti KG. Continuous subcutaneous insulin infusion: an approach to achieving normoglycaemia. British Medical Journal 1978a; 1:204–207.

• Blindness •

Lack of time to attend pump training sessions

•

Affordability

•

Unable or unwilling to perform multiple daily insulin injections (≥3 daily), frequent blood glucose monitoring (≥4 daily), or carbohydrate counting

Current scenario of insulin pumps in India

The proportion of T1DM and T2DM patients who are put on the pump would vary from center to center. T2DM comprises over 95% of all diabetes cases in India. The majority of all pump users are also type 2 DM in India.2 The use of CSII is very limited in India because of the cost and the pumps are not covered in insurance policies in India. Education is also a limiting factor in our country. With the recent advances and growing knowledge amongst the physicians, it will lead to proper patient selection and enhanced motivation of the patient. Various companies have also started to market their products in India with wide after sales support for the products to the patients.

787

9. Hauge C. Insulin Pumps: Evolution of an Industry. Medtronic MiniMed Europe. Switzerland. Business Briefing: European Pharmacology 2003; 1–3. 10. Anonymous (2007c) Megans Insulin Pump Comparison, 1–3. Available at: http://dfw-iug.org/pump_compare3.pdf 11. Scheiner G, Sobel RJ, Smith DE, Pick AJ, Kruger D, King J, et al. Insulin pump therapy: guidelines for successful outcomes. Diabetes Educ 2009 Mar-Apr. 35 Suppl 2:29S-41S; quiz 28S, 42S-43S. 12. Grunberger G, Bailey TS, Cohen AJ, et al. Statement by the American Association of Clinical Endocrinologists Consensus Panel on insulin pump management. Endocr Pract 2010. 16:746-62. [Medline]. 13. WHO; country and regional Date on Diabetes GENEVA :WHO 2016The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977–986. 14. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA: 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359:1577–1589. 15. The DCCT Research Group: Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial. Am J Med 1991; 90:450–459.

CHAPTER 171

Contraindictions

REFERENCES

C H A P T E R

172

SGLT-2 Inhibitor: A Unique Antidiabetic in Type 2 Diabetes Mellitus

INTRODUCTION

Type 2 diabetes is a progressive metabolic disorder characterised by insulin insensitivity, relative insulin deficiency resulting hyperglycaemia.1The pharmacotherapy for type 2 diabetes until the last decade only consisted of biguanides, sulphonylureas, and insulin. Rapid increase in the number of blood glucoselowering agents which have become available including thiazolidinediones (in 2000), dipeptidylpeptidase-4 (DPPIV) inhibitors (in 2007) and glucagon-like peptide-1 (GLP-1) mimetics (in 2007).1 Despite of glucose lowering effect approximately 85% of patients with T2DM are overweight or obese, and failure to lose even part of the excess weight and continual weight gain are powerful forces against acceptable glycaemic control.2 To develop agents that control glycaemia whilst also inducing weight loss or preventing further weight gain was one of the main challenges of the past decade of pharmaceutical innovation. It is now well documented that the kidney has a significant role in glucose homeostasis under both physiological and pathological conditions.3The major renal mechanisms affecting glucose metabolism are gluconeogenesis and reabsorption of filtered glucose.The facilitated glucose transporters (GLUTs) and the sodium-coupled glucose co transporters (SGLTs) control glucose transport and reabsorption in several tissue types, including the proximal renal tubule, small intestine, blood-brain barrier, and peripheral tissues. SGLTs mediate the transport of glucose against a concentration gradient by cotransport with sodium.3 This review will focus on the SGLT inhibitors benefits and their potential benefits.

SGLT2-INHIBITORS MECHANISM OF ACTION

Sodium-glucose co-transporter-2 inhibitors work by inhibiting SGLT2 in the proximal convoluted tubule, to prevent reabsorption of glucose and facilitate its excretion in urine. As a result plasma levels fallleading to an improvement in all glycemic parameters. This mechanism of action is independent of the actions of insulin, unlike the actions of other oral anti-glycemic agents. Thus, there is minimal potential for hypoglycemia, and no risk of overstimulation or fatigue of the beta cells. SGLT2I efficacy is reduced in persons with renal impairment as their mode of action relies upon normal renal glomerulartubular function.4

SGLT2 BENEFITS

All SGLT-2 inhibitors seem to have similar benefits and

AK Chauhan

risks within the class, including significant reductions in HbA1c and fasting glucose. The most interesting, perhaps, is its ability to positively influence other significant factors, including body weight, blood pressure, lipids and uric acid. Older agents have typically been filled with unfavorable effects on body weight (SU, thiazolidinediones, insulin), on the cardiovascular system (SU and TZDs) and lipids (TZDs). There are still unanswered questions about the possible risk for cancer, the durability of these agents, and how its favorable metabolic profiles will influence the risk of micro and macro vascular disease. The SGLT2 inhibitors have an independent action of insulin, are effective to promote weight loss, have a low incidence of hypoglycemia, complement the action of other antidiabetic agents, and can be used regardless of diabetes duration.6 Findings from this post hoc analysis by Kumar KM et al., of pooled Phase 3 studies demonstrated that canagliflozin provided glycemic improvements and reductions in body weight and BP in patients with T2DM from India. The reductions in body weight were consistent with those observed with canagliflozin in the overall population. As canagliflozin lowers blood glucose through an insulin‑independent mechanism, the glycemic improvements and reductions in body weight and BP provided by canagliflozin may be particularly beneficial in treating patient populations that generally have a higher prevalence of insulin resistance and beta‑cell dysfunction.7 Results of the aforementioned studies is shown in figure 1 below.7 The EMPA-REG trial disclose cardiovascular safety study of empagliflozin, assessed the effect of two doses of empagliflozin—10 mg and 25 mg—on cardiovascular events in patients who were being treated with standard care for type 2 diabetes over a median of 3.1 years. Empagliflozin prevented more than one-third of CV deaths, with a 38% relative reduction. A total of 3.7% of empagliflozin-treated subjects experienced CV death vs 5.9% for placebo: HR=0.62 (95% CI: 0.49, 0.77); P<0.001.8 Empagliflozin was associated with slower progression of kidney disease than was placebo when added to standard care in patients with type 2 diabetes who were at high risk for cardiovascular events. Empagliflozin was also associated with a significantly lower risk of clinically relevant renal events as shown in figure 3 below.9 A recently published study on canagliflozin suggested that Canagliflozin slowed the progression of renal disease over 2 years in patients with type 2 diabetes, and canagliflozin

789

CHAPTER 172 Fig. 1: Changes from baseline in (a) HbA1c, (b) FPG, (c) body weight, (d) systolic BP, and (e) diastolic BP in the overall population and in the Indian subgroup at week 52 (Population 1). FPG: Fasting plasma glucose, BP: Blood pressure, CANA: Canagliflozin, LS: Least squares, SE: Standard error may confer renoprotective effects independently of its glycemic effects.

Fig. 2:

A recent meta-analysis suggested that CV benefit is a class effect of SGLT2 inhibitors. SGLT-2 inhibitors as a class significantly reduced cardiovascular mortality (MHOR [95 % CI] 0.43 [0.36â&#x20AC;&#x201C;0.53], p\0.001). There are ongoing CV outcome studies on other SGLT2 inhibitors namely CANVAS (Canagliflozin Cardiovascular Assessment Study) and DECLARE TIMI 58 (Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events) which have a different patient population consisting of a mixture of patients with established CAD and patients with CV risk factors. These

Placebo (N=1555)

Adjusted Mean eGFR (ml/min/1.73 m2)

Empagliﬂozin, 10 mg (N=1642)

Empagliﬂozin, 25 mg (N=1686)

76 74 72 70 68 66

Last measurement Follow-up during treatment

Baseline

DIABETES

-2 -4 -6 -8 -10

Glimepiride Canagliﬂozin 100 mg

-12

Median, 34 days

Median, 3.0 years

UACR ≥30 mg/g subgroup 0 eGFR slope (mL/min per 1.73m2 per year)

Change in eGFR from Baseline to Last Measurement during Treatment and Follow-up

Change in eGFR (mL/min per 1.73 m2)

790

Canagliﬂozin 300 mg

Time (weeks)

104 Least squares mean

-2

-4

-6

Glimepiride Canagliﬂozin 100 mg

-8

Canagliﬂozin 300 mg

Fig. 3: Renal Function over time with Empagliflozin and Canagliflozin A 0.0

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0

B 0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

0.0

0.5 1.0

1.5

2.0

2.5

3.0

3.5 4.0

Ferrannini E et al., SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects A. Nat Rev Endocrinol 2012; 8:495–502

Marsenic O. Glucose Control by the Kidney: An Emerging Target in Diabetes. American Journal of Kidney Disease 2009; 53:875-883.

ALL TRIALS

Cardiovascular endpoint

Non cardiovascular endpoint

Dapagliﬂozin

4. Kalra S. Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors: A Review of Their Basic and Clinical Pharmacology. Diabetes Ther 2014; 5:355–366.

Canagliﬂozin

Empagliﬂozin Favours SGLT2i

Favours comparators

MH-OR [95%, CI] p 0.43[0.36-0.53] <0.001 All trials: 0.43[0.35-0.52] <0.001 CV endpoint Non CV endpoint 0.49[0.27-0.87] 0.016 0.46[0.20-1.07] 0.071 Dapagliflozin 0.44[0.14-1.40] 0.16 Canagliflozin 0.60[0.19-1.85] 0.37 Empaglflozin

Favours SGLT2i

MH-OR [95%, CI] p 0.77[0.63-0.94] 0.010 0.87[0.69-1.09] 0.23 0.53[0.36-0.79] 0.002 0.48[0.26-0.87] 0.017 0.57[0.26-1.25] 0.15 0.53[0.25-1.11] 0.093

Favours comparators

Favours SGLT2i

Favours comparators

MH-OR [95%, CI] p 1.09[0.86-1.38] 0.50 1.19[0.89-1.58] 0.23 0.88[0.57-1.36] 0.57 0.68[0.31-1.46] 0.32 1.36[0.54-3.40] 0.51 0.85[0.45-1.62] 0.63

Fig. 4 : Cardiovascular mortality (a), myocardial infarction (b), and stroke (c) considering all randomized clinical trials with and without cardiovascular endpoints. SGLT2i sodium-glucose transporter 2 inhibitors trials are going to provide broader clinical insights as EMPA-REG OUTCOME study had included only patients with established CAD.

CONCLUSION

In summary, SGLT-2 inhibitors are an exciting and promising class of drugs for the treatment of type 2 diabetes. They provided glycemic improvements and reductions in body weight and BP, slower progression of kidney disease, significantly lower rates of the primary composite cardiovascular outcome and of deathwith some studies suggesting renoprotectionand are generally well‑tolerated in patients with T2DM.

REFERENCES

Nair S et al. From history to reality: sodium glucose cotransporter 2 inhibitors – a novel therapy for type 2 diabetes mellitus. Pract Diab Int 2010; 27:311-316.

Singh SK et al., SGLT2 inhibitors for treatment of Type 2 diabetes mellitus: Focus on Canagliflozin. Muller Journal of Medical Science and Research 2014; 5:166-173

Faustino BS et al., The Benefits of SGLT2 Inhibitors in Cardiovascular Prevention, Glycemic Control and Weight Loss, in the Treatment of Diabetes. Open Journal of Endocrine and Metabolic Diseases 2016; 6:87-94.

Kumar KMP et al., Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from India. Indian Journal of Endocrinology and Metabolism 2016; 20:372-380.

Zinman B etal.,Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England Journal of Medicine 2015; 1-12.

WannerC et al., Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. The New England Journal of Medicine 2016; 1-12

10. Heerspink et al. Canagliflozin Slows Progression of Renal FunctionDecline Independently of Glycemic Effects. J Am Soc Nephrol 2016 Aug 18. pii: ASN.2016030278. [Epub ahead of print] 11. Am Heart J 2013; 166:217-223.e11. 12. http://www.timi.org/index.php?page=declare-timi-58 accessed on 27 October 2016

13. Monami M. Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled Trials. Acta Diabetol 2016; DOI 14. 10.1007/s00592-016-0892-7

SGLT2 Inhibitors

C H A P T E R

173

Vijay Negalur

INTRODUCTION

Type 2 diabetes mellitus (T2DM) is a chronic progressive disease characterized by hyperglycemia that results from insulin resistance, diminished or absent insulin secretion, or both. Morbidity and mortality associated with diabetes is high, resulting from a spectrum of complications, primarily cardiovascular disease and nephropathy. Glucose-lowering therapies with insulin-dependent mechanisms of action, lose efficacy over time as both endogenous insulin secretion and insulin sensitivity decrease. Side effects such as hypoglycaemia and weight gain are significant issues in management, especially in the context of high prevalence of obesity and cardiovascular diseases in this patient population. The sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a new class of medications for the treatment of type 2 diabetes which improve glucose control by increasing urinary glucose excretion. These agents are efficacious as monotherapy and add-on therapy for patients with type 2 diabetes uncontrolled on metformin, sulfonylureas, insulin, and other antihyperglycemic combinations.

HISTORY AND DEVELOPMENT OF SGLT2I

Phlorizin is a bitter white glycoside which acts as a non-selective inhibitor of SGLT-1 and SGLT-2, and was isolated from the root bark of the apple tree by French chemists in 1835. In the late 19th century, phlorizin due to its bitter taste was used as an anti-malarial and other infectious diseases. During its use it was noted that ~10% reabsorption from S2/S3 PCT

Glucose

~90% reabsorption from S1 PCT

Fig. 1: Renal handling of glucose transport. PCT, proximal convoluted gure 1. Renal handling of glucose transport. PCT,tubule proximal convoluted tubule

high doses of phlorizin caused glycosuria. Since then, phlorizin has been shown to normalise blood glucose levels in pancreatectomised diabetic rat models. But it has not been developed as a glucose-lowering drug due to a combination of its poor bioavailability, poor side-effect profile, which is likely to be a result of its non-selective action (its metabolite, phloretin, inhibits SGLT-1 in the intestinal mucosa causing malabsorption of glucose and galactose). Hence, selective SGLT2 inhibitor was the need of the hour.

MECHANISM OF ACTION OF SGLT2I

The mechanism of action of SGLT2i is based on the role of kidneys in glucose metabolism and homeostasis. The kidney plays a significant role in glucose homeostasis through gluconeogenesis and glomerular filtration and reabsorption of glucose in the proximal convoluted tubules. Nearly all of the glucose filtered by the glomeruli (>99%) is reabsorbed in a healthy adult and returned to the circulation (~90% reabsorption take place from S1 segment of proximal convoluted tubule while ~10% reabsorption take place from S2/S3 segment of proximal convoluted tubule) (Figure 1). At plasma glucose concentrations beyond the resorptive threshold (~180 g/d), glucose begins to appear in the urine. Glucose reabsorption occurs primarily within the proximal renal tubule. This occurs through carrier proteins - sodium-glucose transporter 1 (SGLT1) and SGLT2 which catalyze the active transport of glucose across the luminal membrane. The SGLT2 transporter is found primarily in the S1 segment of the proximal tubule and accounts for approximately 90% of reabsorbed glucose, with expression limited to within the kidney. SGLT1 is a low-capacity transporter found more distal in the S2/S3 segment of the proximal tubule and is involved with reabsorption of the remaining glucose load. It is primarily involved with glucose absorption within the gastrointestinal tract. SGLT2 couples glucose with the transport of sodium and actively pumps it against a concentration gradient across the luminal membrane. Glucose passively diffuses out of the cell via facilitative glucose transporters (GLUT) 1 and 2. The filtered glucose load is the product of the plasma glucose concentration and the glomerular filtration rate (GFR). As the plasma glucose concentration increases, the

ucose reabsorption occurs primarily within the proximal renal tubule. This occurs through

792

filtered glucose load also increases in a linear manner. When the reabsorption capacity of the proximal tubule is surpassed, as occurs during hyperglycemia, glucose appears in the urine. This maximum reabsorption capacity is called as ‘the maximum transport rate (Tm)’.

DIABETES

In healthy individuals without diabetes, Tm for glucose is reached at blood glucose concentrations of approximately 200 mg/dL. On the other hand the mean Tm for glucose has been reported to be higher – approximately 20% or more compared with healthy individuals. Consequently, suppressing renal glucose reabsorption and effectively increasing urinary glucose excretion via SGLT2 inhibition is a logical approach to glycemic control. Since SGLT2 is only expressed in the kidney, the effects of SGLT2 i are limited to glycosuria and associated salt and water losses. Several SGLT2i including canagliflozin, dapagliflozin, ipragliflozin, empagliflozin, and ertugliflozin have been developed or are currently undergoing clinical trials. Dapagliflozin, canagliflozin and empagliflozin have now been approved for clinical use in patients with T2DM in several countries. The available SGLT2 inhibitors share similar pharmacokinetic characteristics, with a rapid oral absorption, a long elimination half-life allowing oncedaily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites, the absence of clinically relevant drug-drug interactions and a low renal elimination as parent drug. SGLT2 cotransporters are responsible for reabsorption of most (90 %) of the glucose filtered by the kidneys.

CLINICAL EFFICACY OF SGLT2 INHIBITORS

Glycemic benefits

Results of numerous placebo-controlled randomised clinical trials of 12-104 weeks duration have shown significant reductions in glycated haemoglobin (HbA1c), resulting in a significant increase in the proportion of patients reaching HbA1c targets. Significant lowering of fasting plasma glucose is observed when SGLT2i were administered as monotherapy or in addition to other glucose-lowering therapies including insulin in patients with T2DM. In head-to-head comparison trials of up to 2 years, SGLT2 inhibitors exerted similar glucose-lowering activity compared to metformin, sulphonylureas or sitagliptin. The durability of the glucose-lowering effect of SGLT2 inhibitors has been shown to be good in clinical trials. The 52 week CANTATA-M study assessed the longterm efficacy and safety of canagliflozin monotherapy in patients with T2DM inadequately controlled with diet and exercise. This study showed that canagliflozin monotherapy provided sustained improvement in glycemic control and body weight reduction, and was generally well tolerated in patients with T2DM over 52 weeks compared to sitagliptin.

As an add on to metformin, canagliflozin 100 and 300 mg was associated with significant glycemic improvements and body weight reductions and also found to be well tolerated compared with metformin alone in drug-naive patients with T2DM over 26 weeks. Combination therapy provided statistically significant greater reductions in HbA1c and body weight with a significantly higher proportion of patients achieving their glycemic goals. Dapagliflozin 2.5 or 5 mg twice daily added to metformin was also effective in reducing glycaemic levels in patients with type 2 diabetes inadequately controlled with metformin alone as assessed through reduction in HbA1c and FBG.

SGLT2i as an add on to dual or triple therapy regimens

The efficacy and safety of canagliflozin as an add-on to metformin plus sulphonylurea in patients with T2DM was evaluated in a randomised, double-blind, placebocontrolled, Phase 3 study. HbA1c was significantly reduced with canagliflozin 100 and 300 mg vs. placebo at week 26 (-0.85%, -1.06%, and -0.13%; p < 0.001); these reductions were maintained at week 52 (-0.74%, -0.96%, and 0.01%). Both canagliflozin doses reduced FPG and body weight vs. placebo at week 26 (p < 0.001) and week 52. The efficacy and safety of canagliflozin, has also been similarly evaluated in patients with T2DM inadequately controlled with metformin and pioglitazone and was found to improve glycaemic control, reduced body weight and systolic BP, and also found to be well tolerated. Canagliflozin significantly improved health related quality of life, a benefit attributed to the additional weight loss benefits of the drug.

SGLT2i improves beta cell function

Canagliflozin has been shown to increase beta cell glucose sensitivity compared with placebo. Three separate phase 3 studies demonstrate that sustained treatment with canagiflozin for 6 to 12 months improved measures of beta cell function

Experience in Indian patients

Several Indian studies have shown canagliflozin to provide glycaemic control, body weight reduction, and good tolerability in Indian patients with T2DM similar to that seen in patient populations across the world. Findings from this analysis support canagliflozin as an effective therapeutic option for patients with T2DM in India who may be on a range of background therapies.

EXTRA-GLYCEMIC BENEFITS

SGLT2i and blood pressure reduction

Emerging data suggests that the SGLT2 inhibitors provide a meaningful reduction in blood pressure (BP), although the precise mechanism of the blood pressure drop remains incompletely elucidated. It has been suggested that the blood pressure reduction is partially due to a combination of diuresis, nephron remodelling, reduction in arterial stiffness, and weight loss.

Since the main reason for reduction in BP has been attributed to decrease in intravascular volume associated with osmotic diuresis and natriuresis, the events of hypotension were, more common in patients particularly at risk of volume depletion, such as elderly patients, patients with renal impairment or those on loop diuretics.

Reductions in systolic BP of 3.3–5.4 and 4.3–6.9mmHg with canagliflozin 100 and 300mg, respectively, were noted across studies up to 52 weeks. Canagliflozin has shown to rapidly reduce 24 hour ABPM-assessed SBP both of which are important predictors of clinical CV risk and future events.

SGLT2i and weight loss

Increased renal glucose elimination also assists weight loss and these results have been very consistent across the trials and they represent additional advantages for SGLT2 inhibitors when compared with other oral glucoselowering agents. In a 104 week study evaluating effect of canagliflozin on body weight and body composition, more patients on canagliflozin experienced ≥5% weight loss with canagliflozin with significant reduction in BMI and waist circumference. Moreover, it is also found that the weight loss occurring with SGLT2 inhibitors is majorly due to loss of fat mass.

SGLT2i and risk of hypoglycaemia

In various clinical trials, the lower risk of hypoglycemia is observed with the usage of SGLT2i compared to sulphonylureas and was similarly low as that reported with metformin, pioglitazone or sitagliptin.

Renoprotective effects of SGLT2i

Studies suggest that SGLT2i offer additional renoprotective effects. Canagliflozin 100 or 300 mg/d, compared with glimepiride, slowed the progression of renal disease over 2 years in patients with T2DM, and canagliflozin may confer renoprotective effects independently of its glycemic effects. In patients with T2DM at high cardiovascular risk, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than placebo when added to standard care.

SGLT2i in patients with renal impairment

SGLT2i is associated with an acute, dose-dependent reduction in glomerular filtration rate (eGFR ) by ~5 ml/min/1.73m2 and ~30-40% reduction in albuminuria. These effects suggest that proximal tubular natriuresis activates renal tubuloglomerular feedback through increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction. On the basis of reduced glomerular filtration, glycosuric and weight loss effects are attenuated in patients with chronic kidney disease (CKD, eGFR <60 ml/min/1.73m2). In contrast, BP

The pharmacodynamics response to SGLT2 inhibitors declines with increasing severity of renal impairment, and it is recommended that the prescribing information for each SGLT2i should be consulted regarding dosage adjustments or restrictions in moderate to severe renal dysfunction. Caution is also recommended in the elderly population because of a higher risk of renal impairment, orthostatic hypotension and dehydration, even if the absence of hypoglycaemia represents an obvious advantage in this population.

SGLT2i and diabetic ketoacidosis

Investigations into postmarketing reports of SGLT2 inhibitor–associated diabetic ketoacidosis (DKA), which has been reported to occur in type 1 diabetes and T2DM patients with less than expected hyperglycemia (euglycemic DKA) , are on-going. However after a thorough review of the evidence during an October 2015 meeting, an American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) Scientific and Clinical Review expert consensus group found that the incidence of DKA is infrequent and recommended no changes in SGLT-2 inhibitor labelling. To minimize the risk of SGLT2i associated DKA, the AACE –ACE recommend to stop SGLT2i at least 24 hours prior to elective surgery, planned invasive procedures, or anticipated severe stressful physical activity such as running a marathon. In the event of an emergency surgery or any extreme stress event, the drug should be stopped immediately and appropriate clinical care should be provided. The recommendations also suggest that patients taking SGLT2 inhibitors should avoid excess alcohol intake and very-low-carbohydrate/ketogenic diets. However routine measurement of blood ketones is not recommended because urine ketone measurement can be misleading, and measurement of blood ketones is preferred for diagnosis of DKA in symptomatic patients.

Genital infections and urinary tract infections

High levels of glycosuria induced by SGLT2i raise the risk of developing genital infections (mostly candidiasis) and to a relatively lesser extent, urinary tract infections (UTIs) in treated patients. The most frequently reported adverse events are female genital mycotic infections, while urinary tract infections are less commonly observed and generally benign. Both infections respond to appropriate anti-infective agents.

