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The Asian Journal of

Diabetology VOLUME NUMBER 2 2 VOLUME 13, 13, NUMBER

April-June 2011

xxxxxxxxxxxxxxxxxxxxxxxxx Role of Triple Drug Combination Therapy xxxxxxxxxxxxxxxxxxxxxxxx for Type 2 Diabetes Mellitus - Clinical Perspective xxxxxxxxxxxxxxxxxxxxxxxxx

Diabetes and HIV in Asia: A Review xxxxxxxxxxxxxxxxxxxxxxxx

Oral Agents in the Management of xxxxxxxxxxxxxxxxxxxxxxxxx Postprandial Hyperglycemia xxxxxxxxxxxxxxxxxxxxxxxx Glucose Tolerance in Nondiabetic Patients xxxxxxxxxxxxxxxxxxxxxxxxx after First Attack of Acute Myocardial xxxxxxxxxxxxxxxxxxxxxxxx Infarction and its Outcome

xxxxxxxxxxxxxxxxxxxxxxxxx Updated Recommendations on Daily Aspirin xxxxxxxxxxxxxxxxxxxxxxxx Use in Patients with Diabetes Natural History of Diabetes Mellitus

Dr Vijay Viswanathan Editor

Dr KK Aggarwal

Group Editor-in-Chief

The Asian Journal of

DIABETOLOGY

Volume 13, Number 2

Contents

An IJCP group Publication Dr Sanjiv Chopra Prof. of Medicine & Faculty Dean Harvard Medical School group Consultant Editor Dr Deepak Chopra Chief Editorial Advisor

Dr KK Aggarwal CMD, Publisher and group Editor-in-Chief Dr Veena Aggarwal Joint MD & group Executive Editor

fROM THE DEsK Of gROUP EDITOR-IN-CHIEf

Diabetes Update

KK Aggarwal

Anand Gopal Bhatnagar Editorial Anchor AJD speciality Panel Editor Dr Vijay Viswanathan Joint Editor Dr G Vijaya Kumar Associate Editors Dr V Mohan (Chennai) Dr PG Talwalkar (Mumbai) Assistant Editors Dr Shashank R Joshi (Mumbai) Dr Manisha Talim (Mumbai) Dr Deven V Parmar (Mumbai) Regional Co-ordinators Dr AK Das (South) Dr D Maji (East) Dr PG Raman (Central) Editorial Advisors Dr JK Agrawal (Varanasi) Dr HB Chandalia (Mumbai) Dr DK Hazra (Agra) Dr SD Mehtalia (Mumbai) Dr CV Krishnaswamy (Chennai) Dr C Moonichoodappa (Bangalore) Dr Sam GP Moses (Chennai) Dr KD Nihalani (Mumbai) Dr Sharad Pendsey (Nagpur) Dr BS Raheja (Mumbai) Dr D Rama Rao (Bangalore) Dr BK Sahay (Hyderabad) Dr BB Tripathy (Cuttack)

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IJCP Editorial Board Dr Alka Kriplani Asian Journal of Obs & gynae Practice Dr VP Sood Asian Journal of Ear, Nose and Throat Dr Praveen Chandra Asian Journal of Clinical Cardiology Dr Swati Y Bhave Asian Journal of Paediatric Practice Dr Vijay Viswanathan The Asian Journal of Diabetology Dr KMK Masthan Indian Journal of Multidisciplinary Dentistry Dr Ajay Kumar gastroenterology

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fROM THE IssUE EDITOR Vijay Viswanathan, G Vijaya Kumar

REVIEw ARTICLE

Role of Triple Drug Combination Therapy for Type 2 Diabetes Mellitus Clinical Perspective

Vijay Viswanathan

Diabetes and HIV in Asia: A Review

Asfandkar Khan Niazi, Sanjay Kalra

Oral Agents in the Management of Postprandial Hyperglycemia

Jitendra Singh

COVER PICTURE

Natural History of Diabetes Mellitus

The Asian Journal of

Diabetology

Volume 13, Number 2

Contents

Published, Printed and Edited by Dr KK Aggarwal, on behalf of IJCP Publications Pvt. Ltd. and Published at E-219 Greater Kailash, Part-1 New Delhi - 110 048 E-mail: editorial@ijcp.com

clinical study

Glucose Tolerance in Nondiabetic Patients after First Attack of Acute Myocardial Infarction and its Outcome