Cardiovascular safety of SGLT2i

Although cardiovascular (CV) mortality is the principal cause of death in individuals with T2DM, reduction of plasma glucose concentration alone does not significantly lower CV disease (CVD) risk. SGLT2i exert multiple metabolic benefits, and the risk factors beyond glucose that can potentially be modulated positively with these agents include blood pressure, weight, visceral adiposity,

793

CHAPTER 173

Mean reductions (from baseline) in systolic BP of 3.6–6.7 mmHg with dapagliflozin were noted across studies up to 52 weeks, with no notable increases in the incidence of orthostatic hypotension. Sustained, although somewhat smaller, decreases in systolic BP were noted with dapagliflozin 10mg over 1–4 years.

lowering, eGFR and albuminuric effects are preserved, and perhaps exaggerated in CKD.

794

hyperinsulinemia, arterial stiffness, albuminuria, circulating uric acid levels and oxidative stress.

DIABETES

In a recent CV safety study on empagliflozin in T2DM patients with high CVD risk empagliflozin reduced the primary major adverse cardiac event end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14%. This beneficial effect was driven by a 38% reduction in CV mortality with no significant decrease in nonfatal myocardial infarction or stroke. Empagliflozin also caused a 35% reduction in hospitalization for heart failure without affecting hospitalization for unstable angina. A recently published meta-analysis substantiated this benefit as a class effect providing clear evidence that SGLT2 inhibition protects against major cardiovascular events, cardiovascular death, heart failure, and death from any cause. The reasons for this benefit have been hypothesised in the “thrifty substrate hypothesis”. It has been suggested that under conditions of mild, persistent hyperketonemia, such as those that prevail during treatment with SGLT2 i, b-hydroxybutyrate is freely taken up by the heart (among other organs) and oxidized in preference to fatty acids. This substrate selection improves the transduction of oxygen consumption into work efficiency in the endangered myocardium (and also improves metabolic status and function of other organs, mainly the kidney). These mechanisms in addition to enhanced diuresis and reduced blood pressure probably results in cardioprotection.

Possible factors contributing to CV effects of SGLT2i •

Glycemic control

•

Decrease in body weight and visceral adiposity

•

Decrease in blood pressure and arterial stiffness

•

Decrease in oxidative stress

•

Decrease in uric acid level

•

Decrease in albuminuria

Effect of SGLT2i on bone

Inhibition of tubular glucose reabsorption has the potential to affect mineral metabolism and possibly bone health. On the other hand there is no data relating to the expression of SGLT2 in relevant bone-derived cell types relating to bone homeostasis, such as osteoblasts or osteoclasts suggesting that SGLT2 is unlikely to play a major functional role within bone tissue. Across clinical studies, canagliflozin did not meaningfully affect calcium homeostasis or hormones regulating calcium homeostasis. A meta-analysis based on available randomised clinical trial data also does not support the harmful effect of SGLT2 inhibitors on fracture.

SGLT2i after metformin –comparisons with dipeptidyl peptidase-4 inhibitors (DPP- 4 inhibitors)

There are four head-to-head studies comparing DPP4i with SGLT2i either in treatment naive patient or on

background metformin therapy or background SU plus metformin therapy. There was no significant difference among these agents in A1c reduction but SGLT2i were associated with consistent weight loss and BP reduction compared to DPP4i.

Place of SGLT2 inhibitors in therapy

The Update to the Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes recommends the use of SGLT2 inhibitors as one of the second line therapy when monotherapy with metformin fails. The AACE/ACE 2016 guidelines state that SGLT2 i as one of the acceptable alternatives to metformin as initial therapy. The most recent guidance document from the National Institute of Health and Care Excellence (NICE), UK, on SGLT2i recommends canagliflozin, dapagliflozin or empagliflozin as a monotherapy options for treating T2DM in adults for whom metformin is contraindicated or not tolerated and when diet and exercise alone do not provide adequate glycaemic control, only if: •

a dipeptidyl peptidase-4 (DPP-4) inhibitor would otherwise be prescribed and

•

a sulfonylurea or pioglitazone is not appropriate.

CONCLUSIONS

The kidney plays a key role in glucose homeostasis and the pathophysiology of T2DM. SGLT2 inhibitors, canagliflozin, dapagliflozin and empagliflozin are a new class of antihyperglycemic agents for the treatment of T2DM with a novel insulin-independent mechanism of action that targets the kidney. The SGLT2 inhibitors decrease renal glucose reabsorption, thereby increasing urinary glucose excretion and lowering plasma glucose levels in patients with hyperglycemia. Modest reductions in body weight and blood pressure have also been observed following treatment with SGLT2 inhibitors. SGLT2 inhibitors appear to be generally well tolerated, and have been used safely when given as monotherapy or in combination with other oral antidiabetes agents and insulin. The risk of hypoglycemia is low with SGLT2 inhibitors. Typical adverse events appear to be related to the presence of glucose in the urine, namely genital mycotic infection and lower urinary tract infection, and are more often observed in women than in men. Data from long-term safety studies with SGLT2 inhibitors and from head-to-head SGLT2 inhibitor comparator studies are needed to fully determine their benefitrisk profile, and to identify any differences between individual agents. However, given current safety and efficacy data, SGLT2 inhibitors may present an attractive option for T2DM patients who are failing with metformin monotherapy, especially if weight is part of the underlying treatment consideration.

REFERENCES

1. Whalen K, Miller S, Onge ES. The Role of Sodium-Glucose Co-Transporter 2 Inhibitors in the Treatment of Type 2 Diabetes. Clin Ther 2015; 37:1150-66 2. Moses RG, Colagiuri S, Pollock C SGLT2 inhibitors: New medicines for addressing unmet needs in type 2 diabetes. Australas Med J 2014; 7:405-15. 3.

Nigro SC, Riche DM, Pheng M, Baker WL. Canagliflozin, a novel SGLT2 inhibitor for treatment of type 2 diabetes. Ann Pharmacother 2013; 47:1301-11.

5. Nair S, Joseph F, Ewins D, et al. From history to reality: sodium glucose co-transporter 2 inhibitors – a novel therapy for type 2 diabetes mellitus. Practical Diabetes Int 2010; 27:311–316. 6.

Scheen AJ Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs 2015; 75:33-59. Stenlöf K, Cefalu WT, Kim KA, Jodar E, Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study. Curr Med Res Opin 2014; 30:163-75

8. Rosenstock J, Chuck L. Initial Combination Therapy With Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Naïve Type 2 Diabetes. Diabetes Care 2016; 39:353-62. 9.

Schumm-Draeger PM, Burgess L Twice-daily dapagliflozin co-administered with metformin in type 2 diabetes: a 16week randomized, placebo-controlled clinical trial. Diabetes Obes Metab 2015; 17:42-51.

10. Wilding JP, Charpentier G, Hollander P, Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract 2013; 67:1267-82. 11. Forst T, Guthrie R, Goldenberg R, Yee J, Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab 2014; 16:467-77. 12. Traina S1, Guthrie R, Slee A. The impact of weight loss on weight-related quality of life and health satisfaction: results from a trial comparing canagliflozin with sitagliptin in triple therapy among people with type 2 diabetes. Postgrad Med 2014; 126:7-15. 13. Polidori D1, Mari A, Ferrannini E. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes. Diabetologia 2014; 57:891-901. 14. Prasanna Kumar, Efficacy and safety of canagliflozin in patients with type 2 diabetes from India, Posters / Diabetes Research and Clinical Practice 106S1 (2014) S47–S267

795

16. Heerspink HJ, Desai M. Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects. J Am Soc Nephrol 2016. 17. Wanner C1, Inzucchi SE1Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016; 375:323-34. 18. Heerspink HJ, Perkins BA, Fitchett DH Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation 2016; 134:752-72. 19. Garber AJ, Abrahamson MJ, Barzilay JI, Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm, 2016, Executive Summary Endocr Pract. 2016; 22:84-113 20. AACE/ACE Scientific and Clinical Review: Association of SGLT2 Inhibitors and DKA, October 2015. 21. Inzucchi SE, Zinman B, Wanner C SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res 2015; 12:90-100 22. Abdul- Ghani, M et al SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study. Diabetes Care 2016; 39:717-725 23. Wu JH, Foote C, Blomster J, Toyama T Effects of sodiumglucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2016; 4:411-9. 24. Ferrannini E, Mark M, Mayoux E.CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis. Diabetes Care 2016; 39:1108-14. 25. Alba M, Xie J, Fung A, Desai M. The effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on mineral metabolism and bone in patients with type 2 diabetes mellitus. Curr Med Res Opin 2016; 32:1375-85. 26. Tang HL, Li DD, Zhang JJ Lack of evidence for a harmful effect of sodium-glucose co-transporter 2 (SGLT2) inhibitors on fracture risk among type 2 diabetes patients: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab 2016 Jul 13. 27. Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient- Centered Approach Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2015; 38:140–149. 28. NICE Technology appraisal document, https://www.nice. org.uk/guidance/ta390?unlid=, May 2016, Accessed 16 September 2016.

CHAPTER 173

4. Jung CH, Jang JE, Park JY. A Novel Therapeutic Agent for Type 2 Diabetes Mellitus: SGLT2 Inhibitor. Diabetes Metab J 2014; 38:261-7.

15. Maliha G, Townsend RR. SGLT2 inhibitors: their potential reduction in blood pressure. J Am Soc Hypertens 2015; 9:4853.

C H A P T E R

174

Clinical Impact of Newer Insulins for the Management of Type 2 Diabetes

ABSTRACT

Achieving good glycaemic control while avoiding hypoglycaemia, in order to delay or prevent the long term complications in patients with type 1 or 2 diabetes mellitus is important. Although, insulin plays a vital role in the management of diabetes, conventional human basal insulins like NPH have certain limitations, which have led to the development of more stable and peak less analogues. Although the first generation basal insulin analogues, insulin glargine and insulin detemir are an improvement over NPH, they still exhibit subtle peak effect and some patients may need twice daily administration. Insulin degludec (TresibaÂŽ) is an ultra-long acting basal insulin analogue with flat, stable glucose lowering profile with half-life of >25 hours and duration of action of > 42 hours and less within patient day-to-day variability compared to long acting insulin analogue insulin glargine. A coformulation of insulin degludec with rapid acting insulin aspart (Insulin degludec/Insulin Aspart) [RyzodegÂŽ] is also available, comprising 70% insulin degludec and 30% insulin aspart. This article reviews the clinical impact of these newer insulins in the management of Type 2 diabetes.

INTRODUCTION

Diabetes is a global epidemic with estimated 415 million individuals currently living with diabetes. By 2040, this number is projected to reach 642 million1. Good glycaemic control significantly and importantly reduces the risk of long-term complications of both type 1 and type 2 diabetes. The benefits of tight glycaemic control have been confirmed by the DCCT (Diabetes Control and Complications Trial)/EDIC (Epidemiology of Diabetes Interventions and Complications) in type 1 diabetes and UKPDS (United Kingdom Prospective Diabetes Study) trials in type 2 diabetes, respectively2-4. Intensive glucose lowering therapy was associated with significantly reduced risks of myocardial infarction, stroke and heart failure in an epidemiological analysis of the follow-up to the UKPDS study3. Although, benefits of good glycaemic control have been emphasized, action is needed to increase the proportion of individuals achieving recommended glycaemic goals. Insulin therapy continues to play a vital role in the treatment of patients with diabetes mellitus. Basal insulin has been an important treatment option for patients with diabetes mellitus (DM) and, has undergone major improvements in terms of purity and similarity to the action of physiologic human insulin. Lente and Ultralente

Marc Evans

formulations were used for decades but are no longer available. The use of neutral protamine Hagedorn (NPH) insulin is also being replaced with the basal insulin analogs detemir and glargine5. Basal insulin analogs generally cause less severe and nocturnal hypoglycemia compared with NPH insulin owing to their improved pharmacologic profiles6-8. In comparison to NPH insulin, insulin glargine causes similar weight gain, whereas insulin detemir causes less weight gain. In addition, insulin detemir has been associated with a glucose-lowering effect that is more predictable than that of NPH insulin. Despite the improvements observed with basal insulin analogs, their time-action profiles are not completely flat and are shorter than 24 hours in many patients9,10. Ideal basal insulin is the one which delivers a steady, stable, peakless, continuous insulin concentration for at least 24 hours, in a predictable manner, with low intraindividual and interindividual variability and minimal hypoglycaemia11. Type 2 DM is a progressive disease and meal time glucose control impairment is an early feature of disease progression in Type 2 DM and control of post prandial glycaemia needs to be addressed. But some reluctance to initiate or intensify insulin therapy has been noted among primary care physicians because of fear of hypoglycemia and weight gain, and perceived problems of dependency on the medication and complexity of multiple injections and titration of regimens12-14. Combination therapies in the form of basal insulin plus bolus insulin at the major meal, basal-bolus (Basal insulin and bolus insulin at all meals) or premix strategies were traditionally considered following successful titration with basal insulin only. Although regimens based on injections of premixed biphasic insulin can provide prandial coverage for several meals, they may also be associated with an increased rate of nocturnal hypoglycemia15 as the interaction between the soluble and protaminated insulin components (shoulder effect) produces a prolonged and uneven peak glucoselowering effect compared with rapid-acting insulins. Therefore, insulin combinations comprising a long-acting basal and a distinct rapid-acting prandial insulin in a single pen, suitable for once-daily (OD) or twice-daily (BID) administration, may be suitable insulin initiation and intensification approach. This article reviews the pharmacological properties, efficacy and tolerability of insulin degludec and insulin degludec/insulin aspart in type 2 DM patients.

Table 1: Pharmacological properties of Insulin Degludec Insulin Degludec

Terminal Half-life

25.4 Hrs

Duration of action

>42 Hours

Glycaemic variability

75% lower than insulin glargine

Glucose lowering effect over 24 Hours

Consistent and evenly distributed

Pharmacokinetics in renal failure and hepatic failure patients

Ultra-long pharmacokinetics are preserved in renal failure and hepatic failure patients

Miscibility with bolus insulin and GLP-1 analogues

Yes

INSULIN DEGLUDEC IN TYPE 2 DM PATIENTS

Pharmacological properties

Insulin degludec is a soluble ultra-long acting basal insulin analogue that has same amino acid sequence as human insulin, apart from deletion of Therionine amino acid residue at B30 and addition of 16 carbon fatty acid (Hexadecanedieoic acid) to Lysine at B29 through a glutamic acid spacer. Due to its structure and formulation, insulin degludec forms stable and soluble multihexamers upon injection. Insulin monomers then slowly and gradually dissociate from the multihexamers and are subsequently absorbed into the bloodstream to provide an ultra-long duration of action16. The terminal half-life of IDeg was approximately 25 hr at steady state and the duration of action was found to be >42 Hours17,18. A doubleblind, two-period, incomplete block cross-over trial which investigated the pharmacodynamic and pharmacokinetic properties of IDeg at steady state (SS) in people with type 2 diabetes, concluded that the mean glucose infusion rate (GIR) profiles were flat and stable for all dose levels. The glucose-lowering effect of IDeg was evenly distributed over the dosing interval τ, with area under the curve (AUC) for each of the four 6-h intervals being approximately 25% of the total AUC (AUCGIR,τ,SS)19. The glycaemic variability of insulin degludec is found to be four times lesser than that of insulin glargine20. The pharmacokinetic and pharmacodynamic properties of insulin degludec are enumerated in Table 1.

Efficacy and safety

The efficacy of insulin degludec in Type 2 DM patients was compared with insulin glargine in four randomized, open label, multi-centre phase 3 trials including insulin naïve patients and insulin experienced patients21-24. Another randomised, open-label, multi-centre, 26 Weeks, Phase 3 trial examined the efficacy of a flexible insulin degludec dosing regimen25. The results of the trials have been enumerated in Table 2. In terms of HbA1C reduction, insulin degludec was non-inferior to insulin glargine in insulin naïve and insulin experienced patients.

The injection timing of insulin degludec can be varied without compromising glycaemic control in Type 2 DM patients according to the results from BEGIN Flex study. In this study there was no significant difference between patients receiving insulin degludec according to flexible dose regimen and those receiving insulin degludec with their evening meal in mean reduction in HbA1c, proportion of patients achieving HbA1c of < 7% or mean FPG25. Subcutaneous insulin degludec was generally well tolerated in patients with Type 2 DM. The majority of adverse events among insulin degludec recipients were of mild to moderate severity and were not considered to be related to treatment. The most commonly reported treatment emergent adverse events included nasopharyngitis, upper respiratory tract infection, head ache and diarrhoea21-24. Although there was initial concerns on the cardiovascular safety of insulin degludec, FDA has concluded that currently available data is suggest that the risk associated with insulin degludec is similar to that of other longacting insulin analog products and has given approval for insulin degludec and insulin degludec/insulin aspart on 25th September 201527. The potential limitations of insulin degludec clinical development program was, the lack of blinding, inclusion of non-symptomatic hypoglycemia in the hypoglycemia endpoints, exclusion of patients with one or more hypoglycemia risk factors, and no recording of the timing of IGlar administration. So, a randomized, double-blind, crossover, multicenter, treat-to target phase 3b clinical trial conducted in patients with T2D (Switch 2 Study). Patients previously treated with basal insulin with or without oral antidiabetic drugs were randomised 1:1 to 100 U/mL (U100) of IDeg or IGlar once daily and 1:1 to administer basal insulin in the morning or evening throughout the trial. The primary objective was to confirm superiority of IDeg compared with IGlar in the rates of severe or blood glucose (BG)-confirmed symptomatic hypoglycemia during the maintenance period (after 16 weeks of treatment)28. The results of the study are enumerated in Table 4. Early evidence from the real world has also been encouraging29-32. The results from the real world studies have been enumerated in Table 5.

797

CHAPTER 174

Pharmacological Property

A patient level meta-analysis was done to obtain a comprehensive overview of differences between the two preparations (insulin degludec and insulin glargine). End points analysed were glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), insulin dose and hypoglycemic rates analysed in mutually exclusive groups: non-severe nocturnal, nonsevere daytime, and severe26. The results from the meta-analysis for Type 2 DM patients are enumerated in Table 3.

798

Table 2: Summary of Phase 3a clinical trials of insulin degludec versus insulin glargine in Type 2 DM patients

DIABETES

Trial

Population/ comparator

Duration (wks)

Efficacy

Hypoglycaemia

FPG mmol/L [mg/dL]

Total

Nocturnal

Yes

-0.38 [-6.84]*

 16%

 43%*

Non-inf. HbA1c

ONCE LONG (core and extn)

Insulin naïve, T2D

104

Previously treated with insulin, T2D

Yes

-0.29 [-5.22]

 18%*

 25%*

FLEX*

Insulin naïve and insulin treated, T2D

Yes

-0.42 [-7.56]*

 3%

 23%

Low Volume

Insulin naïve, T2D

Yes

-0.42 [-7.56]*

 14%

 36%

Once Asia

Insulin naïve, T2D

-0.09 [-1.62]

 18%

 38%

*Statistically significant

Table 3: Summary of results (Meta-Analysis of Endpoints in Phase 3a Trials for insulin degludec versus insulin glargine in Type 2 DM patients) Category

Change in HbA1C; Ideg-Iglar Estimate(95% CI)

Change in FPG; IDeg-IGlar Estimate(95% CI)

Daily insulin dose Estimated treatment ratio (95% CI)

T2DM insulinnaive

0.08(–0.01; 0.16)

-0.34(-0.54;0.15)

T2DM B/B

0.08 (0.05; 0.21)

-0.29(-0.65; 0.06

Table 4: Summary of results of Switch 2 Study

Nocturnal hypoglycaemia Full trial period Estimated rate ratio IDeg/ IGlar (95% CI)

Maintenance period Estimated rate ratio IDeg/ IGlar (95% CI)

0.90 (0.85; 0.96)

0.64 (0.47; 0.86)

0.51 (0.36; 0.72)

1.03 (0.97; 1.10)

0.75 (0.57; 0.98)

0.71 (0.51; 0.99)

Table 5: Post approval studies of insulin degludec

Parameter

Result

Properties

Non-inferiority in HbA1C reduction

Yes

Reduction in HbA1C (%)

Severe or BG confirmed symptomatic hypoglycaemia – maintenance phase (rates)

30% Lesser

Severe or BG confirmed symptomatic nocturnal hypoglycaemia – maintenance phase (rates)

42% lesser

Severe Hypoglycaemia maintenance phase rates

46% Lesser

INSULIN DEGLUDEC/INSULIN ASPART (IDEGASP) IN TYPE 2 DM Pharmacological properties

The co-formulation of IDeg and IAsp in IDegAsp is a clear, colourless, neutral pH solution. The molecular structure of two components of IDegAsp (insulin degludec and insulin aspart) allows them to co-exist without affecting their individual PK/PD profile. The basal component, IDeg, exists in the form of stable di-hexamers in the pharmaceutical preparation, forming long multi-hexamer chains after subcutaneous administration. Subsequently, continual release of IDeg monomers from the ends of the chains ensures a ﬂat PK/PD proﬁle, lasting long enough to meet basal insulin requirements over 24 h once at steady state. In contrast, IAsp in IDegAsp exists

Sweden

India

0.30

0.70

0.36

Reduction in insulin dosage (%)

Reduction in overall hypoglycaemia (%)

as hexamers in the vial, which rapidly dissociate into monomers after subcutaneous administration, providing a near-physiological meal-time concentration profile. This has been confirmed by size-exclusion chromatography, in conditions simulating pharmaceutical preparations as well as after subcutaneous administration, clearly showing the existence of two separate components that do not affect each other’s PK/PD profile, either in solution or once injected33. Furthermore, a clamp study carried out in people with type 1 diabetes mellitus (T1DM) at steady state demonstrated the basal and meal-time effects of the two components in a dose-dependent manner34. Also, no clinically relevant differences in the pharmacokinetics of IDegAsp in older people (≥65 years) were found compared to young adults (18-35 years) 35. In addition, no clinically relevant differences have been observed in the PK or PD of IDeg or IAsp in patients with renal or hepatic failure36,37,38.

Table 6: Summary of pharmacological properties of IDegAsp Pharmacological Property IDegAsp Components

Insulin Degludec and Insulin Aspart in a ratio of 70:30 Pharmacokinetics of insulin degludec and insulin aspart distinct in the co-formulation

Glycaemic variability

75% lower than insulin glargine

Dose proportionality

Total exposure proportionally increases with dose

Efficacy and safety

The efficacy of IDegAsp in Type 2 DM patients was compared with insulin glargine/Biphasic insulin Aspart/ Basal-bolus therapy in four randomized, open label, multi-centre phase 3 trials including insulin naïve patients and insulin experienced patients. The results of the trials have been enumerated in Table 6.

IDegAsp in insulin naïve patients

In comparison to insulin glargine, when IDegAsp was administered once daily in insulin naïve patients with Type 2 DM patients, there was superiority in lowering HbA1c with numerically lower nocturnal hypoglycaemic episodes although the difference was not statistically significant39. In a global study in insulin-naıve people comparing twice-daily IDegAsp with twice-daily BIAsp 30, there was no difference in HbA1c, despite FPG being 1.0 mmol/l lower (p < 0.001). However, in this study there was a 75% reduction in nocturnal con-ﬁrmed hypoglycaemia in favour of IDegAsp, together with a 54% reduction in any-time hypoglycaemia40.