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Editorial Policies

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emedinews section

The purpose of IJCP Academy of CME is to serve the medical profession and provide print continuing medical education as a part of their social commitment. The information and opinions presented in IJCP group publications reflect the views of the authors, not those of the journal, unless so stated. Advertising is accepted only if judged to be in harmony with the purpose of the journal; however, IJCP group reserves the right to reject any advertising at its sole discretion. Neither acceptance nor rejection constitutes an endorsement by IJCP group of a particular policy, product or procedure. We believe that readers need to be aware of any affiliation or financial relationship (employment, consultancies, stock ownership, honoraria, etc.) between an author and any organization or entity that has a direct financial interest in the subject matter or materials the author is writing about. We inform the reader of any pertinent relationships disclosed. A disclosure statement, where appropriate, is published at the end of the relevant article. Note: The Asian Journal of Diabetology does not guarantee, directly or indirectly, the quality or efficacy of any product or service described in the advertisements or other material which is commercial in nature in this issue.

From eMedinewS

practice guidelines

Updated Recommendations on Daily Aspirin Use in Patients with Diabetes

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From tHe desK oF group editor-in-cHieF

Diabetes Update

Dr KK Aggarwal

Padma Shri and Dr BC Roy National Awardee Sr. Physician and Cardiologist, Moolchand Medcity President, Heart Care Foundation of India Group Editor-in-Chief, IJCP Group Editor-in-Chief, eMedinewS Chairman Ethical Committee, Delhi Medical Council Director, IMA AKN Sinha Institute (08-09) Hony. Finance Secretary, IMA (07-08) Chairman, IMA AMS (06-07) President, Delhi Medical Association (05-06) emedinews@gmail.com http://twitter.com/DrKKAggarwal Krishan Kumar Aggarwal (Facebook)

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Early-generation sulfonylurea drugs compared with no sulfonylureas or metformin are associated with increased mortality after myocardial infarction. Newer sulfonylureas, gliclazide and glimepiride, are selective for the pancreatic sulfonylurea receptors over the cardiac receptors and are not associated with increased cardiovascular mortality compared with other diabetes medications. In a study of 1,310 patients with diabetes who were hospitalized for myocardial infarction, in-hospital mortality rates were significantly lower in patients previously treated with sulfonylureas compared with other oral medications, insulin or no medication.1 Among the sulfonylurea-treated patients, mortality was significantly lower in patients receiving gliclazide or glimepiride compared with glyburide, which is not selective for the pancreatic sulfonylurea receptors. Bromocriptine is an ergot-derived dopamine agonist that has been used for over two decades for the treatment of hyperprolactinemia and Parkinson’s disease. Bromocriptine is now approved by the US FDA for the treatment of type 2 diabetes.2 Bromocriptine (upto 4.8 mg daily) has been used as monotherapy or as adjunctive therapy to sulfonylureas.

References 1. Zeller M, Danchin N, Simon D, et al. Impact of type of preadmission sulfonylureas on mortality and cardiovascular outcomes in diabetic patients with acute myocardial infarction. J Clin Endocrinol Metab 2010;95(11):4993-5002. 2. Bromocriptine (Cycloset) for type 2 diabetes. Med Lett Drugs Ther 2010;52:97-8.

n Asian Journal of Diabetology, Vol. 13, No. 2

n 5

From tHe issue editor

Editor

Joint Editor

Dr Vijay Viswanathan

Dr G Vijaya Kumar

Managing Director Prof. M Viswanathan Diabetes Research Centre (WHO Collaborating Centre for Research, Education and Training in Diabetes), Chennai

Diabetologist Diabetes Medicare Centre Consultant in Diabetology Apollo Hospital, Chennai Hony. Consultant, Dept. of Diabetes VHS Medical Centre, Chennai

Dear Colleague greetings of the season!

It is our pleasure to bring out this new issue of the Asian Journal of Diabetology. Management of diabetes and its complications still pose significant challenges to both the diabetologist and the patient. The article on ‘Role of triple drug combination therapy for type 2 diabetes mellitus - clinical perspective’ brings out the beneficial effects of using triple drug combination in the clinical intervention of diabetes mellitus. The review on ‘Oral agents in the management of postprandial hyperglycemia’ which has been identified as a contributing factor to the development of atherosclerosis, discusses the importance of detecting and managing PPHG and seeks to evaluate new and emerging options. Metabolic disorders have been correlated with both HIV infection and its treatment. In fact, the highly-active antiretroviral therapy (HAART) intended for HIV intervention has been associated with lipid disorders and insulin resistance. The review article on ‘Diabetes and HIV in Asia’ focuses on the prevalence of diabetes in HIV-infected individuals and the mechanisms leading to the development of hyperglycemia. It is a well-known fact that diabetes is a lifestyle disease, and a positive family history significantly contributes to its occurrence. A clinical study included in this issue, reports on the prevalence of obesity, dyslipidemia, family history and other factors among the diabetic subjects of Western India. Such studies help in designing effective management strategies for screening and controlling diabetes. Besides these articles, the issue also contains short research reviews of articles on interesting aspects such as effect of hot beverages on diabetes and in-hospital complications during aortic valve implantation. The section on eMedinews contains important informative news clippings from various journals and updates in the field. We hope that the informative review articles and the useful clinical study along with other sections in this issue of The Asian Journal of Diabetology would certainly benefit the clinicians and diabetologists and help them to expand their scientific and academic knowledge. n 6

Asian Journal of Diabetology, Vol. 13, No. 2

review article

Role of Triple Drug Combination Therapy for Type 2 Diabetes Mellitus - Clinical Perspective Vijay Viswanathan

aBstract Diabetes mellitus is a metabolic disease associated with great burden that is increasing in epidemic proportions throughout the world including India. Despite its long history and considerable burden, most patients are not able to achieve recommended glycemic control guideline targets. While in most situations, the progressive nature of the disease leading to b-cell fatigue itself is a great impediment, side effects arising due to continued use or use of high dosages also plays an important role in driving home the poor compliance rates usually associated with oral hypoglycemic agents (OHAs) including sulfonylureas and thiazolidinediones (TZDs). Metformin, however, forms the backbone of most OHA regimens and is indicated as monotherapy or in combination for most cases. In light of the current controversy around the use of TZDs as insulin-sensitizing agents and their potential to cause weight gain, low-dose pioglitazone has been looked upon as an useful option in sustaining the benefits of OHAs in terms of positive regulation of glucose metabolism along with dyslipidemia and arterial hypertension. Similarly, triple drug combination involving metformin, glimepiride or low-dose pioglitazone forms an useful tool not only for intensification but also for initiating therapy in patients with high HbA1C (>9%) and is found to be safe on long-term use without the need for further insulin therapy thereby improving patient compliance in most cases. Key words: Triple drug combination, metformin, glimepiride, pioglitazone

India bears a sizeable burden of this epidemic of diabetes, and it is projected that cases of diabetes in India will increase from 31.7 million in 2000 to 79.4 million in 2030.1 Diabetes mellitus is one of the leading causes of lowerextremity amputations, blindness and end-stage renal disease. About 70% of people with diabetes die of a heart attack or stroke. Diabetes increases the risk of death due to heart disease by two-fold in men and four-fold in women. Prevention of these microvascular and macrovascular complications is the ultimate objective of any antidiabetic therapy by aggressive control of glycemic parameters including HbA1C. Managing Director

Prof. M Viswanathan Diabetes Research Centre Chennai, Tamil Nadu

Asian Journal of Diabetology, Vol. 13, No. 2

World Estimated numbers of people with diabetes (millions)

iabetes mellitus is one of the chronic diseases that is associated with high burden, increasing in epidemic proportions throughout the world. It is estimated that the global prevalence of type 2 diabetes will be more than doubled (Fig. 1)1 from 171 million in 2000 to 366 million in 2030.

2000 2030

200 180 160 140 120 100 80 60 40 20 0 20-44

45-64 Age group (years)

65+

figure 1. Estimated number of people with type 2 diabetes mellitus in millions. The most significant demographic change to the global prevalence of diabetes appears to be the increase in the percentage of people above 65 years of age.