IDegAsp in prior insulin users (Table 7)

In studies comparing twice-daily administration of IDegAsp with BIAsp 30, one in a global population and one in an Asian population, IDegAsp was noninferior to BIAsp 30 for change in HbA1c, but superior in lowering FPG and at a lower daily insulin dose. IDegAsp demonstrated a 32% reduction in confirmed hypoglycaemia rate (p = 0.005) and a 73% reduction in the rate of nocturnal confirmed hypoglycaemia (p < 0.001)41. In the Asian population, there was no effect on any time (confirmed) hypoglycaemia and the rate ratio or nocturnal confirmed hypoglycaemia (reduction of33%) did not meet statistical significance42. A study comparing twice daily administration of IDegAsp versus basal plus meal time insulin therapy in prior insulin users, the final HbA1c was comparable although non-inferiority was not achieved. But, the insulin dose was 12% lower using combination insulin and confirmed and nocturnal hypoglycaemia were 19% and 20% lower respectively43. Subcutaneous

insulin

degludec/insulin

aspart

was

799

Dosing and titration of IDeg and IDegAsp

Insulin degludec is indicated for treatment of diabetes in adults. On occasions when administration at the same time every day is not possible, insulin degludec allows for flexibility in the timing of insulin administration; it should be ensured that there is a minimum of 8h gap between 2 injections. For insulin-naïve T2DM patients the recommended daily starting dose is 10 U followed by individual dosage adjustments. In insulin experienced patients, Unit-to-unit switch from any basal insulin OD or BID or basal component of prior basal-bolus or premix insulin can be considered. A 20% dose reduction may be considered when switching from BID insulin. During the transition period, patients may observe higher blood glucose values for 3–5 days following the switch to IDeg. Once-weekly titration based on the average of two preceding FPG measurements is recommended44. Insulin Degludec/Insulin aspart is indicated for once or twice daily subcutaneous administration with the main meals. If needed the timing of administration can be changed as long as IDegAsp is administered with the largest meal when taken once daily. In insulin naïve Type 2 DM patients total daily starting dose for IDegAsp is 10 units with main meal(s) followed by individual dosage adjustments. In insulin experienced Type 2 DM patients, patients receiving OD/BD basal or premix insulins can be converted to IDegAsp at the same total insulin dose as the patients previous total daily dose. Patients with T2DM switching from basal and bolus insulin therapy to IDegAsp will need to convert their dose based on individual needs. In general, patients are initiated on the same number of basal units. Adjust breakfast or lunch dose based on the average of 3 preceding pre-main evening meal SMBG values and main evening meal dose based on the average of 3 preceding pre-breakfast SMBG values45.

CONCLUSION

Insulin degludec is a novel basal insulin analogue with a unique mode of protraction which ensures a flat and stable glucose-lowering effect with half-life of more than 25 hours and duration of action beyond 42 hours. The glucose lowering effect of insulin degludec is consistent over a period of 24 hours compared to insulin glargine and its day-to-day variability is four times lower than that of insulin glargine. The ultra-long pharmacokinetic properties of insulin degludec are preserved in subjects with renal impairment and hepatic impairment. Insulin degludec can be administered at any time of the day, but at the same time every day. IDegAsp is a novel co-formulation that may offer in patients with progressive T2DM a simpler, injectable insulin regimen with fewer injections as compared to basal bolus/basal plus therapy. As compared to premix insulin therapy, IDegAsp shows better reductions in fasting plasma glucose and significant reductions in confirmed

CHAPTER 174

Glucose lowering effect

generally well tolerated in Type 2 DM patients. The majority of adverse events were mild to moderate in severity.

DIABETES

800

Table 7: Summary of Phase 3 clinical trials of IDegAsp Study

Dosing

Comparator

HbA1C difference

Onishi et al. 26 week open label, treat to target study in T2DM insulin naïve Japanese patients

Once daily

Insulin Glargine

-0.28 (-0.46 to -0.10), < 0.01 Superior

Franek et al 26 week, open label, treat to target study in T2DM insulin naïve patients

Twice daily

Biphasic insulin Aspart 0.02 ( 0.12 to 0.17),non-inferior

Overall Hypoglycaemia – 54% reduction Nocturnal hypoglycaemia – 75% Reduction

Fulcher et al 26 week, open label, treat to target study in T2DM insulin experienced patients

Twice daily

Biphasic insulin Aspart -0.03% (-0.18 to 0.13),non-inferior

Overall Hypoglycaemia – 32% reduction Nocturnal Hypoglycaemia – 73% reduction

Kaneko et al. 26 week, open label, treat to target study T2DM insulin experienced Asian patients

Twice daily

Biphasic insulin Aspart 0.05 (-0.10 to 0.20),noninferior

Nocturnal Hypoglycaemia – 33% Lesser

Rodbard et al 26 week, open label, treat to target study T2DM insulin experienced patients

Twice daily

Insulin Degludec + insulin aspart (2-5 times daily)

Overall Hypoglycaemia – 19% reduction Nocturnal Hypoglycaemia – 20% reduction

and nocturnal confirmed hypoglycaemic episodes as compared to biphasic insulin aspart. Both IDeg and IDegAsp have been useful addition in the therapeutic armamentarium for the management of Type 2 diabetes.

REFERENCES

International Diabetes Federation. IDF Diabetes Atlas 7th edition, 2015. Available at (http://www.diabetesatlas.org/) Accessed on 10th November 2016 11:40 AM.

UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:837–53.

Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321:405–12.

4. The Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 2002; 287:2563–9. 5.

Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/ American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic

0.18 ( 0.04 to 0.41),p = NS Non-inferiority not confirmed

Hypoglycaemia difference p

Overall Hypoglycaemia - 27% Reduction Nocturnal hypoglycaemia – 25% Reduction

control [published correction appears in Endocr Pract. 2009;15(7):768-770]. Endocr Pract 2009; 15:540-559. 6. Bartley PC, Bogoev M, Larsen J, Philotheou A. Longterm efficacy and safety of insulin detemir compared to Neutral Protamine Hagedorn insulin in patients with type 1 diabetes using a treat-to-target basal-bolus regimen with insulin aspart at meals: a 2-year, randomized, controlled trial. Diabet Med 2008; 25:442-449. 7.

Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 26:3080-3086.

8. Hermansen K, Davies M, Derezinski T, Martinez Ravn G, Clauson P, Home P. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulinnaive people with type 2 diabetes [published correction appears in Diabetes Care. 2007;30(4):1035]. Diabetes Care 2006; 29:1269-1274. 9.

Heise T, Nosek L, Rønn BB, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes 2004; 53:1614-1620.

10. Ashwell SG, Gebbie J, Home PD. Twice-daily compared with once-daily insulin glargine in people with type 1 diabetes using meal-time insulin aspart. Diabet Med 2006; 23:879-886. 11. Kalra S, Unnikrishnan AG, Baruah M, Kalra B. Degludec

insulin: a novel basal insulin. Indian J Endocrinol Metab 2011; 15(suppl 1):S12-S16. 12. Peyrot M, Rubin RR, Lauritzen T, Skovlund SE, Snoek FJ, Matthews DR, et al. Resistance to insulin therapy among patients and providers: results of the cross-national Diabetes Attitudes, Wishes, and Needs (DAWN) study. Diabetes Care 2005; 28:2673–2679. PMID: 16249538 13. Brod M, Alolga SL, Meneghini L. Barriers to initiating insulin in type 2 diabetes patients: development of a new patient education tool to address myths, misconceptions and clinical realities. Patient 2014; 7:437–450. doi: 10.1007/ s40271-014-0068-x PMID: 24958464.

15. Khunti K, Caputo S, Damci T, Dzida GJ, Ji Q, Kaiser M et al; SOLVE Study Group. The safety and efficacy of adding once-daily insulin detemir to oral hypoglycaemic agents in patients with type 2 diabetes in a clinical practice setting in 10 countries. Diabetes Obes Metab 2012; 14:1129–1136. doi: 10.1111/j.1463-1326.2012.01665.x PMID: 22830956 16. Jonassen I, Havelund S, Hoeg-Jensen T, et al. Design of the novel protraction mechanism of insulin degludec, an ultralong acting basal insulin. Pharm Res 2012; 29:2104–14. 17. Tim Heise, Ulrike Hövelmann, Leszek Nosek, Lidia Hermanski, Susanne G Bøttcher & Hanne Haahr (2015) Comparison of the pharmacokinetic and pharmacodynamic profiles of insulin degludec and insulin glargine, Expert Opinion on Drug Metabolism & Toxicology, 11:8, 11931201, DOI: 10.1517/17425255.2015.1058779 18.

Kurtzhals P, Heise T, Strauss HM, Bøttcher SG, Granhall C, Haahr H, Jonassen I. Multi-hexamer formation is the underlying basis for the ultra-long glucose-lowering effect of insulin degludec. (Abstract no. 1049). Diabetologia 2011; 54 (Suppl 1):S426

19. Heise T, Nosek L, Bottcher SG, et al. Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes. Diabetes Obes Metab 2012; 14:944– 50. 20. Heise T, Hermanski L, Nosek L, et al. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes Obes Metab 2012; 14:859–64. 21. Rodbard HW, Cariou B, Zinman B, et al. Comparison of insulin degludec with insulin glargine in insulin-naïve subjects with Type 2 diabetes: a 2-year randomized, treatto-target trial. Diabet Med 2013; 30:1298–304. 22. Garber AJ, King AB, Del Prato S, et al. Insulin degludec, ultra-long acting basal insulin, versus insulin glargine in basalbolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet 2012; 379:1498–507. 23. Gough SCL, Bhargava A, Jain R, Mersebach H, et al. Low volume insulin degludec 200 U/ml once-daily improves glycemic control similar to insulin glargine with a low risk of hypoglycemia in insulin-naïve patients with type 2 diabetes: a 26-week, randomized, controlled, multinational, treat-to-target trial: the BEGIN™ LOW VOLUME trial). Diabetes Care 2013; 36:2536-42. 24. Onishi Y, Iwamoto Y, Yoo SJ, et al. Insulin degludec

801

25. Meneghini L, Atkin SL, Gough SCL, et al. The efficacy and safety of insulin degludec given in variable oncedaily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, openlabel, parallel-group, treat-to-target trial in people with type 2 diabetes. Diabetes Care 2013; 36:858– 64. 26. Vora J, Christensen T, Rana A, Bain SC. Insulin degludec versus insulin glargine in type 1 and type 2 diabetes mellitus: a meta-analysis of endpoints in phase 3a trials. Diabetes Ther 2014; 5:435-46. doi: 10.1007/s13300-014-00769. Epub 2014 Aug 1. 27. Center for drug evaluation and research. CDER Division Director Summary Review, 29 July 2015. Available at (http://www.accessdata.fda.gov/drugsatfda_docs/nda/201 5/203313Orig1s000_203314Orig1s000SumR.pdf). Accessed on (10th November 2016 at 12:11PM) 28. Lane et al. Presented at the American Diabetes Association, 76th Annual Scientific Sessions, 10–14 June 2016, New Orleans, LA, USA. 29. Evans M, McEwan P, Foos V. Insulin degludec early clinical experience: does the promise from the clinical trials translate into clinical practice--a case-based evaluation. J Med Econ 2015; 18:96-105. doi: 10.3111/13696998.2014.975234. Epub 2014 Oct 29. 30. Landstedt-Hallin L, Changes in HbA1c, insulin dose and incidence of hypoglycemia in patients with type 1 diabetes after switching to insulin degludec in an outpatient setting: an observational study. Curr Med Res Opin 2015; 31:148793. doi: 10.1185/03007995.2015.1058252. Epub 2015 Jul 17. 31. Ghosal S, Sinha B, Gangopadhyay KK. Insulin glargine versus insulin degludec in patients failing on oral therapy in type 2 diabetes: A retrospective real world comparative data from India. Diabetes Metab Syndr 2016; 10:161-5. doi: 10.1016/j.dsx.2016.01.013. Epub 2016 Jan 16. 32. Sinha B, Gangopadhyay KK, Ghosal S. Is insulin degludec a more effective treatment for patients using high doses of insulin glargine but not attaining euglycemia? Some case reports from India. Diabetes Metab Syndr Obes 2014; 7:225-8. doi: 10.2147/DMSO.S63878. eCollection 2014. 33. Havelund S, Ribel U, Hubálek F, Hoeg-Jensen T, Wahlund PO, Jonassen I. Investigation of the Physico-Chemical Properties that Enable Co-Formulation of Basal Insulin Degludec with Fast-Acting Insulin Aspart. Pharm Res 2015; 32:2250-8. doi: 10.1007/s11095-014-1614-x. Epub 2015 Jan 8. 34. Heise T, Nosek L, Roepstorff C, et al. Distinct pran-dial and basal glucose-lowering effects of insulindegludec/insulin aspart (IDegAsp) at steady state insubjects with type 1 diabetes mellitus. Diabetes Ther 2014; 5:255–65. 35. Brunner M, Pieber T, Korsatk o S, Kojzar H, Svend-sen AL, Haahr H. The distinct prandial and basalpharmacodynamics of IDegAsp observed in youngeradults are preserved in elderly subjects with type 1diabetes. Drugs Aging 2015; 32:583–90. 36. Holmes G, Galitz L, Hu P, Lyness W. Pharmacoki-netics of insulin aspart in obesity, renal impairment,or hepatic impairment. Br J Clin Pharmacol 2005; 60:469–76 37. Kiss I, Arold G, Roepstorff C, et al. Insulin deglu-dec:

CHAPTER 174

14. Leiter L, Yale J, Chiasson J, Harris S, Kleinstiver P, Sauriol L. Assessment of the impact of fear of hypoglycemic episodes on glycemic and hypoglycemia management. Can J Diabetes 2005; 29:186–192.

compared with insulin glargine in insulin-naïve patients with type 2 diabetes: A 26-week, randomized, controlled, Pan-Asian, treat-to-target trial. J Diab Invest 2013; 4:605-12.

802

pharmacokinetics in patients with renal impair-ment. Clin Pharmacokinet 2014; 53:175–83. 38. Kupcova V, Arold G, Roepstorff C, et al. Insulindegludec: pharmacok inetic properties in subjects with hepatic impairment. Clin Drug Investig 2014; 34:127–33.

DIABETES

39. Onishi Y, Ono Y, Rabøl R, E ndahl L, Naka mura S. Superior glycaemic control with once-daily insulindegludec/insulin aspart versus insulin glargine inJapanese adults with type 2 diabetes inadequatelycontrolled with oral drugs: a randomized, con-trolled phase 3 trial. Diabetes Obes Metab 2013; 15:826–32. 40. Franek E, Haluzık M, Canecki Varzic S, et al. Twicedaily insulin degludec/insulin aspart provides superior fasting plasma glucose control and a reduced rate of hypoglycaemia compared with biphasic insulin aspart 30 in insulin-naïve adults with type 2 diabetes. Diabet Med 2016; 33:497–505. 41. Christiansen JS, Niskanen L, Rasmussen S, JohansenT, Fulcher G. Lower rates of hypoglycemia duringmaintenance treatment with IDegAsp versus BIAsp30: a combined analysis of two phase 3a studies intype 2 diabetes. J Diabetes 2015. doi:10.1111/1753-0407.12355.

42. Kaneko S, Chow F, Choi DS, et al. Insulin deglu-dec/insulin aspart versus biphasic insulin aspart 30in Asian patients with type 2 diabetes inadequatelycontrolled on basal or pre-/self-mixed insulin: a 26-week, randomised, treat-totarget trial. Diabetes ResClin Pract 2015; 107:139–47. 43. Rodbard HW, Cariou B, Pieber TR, Endahl LA,Zacho J, Cooper JG. Treatment intensiﬁcation withan insulin degludec (IDeg)/insulin aspart (IAsp) co-formulation twice daily compared with basal IDegand prandial IAsp in type 2 diabetes: a randomized,controlled phase III trial. Diabetes Obes Metab 2016; 18:274– 80. 44. Tresiba® SmPC June 2015. Available at (http:// ec.europa.eu/health/documents/communityregister/2013/20130121124987/anx_124987_en.pdf ) (Accessed on 10th November 2016 12:34PM) 45. Ryzodeg SmPC. Available at (http://ec.europa.eu/health/ documents/community-register/2013/20130121124986/ anx_124986_en.pdf) (Accessed on 10th November 2016 12:36PM).

C H A P T E R

175

Prevention and Management of Diabetic Autonomic Neuropathy AK Mukherjee

INTRODUCTION

longest of the autonomic nerves) accounts for 75% of all parasympathetic activity[8] and DAN, being a length dependent disease, manifests first in longer nerves. That’s why even early effects of DAN are widespread in the form of decreased parasympathetic activity and sympathetic predominance. The sympathetic dominance lasts until the late stage of the disease when sympathetic denervation takes place. It is this phase when symptoms of DAN are apparent.

The importance of this diabetic complication is best illustrated by the fact that the mortality rate in patients with Cardiac autonomic neuropathy (CAN) is 5-6 times higher in the period of 5-6years than the mortality in patients with diabetes but without CAN in the same period.[1] Longitudinal studies have shown that the 5-year mortality rates of people with CAN are 16%-50% in patients with type 1 and type 2 diabetes, most often due to sudden cardiac death. A meta-analysis of 15 studies reports a relative risk of mortality of 3.45 in patients with CAN. It is known that CAN significantly increases the risk of lifethreatening arrhythmias and sudden death with the contribution from other risk factors such as hypoglycemia, drug side effects, hypokalemia,hypotensi on,ischemia etc.[2,3]

The symptoms and signs of DAN vary widely and depend on the affected organ[6,7,9]

Diabetic autonomic neuropathy (DAN) is the most neglected, yet one of the most serious complications of diabetes. It is a form of peripheral neuropathy due to damage to parasympathetic and/or sympathetic nerves in people with diabetes,excluding other causes of neuropathy. It is manifested by dysfunction of one or more organ systems (e.g., cardiovascular, gastrointestinal [GI], genitourinary, sudomotor, or ocular).

EPIDEMIOLOGY

Metabolic 1.

Hypoglycemia unawareness

Hypoglycemia associated autonomic failure

Cardiovascular system (CAN) 1.

Loss of circadian rhythm of blood pressure (‘nondipping’)

Resting tachycardia

Exercise intolerance

Intra-operative cardiovascular lability

5. ‘Silent ischemia’ infarction

and

‘painless’

Prevalence rates of DAN from several different studies exhibit a dramatic variability from as low as 7.7% for newly diagnosed patients with type 1 diabetes, when strict criteria to define CAN were used[4], to as high as 90% in potential recipients of pancreas transplant.[5] The prevalence varies from 20% to 73% in patients with type 2 diabetes. The great diversity of data is a result of inconsistencies in the criteria used for the diagnosis of DAN as well as major differencesin the groups of patients selected in research, particularly with respect to risk factors (e.g. patient age,sex, duration of diabetes).[6]

Diabetic cardiomyopathy

Arrhythmias, sudden cardiac arrest

Orthostatic hypotension

After extensive analysis of published reports, the Consensus Panel on Diabetic Neuropathy has concluded that the prevalence of confirmed cardiovascular autonomic neuropathy(CAN) in an unselected group of patients with both type 1and type 2 diabetes is about 20%, but can be up to 65%with increasing age and diabetes duration.[7]

Genitourinary system

CLINICAL MANIFESTATIONS

During the course of DAN, asymptomatic (subclinical) and symptomatic phases can be recognized. Using simple cardiovascular tests, DAN can be detected early during the asymptomatic phase of the disease.Vagus nerve (the

myocardial

Gastrointestinal system 1.

Dysfunction of the esophagus

2. Gastroparesis 3.

Change in gut motility (constipation, diarrhea)

Anorectal dysfunction (fecal incontinence)

Neurogenic bladder (diabetic cystopathy)

Erectile dysfunction

Retrograde ejaculation

Female sexual dysfunction (e.g. loss of vaginal lubrication)

Respiratory system 1.

Central dysregulation of breathing

Reduced bronchial reactivity

804

Table 1: Differential Diagnosis: Diabetic autonomic neuropathy

Inflammatory diseases (Chagas’ disease, HIV, botulism, leprosy, Guillain-Barre syndrome) Cardiovascular disease (syncope, idiopathic orthostatic hypotension, POTS)

CAN could be graded regarding the results of the testing as follows:

Chronic dysautonomies (Shy-Drager syndrome, autonomic dysfunction in Parkinson disease)

•

Toxic(heavy metals, alcohol, chemotherapy-vincristine, cisplatin, paclitaxel)

Presence of one abnormal finding indicates a possible CAN

•

Atleast two abnormal findings are required to confirm the diagnosis of CAN

•

Presence of orthostatic hypotension in addition to other abnormal findings indicates Advanced CAN[1]

Hereditary neuropathies Metabolic diseases (amyloidosis, chronic liver and kidney disease) Endocrine diseases (panhypopituitarism, pheochromocytoma)

DIABETES

AUTONOMIC NERVOUS SYSTEM TESTING

To confirm the diagnosis of DAN, a series of tests (depending on the organic system to be tested) can be used. Cardiovascular autonomic neuropathy (CAN) is the most clinically important and well-studied form of DAN due to its association with a variety of adverse outcomes including cardiovascular deaths. Also because of noninvasiveness, sensitivity, specificity and standardization, a standard ‘battery’ of cardiovascular tests (Table 2) is used as gold standard.[10]

Paraneoplastic neuropathy Drugs (Vasodilators, sympathetic blockers, diuretic induced hypovolemia, insulin therapy)

Sudomotor 1.

Hyperhydrosis of upper limbs

Gustatory sweating

Anhidrosis of lower limbs, dry skin

Heat intolerance

Changes in skin blood flow (warm skin, varicose veins, peripheral edema)

Pupillomotor 1.

Pupil dysfunction (decreased diameter of dark adapted pupil)

Argyll-Robertson pupil

DIAGNOSIS

The diagnosis of diabetic autonomic neuropathy is one of exclusion, and many other causes of autonomic dysfunction should first be ruled out (Table 1). It should also be borne in mind that even about 10% of symptomatic DAN patients in general have another cause of neuropathy other than diabetes. The clinician should take a careful history, asking about diabetes, cancer,drug use, alcohol use, HIV exposure, and familyhistory of familial amyloidosis. Patients should be asked whether they have traveled to South America, where they might have been exposed to Trypanosoma cruzi, the cause of Chagas disease. Serologic testing for antibodies to this organism may be valuable. Testing the norepinephrine response to standing may help identify the cause of idiopathic orthostatic hypotension. Basal valuesand the response to standing are normal in diabetic autonomic neuropathy; whereas are severelyreduced in multiple system atrophy or idiopathic orthostatic hypotension and impaired in ShyDrager syndrome.

Other Methods

Among other methods used to confirm the diagnosisof DAN are Baroreflex sensitivity measures, Quantitative sudomotor axon reflex test (QSART), Muscle sympathetic nerve activity, Dynamic pupillometry and more rarely, direct scintigraphic analysis of cardiac sympathetic fibers using SPECT or PET scans.[7,11,12] As the mentioned tests are often very demanding, the standard battery of CAN tests is considered a surrogate for confirmation of DAN in general.