Treating to Target Goals with Combination Therapy Because of the relentlessly progressive nature of the disease most patients are not at, or are unable to achieve, recommended glycemic control guideline targets. This may be attributable to the current diabetes treatment paradigm, which is characterized by ineffective lifestyle interventions, followed by monotherapy and frequent early treatment failure with prolonged periods of elevated glucose as a consequence of clinical inertia. In fact, monotherapy 9

review article allows glycemic control in only 25% of type 2 patients;2 whereas combination therapy is required in 75%. In a UK Prospective Diabetes Study, more than 4,200 patients with type 2 diabetes were randomized to conventional therapy with diet and exercise or intensive therapy with metformin, a sulfonylurea or insulin.3 As in the Diabetes Control and Complications Trial (DCCT),4 it was found that higher levels of HbA1C (irrespective of treatment used) were associated with a greater risk of microvascular complications. For every 1% reduction in HbA1C, there was a 37% reduction in microvascular complications. Current guidelines by the American Diabetes Association (ADA),5 the American Association of Clinical Endocrinologists (AACE),6 the International Diabetes Federation (IDF),7 the UK National Institute for Clinical Excellence (NICE),8 and the Canadian Diabetes Association (CDA)9 for the pharmacologic management of type 2 diabetes recommend lifestyle modifications (weight reduction, dietary adjustments and physical exercise) followed by initial monotherapy and, subsequently, a step-wise intensification of therapy, if glycemic control is inadequate. Metformin monotherapy is uniformly designated as the preferred initial intervention. In patients with excessive HbA1C levels after initiating metformin, additional antihyperglycemic agents should be introduced into their treatment regimens until target glycemia

(whether defined as ≤6.5% or ≤7.0%) is achieved. Several antihyperglycemic agents are available for HbA1C reduction either alone or in combination; however, they differ in their ability to control postprandial glucose (PPG) or fasting plasma glucose (FPG), as shown in Table 1.10 Treatment is often individualized for each patient with type 2 diabetes to achieve control of blood-glucose and co-morbid conditions. However, it is well-documented that patients with A1C in the lower range (<8.4%) tend to have postprandial hyperglycemia and should therefore be treated with pharmacotherapy designed to lower PPG including alpha-glucosidase inhibitors (AGIs) as recommended by AACE/ACE guidelines.6 Conversely, patients with A1C in the higher range (>8.4%) tend to have fasting hyperglycemia and should be treated with pharmacotherapy designed to lower FPG including sulfonylureas (SUs) or thiazolidinediones (TZDs).6,11 However, SUs alone have a 25% primary failure rate and secondary failure rate of 5-10% per year. In addition, there may be greater safety using combination therapy rather than prescribing a maximum dosage of one medication. If dual therapy fails, even after each component has been titrated to its maximally effective dose (commonly, only 50-66% of the stated upper limit for recommended dosage), one can usually advance to triple therapy or institute insulin therapy.

Table 1. Summary of glucose-lowering Interventions Intervention

Mechanism

Fasting and/or postprandial glucose reduction

Weight (±)

Risk of hypoglycemia

Sulfonylurea

Enhance insulin secretion

Fasting and postprandial

↑

Thiazolidinedione

Increase the muscle, fat and liver sensitivity to endogenous and exogenous insulin

Fasting > postprandial

↑

N/A

GLP-1 receptor agonist Potentiate glucose-stimulated insulin secretion

Postprandial > fasting

↓

N/A

AGIs

Prevent conversion and absorption of carbohydrates, enhancing GLP-1 while decreasing GIP levels

Postprandial

Neutral

N/A

Glinide

Enhance insulin secretion

Postprandial > fasting

↑

DPP-4 inhibitor

Enhance the effects of GLP-1 and GIP

Postprandial > fasting

Neutral

N/A

Increase glucose-mediated insulin secretion Suppress glucagon secretion DPP-4 = Dipeptidyl peptidase-4; GIP = Glucose-dependent insulinotropic polypeptide; GLP-1 = Glucagon-like peptide-1 agonist; N/A = Not applicable.