SPECIFIC INVESTIGATIONS

If CAN testing is abnormal, specific investigations (Table 3)depending on symptoms and organ involvement can be carried out.[10]

PREVENTION

Successful prevention of diabetic autonomic neuropathy lies in the strategy of intensive glycemic control and treating risk factors mainly. Risk factors are age, duration of diabetes, glycemic control, microvascular complications (polyneuropathy, retinopathy, nephropathy) and other factors such as hypertension, dyslipidemia, smoking, obesity and alcohol consumption. The results of the Diabetes Control and Complication Trial (DCCT) showed that tight glycemic control resulted in 50% reduction of the incidence of CAN during 6.5-year follow up. This protective effect persisted for 14 years after the end of the study despite the disappearance of HbA1c differences that were reached between the groups during the randomized phase.[13] There has been a number of agents designed to improve the underlying pathophysiology of the the disorder rather than for symptomatic relief. Of the proposed mechanisms that underlie the diabetes induced damage to peripheral nerve, two are linked to ‘oxidative stress’. These include advanced glycosylation end product(AGEs) and the accumulation of sorbitol. There have been no clinical

Table 2: Diagnostic tests for cardiovascular autonomic neuropathy [10]

Table 3: Specific Investigations in DAN Organ involved

Specific Tests

Resting heart rate

Orthostatic hypotension

Measure blood pressure standing and supine

> 100 beats/minute is abnormal Beat-to-beat heart rate variation The patient should abstain from drinking coffee overnight Test should not be performed after overnight hypoglycemic episodes

Measure catecholamines* Cardiac

123I metaiodobenzylguanidine (MIBG) scan Gastrointestinal

Foregut carcinoid markers: substance P and CGRP(calcitonin gene-related peptide)*

Heart rate response to standing

A 30:15 ratio of less than 1.03 is abnormal

Sexual Dysfunction

The patient forcibly exhales into the mouthpiece of a manometer, exerting a pressure of 40 mm Hgfor 15 seconds

Nocturnal penile tumescence (Normal study & intact morning erection: psychogenic)

A ratio of longest to shortest R-R interval of less than 1.2 is abnormal Systolic blood pressure response to standing

Testosterone, Prolactin assay*, Thyroid function test Bladder

A fall of more than 30 mm Hg is abnormal

The patient squeezes a handgrip dynamometer to establish his or her maximum The patient then squeezes the grip at 30% maximum for 5 minutes A rise of less than 16 mm Hg in the contralateral arm is abnormal Electrocardiography A QTcinterval of more than 440 ms is abnormal Depressed very-low frequency peak or low-frequency peak indicate sympathetic dysfunction Depressed high-frequency peak indicates parasympathetic dysfunction Lowered low-frequency/high-frequency ratio indicates sympathetic imbalance Neurovascular flow Noninvasive laser Doppler measures of peripheral sympathetic responses to nociception *E/I ratio lowest normal value: 1.17 (age 20-24 y), 1.15 (25-29 y), 1.13 (30-34 y), 1.12 (35-39 y), 1.10 (40-44 y), 1.08 (45-49 y), 1.07 (50-54 y), 1.06 (55-59 y), 1.04 (60-64 y), 1.03 (65-69 y), 1.02 (70-75 y)

Cystometrogram Postvoiding sonography (Post-void Residual volume>150 ml indicates cystopathy)

A fall of 10 to 29 mm Hg is borderline Diastolic blood pressure response to isometric exercise

Penile-brachial pressure index(less than 0.7 indicates vascular cause) Penile Doppler Sonography (evaluates a venous leak manifested as vasodilator unresponisveness)

Heart rate response to Valsalva maneuver

Systolic blood pressure is measured when the patient is lying down and 2 minutes after the patient stands

Emptying study , Barium study, Endoscopy, Manometry Fasting serum Vaso-intestinal peptide, urinary 5HIAA(5hydroxyindoleacetic acid)*

An expiration:inspiration R-R ratio > 1.17 is abnormal (age dependent index)* The R-R interval is measured at beats 15 and 30 after the patient stands

Multigated angiography (MUGA), Thallium scan

Sudomotor

Quantitative sudomotor axon reflex, Sweat test,Skin blood flow

*consider on clinical suspicion only

trial of AGE in patients with diabetic neuropathy. Aldose reductase inhibitor(ARI) have been used in a number of trials over the past 30 years, which demonstrated an improvement in sensory and motor conduction velocity(CV) compare to placebo in some RCT.[25] Subsequent large, multicenter studies of others ARI, including tolrestat, ponalrestat, epalrestat, zenarestat and ranirestat did not demonstrate a convincing clinical efficacy. Recombinant human nerve growth factor (rhNGF) has been the subject of several trials. A phase II trial of rhNGF over six months showed preliminary evidence of efficacy in patient with diabetic neuropathy.[26] C-peptide replacement therapy in patients with type 1 diabetes with short term use had early beneficial effects on sensory nerve conduction studies and some measure of sensory function.[27] Dietary supplementation with myoinositol over 6 months

CHAPTER 175

When the patient lies supine and breathes 6 times per minute, a difference in heart rate less than 10 beats/ minute is abnormal

805

806

improve NCSs in rats, but no definitive clinical or electrophysiologic benefits were seen in human trials.[28] Others vitamine like thiamine, B12, and pantothenic acid, were ineffective when performed as controlled clinical trials.[29]

DIABETES

As all diabetic microvascular complications share a common pathogenic mechanism and same risk factors; diabetic nephropathy, retinopathy and polyneuropathy are considered clinical predictors for DAN. Screening and management aimed at these complications play a pivotal role in DAN prevention as well.[15,16] Steno-2 study in patients with type 2 diabetes and microalbuminuria has shown that intensive pharmacological treatment of hypertension, hyperlipidemia and microalbuminuria together with lifestyle changes significantly diminishes not only the risk of DAN, but the risk of cardiovascular disease as well and reduces overall diabetic patient mortality.[14] Use of antioxidants [20]and ACE inhibitors [21] along with management of risk factors, hyperglycemia reduce the odds ratio for autonomic neuropathy to 0.32. It has been shown in DIGAMI study that mortality is a function of loss of beat-to-beat variability with myocardial infarction which can be reduced by 33% with acute administration of insulin.[22] Kendall and coworkers[23] reported that successful pancreatic transplantation improves epinephrine response and normalizes hypoglycemia symptom recognition in patients with longstanding diabetes and established autonomic neuropathy.

Getting up in gradual stages; perform physical countermaneuvers (leg crossing, stooping, squatting); wearing elastic stockings reaching to the waist; increasing fluid and salt intake;reducing the dosage or excluding medications that may precipitate orthostatic hypotension e.g. thiazides, beta blockers, phenothiazines, tricyclic antidepressants etc;raising the head of the bed by 10-20° (stimulation of renin-angiotensin-aldosterone system). • Gastroparesis

Multiple, small meals; staying upright for half an hour after each meal; if necessary semi-liquid or liquid food; low fat/fiber diet; omission of drugs that slow gastric emptying (e.g., calcium channel blockers, GLP-1 analogs, tricyclic antidepressants)

Modify insulin dosage & timing (Even when mild, gastroparesis interferes with nutrient delivery to the small bowel, disrupting the relationship between glucose absorption and exogenous insulin administration. This may result in wide swings of glucose levels, unexpected episodes of postprandial hypoglycemia, and apparent “brittle diabetes.”).

• Constipation

Rule out other causes such as hypothyroidism,drug effects e.g. amitriptyline or calcium channel blockers and colonic carcinoma by fecal occult blood test.

Increased fluid intake; regular exercise;increased intake of foods rich in fiber

• Diarrhea

Restriction of gluten and lactose in the diet

•

Loss of hypoglycemic signs

Often self-control; recognition of some unusual symptoms (e.g., tingling in the hands or feet); higher target plasma glucose level

•

Bladder dysfunction

Patients are instructed to palpate their bladder and to try to urinate when it is full. If they are unable to start urination, they should massage or press the abdomen just above the pubic bone (Credé maneuver) to start the flow.

•

Sexual dysfunction

Avoidance of alcohol and smoking, cease taking medications known to cause erectile dysfunction e.g. beta-blockers, thiazides, phenothiazines, tricyclic antidepressants, spironolactone, fibrates, marijuana etc.

•

Anhidrosis of lower limbs & gustatory sweating

If the symptoms of DAN are already present, patients need to be advised about simple behavioral measures and lifestyle changes that can alleviate the symptoms[19]:

Foot care, Avoid particular inciting food if present in case of gustatory sweating.

*Orthostatic hypotension

In cases of advanced, symptomatic DAN, it is sometimes

Buerger’s group[24] showed a reversible metabolic component in patients with early cardiac autonomic neuropathy in diabetes.

SCREENING

According to the American Neurological Society guidelines, screening for autonomic dysfunction should be carried out immediately after the diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes. Patients at a greater risk because of poor glycemic control, cardiovascular risk factors and with the presence of other micro- and macrovascular complications of diabetes should be tested in particular. Clinician should repeat testing yearly if CAN testing comes normal.[1,11,17] Every patient who is about to begin any kind of intense physical activity except for vigorous walk and any patient that is going to have a surgery in general anesthesia should also be tested as well.[18]

TREATMENT

Basic measures

Symptomatic treatment: Pharmacological therapy

necessary to use drugs which should be prescribed by specialists depending on the affected organ. Unfortunately, there are currently no generally accepted guidelines for the treatment of DAN.[19] •

Orthostatic hypotension

Central α-2 agonist- clonidine (0.1-0.5 mg bedtime); mineralocorticoid – 9 alpha-fludrocortisone (0.5-2 mg/day); somatostatin analog-octreotide.

• Gastroparesis

• Constipation

Osmotic laxatives – lactulose; motility or secretion stimulating laxatives – magnesiumsulfate, sodium sulfate

Prokinetics (dopamine metoclopramide

antagonists)

REFERENCES

Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact,assessment, diagnosis and management. Diabetes Metab Res Rev 2011; 27:639-653.

Ziegler D: Cardiovascular autonomic neuropathy: clinical manifestations and measurement. Diabetes Reviews 1999; 7:300-315.

Pop-Busui R, Evans GW, Gerstein HC, Fonseca V, Fleg JL, et al. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care 2010; 33:1578-1584.

–

• Diarrhea Broad-spectrum antibiotics –ampicillin; Metronidazole (250 mg thrice a day for atleast 3 weeks); synthetic opioids –loperamide (2 mg 4 times a day); α-2 agonist-clonidine (0.1 mg twice or thrice a day); somatostatin analog–octreotide (50 microgm thrice a day) •

Bladder dysfunction

Mechanical methods catheterization);

Anticholinergics (in detrusor hyperreflexia); parasympathomimetics (in reduced contractility of the detrusor)-Bethanechol 10 mg four times a day

α-1blocker- Doxazosin(1-2 mg 2-3 times a day) relaxes sphincter

•

Sexual dysfunction

5-phosphodiesterase inhibitors- Sildenafil (50 mg 1 hr before sexual activity,once only per day); intracavernous injection of vasodilator; transurethral application of prostaglandins

(intermittent

self-

Penile implants; vacuum devices (in vascular cause of erectile dysfunction)

Vaginal lubricants in females

•

Hyperhidrosis and gustatory sweating

Anticholinergics; agonist of α-2 receptors – clonidine.

CONCLUSION

Diabetic autonomic neuropathy is a common and serious complication of diabetes, presenting most commonly as exercise intolerance, silent myocardial ischemia, orthostatic hypotension, impaired intestinal

4. Ziegler D, Gries FA, Spuler M, Lessmann F, Diabetic Cardiovascular Autonomic Neuropathy Multicenter Study Group:The epidemiology of diabetic neuropathy. J Diabetes Complications 1992; 6:49-57. 5.

Kennedy WR, Navarro X, Sutherland DER: Neuropathy profile of diabetic patients in a pancreas transplantation program. Neurology 1995; 45:773-780.

6. Dimitropoulos G, Tahrani AA, Stevens MJ.Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes 2014; 5:17-39. 7.

Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig 2013; 4:4-18.

8. Maser RE, Mitchell BD, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care 2003; 26:1895-1901. 9. Deli G, Bosnyak E, Pusch G, Komoly S, FeherG. Diabetic neuropathies: diagnosis and management. Neuroendocrinology 2013; 98:267-280. 10. Vinik, A. I., and T. Erbas. “Recognizing and treating diabetic autonomic neuropathy.” Cleveland Clinic journal of medicine 2001; 68:928-30. 11. England JD, Gronseth GS, Franklin G, Carter GT, Kinsella IJ, Cohen JA, et al. Practice parameter:evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy and skin biopsy (an evidence-based review). Neurology 2009; 72:177-184. 12. Pop-Busui R. What do we know and we do not know about cardiovascular autonomic neuropathy in diabetes. J Cardiovasc Transl Res 2012; 5:463-478. 13. Martin CL, Albers JW, Pop-Busui R. Neuropathy and

807

CHAPTER 175

Antiemetics – metoclopramide, domperidone(10 mg 30-60 mins before meals and bedtime); levosulpiride(25 mg thrice daily); gastric electrical stimulation

motility, bladder and erectile dysfunction, sweating disturbances and hypoglycemia unawareness. The consequences of DAN significantly affect the survival of diabetic patients and are associated with increased mortality from malignant arrhythmias and sudden cardiac death. DAN is unfortunately often recognized too late. Thanks to a standard battery of cardiovascular autonomic tests used as gold standard screening tests in diabetic patients,especially in those who have additional riskfactors such as poorly controlled glycemia, vascular risk factors,other microvascular complications; DAN can be detected early. Strict blood glucose control is still the only major therapy that allows delaying, halting or slowing theprogression of DAN. Symptomatic treatment consistsof simple measures and lifestyle modifications and insevere cases, pharmacological treatment.

808

related findings in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study. Diabetes Care 2014; 37:31-38. 14. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008; 358:580-591.

DIABETES

15. Low PA, Benrud-Larson LM, Sletten DM, Opfer-Gehrking TL, Weingand SD, O’Brien PC, Suarez GA, Dyck PJ. Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care 2004; 27:2942-2947. 16. Duvnjak L, Vučković S, Car N, MetelkoŽ.Relationship between autonomic function, 24-h blood pressure and albuminuria in normotensive, normoalbuminuric patients with type 1 diabetes. J Diabetes Complications 2001; 15:314315.

22. Malmberg K, Norhammar A, Wedel H et.al. Glycometabolic state at admission:important risk factor of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction. Long-term results from the diabetes and insulin-glucose infusion in Acute Myocardial infarction(DIGAMI) study. Ciculaton 1999; 99:2626-2632 23. Kendall DM, Rooney DP, Smets YF et. al. Pacreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with longstanding type 1 diabetes and autonomic neuropathy. Diabetes 1997; 46:249-257 24. Burger AJ, Weinrauch LA, D’Elia JA et.al. Effects of glycemic control on heart rate variability in type 1 diabetic patients with cardiac autonomic neuropathy. Am J Cardiol 1999; 84:687-691

17. Tesfaye S, Boulton AJM, Dyck PJ, Freeman R,Horowitz M, Kempler P, Lauria G, Malik R,Spallone V, Vinik A, Bernardi L, ValensiP.Diabetic neuropathies: update on definitions,diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010; 33:2285-2293.

25. Judzewitsch RG, Jaspan JB, Polonsky KS, et al. Aldose reductase inhibitorimproves nerve conduction velocity in diabetic patients. N Engl J Med 1983; 308:119-25.

18. Kadoi Y. Anesthetic considerations in diabetic patients. Part I: Preoperative considerations of patients with diabetes mellitus. J Anesth 2010;24:739-747.

27. Ekberg K, Brismar T, Johnson BL et al. Amelioration of sensory nerve dysfunction by C-peptide in patients type 1 diabetes. Diabetes 2003; 52:536-41.

19. Tesfaye S. Neuropathy in diabetes. Medicine 2010; 38:649655.

28. Greene DA, Brown MJ,Braunstein SN, et al. Comparison of clinical course and sequential electrophysiological test in diabetics with symptomatic polyneuropathy and its implications for clinical trials. Diabetes 1981; 30:139-47.

20. ZieglarD,Gries FA. Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes 1997; 46:S62-S66 21. Athyros VG,Didangelos TP,Karamitsos DT et.al. Long term effect of converting enzyme inhibition on circadian sympathetic and parasympathetic modulation in patients with diabetic autonomic neuropathy. Actacardiol 1998; 53:201-209

26. Zochodne DW. Neurotrophins and others growth factors in diabetic neuropathy. Semin Neurol 1996; 16:153-61.

29. Lewellyn J, Tomlinson D, Thomas P. Diabetic neuropathies. In:Dyck P, Thomas P, editors. Peripheral neuropathies, vol2. 4th ed. Philadelphia: Elsevier Saunders;2005. P.1951-91.

C H A P T E R

176

Management of Autonomic Neuropathy in Diabetes

INTRODUCTION

Diabetic autonomic neuropathy affects many systems of our body namely cardio vascular, gastro intestinal, urogenital and sudo motor systems. This inturn results in many abnormalities varying from milder one like subclinical impaired heart rate variability(HRV),to severe one clinically manifesting as resting tachycardia, increased preponderance for various arrhythmias postural hypotension, altered bowel movement, decreased bladder contractility, erectile dysfunction (ED), lower urinary tract symptoms and sweating disorders. Though autonomic neuropathy is less common than other complications, once occurs, it is rather debilitating and difficult to treat.

NATURAL HISTORY

Cardiac Autonomic Neuropathy (CAN) increases with duration of diabetes irrespective of diabetes type. The natural history of autonomic neuropathy is not clear. Though the clinical features of overt autonomic neuropathy are not present at the time of diagnosis of diabetes, abnormalities in HRV or cardio vascular reflex test may be present early in its course. Framingham Heart Study shows changes in CAN i.e. a shift in sympathetic –parasympathetic balance showing sympathetic tone alteration in patients in prediabetic state. A similar observation was noted in many persons with impaired glucose tolerance. Many studies have shown that children with diabetes have higher average heart rate than those without diabetes. The reason remains unclear but may be due to autonomic dysfunction. Resting tachycardia in children or adults may be due to anemia, thyroid dysfunction, underlying cardio vascular disease, obesity and poor fitness. So before arriving at a diagnosis of CAN. These conditions have to be excluded. A fixed heart rate that is not responsible to exercise, stress, hypoglycemia, sleep is due to cardiac denervation. Though subtle autonomic dysfunction is the cause for elevated heart rate in diabetes, hyperglycemia and myocardial dysfunction also can be the causes.

STUDIES

DCCT (Diabetes Control and Complication Trial) reveals intensive insulin therapy for type 1 diabetes, reduced the incidence of CAN by 53% compared with conventional treatment. EDIC study reveals CAN has progressed in both treatment groups, revealing metabolic memory decides it. T1D treatment has to be initiated as soon as possible. In T2D impact of glycemic control on CAN is less conclusive.

R Rajasekar

In some studies like veterans affairs co operative study and Veterans Affairs Diabetes Trial(VADT), no difference was noted in both tight control and without control groups. Similarly,in a trail of Japanese patients with T2D, no significant difference was noted in CAN – Postural Hypotension, HRV. Several studies have shown association between CAN and glucose levels but the data relating to role of glucose variability causing CAN are limited. In one study CAN was not associated with glucose variability. In many studies, CAN is associated with hypertension hyperlipidemia smoking and metabolic syndrome. Diabetes prevention program shows life style modification like diet and exercise are beneficial to prevent CAN.

PATHOGENESIS

The development of diabetic neuropathy results from complex interactions between degree of glycemic control,disease duration, age related neuronal involvement and other risk factors like blood pressure, lipids and weight. These factors facilitate autonomic neuronal dysfunction in a manner that starts distally and progress proximally. Many studies have shown CAN complicating T1D, there is a compensatory increase in cardiac sympathetic tone as a response to subclinical peripheral denervation, Subsequently, sympathetic denervation ensues ie- begin at apex of the ventricles and progress towards base.

CLINICAL FEATURES

Autonomic neuropathy is asymptomatic in its early stages. This delays initiation of apt treatment. The advanced form of autonomic neuropathy is manifested by orthostasis, fixed tachycardia, severe diarrhea and impaired response to hypoglycemia.

CARDIO VASCULAR AUTONOMIC NEUROPATHY (TABLE 1)

Impaired Heart Rate Variability (HRV)- It is the earliest sign of CAN. It may not be associated with symptoms.

Resting Tachycardia and Exercise Intolerance – This may present in advanced cases and is due to reduced response in heart rate, BP and blunted increase in cardiac output in response to exercise. As already pointed out, Resting tachycardia has to be ruled out due to other causes. Resting tachycardia the fixed heart rate > 100 Beats /minute i.e- unresponsive to moderate exercise, stress or sleep point out more advanced disease.

DIABETES

810

Table 1: CV Autonomic Neuropathy

Table 2: Gastrointestinal-Symptoms

Impaired Rate Variability

Orthostatic Hypotension

Gastroparesis

Esophageal Dysfunction

Exercise Intolerance

While Standing.

Nausea

Heartburn

Resting Tachycardia

Lightheadness

Bloating

Dysphagia for Solids

Weakness

Loss of Appetite

Abnormal BP Regulation

Faintness

Early Satiety

Diabetic Diarrhea

Non Dipping

Dizziness

Reverse Dipping

Visual Impairment

Post Prandial Vomiting

Profuse and Watery Diarrhea

Syncope

Silent Ischemia: Many studies show association of CAN with silent ischemia in diabetes. A slow heart rate recovery after exercise is an indirect reflexion of CAN which was shown to be associated silent myocardial ischemia. The association of CAN and silent ischemia has important therapeutic implications, as reduced appreciation of ischemic pain hampers appropriate recognition of myocardial ischemia or infarction, thereby delaying apt therapy. Myocardial Dysfunction: CAN is also associated with development of diabetic cardiomyopathy. Diastolic dysfunction i.e. impairment in left ventricle relaxation and passive filling is found to be the earliest manifestation of cardiomyopathy. In the natural presentation of CAN, isolated diastolic dysfunction may contribute to impaired exercise tolerance. Some studies in T1D patients revealed LV dysfunction may precede or occur in the absence of coronary heart disease or hypertension often with normal ejection fraction. This was also confirmed in large cohort studies in patients who show increased LV mass with concentric remodelling assessed by cardiac magnetic resonance imaging independent of age,sex and other factors. The recent studies have shown T1D patients present with increased LV torsion as an early presentation of LV dysfunction. Abnormal Blood Pressure Regulation: Normally, there is nocturnal dip of blood pressure due to predominance of vagal tone and decreased sympathetic tone.In CAN this is altered, resulting nocturnal sympathetic predominance during sleep,causing nocturnal hypertension due to non dipping and reverse dipping of blood pressure. Orthostatic Hypotension: It is a fall in systolic or diastolic BP in response to position change from supine to standing. It occurs in diabetes as a result of efferent sympathetic vasomotor denervation causing reduced vasoconstriction of splanchnic and other peripheral vascular beds. It manifests late in CAN and indicates poor prognosis. Symptoms of postural hypertention are shown in Table 1.

Intractable lower limb edema is bothersome. It is a complication of peripheral sympathetic denervation

Fecal Incontinence Constipation

resulting in ulceration. CAN and Chronic Kidney disease(CKD): The sympathetic activation in CAN plays a key roll in the pathogenesis of CKD, due to changes in glomorular hemodynamics and in circadian rhythm of BP and albuminuria. A high resting heart rate was also reported in overt nephropathy in T1D patients in another study –Atherosclerosis Risk in Communities(ARIC) Study as shown higher resting heart rate and lower HRV were associated with high risk of developing end stage renal disease. The most serious consequences of CAN is its association with mortality risk

GASTRO INTESTINAL AUTONOMIC NEUROPATHY

Esophageal dysfunction –symptoms shown in Table 2.

Gastro peresis; It is due to delayed gastric emptying and is seen in 50% of long standing diabetic patients, The symptoms are many but non specific.Severe nausea and post prandial vomiting are present in advanced cases.It can complicate diabetes control and affects the quality of life.

Diabetic diarrhea: it is intermittent in 20 % of DM patients. It is present in those with other forms of autonomic dysfunction. Profuse watery diarrhea esp at night is reported in T1D patients.It may alternate with constipation and its rather difficult to treat and.rule out other causes of diarrhea like ingestion of lactose, non absorbable hexitol or drugs.

Other feature: Diabetic patients may experience fecal incontinence due to poor sphicnter tone or severe constipation.

UROGENETAL AUTONOMIC NEUROPATHY

Bladder dysfunction; It occurs upto 50% of diabetic patients and symptoms are varied –shown in Table 3.

Erectile dysfunction(ED); It is present in 30 to 75% of men with diabetes. Etiology is multifactorial viz autonomic neuropathy, vascular risk factors like Hypertension Hyperlipidemia, Obesity, Endothelial dysfunction,Smoking, CVD, Drugs and Psychogenic causes.

811

Table 3: Urogenital-Symptoms Bladder Dysfunction

Male Sexal Dysfunction

Female Sexual Dysfunction

Frequency

Erectile Dysfunction

Decresed Sexual Desire

Urgency,Nocturia

Decreased Libido

Increased Pain During Intercourse

Hesitancy,Dibbling

Abnormal Ejaculation

Decresed Sexual Arousal

Weak Stream

Inadequiate Lubrication

Urinary Incontinence

Urinary Retention

DIAGNOSIS

Cardiovascular autonomic neuropathy(CAN)

Assess symptoms as shown in table 1

II.

Cardiovascular autonomic reflex test(CART)- They are sensitive specific reproducible safe and gold standard tests as per Toranto Consensus Panel on diabetic neuropathy.

A change in RR interval with deep breathing is a test of sinus arrhythmia during quite respiration denoting parasympathetic function.

RR response to standing inducing reflex tachycardia followed by bradycardia is due to vagal and baroreflex centered.

Valsalva ratio; It evaluates cardio vagal function in response to standard increase in intra thoracic pressure.

VII. Head-up tilt-Table Testing(HUTT) – it is used to investigate CAN, a neutrally mediated – vaso vagal syncope.It records wide range of changes in the autonomic input to heart and in the RR intervals induced by rapid positional changes during the test.HUTT requires skilled personnel and so not used as a routine.

Orthostatic hyportension

BP response to vasalva maneuver and sustained isometric muscular strain – it is used in clinical research only.

Though no test is superior, the deep breathing test is the widely accepted test because of its high reproducibility,specificity and simplicity. Valsalva maneuver requires patients co-operation.

Beaware of increased intra thoracic,intra ocular and intra cranial pressure, as it may result in intra ocular hemorrhage or lens dislocation.

III.

Heart rate variability (HRV) a decrease in HRV is the earliest indicator of CAN.

IV.

Baroreflex sensitivity (BRS): It is useful to assess the capability to reflex increase in vagal activity and decrease in sympathetic activity due to sudden rise of BP.It is again used for research purpose. BRS detects sub clinical CAN even before other tests of CAN.It is an independent risk predictor of cardiac mortality in patients with heart failure, a recent MI or diabetes.

V. Imaging

Techniques

for

CAN.

Quantitative

VI.

Muscle sympathetic Nerve Activity (MSNA) – It is done by recording electrical activity of a skeletal muscle like peronial, tibial,or radial at rest or in response to physiological excursions via micro electrodes placed on a fascicle of a distil sympathetic nerve.to the skin or muscle and identification of sympathetic burst. Fully automated sympathetic neurogram provides good MSNA. It is not indicated as routine but used as a research tool.

Gastro Intestinal Autonomic Neuropathy (Gastro paresis)

A. Symptoms – Diabetes bowel symptoms questionnaire is used in diabetic patients to quantify gastro intestinal symptoms. But its predictive value is poor. Objective measurements of gastric emptying are used to diagnose gastro paresis B.

Gastric emptying study: it is a sensitive test but affected by many factors like drugs smoking and blood glucose levels. The standardization of testing is vital. The use of this test is limited by poor correlation with symptoms and individual variability.A barium meal or upper endoscopy are recommended to rule out mucosal obstruction. Scintigraphy is a gold standard test for measurement of gastric emptying. It also helps to find the intra gastric distribution of meal. It is frequently abnormal in diabetic patients. Scintigraphy has its own limitation as it involves radiation expense and standardization. Breath test is safe and inexpensive and correlates with scintigraphy result. Ultra sonography is another diagnostic non invasive method.

Magnetic resonance Imaging(MRI) is useful to

CHAPTER 176

scintigraphic assessment of sympathetic denervation of human heart is done with positron emission tomography by using many techniques. Though it is valuable test, it is not much applied due to cost constraint and sophisticated infrastructure and skilled personnel.

OTHER MANIFESTATION OF AUTONOMIC NEUROPATHY

They are Sudomotor dysfunction like anhydrosis,heat intolerance, dry skin, and hyperhydrosis. Hypoglycemia unawareness is probably due to autonomic neuropathy.

measure gastric emptying and motility with excellent reproducibility. But it is limited for research. Other investigations are surface electro gastrography,monometry are all used to assess gastric, intestinal motility,but reserved for research purpose.

DIABETES

812

3. Erectile Dysfunction: Clinical assessment : Assess the patients with ED by eliciting sexual, medical history, drug use like tranquillizers, antidepressants, anti hypertensives psychic and organic factors.It aids to assess the nature of erectile problem and to differentiate from other sexual problems like penile curvature or pre mature ejaculation. Elicit history from the partner also and it will help to show other causes like vaginal dryness, dysparunia. International index of erectile function and sexual encounter profile are helpful to assess severity of ED.

Lab investigations: Routine lab test like A1c, Fasting blood glucose and lipid profile are done. Testosterone level is also done to rule out primary or hypo gonadotropic hypogonadism esp in patients not responding to phospodiasetrase type 5 inhibitors (PDE-5). The other useful tests are evaluation of nocturnal penile tumnescence,penile Doppler ultra sound, bulbocavernosus reflex,dorsal sensory nerve conduction of the penis, amplitude and latency of penile sympathetic skin response, pudendal nerve somatosensory evoked potentials, assessment of prostaglandin E1 (PGE1) effect on erection, psychological evaluation, and urodynamic studies.

autonomic dysfunction reveal impaired bladder sensation, increased cystometric capacity, decreased detrusor contractility and increased post voidal residual urine. 5.

Sudomotor Dysfunction

Though there are several methods like quantitative sudomotor axon reflex test, it has own limitation Recently sudoscan + is a non invasive device that uses reverse iontophoresis and chrono amperametry to test for sudomotor dysfunction.It is an easier technique.

Micro Vascular Function Assessment: Laser Doppler (LD) is useful to assess micro vascular blood flow and endothelial function.

7. Treatment: a.

Glycemic intensive control in T1D patients has shown reversal of CAN or delayal of progression of CAN,as shown in DCCT and EDIC. They all indicate, it is advisable to initiate treatment of T1D intensively as early as possible. But in T2D the effects of glycemic control is less clear.

Stratification of multiple risk factors – cardiovascular risk intervention targeting glucose, BP, Lipids Smoking etc., reduced the progression or development of CAN in diabetic patients.

Other treatment – Anti oxidants have not shown any benefit.

Symptomatic Treatment –

Orthostatic hypo tension

Bladder Dysfunction:

Life Style Measures.

Clinical assessment – lower urinary tract symptoms (LUTS) can be assessed by eliciting history of nocturia, frequency, urgency, weak urinary stream, intermittency, straining and sensation of incomplete emptying.The American urological association symptom index can assess the severityscores range from 0 to 35.0 to 7- none, 8 to 19 –mild, 20 to 35 –severe.

•

Avoid sudden changes in body positions from lying to sitting then sitting to standing and sub sequently standing to walking

•

Avoid drugs that precipitate hypotension-tricyclic antidepressants, pheno thaizines, diuretics.

•

Eat small but frequent meals

•

Avoid stressful activity.

•

Elevate the Head end of the bed to 1.5 feet at night.

•

Use stockings over legs and inflatable band on abdomen.

•

Avoid physical manoeuvers like leg crossing, squatting, have fluid and salt unless contra indicated.

Checking perinial sensation, sphincter tone and bulbocavernous reflex can recognize peripheral neuropathy in diabetes.Uro gynecological evaluation is required to exclude pelvic organ prolapsed or other pelvic disorder. b.

Lab investigations: as diabetic patients are at increased risk of bacterial cystitis, microscopic urine analysis and culture are essential to assess the patients complaining of LUTS.

Do a total count as poly morpho leucocytes function is altered in LUTS.

Urodynamic Study- It is indicated if initial management is unsuccessful or there is doubt about the diagnosis.It includes cytometry, uroflow study etc., urodynamic findings associated with

B. Drugs1.

Midodrine is a alpha 1 adreno receptor agonist, approved by FDA. Dose 2.5 to 10 mg tid – qid, first dose to be taken before arising.

Avoid taking several hours before lying posture.

Adverse effects –Piloerection. pruritus, parasthesia supine hypertension, urinary retention.

Erythyropoietin - It improves Standing BP in patients with orthostatic hypertension.It acts by increasing red cell mass central blood volume, correcting the anemia, altering blood viscosity regulating neuro humoral effect of vascular wall and tone. Be cautious of cardio vascular effects. Somotostatin analogues – It regulates post prandial BP fall and orthostatic hypertension in patients with autonomic failure. It acts by influencing splanchnic vessels by inhibiting release of vasoactive gastro intestinal peptides. It enhances cardiac output and increase in foream and splanchnic vascular resistance. Dose; 25 to 200 mcg per day subcutaneously tds. Long acting depot 20 to 30 mg IM once monthly. Adverse effects- severe hypertension Caffeine citrate- It is a methyl Xanthene derivative it has a pressor effect by blocking vasodilating adenosine receptors. It improves orthostatic hypotension and reduces post prandial hypotension- Dose- 100 to 250 mg orally tds. It is taken as tablet or caffeinated drinks.Tachyphylaxis may occur due to prolonged use.

GASTROPARESIS

Diet changes- Eat multiple small meals and reduce dietery fat and fibre.

Drugs-1) Metoclorpropamide – yet to be approved by FDA.

It is an anti emetic. It stimulates acetyl choline release in myentric plexus and is a dopamine agonist.Be cautious of its adverse effects lik extra pyramidal symptoms.

Do not use more than 5 days. It is not advised on long term basis.It is reserved for severe cases not responding to other treatment.

Domperidone – Not FDA approved- It is a dopamine receptor antagonist.It is an anti emetic. It is a prokinetic stimulating gastric motility-both liquid and solid phase gastric emptying. Its role is controvesrsial due to its adverse effects.

Erythromycin- It increases gastric emptying.It stimulates motilin receptors in the gut.Oral or iv

Onabotulinumtoxin A (BOTULINUM TOXIN TYPE A); It is for severe diabetic gastroparesis, not

responding to dietary modifications and high dose prokinetic drugs.

813

C. Other non drug therapy 1) Gastric Pacing (stimulation) – it has shown improvement in nausea and vomiting in patients with gastric peresis

Surgery- Feeding jejunostomy bypassing an atonic stomach and radical approach by resection of large part of stomach by Roux- en –Y loop.

DIABETIC DIARRHEA- DRUGS

Metronidazole 500mg qid for 3 weeks

Ampicillin or tetracycline 250 mg tds or qid for 2 wekks

Amoxycillin(875 mg) / clavulanate bd for 2 weeks.

4. Cholestyramine 5.

Octratide- it enhances gastric emptying and delays small bowl to large bowl transit. It is useful if other treatment is not beneficial.

ERECTILE DYSFUNCTION

Drugs: Phosphodiatrease -5 inhibitors (PDE-5) are helpful ex., Sildenafil Tadalafil Vardenafil.,Be cautious in prescribing for patients taking nitrates. Frequent side effects are head ache,flushing. Non drug therapy: Intra cavernosal injection – success rate 90%, vaccum devices, penileimplants, inflatable prosthesis –show mild to moderate benefit.

BLADDER DYSFUNCTION

Bethanechol-parasympathomemetic agent helps. Bladder training like scheduled voiding, credes method –suprapubic compression by self to evacuate urinary bladder to avoid retention.

CONCLUSION

Autonomic neuropathies complicate diabetes commonly with varied manifestations and high morbidity. The exact pathophysiology is yet to be understood. We are still behind the therapeutic approach.Glycemic control is effective esp in T1D patients.Life style modification may be helpful in some T2D Patients or pre diabetics. Though there are so many modalities of treatment, we can only offer symptomatic relief to many patients with severe autonomic neuropathy.

REFERENCES

1. VINIK et al -Diabetic Autonomic Neuropathy- Diabetes care, 2003 May 2. SCHMIDT-RE -Neuro pathology and pathogenesis of Autonomic Neuropathy- INT.REV.Neurobiol.2002 3. Navpreet Kaur et.al -Diabetic Autonomic Neuropathy – journal of Diabetes and Metabolism-2014 july. 4. ADA update 2016 5. Harrisons Text book of medicine. 6. Joslin Diabetes Centre, Joslin’s Diabetes Mellitus, 14th edition 2015. 7. Pickup JC, Williams G (EDS), Text Book of Diabetes, 2nd Edition. Boston: Blackwell Science; 1997.

CHAPTER 176

Fludrocortisone- It is a synthetic mineralo corticoid of long duration of action inducing plasma expansion. It increases sensitivity of blood vessels to catecholamines. The drug effects are not immediate. It may take 1 to 2 weeks to act. Dose; Begin with 0.05 mg at bed time titrate it gradually to a maximum of 0.2 mg per day. High doses may have side effects- supine hypertension, hypokalemia, hypomagnesimia, congestive heart failure and peripheral edema,.Be cauteious in congestive heart failure to avoid fluid over load.

Approach to Hypoglycemia

C H A P T E R

177

Benny Negalur

DEFINITION

Normally blood glucose levels are tightly regulated between 70 to 150 mg/dl in healthy persons. Hypoglycemia, defined as blood glucose levels of less than 70 mg/dl, occurs as a consequence of fasting for longer than 24 hours or in disease conditions including insulinomas, Addison’s disease, pituitary failure, diabetes, etc. Allen Whipple first described the clinical diagnosis of hypoglycemia which includes the symptoms of hypoglycemia, low circulating plasma glucose and prompt relief of symptoms after glucose administration called Whipple’s triad. The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) have both clearly demonstrated that intensive control of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) delays the onset and slows the progression of long-term microvascular complications. However, in both T1DM and T2DM, intensive versus conventional glucose control also contributes to a significant increase in severe hypoglycemia. In fact, the DCCT found a three-fold increase in severe hypoglycemia (blood sugar less than 50 mg/dl where the patient needed external resuscitative assistance) when hemoglobin A1c (HbA1c) was 7.2% as compared to 9.0%.

ETIOLOGY

In all diabetic patients, hypoglycemia can be caused by excess exogenous insulin administration (and the use of some oral agents in T2DM), lack of appropriate food intake and reduced physiologic defenses against falling blood glucose (lack of ability to recognize and treat as well as abnormal counter regulation). Also, insulin clearance is decreased by renal failure which contributes to a relative

T1DM Glucse Counterregulation

hyperinsulinemia and subsequently a rapid lowering of blood glucose.

PATHOPHYSIOLOGY

Normal Glucose Counterregulation  Glucose

 Epinephrine

Glucagon 

Other hormones/ neurotransmitters

Other hormones / neurotransmitters

 Glucose

In normal individuals when blood glucose level falls, a variety of autonomic and neuroendocrine hormonal defense mechanisms are initiated by glucose sensors in the hypothalamus. There is also stimulation of the alpha cell sensors to release glucagon and β cells to suppress endogenous insulin. Glucagon increases glucose output by the liver via glycogenolysis and gluconeogenesis and reduces glucose uptake by the periphery, thus providing adequate glucose to the brain. Epinephrine also stimulates lipolysis and skeletal muscle glycogenolysis, providing substrates (alanine, lactate, and glycerol) for gluconeogenesis in the liver. Other hormones, like cortisol and growth hormone, play a role in prolonged hypoglycemia (longer than 2 hours). In T1DM patients, loss of endogenous insulin removes one of the many defenses. They also have impaired glucagon response which results in reduction of glucose recovery. T2DM patients do have endogenous insulin and so incidence of hypoglycemia is small as these people have binge eating responses. However, in advanced T2DM, the counter regulatory mechanism does get compromised and hypoglycemia can be prolonged. T2DM glucose counterregulation  Glucose

Insulin   Growth hormone,

cortisol, glucose autoregulation

 Glucose

Insulin 

 Growth hormone, cortisol, glucose autoregulation

 Glucose

 Epinephrine

Glucagon 

 Epinephrine

Glucagon 

Other hormones/ neurotransmitters

Insulin 

 Growth hormone, cortisol, glucose autoregulation

 Glucose

Symptoms of Hypoglycemia

treating gastroparesis. 90 

Normal glucose level

70 

Counter regulatory hormone release

60 

Adrenergic symptoms

50 

Neuroglycopenic symptoms

40 

Lethargy

30 

Coma

20 

Convulsions

10 

Permanent damage

Fig. 1: Symptoms of Hypoglycemia

HYPOGLYCEMIA ASSOCIATED AUTONOMIC FAILURE - HAAF

In recurrent hypoglycemic attacks, prior episodes blunt the autonomic nervous system (norepinephine + epinephrine), neuro endocrine (glucagon, cortisol and growth hormone) and metabolic (endogenous glucose production) counter regulatory responses to subsequent episodes. This can occur within hours with sugars as little as 70 mg/dl known as hypoglycemia associated autonomic failure. HAAF produces a vicious cycle making the patient susceptible to both deeper and more frequent episodes of hypoglycemia. Inability to recognize the symptoms of hypoglycemia due to blunting of the above systems is known as hypoglycemia unawareness.

HYPOGLYCEMIA IN INSULIN TREATED PATIENTS

The goal of insulin treatment is to reproduce the normal physiologic insulin secretion of healthy persons. Regular insulin has a time of onset of 30 minutes, a peak of 2 hours and duration of action of 4 to 6 hours in most patients. This was inconvenient for patients, requiring them to wait 30 minutes after an injection to consume their meal. This regimen can also create a problem for glucose control because blood glucose could peak before insulin action, resulting in postprandial hyperglycemia and later preprandial hypoglycemia. Shorter-acting insulin analogs (aspart and lispro) are used either as multiple-dose injections (MDIs) or in a continuous subcutaneous infusion (CSII; insulin pump). The molecular structure of lispro and aspart allow for rapid onset of action, within 10 minutes, peak is at 90 minutes, and duration of action is 2 to 4 hours in most patients. In fact, several studies have reported that lispro and aspart produce similar or even better glucose control and reduce hypoglycemia compared to regular insulin, probably because they better match the timing of insulin peak and action with food absorption. This unique property allows patients to calculate their actual food intake and dose their insulin much like the normal pancreatic insulin response in non-diabetic persons. In addition, the fast action of these analogs allows patients to inject immediately after a meal if they were unsure how much food was going to be consumed. This will also reduce postprandial hypoglycemia and may be useful in

Traditional long-acting insulin’s (NPH, Ultralente, glargine) can contribute to an increased rate of hypoglycemia. This is due to their pharmacokinetics, with a rapid onset of action (1 to 2 hours and a broader peak at about 4 hours) that may rapidly decline within 8 to 16 hours. Bedtime injections can lead to nocturnal hypoglycemia because action peaks at about 2.00 am, when patients are more insulin sensitive. Conversely, NPH action wanes in the early morning hours when patients are more insulin resistant (dawn phenomenon), making hyperglycemia a problem. Glargine, a new basal insulin analogue, produces very little, if any, peak due to its lower solubility at the injection site. Glargine action lasts up to 24 hours and provides the closest to physiologic basal insulin coverage of the long-acting insulin’s. The newer long acting insulin basal analogue degludac produces less hypoglycemia like glargine.

HYPOGLYCEMIA WITH ORAL AGENTS

Oral agents have lower reported rates of hypoglycemia compared with multiple doses of traditional insulin’s. Oral insulin secretagogues such as sulfonylurea agents or meglitinides bind to the sulfonylurea receptor in the pancreatic beta cell, which causes insulin secretion. The onset and duration of action might not coincide with the ambient blood sugar either due to an inaccurate dose or a lack of carbohydrate intake, or both. This in turn leads to over-secretion of insulin in relation to the blood glucose, which causes relative hyperinsulinemia. Reported rates of hypoglycemia in patients with T2DM are reported to be 7-fold to 10-fold lower with glimepiride 2nd generation as compared with glyburide which is a 1st generation SU. The newer agents like DPP4 inhibitors, GLP receptor agonists and SGLT2 are higher than inhibitors generally do not cause hypoglycemia, but they may induce it when combined with insulin or sulphonylureas. The hypoglycemia induced by oral agents tends to be of longer duration and most of the times require parenteral treatment with glucose.

HYPOGLYCEMIC SYMPTOMS

The onset of hypoglycemic symptoms in healthy subjects occurs at plasma glucose levels between 49 and 58 mg/ dl. Symptoms are categorized as neuroglycopenic or autonomic. Neuroglycopenic symptoms are caused by low cerebral glucose levels there is a gradual order of symptoms as the blood glucose decline as shown below: The threshold of absolute plasma glucose that triggers these symptoms may be higher (conventional control) or lower (intensive control) depending upon the overall glycemia control of the patient. In other words, patients who tend to have a higher HbA1c percentage (overall higher ambient blood sugars) can perceive symptoms of hypoglycemia at a higher plasma glucose level than patients whose glycemia is more intensively controlled. This is particularly true for patients with T2DM, who can perceive hypoglycemia symptoms at blood glucose levels greater than 100 mg/dl, which is termed relative

815

CHAPTER 177

Neuroglycopenic symptoms • Coma • Diﬃculty thinking • Diziness • Fatigue • Seizures • Sleepiness • Slurred speech • Weakness Autonomic Symptoms • Anxiety • Hunger • Palpitations • Paresthesias • Sweating • Tremulousness

816

hypoglycemia. The converse is true in those patients whose glycemia is intensively controlled might not recognize low blood sugar until their plasma glucose is much lower. Hypoglycemia that requires assistance from another person to treat it is severe hypoglycemia.

DIABETES

TREATMENT

The “rule of 15” is a helpful treatment regimen when patients are able to self treat. Typically 15 gms of carbohydrate (rapidly absorbing forms of glucose such as glucose gel, sugar containing soda or sugar tablets should raise the blood glucose by 50 mg/dl glycemia in 15 minutes. The response to oral glucose is transient; therefore ingestion of a small complex carbohydrate snack shortly after the plasma glucose concentration rises is generally advisable, especially if the next meal is larger than 1 hour away. Hypoglycemic patients who are unconscious or unable because of hypoglycemia to take in oral carbohydrates can be treated with a parenteral glucagon injection if available. Intravenous glucose is the preferable treatment of severe iatrogenic hypoglycemia, particularly that caused by a sulfonylurea. These reactions are more likely to occur in elderly patients in whom hypoglycemia is often prolonged and require continuous glucose infusion and frequent feeding. At other times, patients should be instructed to carry with them any form of rapidly available source of glucose at the first sign of hypoglycemia. .

COMPLICATIONS

Other factors influencing incidence of Hypoglycemia are age, exercise, gender and ethanol. Hypoglycemia can increase the QT interval and give rise to various arrthymias which can be detrimental causing sudden death. Increase in inflammatory markers & oxidants stress is known in hypoglycemia.

CONCLUSIONS

Hypoglycemia in a major limiting factor in intensive glycemic control of diabetes. Hypoglycemia is problematic in T1DM and in advanced T2DM because of compromised glucose counter regulatory systems. Therefore, patients should be educated in self-monitoring of blood glucose, diet and exercise effectively.

REFERENCES

The Diabetes Control and Complications Trial Research Group: Epidemiology of severe hypoglycemia in the diabetes control and complications trial. Am J Med 1991; 90:450-459.

2. UK Prospective Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837-853. 3.

The Diabetes Control and Complications Trial Research Group: Hypoglycaemia in the diabetes control and complication trial. Diabetes 1997; 46:271-286.

4. Havel PJ, Parry SJ, Stern JS, et al: Redundant parasympathetic and sympathoadren sympathoadrenal mediation of increased glucagon secretion during insulininduced hypoglycemia in conscious rats. Metabolism 1994; 43:860-866. 5.

Campbell RK: Glimepiride: Role of a new sulfonylurea in the treatment of type 2 Diabetes mellitus. Ann Pharmacotherapy 1998; 32:1044-1052.

DeFronzo RA: Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999; 131:281-303.

Davis SN, Shavers C, Mosqueda-Garcia R, Costa F: Effects of differing antecedent hypoglycemia on subsequent counter regulation in normal humans. Diabetes 1997; 46:1328-1335.

8. Heller SR, Cryer PE: Reduced neuroendocrine and symptomatic responses to Subsequent hypoglycemia after one episode of hypoglycemia in non-diabetic Humans. Diabetes 1991; 40:223-226. 9.

Davis SN, Mann S, Tate DB, et al: Effects of antecedent hypoglycemia on counter regulatory response to subsequent hypoglycemia in patients with Type 2 diabetes. Diabetes 1999; 48:A363.

10. Boyle PJ, Kempers SF, O’Connor AM, Nagy RJ: Brain glucose uptake and awareness of hypoglycemia in patients with insulin-dependent diabetes mellitus.N Engl J Med 1995; 333: 1720-1731. 11. Schwartz NS, Clutter WE, Shah SD, Cryer PE: Glycemic thresholds for activation of glucose counter regulatory systems are higher than the threshold for symptoms. J Clin Invest 1987; 79:777-781. 12. Potter J, Clarke P, Gale EA, et al: Insulin-induced hypoglycaemia in an accident and emergency department: The tip of an iceberg: BMJ 1982; 285:1180-1182.

C H A P T E R

178

Prevention of Diabetes Mellitus Anupam Prakash, Yash Pal Munjal, Aparna Kansal, Ghan Shyam Pangtey

INTRODUCTION

Diabetes has assumed pandemic proportions. In India, diabetes mellitus occurs at least a decade or two earlier than the Western world where it occurs in adults > 50 years of age. Therefore, diabetes affects the productive age group in India, and the complications too occur earlier. The prevalence of diabetes in India is reported to be 12% in the urban and 5% in the rural population, but of late, with increasing urbanisation, the urban-rural difference is narrowing. India thus, faces a major socioeconomic burden due to diabetes. An equal number of pre-diabetes population exists in India, which has the potential to add-on to the existing diabetes population in the future, compounding the burden of diabetes and its socio-economic impact manifold. With no cure in sight for diabetes, it is imperative that one makes efforts to prevent diabetes. From an epidemiological perspective, prevention of diabetes can be done at various levelsi.