Asian Journal of Diabetology, Vol. 13, No. 2

review article Triple Drug Combination Therapy to Reach Target Levels

Using this approach, combination of TZD with metformin has been used extensively and is efficacious since it controls both insulin resistance and high FPG levels observed in patients with HbA1C levels of ≥8.4%. Similarly, the same may be further supplemented by SUs who have therapeutic effects on FPG or PPG without causing further b-cell fatigue or hypoglycemia when used at lowered dosages. This was well-highlighted in a multicentric, randomized, double-blind study involving 170 patients with uncontrolled type 2 diabetes where addition of glimepiride to conventional therapy of metformin and TZD resulted in significantly higher percentage of patients achieving ideal goals of HbA1C levels (≤7%).12 Similarly, initiation of TZDs early in the disease course, and subsequent use over the long-term, carries potential risks for achieving the goals of diabetes therapy. TZD use is associated with weight gain; in ADOPT, the average gain in body weight over five years was 4.8 kg.13 This is clearly undesirable and problematic in the context of patient lifestyle advice and adherence to treatment. Secondly, in view of the controversy around the cardiovascular risk associated with rosiglitazone, pioglitazone remains the only other TZD available for use to tackle insulin resistance. In this line, the PROACTIVE study conducted with pioglitazone highlights its ability to reduce macrovascular complications. This was a prospective, randomized controlled trial conducted with pioglitazone involving 5,238 patients with type 2 diabetes who had evidence of macrovascular disease. Patients were randomized to receive oral pioglitazone titrated from 15 to 45 mg (n = 2,605) or matching placebo (n = 2,633), to be taken in addition to their glucoselowering drugs (metformin and/or sulfonylureas) and other medications (concomitant risk factors). Pioglitazone significantly reduced the composite of Asian Journal of Diabetology, Vol. 13, No. 2

10 % change from baseline

Type 2 diabetes is a multiorgan, multifactorial condition, characterized by b-cell dysfunction, insulin resistance in peripheral tissues, increased hepatic output of glucose, with elevated levels of free fatty acids (FFAs) and proinflammatory mediators, that often requires a multipronged approach to tackle simultaneously the several pathogenetic defects observed.

** *

5 0 -5

FPG

HbA1C

IRI

Body weight

TG HDL

-10 ** -15

** **

-20

Figure 2. Effect of pioglitazone 7.5 mg (■) and 15 mg (□) on body weight, FPG, HbA1C, insulin resistance index (IRI), total cholesterol (TC), triglyceride (TG) and high-density lipoprotein (HDL);*p < 0.05 and **p = NS vs low-dose pioglitazone.

all-cause mortality nonfatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high-risk of macrovascular events (hazard ratio [HR] 0.84; p < 0.027).14 Similarly, literature search reveals poor or inadequate control of confounding risk factors including lipids or hypertension in most patients of type 2 diabetes. In this regard the metabolic profile of TZDs plays an important role in determining the success rates with long-term therapy with such drugs. Boyle15 and Gegick16 demonstrated favorable effects of pioglitazone on lipid parameters showing significant reductions in low-density lipoprotein and triglycerides or FFA levels compared to rosiglitazone. In addition, Majima17 confirmed the efficacy and safety of low-dose pioglitazone (7.5 mg) in 95 treatment naïve Japanese women with type 2 diabetes. Compared to the standard dose of 15 mg, the low-dose group did differ in HbA1C lowering capacity but offered significant reduction in incidence of peripheral edema and weight gain (p < 0.05) as shown in Figure 2. Taking this profile into consideration, the results of a long-term study on 35 patients with type 2 diabetes assumes significance since nearly 74% had wellcontrolled blood glucose levels on triple oral therapy involving metformin, SUs and TZD without the need for further insulin therapy at the end of 37 months of follow-up.18 Conclusion Combination therapy provides enhanced glucoselowering efficacy compared to monotherapy regimens, 11

review article with greater ability to target several pathogenetic aspects of type 2 diabetes including b-cell dysfunction, insulin resistance in peripheral tissues or liver, and elevated levels of FFAs along with proinflammatory mediators. Triple-drug combination involving metformin, glimepiride or pioglitazone forms an useful option for intensification of therapy to avoid drug-related side effects in patients with uncontrolled diabetes or while initiating with the same in drug-naive cases having high HbA1C levels (>9%). Low-dose pioglitazone in this combination therapy offers ancillary benefits of negligible incidence of weight gain or edema while significantly improving glucose or lipid metabolism in addition to its cardioprotective properties. References 1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27(5):1047‑53. 2. Turner RC, Cull CA, Frighi V, Holman RR. UK Prospective Diabetes Study (UKPDS) Group. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 1999;281(21):2005-12. 3. United Kingdom Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKDPS 33). Lancet 1998;352:837-53. 4. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329(14):977-86. 5. American Diabetes Association. Standards of medical care in diabetes - 2010. Diabetes Care 2010;33 (Suppl 1):S11-61. 6. Rodbard HW, Blonde L, Braithwaite SS, Brett EM, Cobin RH, Handelsman Y, et al; AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract 2007;13 Suppl 1: 1-68. 7. IDF Clinical Guidelines Task Force. Global guideline for type 2 diabetes. International Diabetes Federation: Brussels, 2005. Available at: http://www.idf.org/webdata/ docs/IDF%20GGT2D.pdf. Accessed August 23, 2010. 8. National Institute for Health and Clinical Excellence. Type 2 diabetes: national clinical guideline for

management in primary and secondary care (update).‑Available‑at:‑http://www.nice.org.uk/ nicemedia/pdf/CG66diabetesfullguideline.pdf. Accessed August 23,2010. 9. Canadian Diabetes Association. Clinical practice guidelines for the prevention and management of diabetes in Canada. 2008. Available at: http://www.diabetes.ca/ files/cpg2008/cpg-2008.pdf. Accessed August 23, 2010. 10. Blevins T. Therapeutic options that provide glycemic control and weight loss for patients with type 2 diabetes. Postgrad Med 2010;122(1):172-83. 11. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1C. Diabetes Care 2003;26(3):881-5. 12. Roberts VL, Stewart J, Issa M, Lake B, Melis R. Triple therapy with glimepiride in patients with type 2 diabetes mellitus inadequately controlled by metformin and a thiazolidinedione: results of a 30-week, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 2005;27(10):1535-47. 13. Kahn SE, Haffner SM, Heise MA, Herman HW, Holman RR, Jones NP, et al; ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355(23):2427-43. 14. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al; PROactive Investigator. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279-89. 15. Boyle PJ, King AB, Olansky L, Marchetti A, Lau H, Magar R, et al. Effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus: a retrospective review of randomly selected medical records. Clin Ther 2002;24(3):378-96. 16. Gegick CG, Altheimer MD. Comparison of effects of thiazolidinediones on cardiovascular risk factors: observations from a clinical practice. Endocr Pract 2001;7(3):162-9. 17. Majima T, Komatsu Y, Doi K, Shigemoto M, Takagi C, Fuko A, et al. Safety and efficacy of low-dose pioglitazone (7.5 mg/day) vs. standard-dose pioglitazone (15 mg/ day) in Japanese women with type 2 diabetes mellitus. Endocr J 2006;53(3):325-30. 18. Bell DS, Ovalle F. Long-term efficacy of triple oral therapy for type 2 diabetes mellitus. Endocr Pract 2002;8(4):271-5. Asian Journal of Diabetology, Vol. 13, No. 2

review article

Diabetes and HIV in Asia: A Review Asfandkar Khan Niazi*, sanjay Kalra**

aBstract This article reviews the prevalence of diabetes in HIV-infected individuals with especial reference to Asia, the mechanisms leading to the development of hyperglycemia, classification of patients on the basis of these different mechanisms and different treatment strategies. It also compares the different drugs used in the treatment of HIV, and their effects on the blood glucose control. Key words: HIV infection, highly active antiretroviral therapy, impaired glucose tolerance