Primary prevention of Diabetes- Prevention of onset of diabetes in an individual.

ii.

Secondary prevention- Prevention of progression of diabetes and prevention of onset of complications.

iii.

Tertiary prevention- Prevention of progression of diabetes-related complications and their prompt management including rehabilitation.

Primordial prevention is promotion of a healthy life-style and is aimed at controlling the risk factors for development of diabetes, thus preventing the development of diabetes at the community level. By promoting a healthy-lifestyle and controlling the risk factors, as part of primordial prevention, we can prevent onset of a number of other lifestyle diseases too, viz. hypertension, obesity, coronary artery disease, etc. Type 1 diabetes mellitus (T1DM) offers limited scope for prevention in view of an incomplete understanding of the disease pathogenesis and heterogeneity, and the risk factors are also largely unknown, besides validated biomarkers for precise staging of the disease are lacking. Moreover, type 1 diabetes contributes to only 5% of the total diabetes pool in our country. Primary prevention of T1DM should target the general childhood population with vaccines (viral or tolerogenic) or by altering microbiota-induced immunoregulation. Secondary

prevention will likely require combination therapies (anti-inflammatory agents, immunomodulatory agents, beta cell survival agents, and/or agents improving glucose control) used sequentially or simultaneously to preserve residual beta cell function and prevent symptomatic disease. Unlike type 1 diabetes, type 2 diabetes mellitus (T2DM) has a long asymptomatic pre-clinical period, has established risk factors where intervention is possible, and constitutes 95% of the diabetes pool in our country. Therefore, primary prevention of type 2 diabetes is plausible and there have been several studies which have tried to prevent the onset of type 2 diabetes from the prediabetes state. This article will try to restrict discussion to primary prevention of diabetes, since the secondary and tertiary prevention aspects would be discussed in detail by other authors, and moreover, including those aspects would make this write-up too exhaustive. Suffice it to say, that recent trials have confirmed that a good control of diabetes can prevent microvascular complications of diabetes. Although there is a reduction in macrovascular complications but the figures are not statistically significant. It has also been observed that some of the complications especially macrovascular complications may antedate the overt manifestation of diabetes. This is another major reason for concentrating on prevention and early screening for diabetes. As already stated, type 2 diabetes can have a long and variable period of insulin resistance before diabetes is diagnosed, so it is an advantage in the sense that this stage can be aimed for prevention but it is also a handicap since it requires a long duration of clinical trials to see the effect of any intervention. In recent times a series of trials with lifestyle measures and/or pharmacotherapy attempted prevention of diabetes in individuals at high risk with considerable success and favourable results.

STRATEGIES FOR PREVENTION OF DIABETES

Two major strategies have been evaluated for reducing the incidence of diabetes, i.e. lifestyle interventions and drugs (pharmacotherapy). These are aimed at changing the risk factor profile of diabetes mellitus. Diabetes risk factors can be classified into modifiable risk factors and non-modifiable risk factors (Table 1). The modifiable risk factors are the subject matter of intervention. The present epidemic of diabetes is very significantly fuelled because of growing problem of overweight and

818

Table 1: Risk factors for diabetes Modifiable

Non-modifiable

Overweight and obesity

Ethnicity

Sedentary lifestyle

Family history

Previously identified impaired glucose tolerance (IGT) and impaired fasting glucose (IFG)

Age

DIABETES

Metabolic syndrome Hypertension

Gender History of gestational diabetes mellitus High-birth weight baby (>4kg)

Dyslipidemia Dietary factors Drugs viz. corticosteroids, diuretics Inflammation *Intrauterine environment and Polycystic ovarian disease can be possibly kept as modifiable risk factors, since dietary factors and medications can help reduce the risk of diabetes.

morbid obesity, which also is a major global health problem. Excessive truncal adiposity is very well corelated with the risk for diabetes, hypertension and cardiovascular disease. The other important reason in the changing lifestyle is the lack of physical activity. This is associated with stress at work. To sum it up there is a marked increase in the intake of energy dense food with very little or no physical activity. Therefore, the question arises whether we can prevent type 2 diabetes by lifestyle interventions?

NUTRITION

In the prospective Nursesâ&#x20AC;&#x2122; Health Study conducted in 84941 female nurses followed for 16 years, a series of risk factors related to dietary behaviour, physical activity, weight and cigarette smoking were identified and targeted, and this was associated with a remarkable 91% reduction in the risk of developing diabetes. Even with a family history of diabetes the risk reduction was 88%. In theory, therefore, diabetes can be prevented, largely by lifestyle changes irrespective of genetic background. Some pioneering studies showed that this is feasible. In case of over-weight individuals reduction of weight by restricting calories and increasing exercise is of vital importance. However it has been observed that it is not necessary to reduce the weight to the level of ideal body weight; but a reduction of about 5-10% in the body weight gives substantially good results.

Physical Activity

Physical activity is important both in the prevention as well as the management of diabetes in all its stages. It is recommended that around 30-40 minutes of aerobic activity like brisk walking should be encouraged for at least 5 days a week and preferably for all 7 days (equivalent to 150 minutes/week). The beneficial effects of physical activity are manifold viz. improved insulin

sensitivity, reduction in overall adiposity and central obesity, improved glucose tolerance, and increased vitality. It is universally accepted that sticking to an exercise schedule over the years is difficult. However, a combination of dietary modification and physical activity is considered the best bet for prevention of diabetes and for health promotion.

Lifestyle Interventions

Lifestyle measures which include medical nutrition therapy and physical activity aim to address the issue of overweight and obesity, improve insulin sensitivity, prevent progression of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) to overt diabetes and control inflammation. The Swedish Malmo study was one of the earliest lifestyle intervention studies for the prevention of type 2 diabetes and was conducted in male subjects aged 47-49 years. Men who participated in the lifestyle intervention had a lower incidence of type 2 diabetes and a greater reversal of glucose intolerance compared to those men who received usual care. At the end of 12 years, the IGT men who underwent lifestyle intervention had similar mortality as compared to normal glucose tolerance men, but had less than half the mortality rate when compared to IGT men who received usual care. The Chinese Da Qing study showed that diet intervention alone was associated with a 31% reduction, while the exercise alone showed a 46% reduction in the risk of developing type 2 diabetes. However, the combined diet and exercise group had a similar 42% reduction in the risk of developing type 2 diabetes during a 6-year follow-up period. In the Finnish Diabetes Prevention Study (DPS), weight loss in overweight subjects with impaired glucose tolerance, averaging just 3-4 kg over 4 years, led to improvement in measures of lipemia and glycemia, and reduced diabetes risk. At 2-year follow-up, incidence of type 2 diabetes in the intervention group was less than half that observed in the control group. It was also reported that the impact of lifestyle changes in reducing incidence of diabetes was maintained for at least 4 years after the intensive intervention finished. A similar result was achieved in the Diabetes Prevention Program (DPP) in the United States, in which lifestyle intervention involving exercise and dietary change over a 3-year period in subjects with impaired glucose tolerance reduced incident diabetes by 58%. Although the results of these lifestyle intervention programmes look impressive, but in routine day-to-day practice, lifestyle management is not easy to execute, as these interventions are labour intensive, and moreover, the results may not be as replicable as to a research setting, even in well-funded healthcare systems.

Pharmacotherapy for Prevention

Considerable interest has been focused on the prevention

819

Table 2: Review of Pharmacological Interventions for Prevention of Diabetes Drug

Relative risk reduction (%)

Duration of study (years)

DPP

Study

Metformin

India DPP

Metformin

Troglitazone

Acarbose

Xendos

Orlistat

DREAM

Rosiglitazone

DPP STOP- NIDDM

PREVENTION IN THE INDIAN CONTEXT

The Indian Diabetes Prevention Programme (IDPP) was the first study to show that lifestyle modification was effective in preventing diabetes in native Asian Indians. IDPP was a randomised, controlled, 3-year prospective community-based study in native Asian Indian subjects with IGT. These were younger, leaner and more insulin resistant than the other populations studied (multiethnic American, Finnish and Chinese populations). The study groups were as follows: Group 1, control group with no intervention (n=133); Group 2, subjects advised with lifestyle modification (n=120); Group 3, subjects treated with 500 mg of metformin (n=128); and Group 4, subjects treated with both lifestyle modification plus metformin (n=121). The median follow up period was 30 months and the 3 year cumulative incidence of diabetes was 55%, 39.3%, 40.5% and 39.5% in groups 1 to 4, respectively. The relative risk reduction in lifestyle modification (28.5%; P=0.018), metformin (26.4%; P=0.029) and lifestyle modification + metformin (28.2%; P=0.022) compared with the control group was very similar. The study showed that progression from IGT to diabetes was high in native Asian Indians. Both lifestyle modification and metformin were equally effective and there was no added benefit from combining them. The study thus showed that primary prevention of diabetes was possible in a comparatively lean, but highly insulin resistant Indian population by moderate changes in physical activity and diet. Screening for glucose intolerance for preventive measures at an early age is a requisite in Indians, as they develop hyperglycaemia at a younger age. It is ideal to achieve primary prevention of type 2 diabetes by means of a non-pharmacological intervention in the relatively lean Asians compared with Western population.

The Diabetes Community Lifestyle Improvement Program (D-CLIP) study published recently (August 2016) also reinforced the proven benefits of lifestyle intervention with the addition of metformin, when required. D-CLIP was a randomised controlled translational trial of 578 overweight/obese Asian Indian adults with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) from Chennai, India, and were randomised to standard lifestyle advice (control group) or US DPP-based lifestyle curriculum plus stepwise addition of metformin 500 mg bid. During 3 years follow-up, 34.9% of control and 25.7% of intervention participants developed diabetes, relative risk reduction (RRR) was 32%, and the number needed to treat one case of diabetes was 9.8. Further the study reported that RRR was lowest 12% for the impaired fasting glucose (IFG) group as compared to 31% for the impaired glucose tolerance (IGT) group and 36% for the combined IFG+IGT group. Notably, most participants (72%) required metformin in addition to lifestyle.

IDF Consensus on Targeting Population in various Countries

WHO and other member countries who are seized with the problem of chronic diseases especially Diabetes have formulated a series of guidelines for implementation at the community level for the control of Diabetes. IDF has also given its guidelines. The approach with each country and subpopulation will vary from region to region. However, the basic plan of prevention will remain the same globally. The prevention strategies can be grouped in three steps: •

Identification of People at High Risk: Large population based surveys may not be cost-effective strategy and therefore identification of people at high risk is a useful and cost-effective exercise. This is based on a screening questionnaire, which can be based on weight, waist circumference, age, gender, family history of diabetes, diet and physical activity.

•

Identify These People at High Risk and Grade Them: According to the level of their risk as determined by the screening questionnaire, the individuals need to be further graded, so that groups requiring interventions can be identified, based on their relative risk category. This requires blood sugar/HbA1c testing and may be other indices of atherosclerosis and dyslipidemia.

•

Interventions: The possible role of interventions

CHAPTER 178

of diabetes with the use of drugs which are used for the treatment of diabetes as well. Table 2 gives the important drug trials in prevention of type 2 diabetes. For instance, the Diabetes Prevention Programme Research Group study found a 31% reduction in the incidence of diabetes with metformin (at 2.8 years). Previously troglitazone was shown to be effective in controlling blood sugar levels but had to be withdrawn because of serious liver toxicity during the TRIPOD (TRoglitazone In Prevention Of Diabetes) study. In people with obesity, orlistat (pancreatic lipase inhibitor) has been shown to reduce the risk of diabetes by 37% when compared with placebo.

(lifestyle and/or metformin, and other drugs) has been discussed already, and the groups decided to be intervened should be initiated accordingly.

820

Various diabetes risk scores have been formulated and it has been found that the parameters vary from continent to continent and therefore the parameters to be used for Asian Indians are different from the Caucasian populations.

DIABETES

A simplified Indian Diabetes risk Score (IDRS) has been developed and is in vogue. The information for these risk factors (IDRS) can be obtained based on four simple questions and one anthropometric measurement namely waist circumference. The four questions are:

although acarbose and orlistat also have evidence in their favour. Newer agents viz. the DPP-4 inhibitors may be suitable candidates, alone or as an adjunct, but results from newer trials only can provide the evidence in their favour. Exercise and Nutrition counselling in office visits, at society level, at the level of school children and college students will go a long way in promoting healthy lifestyle and preventing diabetes mellitus. Providing healthy food alternatives, encouraging and rewarding physical activity in formative years are measures which need to be adopted to prevent diabetes in the community setting.

What is your age?

The approach should therefore focus on both the population at large by generic measures and focused measures as outlined in high risk group and in individuals in clinical setting.

Do you have a family history of diabetes? If yes, does your father or mother or both have diabetes?

work

Diabetes Prevention Program Research Group. Reduction in the Incidence of Type 2 Diabetes with lifestyle intervention or Metformin. N Engl J Med 2002; 346:393-403.

Joshi SR. Indian Diabetes Risk Score. J Assoc Physicians India 2005; 53:755-757.

It gives a minimum score of 0 and a maximum of 100, with a score â&#x2030;Ľ60 suggesting a higher risk of developing diabetes, and in this scenario the individual should get blood sugar or HbA1c tested as a screening for Diabetes.

Mohan V, Deepa R, Deepa M, Somannavar S, Datta M. A simplified Indian Diabetes Risk Score for screening for undiagnosed diabetic subjects. J Assoc Physicians India 2005; 53:759-763.

REFERENCES

Do you exercise regularly?

4. How physically [occupation]?

demanding

your

With advent of newer pharmacological agents viz. DPP4 inhibitors and SGLT-2 inhibitors in the last decade, their role will also soon be investigated in the primary prevention of diabetes. In fact, the Sitagliptin and Metformin in Prediabetes (SiMePreD) study is on the anvil, wherein the effect of sitagliptin and meformin on progression from prediabetes to type 2 diabetes will be ascertained. It will be a randomised double-blind multicentric clinical study over a period of 5 years and is presently in the process of acquiring research funding.

CONCLUSION

The evidence base for prevention of diabetes mellitus is quite robust with risk factor based identification of individuals followed by confirmation of their prediabetes stage (IFG or IGT or both, or HbA1c between 6-6.5%). Lifestyle interventions- diet and activity, although difficult to adhere to in the long run, are better than use of pharmacological agents. Among the pharmacological agents, metformin is the most studied and robust,

4. International Diabetes Federation. Diabetes Prevention Studies. http://www.idf.org/diabetes-prevention/ prevention-studies 5. Clinical Guidelines Task Force, International Diabetes Federation 2012. Global Guideline for Type 2 diabetes. http://www.idf.org/sites/default/files/IDF-Guideline-forType-2-Diabetes.pdf 6. Munjal YP. Prevention of Diabetes mellitus. In: Munjal YP (ed.) API Textbook of Medicine 10th edn 2015, pp.557-563. 7.

Insel R, Dunne JL. JDRFâ&#x20AC;&#x2122;s vision and strategy for prevention of type 1 diabetes. Pediatr Diabetes 2016; Suppl 22:87-92.

8. Weber MB, Ranjani H, Staimez LR, et al. The stepwise approach to Diabetes prevention: Results from the D-CLIP randomized Controlled Trial. Diabetes Care 2016; 39:1760-7. 9.

Naidoo P, Wing J, Rambiritch V. Effect of sitagliptin and metformin on prediabetes progression to type 2 diabetesa randomized, double-blind, double-arm, multicenter clinical trial: Protocol for the Sitagliptin and Metformin in preDiabetes (SiMePreD) Study. JMIR Res Protoc 2016; 5:e145.

C H A P T E R

179

Hyperglycemia in Pregnancy

INTRODUCTION

Hyperglycemia is one of the most common medical disorders seen in women enco during pregnancy. The International Diabetes Federation (IDF) estimates that one in six live births (16.8%) are to women with some form of hyperglycemia in pregnancy. Of them, 84% are gestational diabetes mellitus (GDM), while 16% may be due to diabetes in pregnancy (either pre- existing diabetes—type 1 or type 2—which antedates pregnancy or is first identified during testing in the index pregnancy.1 The GDM prevalence correspondences with the prevalence of impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) in any given population. Unfortunately, the age of onset of pre-diabetes and diabetes is declining, whereas childbearing age is increasing. Moreover, overweight and obesity is increasing in women of reproductive age; thus, more women are entering pregnancy have risk factors that make them vulnerable to hyperglycemia during pregnancy. GDM is associated with a higher incidence of cesarean deliveries, shoulder dystocia, birth trauma, hypertensive disorders of pregnancy (including pre-eclampsia), and these women are at higher risk for development of T2DM. The perinatal and neonatal morbidities also increase; the latter include macrosomia, neonatal hypoglycemia, birth injury, polycythemia, and hyperbilirubinemia. Moreover, offspring in utero, if exposed to maternal hyperglycemia may remain at higher risks for childhood obesity and diabetes later in life. The relevance of GDM as a priority for maternal health and its impact on the future burden of noncommunicable diseases is no longer in doubt.2 By early detection, aggressive management and adequate education, we will be protecting two generations, one the mother and other is offspring of diabetic mother. Thus, keeping uniformity in diagnosis criteria and treatment

Fig. 1: Types of hyperglycemia in pregnancy

Sunil Gupta, Gurleen Wander

strategy across is the need of the hour. Definition: The earlier GDM definition was “any degree of glucose intolerance with onset or first recognition during pregnancy.” 3 This definition doesn’t differentiate between clinically pre-existing T2DM and rarely T1DM, which get detected during screening of hyperglycemia in pregnancy. Therefore, hyperglycemia first detected at any time during pregnancy should be classified either as diabetes mellitus in pregnancy (DIP) or GDM.4

CLASSIFICATION

Diabetes in pregnancy (DIP)

DIP may either have been pre-existing diabetes (type 1 or type 2) antedating pregnancy, or diabetes first diagnosed during pregnancy (Figures 1 & 2)2. Women with preexisting hyperglycemia at conception and embryogenesis, increases the vulnerability and risk of complications in women. Similarly, any undiagnosed diabetes antedating pregnancy may also have undiagnosed diabetic complications including retinopathy and nephropathy, which significantly increases pregnancy risks5 Moreover, hyperglycemia during the critical period of organogenesis may lead to a high risk of congenital anomalies and spontaneous abortions. Additionally, Macrosomia, shoulder dystocia, obstructed labor, neonatal hypoglycemia, risk of neurological damage, risk of exacerbation of retinopathy or nephropathy also

Fig. 2: The difference between diabetes in pregnancy and gestational diabetes mellitus

822

increases in women with DIP. Thus, meticulous blood glucose control before conception and then throughout pregnancy is recommended. Compared with gestational diabetes, DIP is more likely to be detected as early as the first trimester provided appropriate testing is undertaken.

DIABETES

Gestational diabetes mellitus

When hyperglycemia detected during routine testing in pregnancy (generally between 24 and 28 weeks) does not meet the criteria of DIP it is called GDM. GDM implies a relatively milder form of hyperglycemia compared with that of DIP, but is also associated with a increased risk of poor pregnancy outcome and future risk of diabetes and cardiovascular disease, and should be managed judiciously. GDM prevalence has been reported to vary between 1%−28% in different region globally, while the International Diabetes Federation (IDF) estimates that one in six live births (16.8%) are to women with some form of hyperglycemia in pregnancy; 16% of these may be due to DIP, while the majority (84%) is related to GDM.1 A south Indian study showed the prevalence to be 13.9%. It was 17.8% in Urban, 13.8% in semiurban and 9.9% in rural Indian women. Among the women with GDM, 12.4% were detected within 16 weeks of pregnancy, 23% between 17 and 23 weeks, and the remaining 64.6% at more than 24 weeks of pregnancy. The mean age of the pregnant women screened in the urban, semi-urban, and rural areas was 23.7± 3.55 years, 23.4±3.30 years, and 22.5±3.09 years, respectively. There was a consistent increase in the prevalence of GDM in all 3 areas as BMI increased, and the trend was statistically significant (P <0.0001).6 Among the women with GDM, the highest prevalence was observed in women with a BMI greater than 25, with 28.4% in the urban area, 23.8% in the semi-urban area, and 16.1% in the rural area. A positive family history of diabetes mellitus was present in 25% of the women with GDM in the urban, 19.2% in the semi-urban, and 14.1% in the rural area. There was a significant association (P<0.001) between family history of diabetes mellitus and the occurrence of GDM among pregnant women. Based on univariate analysis, author observed in all 3 areas that age greater than 25 years, BMI greater than 25, and family history of diabetes were significantly associated with the prevalence of GDM in India. Based on multiple logistic regression analysis taking all 3 areas into consideration, family history and BMI greater than 25 were found to have a significant independent association (P<0.001) with GDM.6

Risk Factors

Indians have higher risk of developing GDM v/s Caucasians. Other risk factors are: obesity older age, multi-parity, excessive weight gain during pregnancy, short stature, polycystic ovarian syndrome (PCOS), family history of diabetes mellitus in first degree relatives, a past history of abortion, fetal loss, macrosomia, GDM, preeclampsia, and multifetal pregnancy.7

Pathophysiology

Mother during pregnancy, eats intermittently, while fetus gets feed continuously. This is being mediated through secretion of hormones like human placental lactogen (HPL), estrogen, progesterone etc with complex interactions of the feto-placental- maternal unit, and metabolic mediators that create insulin resistance and modify maternal carbohydrate, lipid, and amino acid metabolism to ensure sufficient nutrient supply to the fetus. Maternal insulin secretion increases due to increasing insulin resistance, to maintain euglycemia. These is achieved at the cost of higher maternal insulin level. While fasting glucose levels remain lower than nonpregnant fasting levels. Insulin resistance continuously increases with advancing pregnancy. Till the maternal beta cells continues to increase insulin production and secretion, hyperglycemia is prevented. When this capacity is decompensated due to rising insulin resistance, maternal hyperglycemia ensues. Thus, it is said that pregnancy is a stress test for beta cells of pancreas.

Fetal implications

An abnormal intrauterine environment has consequences in later life mediated through epigenetic changes. This phenomenon is known as developmental programming. Abnormal metabolic environment of the mother with hyperglycemia may affect certain developing fetal tissues and organs, eventually leading to permanent long-term functional implications in adult life. The fetal tissues most likely to be affected are neural cells, pancreatic beta cells, muscle cells and adipocytes. Early exposure to the aberrant fuel mixture in the first trimester may cause intrauterine growth restriction and organ malformation, described by Freinkel as “fuel-mediated teratogenesis”. During the second trimester, at the time of brain development and differentiation, behavioral, intellectual, or psychological damage may occur. During the third trimester, abnormal proliferation of fetal adipocytes and muscle cells, together with hyperplasia of pancreatic beta cells and neuroendocrine cells may be responsible for the development of obesity, hypertension, and T2DM mellitus later in life.8

Diagnosis of GDM

International Association of Diabetes in Pregnancy Study Group (IADPSG, 2010) and WHO (2013) recommended that the diagnosis of GDM should be made through single-step 75-g OGTT when one or more of the following results are observed during routine testing specifically between 24 and 28 weeks of pregnancy or at any other time during the course of pregnancy: a.

Fasting plasma glucose 92−125 mg/dL;

1-hour post 75-g oral glucose load ≥ 180 mg/dL;

2-hour post 75-g oral glucose load 153−199 mg/dL

DIPSI (Diabetes In Pregnancy Study group in India) & Government of India Guidelines

DIPSI and Government of India recommend universal screening for GDM at their initial prenatal visit, using

standard diagnostic criteria, as it is generally accepted that women of Asian origin and especially ethnic Indians are at a higher risk of developing GDM and subsequent type 2DM.9

Management & Targets In GDM

The 5th International Workshop Conference on GDM made recommendations relating to targets for glycaemia during GDM pregnancy, and the potential role of fetal growth targets. The workshop recommended maintaining capillary blood glucose at <96 mg /dl in the fasting state, <140 mg /dL) at 1 h and <120 mg/ Dl at 2 h after starting a meal. These targets were based on the then knowledge of normal glycaemia in pregnancy and the outcomes of the ACHOIS study. They commented that data from controlled trials of lower versus higher targets were lacking.11

Monitoring Of Glycaemia in GDM

Close monitoring and treatment of GDM are important to the long-term health of a pregnant woman and her baby. Women with GDM should monitor Fasting, 2hr Post Breakfast, 2hr Post Lunch and 2hr post-dinner regularly. Baseline and interval hemoglobin A1c levels during treatment are helpful, particularly in women who have fasting hyperglycemia.