ortality and morbidity from HIV infection have considerably declined since the introduction of highly active antiretroviral therapy (HAART). However, metabolic disorders such as impaired glucose tolerance and diabetes as well as lipid disorders have emerged in association with both HIV infection and its treatment. HAART is associated with lipodystrophy,1 dyslipidemia1 and insulin resistance.2 HIV protease inhibitor (PI) therapy has been implicated in the pathogenesis of fasting hyperglycemia.3 Since both HIV and diabetes are chronic diseases, requiring extensive lifestyle modifications and pharmacotherapy, their co-existence can make the challenge of management of the diseases overwhelming for the patient. With the availability of better treatment for HIV and increased life expectancy for HIV-infected individuals, the prevalence of HIV associated diabetes is expected to rise. Prevalence in Asia Although the first cases of HIV were reported in 1984, it was recognized as an epidemic only after 1990, when it spread extensively in Cambodia, India, Burma and Thailand.4 As many of the countries included in this region are low-income countries, HIV and its comorbidities place an additional burden on the already limited health resources available.

*Shifa College of Medicine, Pakistan **Bharti Hospital, Karnal, India

Asian Journal of Diabetology, Vol. 13, No. 2

According to the 2009 UNAIDS statistics, the estimated prevalence of HIV among adults in China, Pakistan and Singapore is 0.1%; in Bhutan and Indonesia is 0.2%, in India is 0.3%, in Nepal and Vietnam is 0.4%, in Cambodia and Malaysia is 0.5%, in Myanmar is 0.6%, and in Thailand it is 1.3%.5 High population in Asia exaggerates the impact of these percentages. The literature available regarding the prevalence of diabetes associated with HIV in Asia is limited. A retrospective study conducted in Taiwan found the prevalence of diabetes to be 6.06% of all HIV infected cases.6 A positive correlation of a family history for diabetes, exposure to zidovudine, use of PIs with development of diabetes after HIV infection was found. Although, data regarding a large scale evaluation of the prevalence of diabetes in HIV-infected patients in Asia could not be found, an international survey conducted at 32 centers found that 14% of the patients had metabolic syndrome and that the prevalence of diabetes was five- to nine-fold higher in these patients.7 Another study conducted in Europe showed the prevalence of diabetes and metabolic syndrome to be 4.5% and 9.1%, respectively.8 Effects of HIV on Glucose Homeostasis Although most studies have focused on the link between the use of PI and development of diabetes, recent evidence shows that there might be a direct contribution from HIV infection itself.3 The type of diabetes found in association with HIV is usually 13

review article classified as type 2 diabetes, though recent reports of type 1 diabetes in HIV have been published. The development of diabetes in HIV-infected patients can be linked to several factors including genetic (a positive family history for diabetes), iatrogenic (use of PIs), insulin resistance, autoimmune mechanisms and co-infection with hepatitis C. Autoimmune diabetes has been reported in HIV-infected patients treated with HAART following immune restoration.9 HIV infection is linked with hepatitis C infection (HCV), which is associated with insulin resistance and diabetes, due to increased intrahepatic tumor necrosis factoralpha (TNF-Îą) and hepatic steatosis.10 Recent evidence supports the existence of a significant extrahepatic component of HCV-induced insulin resistance.11 In a survey of patients infected with HCV, a 24% prevalence of diabetes was found.12 Since, more than one-third of HIV-infected individuals have a co-infection by HCV,13 HCV also forms an additional risk factor for diabetes in patients with HIV infection. HIV-infected individuals show instability in inflammatory products and adipokines. These changes also contribute to the pathogenesis of diabetes.7 Changes in Glucose Homeostasis Associated with Medications

HAART substantially reduces viral load, slowing HIV replication, increasing CD4 lymphocyte numbers, reducing the incidence of opportunistic infections and improving the rate of morbidity and mortality among these patients.14 It is, however, associated with significant adverse effects, including associated diabetes. An analysis conducted in the Multicenter AIDS Cohort Study showed the incidence of diabetes in HIV-infected patients with HAART exposure at four times greater than that of HIV-seronegative patients.15 This hyperglycemia has been shown to be reversed after discontinuing PIs.16 Binding of insulin-to-insulin receptors on cell surfaces stimulates a cascade of phosphorylation steps of key cellular substrates that result in a shift of glucose transporter 4 (GLUT-4) from inside the cell to its surface, where it facilitates glucose entry into the cell. This process may be interrupted anywhere in the various steps. Such interruption may lead to insulin resistance. 14