MANAGEMENT

Medical Nutrition Therapy

The initial treatment for GDM continues to be diet and exercise. The nutritional counseling, if possible should be given by a registered dietitian, with individualization of the nutrition plan based on height and weight. For normalweight women (BMI: 20-25 kg/m2) 30 kcal/kg should be prescribed; for overweight and obese women (BMI > 24-34 kg/m2) calories should be restricted to 25 kcal/kg, and for morbidly obese women (BMI > 34 kg/m2) calories should be restricted to 20 kcal/kg or less. Moses and colleagues12 showed that a low-glycemic diet decreased the need and timing for insulin in GDM women. The Fifth International Workshop-Conference on GDM recommends a relatively small gain during pregnancy of 7 kg or more for obese women (BMI ≥ 30 kg/m2) and a proportionally greater weight gain (up to 18 kg ) for underweight women (BMI < 18.5 kg/m2) at the onset of pregnancy. However, there are no data on optimal weight gain for women with GDM.13,14

823

Exercise plays a major role in both prevention and management of GDM. Experts at the Third International Workshop-Conference on Gestational Diabetes Mellitus15 suggested that active women who have GDM may continue moderate exercise. Active lifestyle program in a group of inherently inactive pregnant woman may not only improve glycemic control acutely, but may reduce the risk or delay the onset of developing diabetes. Artal and colleagues16 provided exercise guideline for women with GDM as below: •

Rests for 30 min before breakfast, lunch, and dinner, and monitors fetal activity.

•  Monitors fasting and 2-hr postprandial blood glucose by glucometer. •

If fetal activity & glucose level are acceptable, women should exercise for 20 to 30 min, keeping heart rate <140 beats/ minute

•

Then rests for 30 min and counts fetal movements

•

If uterine contractions become less,  one should report obstetrician

•

Maintain records of blood glucose, food intake, exercise and fetal movements.

•

After 32 weeks gestation, non-stress testing to be done weekly;

PHARMACOTHERAPY

Insulin Therapy

Pharmacologic therapy is instituted once diet and exercise fail to achieve the glycemic goals.. Traditionally, insulin has been the drug of choice because of its safety in pregnancy, lack of significant transplacental passage, and history of its use. Most women can be treated as outpatients. Insulin dose should be individualized. The recommended initial insulin dose for pregnancy is based on maternal weight and can be calculated by the following guidelines to determine total daily insulin needs: 0.7 U/kg actual body weight in the first trimester, 0.8 U/kg actual body weight in the second trimester, and 1.0 U/kg actual body weight in the third trimester. However, because women with GDM have varying degrees of severity, in practice, insulin is started at 0.7 U/kg actual body weight to prevent hypoglycemia at home. Clinical judgment and experience assist in the selection of the starting dose of insulin. Once the total daily insulin dose is calculated, two-thirds of the daily dose is given before breakfast, divided into two-thirds Neutral Protamine Hagedorn (NPH) insulin and one-third regular insulin, and the remaining one-third of the daily dose is divided into half regular insulin before dinner and half NPH insulin at bedtime. Being GDM a postprandial hyperglycemic state, short-acting or rapid acting insulin can a be used and is best dosed with each meal in place of the twice-daily regular insulin.17 Our own data has shown that 56% of women with GDM may require insulin to achieve their goals. Mean Insulin

CHAPTER 179

DIPSI recommends that in the antenatal clinic, a pregnant woman after undergoing preliminary clinical examination, has to be given a 75 g oral glucose load, irrespective of whether she is in the fasting or nonfasting state and without regard to the time of the last meal. A venous blood sample is collected at 2 hours for estimating plasma glucose by the GOD-POD method. GDM is diagnosed if 2-hour PG is ≥ 140 mg/dl. This test serves as both screening and diagnostic procedure. DIPSI has also recommended in their earlier publication, that any 2hr 75gm OGTT value < 120mg% is normal, but blood glucose between 120 & 140 mg% should also be classified as GGI (Gestational Glucose Intolerance) and should also be treated.10

Role of Exercise

DIABETES

824

dose required in GDM women was 0.4 U/Kg/day. In the basal-bolus dose regimen, dose requirement our population required lowest dose during breakfast, higher in lunch (p=0.0002) while highest dose of short acting insulin with dinner (p<0.0001). The insulin dose was directly proportional to FBG (p<0.0001) and pre pregnancy weight (p<0.008), but it couldn’t be correlated to Age, Pre Pregnancy BMI.18 For many years, fast-acting (regular) insulin, and intermediate-acting (isophane) insulin have been the preferred insulins for the treatment of GDM. Human insulin does not normally cross the placenta, though antibody bound animal insulin has been reported to do so. However, it has been shown by Jovanovic that it is maternal glucose control, rather than maternal antiinsulin antibody levels which influence birth weight. Lispro, Aspart & Levemir Long acting analogue, have been already approved by US FDA as class B drug for its use in pregnancy. Levemir has been recently approved by USA FDA for its use in pregnancy as class B drug.19

a significantly increased rate of premature deliveries, but these were noted to be spontaneous, rather than iatrogenic in response to complications, and resulted in the delivery of healthy infants. Moreover, over half the metformin treated group were able to maintain glycaemic control on OADs alone, and mothers found it preferential to insulin therapy.22 NICE has advocated the use of metformin as an adjunct or alternative to insulin in the pre-conceptual and gestational period, in both GDM and pre-existing T2DM, whilst considering the risk/benefit ratio of treatment with the OAD, and hyperglycaemia.23

There are papers available in favour of use of glargine in pregnancy, but it, has not been approved yet.

Most women with GDM will not need any insulin during labour or LSCS. Blood glucose should be kept between 90mg% to 120mg% during this period, to avoid neonatal hypoglycemia. If blood glucose is higher than these values, then patient need to take Insulin, either by infusion or by subcutaneous route on individual basis.

ROLE OF ORAL ANTIDIABETIC AGENT

Traditionally, insulin therapy has been considered the gold standard for management because of its efficacy in achieving tight glucose control and the fact that it does not cross the placenta. Insulin is, however, is invasive treatment. Insulin therapy involves daily injections, and patient compliance is often suboptimal. Clinicians and women with diabetes would prefer tablets rather then multiple injections, if safety data of SU & Metformin become available in future, along with approval from drug controller authorities and global recommendation.

Glibenclamide

Importantly, glibenclamide is currently the only sulphonylurea that has been investigated with a randomised controlled study. There are conflicting studies regarding transfer of glyburide (Glibenclamide) across placenta. The in vitro studies have shown minimal transfer.20 A recent in vivo study has shown transfer at term but mentions that glyburide appears safe to fetus at maternal doses up to 20 mg/d and that the glyburide concentration-response relationship remains uncertain.21 NICE has suggested it may offer an alternative to insulin in selected patients with GDM, where insulin therapy is either declined or poorly tolerated. Currently ADA & DIPSI did not recommend use of SU in GDM or Pre GDM women

Metformin

Metformin does cross placenta but targets insulin resistance & thus, it does not cause hypoglycaemia. There is no convincing evidence for teratogenicity with metformin. The large-scale randomized trial, metformin in gestational diabetes (MiG) study looked at the effects on perinatal complications with metformin use in the second and third trimester, with mothers suffering from GDM. They found no difference in primary composite endpoints between metformin and insulin groups. There was

Role of Other Antidiabetic drugs in GDM

Scanty data is available for use of Acarbose in pregnancy Because of the lack of human data regarding acarbose in pregnancy, the assessment of risk is impossible, so it is not recommended. Glitazones. Gliptins, Gliflozins & GLP1 analogues are contraindicated in pregnancy.

Intrapartum Management

CONCLUSION

Prevalence of Gestational Diabetes Mellitus is increasing in the same proportion as that of Type 2 DM or Impaired Glucose Tolerance, especially in India. Screening of GDM is an opportunity to diagnose those women who are likely to develop diabetes in future. Moreover, good control of intrauterine metabolic milieu is expected to prevent long term metabolic complications in adult life of offspring of GDM mother. Thus, two generations are being taken care, by detecting a GDM women. Apart from diet and exercise, insulin remains the drug of choice. Newer rapid acting insulin analogues are more physiological in their action, to get better postprandial control. Oral antidiabetic drugs, like sulphonylurea, is not recommended for its use in GDM or PreGDM women. Metformin, if being used for PCOD, may be continued during pregnancy. In rare circumstances, it may be used in combination with insulin, as an insulin sensitizer.

REFERENCES

1. International Diabetes Federation. IDF Atlas Sixth Edition Brussels Belgium: International Diabetes Federation; 2013. 2. Moshe Hod, Anil Kapur, David A. Sacks, Eran Hadar, Mukesh Agarwal, Gian Carlo Di Renzo, Luis Cabero Roura, Harold David McIntyre, Jessica L. Morris, Hema Divakar, The International Federation of Gynecology and Obstetrics (FIGO) Initiative on gestational diabetes mellitus: A pragmatic guide for diagnosis, management, and care. International Journal of Gynecology and Obstetrics 131 S3 (2015) S173–S211 3. Proceedings of the 4th International Workshop-Conference on Gestational Diabetes Mellitus. Chicago, Illinois, USA. 14−16 March 1997. Diabetes Care 1998; 21 (Suppl. 2):B1– B167.) 4. World Health Organization. Diagnostic Criteria and

Classification of Hyperglycaemia First Detected in Pregnancy. http://apps.who.int/iris/bit- stream/10665/85975/1/WHO_ NMH_MND_13.2_eng.pdf. Published 2013. 5. Omori Y, Jovanovic L. Proposal for the reconsideration of the definition of gestational diabetes. Diabetes Care 2005; 28:2592–3. 6. V. Seshiah, V. Balaji Madhuri Balaji, et al, Pregnancy and diabetes scenario around the world: India. International Journal of Gynecology & Obst 2009; 104:S35-S38. 7. Berger H, Crane J, Farine D, Armson A, De La Ronde S, Keenan-Lindsay L, et al. Screening for gestational diabetes mellitus. J Obstet Gynaecol Can 2002; 24:894–912.

Government of India, Ministry of Health and Family Welfare, Nirman Bhavan, New Delhi (DO No. M-12015/93/2011MCH/2011

10. V Seshiah, AK Das, Balaji V, Shashank R Joshi, MN Parikh, Sunil Gupta For Diabetes In Pregnancy Study Group (DIPSI) , Gestational Diabetes Mellitus – Guidelines, JAPI - DIPSI Guidelines JAPI ,Vol. 54, August 2006, 11. Diagnosis and treatment of gestational diabetes; Royal college of Obstetricians & Gynaecologist , Scientific Advisory Committee, opinion paper 23 Jan 2011. 12. Robert G. Moses, N. Wah Cheung, Universal Screening for GDM. Diabetes Care 2009; 32:7. 13. Metzger BE, Buchanan TA, Coustan DR et al. Summary and Reccomendations of the Fifth International WorkshopConference on Gestational Diabetes Mellitus. Diabetes Care 2007; 30:S251-S260.

825

15. MetzgerBE. Summary and recommendations of the Third International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes 1991; 40(Suppl 2):197–201 16. Artal R, Dorey FJ, Kirschbaum TA. Effect of maternal exercise on pregnancy outcome. In: Artal R, Wiswell RA, Drinkwater BL, editors. Exercise in pregnancy. 2nd edition. Baltimore (MD): Williams & Wilkins; 1991. p. 225–9. 17. Gabriella Pridjian, Tara D. Benjamin, Update on Gestational Diabetes. Obstet Gynecol Clin N Am 2010; 37:255–267. 18. Sunil Gupta, Editorial, Editorial – International Jour. of Diabetes in Developing Countries, Sunil Gupta 2004; 24:58– 64. 19. Reference ID: 3132940, Levemir Prescribing Information Revised: 5/2012 www.fda.govt/medwatch 20. Elliott BD, Langer O, Schenker S, Johnson RF. Insignificant transfer of glyburide occurs across the human placenta. Am J Obstet Gynecol 1991; 165;807-12. 21. Hebert MF, Ma X, Naraharisetti SB, et al. Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther 2009; 85:607-14. 22. Rowan J, Hague WM, Gao W, Battin et all.. MiG Trial   Investigators: metfomin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008; 358: 2002-15. 23. Available from: http://www.nice.org.uk/guidance/index. jsp?action=byID&o=11626 [Accessed: March 2009].

CHAPTER 179

8. Freinkel N. Banting Lecture 1980. Of pregnancy and progeny. Diabetes 1980; 29:1023–35.

14. Gabbe SG, Graves CR. Management of diabetes mellitus complicating pregnancy. Obstet Gynecol 2003; 102:857-868.

C H A P T E R

180

Basal Insulin in Type 2 Diabetes Mellitus

INTRODUCTION

India is one of the largest and most diverse populations of people living with diabetes. Limitations in appropriate and timely use of insulin impede the achievement of good glycemic control. Epidemiological studies for India and international bodies have raised alarm on diabetes prevalence. Current global prevalence of diabetes is 415 million in which China rank first with 109.6 million and India gets second with 69.2 million.1 More than 60 % of world population with diabetes comes from Asia. Estimates from a recent Indian Council of Medical Research -India Diabetes study indicates that in India, there are 62.4 million people with diabetes and 77.2 million with pre-diabetes condition.2 Early intensive insulin therapy in newly diagnosed T2DM patients which gives favourable outcomes on recovery and maintenance of β-cell function.3 It is also protracted glycaemic remission as compare to oral anti diabetic agents and improve both insulin sensitivity and insulin secretion. Short-term insulin treatment may have long-lasting effects when introduced in the early stages of T2DM.4

THE CONCEPT OF BASAL GLUCOSE – MEASURE AND ESTIMATE

It takes 3 days to estimate the basal blood sugar levels. Pre-meal glucose needs to be evaluated for 3 days with 2 hours post prandial and then followed by next premeal reading. It takes at least 3 blood sugar readings for 3 consecutive days to determine a pattern. The period of 3

Parikshit Goswami

days is important as high carbohydrate / high fat meal or an unexpected activity can cause blood sugar excursions and the 3-day period will determine whether the issue is consistent. Basal rate testing is not done regularly unless a problem is suspected or there’s been a shift in the regular routine. If the daily schedule, activity or eating habits change, a basal test may be required to match the changed need. A basal test requires refraining from consuming any carbohydrates during the entire testing period, which often means skipping a meal. Overnight basal testing is often the first focus that is evaluated. The 4-hour window allows the carbohydrates to be digested and out of the bloodstream, for the most part, and the fast-acting insulin used to cover the food to also be out of the system. The night before the testing it is recommended to eat a low-carb meal for dinner, so that both the carbohydrates and the insulin have been utilised before the sleep. If a basal test is started before this 4-hour window has lapsed, there may be blood sugar fluctuations not related to basal insulin. Normally, the expected range should be between 70 and 250 mg/dl and if the follow up readings every 2-3 hours until breakfast are within 30 mg/ dl, the basal rate is fine. If the readings vary more than that then the insulin dosage may need adjustment.

PATHOPHYSIOLOGY OF TYPE 2 DM

Type 2 DM is characterized by insulin insensitivity as a result of insulin resistance, declining insulin production, and eventual pancreatic beta-cell failure. T2DM is a complex metabolic/cardiovascular disorder with multiple pathophysiologic abnormalities. Insulin resistance in muscle/liver and b-cell failure represent the core defects.5,6 This leads to a decrease in glucose transport into the liver, muscle cells, and fat cells. There is an increase in the breakdown of fat with hyperglycemia. The involvement of impaired alpha-cell function has recently been recognized in the pathophysiology of type 2 DM.7 As a result of this dysfunction, glucagon and hepatic glucose levels that rise during fasting are not suppressed with a meal. Given inadequate levels of insulin and increased insulin resistance results in hyperglycemia. Collectively, the eight players comprise the “ominous octet” (Figure 1).

TYPES OF BASAL INSULIN

There are two types of basal insulin available,

Fig. 1: The ominous octet depicting the mechanism based upon the pathophysiologic disturbances present in T2DM.

Intermediate-acting insulin - Neutral Protamine Hagedorn (NPH)

Long-acting insulin - detemir (Levemir), glargine (Lantus), degludec (Tresiba)

Neutral Protamine Hagedorn (NPH) insulin

Insulin Glargine

Glargine is a recombinant human insulin analogue. It differs from human insulin in that after subcutaneous injection, the acidic solution is neutralized which leads to the formation of a precipitate within the depot from which glargine is slowly released. Pharmacokinetic and pharmacodynamics studies show that a single injection of insulin glargine leads to a smooth 24-hour timeâ&#x20AC;&#x201C; action profile with no undesirable pronounced peaks of activity which also resembles basal insulin secretion of non-diabetic pancreatic beta cells.9 A bedtime injection of insulin glargine produces a much lower frequency of nocturnal hypoglycemia, but similar glycemic control. Furthermore, for similar HbA1C reduction, glargine allowed significantly less weight gain than NPH Insulin. A potential major advantage of insulin glargine over NPH insulin is a lack of pronounced peaks in plasma insulin concentrations and a more constant delivery of insulin over a 24-hour period. The combination of glargine and oral agents resulted in a 56% reduction of nocturnal hypoglycemia and lower post-dinner plasma glucose levels than NPH plus oral agents.20

Insulin Detemir

Detemir is a normal analogue of human insulin in which a 14-carbon fatty acid is acrylates to the detemir, and buffers against changes in absorption rate from the subcutaneous injection site. Fatty acid acylation enhances detemir insulinâ&#x20AC;&#x2122;s affinity to albumin, enabling a longer duration of action via delayed absorption from the subcutaneous adipose tissue depot. Once in the bloodstream hexamers or dimers of detemir rapidly dissociate into monomers. This is a dynamic process. Detemir monomers sporadically disassociate only to reattach to other albumin. Albumin binding further protracts the action of detemir, and in addition, it may buffer against oscillations in the absorption rate from the injected site. Insulin detemir is soluble at neutral pH, which enables it to remain in a liquid form following subcutaneous injection, unlike NPH insulin and glargine. Compared with NPH, use of insulin detemir may be associated with a lower risk of hypoglycemia, especially

827

Insulin Degludec

Insulin degludec is a new basal insulin that forms soluble multihexamer assemblies after subcutaneous injection, resulting in an ultra-long action profile. Degludec has an action duration of more than 24 hours. The protein sequence of Insulin Degludec was based on human insulin, modified by acyl ting DesB30 at the e-amino group of LysB29 with hexadecandioic acid via a c-L-glutamic acid linker. To date Insulin Degludec is the only insulin analogue to self-associate into multi-hexamers upon subcutaneous (SC) injection, resulting in a soluble depot from which Insulin Degludec is slowly and continuously absorbed into the circulation.23 in the presence of phenol and zinc, the IDeg hexamers adopt a conformation where only one of the ends is available to interact with the side chain of another IDeg hexamer and thus forms stable dihexamers. Upon diffusion of phenol following injection, the IDeg di-hexamers open at both ends and lead to the formation of multi-hexamers.24 Insulin Degludec compared with first-generation basal insulin analogues like NPH, Insulin Glargine and Insulin Detemir, Insulin Degludec offers the possibility for a simple titration algorithm and the potential for a more flexible dosing interval to accommodate varying patient lifestyles. This could help improve adherence and ultimately contribute towards improved glycemic control in patients with diabetes.10

BASAL INSULIN IN CLINICAL PRACTICE

Basal insulin requirements are provided by long-acting (NPH insulin, insulin glargine, or insulin detemir) insulin formulations. These are usually prescribed with short acting insulin to mimic physiologic insulin release with meals. Although mixing of NPH and short-acting insulin formulations is common practice, this mixing may alter the insulin absorption profile (especially the short-acting insulins). For example, lispro absorption is delayed by mixing with NPH. The alteration in insulin absorption when the patient mixes different insulin formulations should not prevent mixing insulins. However, the following guidelines should be followed: 1.

mix the different insulin formulations in the syringe immediately before injection (inject within 2 min after mixing)

do not store insulin as a mixture

follow the same routine in terms of insulin mixing and administration to standardize the physiologic response to injected insulin; and

do not mix insulin glargine or detemir with other insulins. The miscibility of some insulins allows to produce combination insulins that contain 70% NPH and 30% regular (70/30), or equal mixtures of NPH and regular (50/50).

Multiple-component insulin regimen consisting of

CHAPTER 180

NPH or isophane insulin is a crystalline suspension of insulin with protamine and zinc. This enhances its aggregation into dimers and hexamers after subcutaneous injection. A depot is formed after injection and insulin is released slowly, providing intermediate-acting insulin with a slow onset of action and a longer duration of action than regular insulin. The duration of action of NPH insulins is variable. Due to the variable absorption and peaks of NPH, side-effects such as early morning hypoglycaemia and fasting hyperglycaemic episodes are more likely, especially with higher doses. These limitations have been largely reduced by the introduction of basal insulin analogues like glargine and detemir.8

nocturnal hypoglycemia and the added clinical benefit of no appreciable bodyweight gain in patients with type 1 or type 2 diabetes.

DIABETES

828

Fig. 2: Representative insulin regimens for the treatment of diabetes. For each panel, the y-axis shows the amount of insulin effect and the x-axis shows the time of day. B, breakfast; HS, bedtime; L, lunch; S, supper. *Lispro, glulisine, or insulin aspart can be used. The time of insulin injection is shown with a vertical arrow. The type of insulin is noted above each insulin curve Table 1: Initiation, Optimization and Titration Schedule for Patients Using Basal and/or Prandial Insulin Therapy Fasting plasma glucose Levels Adjustment of basal insulin dose, U

Fig. 3: Insulin initiation and intensification with beta-cell function long-acting insulin (glargine or detemir) to provide basal insulin coverage and three shots of glulisine, lispro, or insulin aspart to provide glycemic coverage for each meal. B.

Injection of two shots of long-acting insulin (NPH) and short-acting insulin analogue (glulisine, lispro, insulin aspart [solid red line], or regular insulin [green dashed line]). Only one formulation of short-acting insulin is used. Insulin administration by insulin infusion device is shown with the basal insulin and a bolus injection at each meal. The basal insulin rate is decreased during the evening and increased slightly prior to the patient awakening in the morning. Glulisine, lispro, or insulin aspart is used in the insulin pump.

If the pre-meal blood sugar starts within ‘goal range’ (70130 mg/dl) and the 2-hour post-meal blood sugar is greater than 180 mg/dl, then the bolus ratio is likely responsible for the hyperglycemia. If the blood sugar is spiking more than 2 hours after a meal or climbs back up by the next meal, then the basal rate is the target.

BASAL INSULIN INITITION, OPTIMIZATION, INTENSIFICATION

Rational for Early Basal Insulin Initiation

Timely initiation of insulin therapy is an important component of diabetes management. Early initiation followed by timely intensification can help reverse glucotoxicity, reduce insulin resistance and preserve

Blood glucose levels for 3 consecutive Days, mmol/L (mg/dL)

Preprandial or bedtime glucose levels Adjustment of Rapid-acting insulin dose, U/ injection

≥9.90 (>180)

8.80 to 9.90 (160 to 180)

7.70 to 8.75 (140 to 159)

6.60 to 7.65 (120 to 139)

5.50 to 6.55 (100 to 119)

Maintain dose

4.40 to 5.45 (80 to 99)

-1

-2

3.30 to 4.35 (60 to 79)

-2

-4

<3.30 (<60) *

-4

#Fasting glucose levels for 3 consecutive Days: mmol/L (mg/dL)

>9.90 (180)

beta-cell function for longer than is possible with OADs alone. Insulin therapy may also slow or even halt diabetes progression. The ORIGIN trial has demonstrated that insulin slows disease progression in type 2 diabetes. In addition, the UKPDS showed that early addition of insulin to oral therapy reduced the risk of complications.

Dose optimization of basal insulin

Evidence from several large RCTs that self-titration of insulin based on SMBG, can improve HbA1C control, can improve reductions in FBG and does not increase risk of hypoglycemia. [11 Basal Insulin Intensification The stepwise addition of prandial insulin has been investigated in several clinical trials. The addition of a single prandial insulin injection to the existing basal regimen before breakfast or the main meal, or before the meal consistently with the highest postprandial

glucose, is referred to as a ‘basal-plus’ strategy. Rapidacting prandial insulin analogues, such as insulin glulisine, insulin aspart, and insulin lispro, have a more rapid onset, earlier peak, and shorter duration of action than regular human insulin, thereby allowing greater convenience in timing injections and a reduced risk of postprandial hypoglycemia. This basal-plus strategy has been identified as effective when intensifying insulin therapy, before a full basal–bolus regimen is considered Initiation: Maintain oral glucose lowering drugs

•

Start on 10-20 units of insulin glargine (according to body weight and BG)

Optimization: •

Adapt dosage every 3 to 5 days according to FBG

•

Goal: FBG < 100 mg/dl

ADVERSE EVENTS

Hypoglycemia, weight gain, Bronchitis, allergic reaction, Peripheral edema, sinusitis, back pain, infection, cataracts.

CONCLUSION

Insulin is an important component of diabetes treatment management. Addition of basal insulin to previous therapy is considered the most effective and simplest way to initiate insulin therapy. However, due to progressive nature of dabetes proactive escalation of the existing insulin therapy is eminent as it minimizes patients’ exposure to chronic hyperglycaemia and weight gain, and reduces patients’ risk of hypoglycaemia, while achieving individualized glycaemic targets. As Per the ADA EASD 2015 guidelines, basal insulin is the most convenient insulin to start with due to long action, single daily dose and low risk of hypoglycemia.

829

REFERENCES

IDF Diabetes Atlas, 7th Edition, 2015

2. Anjana RM, Pradeepa R, Deepa M, et al. ICMR–INDIAB Collaborative Study Group. Prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in urban and rural India: phase I results of the Indian Council of Medical Research-India Diabetes (ICMRINDIAB) study. Diabetologia 2011; 54:3022-3027. 3.

J, et al. Lancet. 2008; 371:1753–1760

4. Palumbo PJ. Cleve Clin J Med 2004; 71:385-386,391392,394,397,400-401,405 5. DeFronzo RA. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Res 1997; 5:177–269. 6. Fujioka K. Pathophysiology of type 2 diabetes and the role of incretin hormones and beta-cell dysfunction. JAAPA 2007; suppl 3-8. 7. DeFronzo RA, Eldor R, Abdul-Ghani M.: Pathophysiologic Approach to Therapy in Patients with Newly Diagnosed Type 2 Diabetes. Diabetes Care 2013; 36: S127-S128. 8. Joshi S, Joshi P: A review of insulin and insulin regimens in type 2 diabetes: south African family practice 2014; 51:2, 97-102. 9.

Barnett AH: Insulin glargine in the treatment of type 1 and type 2 diabetes. Vascular Health and Risk Management 2006: 2:59–67

10. Josse RG, Woo V. Flexibly timed once-daily dosing with degludec: a new ultra-long- acting basal insulin. Diabetes Obes Metab 2013; 15:1077–84. 11. Davies M et al. 2005, Meneghini L et al. 2007, Garber AJ et al. Diabetes Obes Metab 2006).

CHAPTER 180

•

Addition of prandial as a basal plus after fixing the fasting first can provide precise and flexible prandial coverage. Tailoring the insulin requirement to suit the needs of the patients will increase the success of therapy and in achievements of glycaemic goals.

C H A P T E R

181

Empagliflozin: Potential Mechanisms of Cardiovascular Benefits

T2DM individuals manifest a two- to threefold greater risk of CV events compared with nondiabetics, and CV mortality is responsible for 80% of the mortality. In T2DM patients without MI, risk of CV death is similar to individuals without diabetes with prior MI. Although hyperglycemia is the principal risk factor for microvascular complications, it is a weak risk factor for CV disease (CVD), and interventional studies focused on reducing plasma glucose in T2DM have only a minor effect in reducing CV risk. Metabolic syndrome with its cluster of obesity, insulin resistance, dyslipidemia, hypertension and its metabolic abnormalities are major CV risk factors even in individuals without diabetes, supporting the concept that hyperglycemia is not a major determinant for the development of CVD in T2DM. Consequently, lowering blood pressure and improving lipid profile have a greater effect to reduce CVD risk than lowering plasma glucose concentration in T2DM Antihyperglycaemic agents like insulin, sulfonylureas, dipeptidyl peptidase inhibitors that lower plasma glucose without affecting other metabolic abnormalities associated with insulin resistance syndrome have not much effect in lowering CVD risk in T2DM especially when these agents are started late in the natural history of T2DM and atherosclerosis. Antidiabetic agents like metformin and pioglitazone and possibly GLP-1 RA that improve insulin sensitivity and have effects on lipids, blood pressure and weight have a favourable effect on CVD risk in T2DM independent of their glucose lowering effects. Newer strategies and therapies are needed for the treatment of T2DM to reduce the CVD risk. The recently published BI 10773 (Empagliflozin, an SGLT2 inhibitor) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) study demonstrated that in T2DM patients with high CVD risk empagliflozin reduced the primary major adverse cardiac event end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14%. This beneficial effect was driven by a 38% reduction in CV mortality with no significant decrease in nonfatal myocardial infarction or stroke. Empagliflozin also caused a 35% reduction in hospitalization for heart failure without affecting hospitalization for unstable angina. The potential mechanisms for these intriguing benefits is discussed.

METABOLIC EFFECTS OF SODIUM–GLUCOSE COTRANSPORTER 2 INHIBITORS

Sodium–glucose cotransporter 2 (SGLT2) inhibitors have

Aparna Kansal, Suman Kirti, YP Munjal

insulin independent action. By inhibiting SGLT2 in the renal proximal tubule, they lower plasma glucose by producing glucosuria. In addition to lowering plasma glucose, they correct other metabolic and hemodynamic abnormalities that are risk factors for CVD. Urinary glucose loss produces negative caloric balance, resulting in a weight loss of 2–3 kg. Approximately two-thirds of the weight loss is fat, with subcutaneous and mesenteric fat loss contributing equally to the reduction in total body fat. SGLT2 inhibition decreases sodium reabsorption in the proximal tubule and exerts diuretic/natriuretic effects. SGLT2 inhibition also promotes urinary sodium excretion by causing osmotic diuresis. The result is a modest decrease in extracellular volume of 5–10%. This natriuretic effect combined with the more long-term reduction in body weight, contributes, in part, to decreases in systolic/diastolic blood pressure (4–5/1–2 mmHg), which is observed with all SGLT2 inhibitors. Blood pressure reduction is not accompanied by an increase in heart rate and is independent of background antihypertensive therapy, suggesting that SGLT2 inhibition might reduce sympathetic tone or influence other hormonal factors that contribute to decreased blood pressure without increasing heart rate. SGLT2 inhibitors cause a small increase in plasma LDL and HDL cholesterol and a decrease in plasma triglycerides; LDL/HDL cholesterol ratio remains unchanged. The mechanism by which SGLT2 inhibitors cause changes in lipid profile remains unknown. Weight loss partly explains the decrease in triglycerides and increase in HDL cholesterol. The mechanisms responsible for increased LDL cholesterol and its clinical significance requires further study. Insulin resistance per se contributes to the pathogenesis of atherosclerosis, independent of accompanying metabolic abnormalities, i.e. obesity, dyslipidemia dysglycemia or hypertension. Improving insulin sensitivity would be anticipated to reduce CV risk. Ghani et al have demonstrated that SGLT2 inhibitors by alleviating glucotoxicity improve insulin sensitivity. Two weeks of dapagliflozin treatment improved wholebody insulin-mediated glucose uptake by 20–25%, measured by euglycemic insulin clamp. Because of the beneficial cardiometabolic/hemodynamic profile associated with SGLT2 inhibitor therapy, one might expect these drugs would lower CVD risk in T2DM, independent of their glucose-lowering effect. THE EMPA-REG OUTCOME STUDY is the first study to provide evidence that an antidiabetes agent decreases CV events. In 7,020 T2DM patients with established

CVD, empagliflozin significantly reduced (hazard ratio [HR] 0.86 [95% CI 0.74–0.99], P = 0.04) the primary major adverse cardiac event (MACE) outcome (CV death, nonfatal MI, nonfatal stroke). Other surprising outcomes were: First, the primary outcome was driven by decreased CV mortality and a striking disconnect between the three MACE components was observed: 1) for nonfatal MI, HR (0.87) decreased slightly but not significantly (P = 0.22); 2) for stroke, HR (1.24) increased slightly but not significantly (P = 0.22); and 3) for CV death, HR (0.62) decreased significantly by 38% (P = 0.001). Second, unlike other interventions that reduce CV risk, e.g., lowering LDL cholesterol and blood pressure, separation between empagliflozin and placebo curves occurred very early, and reduction in the primary outcome was evident 3 months after starting empagliflozin. Third, the beneficial effect of empagliflozin on mortality and hospitalization for heart failure widened progressively over the 3.1 years of treatment. Fourth, both empagliflozin doses of 10 and 25 mg had a similar effect on outcome measures with no dose-response relationship.

0.28% at 204 weeks. Third, it took 10 years in UKPDS and VADT to demonstrate a small (10%), though significant, reduction in CV events by tight glycemic control, while the effect of empagliflozin on CV mortality was evident at 3 months and well established at 6 months.

POSSIBLE MECHANISMS OF CVD BENEFIT WITH EMPAGLIFLOZIN

SGLT2 inhibitors cause a shift from glucose to fat oxidation. The end product of fatty acid oxidation is acetyl CoA, which can enter the tricarboxylic acid cycle or be converted to ketones, the latter being favored by SGLT2 inhibitor–induced stimulation of glucagon secretion. The rise in plasma ketone concentration is small (0.3– 0.6 meq/L). Like free fatty acids, the amount of oxygen required to generate the same amount of ATP is greater with ketones compared with glucose. However, the heart avidly extracts and consumes ketone bodies and ketone body oxidation may improve cardiac muscle efficiency. Further studies will be required to examine whether the preferential oxidation of ketones by the heart provides an energetic benefit to the failing myocardium.

Reduction in HbA1c, Weight loss, increased fat oxidation, increased glucagon can affect cardiac function and potentially influence CV mortality. Reduction in CV death without decrease in MI or stroke suggests that the beneficial effect of empagliflozin is to improve survival among patients experiencing an acute CV event rather than to slow the atherosclerotic process and prevent atherosclerotic events, i.e., MI and stroke. Reduction in CV death (5.9 to 3.6%, P< 0.001) was observed across all diagnostic categories (sudden death, 1.6 to 1.1%; worsening heart failure, 0.8 to 0.2%; acute MI, 0.5to 0.3%; stroke, 0.5 to 0.3%; other CV death, 2.4 to 1.6%). The latter category includes deaths not explained by other known causes. The majority of such cases result from acute MI and arrhythmias. Empagliflozin failed to reduce hospitalization from unstable angina (HR 0.97, P = 0.97). Because of 1) the lack of beneficial effect of empagliflozin on nonfatal stroke and nonfatal MI, 2) the absence of reduction in unstable angina, and 3) the rapidity of onset of decrease in CV mortality, it is not likely that decrease in MACE outcome in EMPA-REG OUTCOME study is due to slowing the atherosclerotic process by empagliflozin.

Glycemic Control

It is unlikely that empagliflozin reduced mortality in the EMPA-REG OUTCOME study by improving glucose control. Firstly hyperglycemia is weak risk factor for CVD. Intensive glycemic control failed to decrease CV events in the UK Prospective Diabetes Study (UKPDS), Action to Control Cardiovascular Risk inDiabetes (ACCORD) study, Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, and Veterans Affairs Diabetes Trial (VADT). Secondly, difference in HbA1c between empagliflozin and placebo groups was modest: 0.45% at 90 weeks and

Shift in Fuel Metabolism

SGLT2 inhibitors shift whole-body metabolism from glucose to fat oxidation as seen in 4 weeks of treatment with empagliflozin, reduced the respiratory quotient (RQ) during fasting state and during a mixed meal, glucose oxidation decreased by 60% and fat oxidation increased by 20%. The amount of oxygen required to generate the same amount of ATP is greater with fat than with glucose, therefore the shift from glucose to fat oxidation would increase myocardial oxygen demand, and would worsen myocardial ischemia in T2DM patients. Thus, increased myocardial fat oxidation caused by empagliflozin in the EMPA-REG OUTCOME study cannot explain the reduction in CV mortality caused by the drug.

Ketones

Uric Acid

SGLT2 inhibitors promote uric acid excretion and reduce plasma uric acid by 0.7% mg/Dl. Increased uric acid levels are associated with increased CVD. Studies indicate that elevated uric acid can cause hypertension, vascular damage, and impaired renal function. Although unlikely to explain the early reduction in CV mortality, the potential benefits of uric acid reduction to reduce blood pressure and prevent vascular damage may play a role in the progressive late separation in the mortality curves between empagliflozin and placebo. Reduction in plasma uric acid concentration also may contribute to slowing of diabetic nephropathy observed in the EMPA-REG OUTCOME study.

Glucagon

SGLT2 is expressed in pancreatic a-cells and plays an important role in regulating glucagon secretion. Empagliflozin causes a robust increase in plasma glucagon in T2DM patients. In experimental animals, glucagon receptor activation has detrimental effect on myocardial function and glucagon infusion in humans has no effect on left ventricular (LV) function. Thus, it is unlikely that increase in plasma glucagon contributed to

CHAPTER 181

Metabolic Actions

831

832

reduced CV mortality or hospitalization for heart failure by empagliflozin.

Weight Loss

SGLT2 inhibitors, cause caloric loss and decrease body weight. In the EMPA-REG OUTCOME study, empagliflozin-treated subjects lost 2 kg. Although possible, it is unlikely that this small amount of weight loss contributed to the reduction in CV mortality that was observed within 2–3 months after the start of empagliflozin.

DIABETES

Direct Effect of Drug

SGLT2 is not expressed in cardiac myocytes, while SGLT1 is present in myocardial tissue. Therefore, possible partial SGLT1 inhibition by empagliflozin could affect cardiac function. However, most of the circulating drug is bound to plasma proteins and the expected plasmafree empagliflozin concentration in the EMPA-REG OUTCOME study would be very low, and not likely to affect SGLT1 function. Further, if SGLT1 were inhibited by empagliflozin, myocardial function is expected to decline, not improve as seen with phlorizine a dual SGLT1/2 inhibitor. Direct myocardial effects by empagliflozin are unlikely to explain the beneficial effect of the drug on CV mortality.

Plasma Electrolyte Changes

SGLT2 inhibition produces negative sodium balance in the first 2–3 days after starting the drug without a change in plasma sodium concentration. This natriuresis may lead to sodium redistribution between the intra and extracellular compartments. In animal models of heart failure, increased intracellular sodium has been reported. Preclinical studies also have reported heart tissue remodelling after the administration of SGLT2 inhibitors in association with a marked reduction of interstitial fibrosis.The latter, however, requires time and is unlikely to explain the early deviation of curves for CV mortality and heart failure hospitalization. Small increases in serum potassium, magnesium and phosphate occur with SGLT2 inhibitors and are not contributory to CV benefit.

Blood Pressure

Most participants in the EMPAREG OUTCOME study were hypertensive, 90% received antihypertensive therapy, starting blood pressure was well controlled (135/77 mmHg). The decrease in systolic/diastolic blood pressure in the EMPA-REG OUTCOME study was 5/2 mmHg, and was maintained throughout the 3.1-year study duration. This could contribute to the reduction in CV events in the study. However, in studies that examined the effect of blood pressure reduction on CV events, the decrease became evident only after 1year. Moreover, lowering blood pressure generally has a greater impact on stroke reduction than on other cardiac events. In the EMPA-REGOUTCOME study there was a small, nonsignificant, increase in nonfatal stroke. Thus, it is unlikely that the decrease in CV events in empagliflozintreated individuals can be explained solely by the decrease

in brachial artery blood pressure. Also reduction in brachial artery blood pressure may underestimate central aortic pressure and provides no information about aortic stiffness, both of which are independent predictors of CV mortality and LV function. Results from the Conduit Artery Function Evaluation (CAFE) study showed reduction in central aortic blood pressure by perindopril and amlodipine was strongly associated with reduced CV events. If empagliflozin caused a greater decrease in central aortic pressure than evident by the decrease in brachial artery blood pressure and reduced aortic stiffness, it could have greater impact on cardiac events and heart failure than on stroke. Consistent with this hypothesis, empagliflozin reduces aortic stiffness in subjects with diabetes, possibly by reducing oxidative stress or suppressing inflammation. Changes in nitric oxide and systemic renin-angiotensin aldosterone system (RAAS) activity were unrelated to the decline in aortic stiffness following empagliflozin therapy. Further, the diuretic effect of empagliflozin and the accompanying decrease in intravascular volume could further decrease central aortic pressure and produce an afterload reduction effect that improves LV function, reduces cardiac workload, and decreases myocardial oxygen demand. These hemodynamic effects of empagliflozin would be expected to reduce cardiac events, particularly in subjects with ischemic heart disease, impaired LV function, and congestive heart failure (CHF). Consistent with this scenario, participants with history of heart disease benefited most from empagliflozin treatment. Thus, it is possible that these hemodynamic effects of empagliflozin contributed to its beneficial CV effect, particularly in subjects with reduced LV function and CHF. Future studies examining the impact of SGLT2 inhibitors on central aortic and brachial artery blood pressure, aortic stiffness, and LV function will add insight about this hypothesis. Such hemodynamic effects of empagliflozin also could explain lack of relationship between empagliflozin dose and CV outcomes. As empagliflozin 10 mg produces near-maximal glucosuric, natriuretic, and blood pressure–lowering effects, the beneficial CV effect of 10 and 25 mg doses would be expected to be similar. Last, empagliflozin caused a 5/2 mmHg decrease in systolic/diastolic blood pressure without any increase in heart rate. This is consistent with the action of the drug to reduce sympathetic tone, which could have favorable effects on CV mortality. However, previous studies from suggest that increase in endogenous (hepatic) glucose production observed with SGLT2 inhibitors is mediated by stimulation of renal sympathetic nerves. If there was a generalized activation of the sympathetic nervous system, the heart rate would increase, not decrease, as seen in EMPAREG OUTCOME study. Further studies are needed to examine the effect of SGLT2 inhibitor therapy on the sympathetic nervous .system.

833

Table 1: Possible mechanisms that could contribute to the reduction of CV mortality by empagliflozin in the EMPA-REG OUTCOME study Effect

Likelihood

Reason

Lowered plasma glucose

Unlikely

Hyperglycemia weak CV risk factor benefit of HbA1c on CVD takes 10y

Increased fat oxidation

Unlikely

Increased oxygen demand per ATP generated

Increased plasma ketones

Unlikely

Increased oxygen demand per ATP generated

Increased plasma uric acid

Unlikely

Causal association with CVD not established

Increased plasma glucagon

Unlikely

Physiological increase in glucagon has no effect on CV function

Weight loss

Unlikely

Weight loss modest, contribute to longterm benefit in BP,CVD

Change in plasma electrolyte

Unlikely

No consistent changes observed

Decrease in blood pressure

Likely

Rapid reduction in BP early CV benefit; proven CV protection

Diuretic effect and decrease ECVF

Likely

Rapid reduction ECFV- early CV benefit proven protect from CHF

Impaired arterial elasticity

Possible

Arterial stiffness CV risk factor; empa reduces arterial stiffness

Metabolic actions

Direct effect on the Unlikely myocardium

No evidence

Decreased sympathetic tone

No increase in heart rate despite decrease in BP and ECFV

Possible

Cited from Ghani et al. SGLT2 Inhibitors and Cardiovascular Risk. Diabetes Care 2016;39: p 723

Empagliflozin reduced hospitalization from CHF by 35%. Possibly empagliflozin reduced CV mortality by improving survival specifically among patients with compromised LV function and/or clinically symptomatic CHF. A recent subanalysis showed that empagliflozin

similarly reduced CV mortality in subjects with/without heart failure at time of entry into EMPA-REG OUTCOME study. However, diagnosis of heart failure at baseline was based on self-reporting rather than on measured LV function. Further, subjects who did not report a history of heart failure and developed heart failure during the study were placed in the category without heart failure. It is likely that many individuals who developed heart failure during the study actually had heart failure at baseline and were misclassified. Last, the reduction in CV mortality became evident shortly after starting therapy. This time course is similar to the effect of spironolactone on survival in subjects with CHF. It is possible that the entire benefit of empagliflozin on CV mortality occurs secondary to the drugâ&#x20AC;&#x2122;s unique action to simultaneously reduce both preload (reduction of plasma volume) and afterload (improved blood pressure and aortic stiffness) in patients with reduced LV function and heart failure Measurement of B-type natriuretic peptide can add insight about this hypothesis and help identify this high-risk population. Exploring this possibility would improve our understanding of how empagliflozin reduces CV mortality and would identify a subgroup of patients with diabetes and existing heart failure who would benefit most from SGLT2 inhibitor treatment.

CHAPTER 181

Hemodynamic actions

Fig. 1: Schematic representation of the possible metabolic and hemodynamic mechanisms via which empagliflozin reduced mortality and hospitalization for heart failure in the EMPA-REG OUTCOME study. Because of the rapidity of onset of these beneficial effects and the known CV benefits of blood pressure and volume reduction from previous trials with antihypertensive agents and diuretics, it is likely that the hemodynamic and volume-depleting actions play a pivotal role in the cardioprotective effects of empagliflozin. It seems less likely that the metabolic/ hormonal effects (shift from glucose to fat/ketone oxidation, reduced plasma uric acid concentration, weight loss, increased glucagon secretion, increased angiotensin [Ang] 1-7, and AT2 receptor activation) of empagliflozin therapy could play a role in the drugâ&#x20AC;&#x2122;s cardioprotective effects. ECFV, extracellular fluid volume. Ghani et al.SGLT2 Inhibitors and Cardiovascular risk. Diabetes Care2016;39: p720.

DIABETES

834

Reduction in the intravascular volume by empagliflozin could lead to activation of the RAAS leading to an exacerbation of the underlying CVD by stimulating the type 1 angiotensin (AT1) receptor. However, 81% of patients with diabetes in the study were receiving ACE inhibitors or angiotensin receptor blockers. This would favour activation of the AT2 receptor and angiotensin 1-7 pathway, resulting in vasodilation; antiproliferation; antihypertrophy; antiarrhythmic, antiinflammatory, positive inotropic effects; and reduction in microalbuminuria. Microalbuminuria is a known risk factor for CVD, although a direct causal association has not been established.

Atherosclerosis

Empagliflozin-treated subjects experienced 2 kg weight loss, 2 mg/dL increase in HDL cholesterol, and 5 mmHg decrease in systolic blood pressure compared with placebo-treated subjects. These benefits expect to slow the atherosclerosis and reduce nonfatal CV events. However, nonfatal CV events (MI and stroke)were not affected by empagliflozin. However study duration was too short to observe impact of metabolic/hemodynamic effects on atherosclerosisrelated events or antiatherosclerotic effect may have been

obscured by the advanced atherosclerotic condition of the participants. It is also possible that the increase in plasma LDL, although small, negated some beneficial effect of empagliflozin on CV risk factors. An 11% and 7% increase in insulin and sulfonylurea use in the placebo group could cause weight gain, hypoglycemia and adverse CV outcomes in placebo group. Although sodiumâ&#x20AC;&#x201C;glucose cotransporter 2 inhibitors exert multiple metabolic benefits (decreases in HbA1c, body weight, and blood pressure and an increase in HDL cholesterol), all of which could reduce CVD risk, it is unlikely that the reduction in CV mortality can be explained by empagliflozinâ&#x20AC;&#x2122;s metabolic effects. More likely, hemodynamic effects, specifically reduced blood pressure and decreased extracellular volume, are responsible for the reduction in CV mortality and heart failure hospitalization.

REFERENCES

Ghani MA, Prato et al SGLT2 Inhibitors and Cardiovascular Risk: Lessons learned from the EMPA-REG OUTCOME Study. Diabetes Care 2016;39:717-725.

2. Heerspink et al. SGLT2 Inhibitors in the Treatment of Diabetes: Cardiovascular and Kidney Effects, Potential Mechanisms and Clinical Applications. Circulation 2016.