Different PIs have different effects on glucose homeostasis of the patients. Some PIs, such as indinavir and ritonavir, block insulin-mediated glucose disposal by a direct blockade of GLUT-4, causing insulin resistance. Other PIs, such as amprenavir and atazanzvir, have no effect on this mechanism.3 Indinavir has a different mechanism of action. It causes the insulin to lose its ability to suppress hepatic glucose production; therefore gluconeogenesis increases.17 Although, the use of PI has been associated with weight gain,18 this weight gain has not explained the development of diabetes. A study showed a 30% decrease in insulin sensitivity in HIV seronegative individuals after injecting a single dose of indinavir.19 In a similar study design, where single dose PIs were administered to HIV seronegative individuals to test differences in the effects of different PIs, ritonavir showed a decrease in insulin sensitivity by 15%, whereas amprenavir had no effect.20 In vitro studies, conducted to better understand the mechanisms involved in PI associated insulin resistance, showed a decrease in glucose uptake by cells in response to insulin,21 reduced shift of GLUT-4 to the surface of cells,22 reduced postreceptor insulin signaling23 and reduced mitochondrial DNA.24 These studies also showed a reduction in secretion of insulin by b cells by 25-50% in response to these drugs.25 This reduction was seen in response to ritonavir, nelfinavir and saquinavir but not amprenavir or indinavir.26 Megesterol acetate, a drug used to stimulate appetite in HIV-infected patients, acts like glucocorticoid inside the body; its activity predisposes the patient to hyperglycemia.27 A decrease in high- and low-density lipoproteins and an increase in very low-density lipoproteins is also seen in response to use of PI; a finding also seen in uncontrolled diabetes.28 Classification of Patients with Co-existing Diabetes and HIV Three distinctive groups of patients can be identified from the data on diabetes and HIV: Patients with diabetes who later become infected with HIV, those who develop diabetes at the onset of infection and those who develop diabetes after start of therapy. Asian Journal of Diabetology, Vol. 13, No. 2

review article As the prevalence of diabetes in the general population is high, it is obvious that the at least the same or higher rates of prevalence will apply to HIV-infected people. However, as the HIV infection is usually contracted at a young age, the patients may have a lower prevalence of pre-existing diabetes.29 Screening of Diabetes in HIV-infected Patients

The optimal procedure, method and frequency for screening for diabetes among HIV positive individuals have not yet been determined. Research, however, has provided some insight for designing a basic template. In 2000, a panel of international experts in the field of HIV and the International AIDS SocietyUSA Panel held a meeting where they reviewed the literature available regarding metabolic complications of antiretroviral therapy. The recommendations of this meeting were published in 2002. They recommended routine assessment and monitoring of glucose and lipid levels and assessment and monitoring of lactic acidemia and bone abnormalities if clinical signs or symptoms are detected. With the exception of body fat distribution abnormalities, specific treatments for these abnormalities were also recommended.30 Most clinicians support screening those HIV patients with risk factors, particularly those in the positive family history and central adiposity, and those who need HAART or NRTIs. Re-screening should be conducted after 3-6 months of start of HAART in patients who test negative for diabetes at the start of therapy.3 The International AIDS Society recommends the fasting plasma glucose level as the appropriate screening test; which should be conducted at the start of therapy and regularly after the initiation of HAART.30 However, there has been some controversy regarding the best available screening instrument for diabetes. Some clinicians are of the view that since the greater role in development of diabetes in HIV is of insulin resistance; the postprandial glucose values, or an oral glucose tolerance test, should be performed in addition to fasting glucose.29 Management of Diabetes in HIV-infected Patients

Although OADs, especially metformin, are used as a first-line treatment in type 2 diabetics, HIV-infected patients require special consideration. Owing to Asian Journal of Diabetology, Vol. 13, No. 2

impaired renal and hepatic functions and the usage of more than one class of drugs due to co-morbid infections, the probability of drug interactions in these patients is greater. Gastrointestinal dysfunction may affect their absorption and tolerability.3,31 Metformin has been shown to cause diarrhea and reduction in subcutaneous fat more often than by the other drugs.32 The reduction of fat associated with metformin may worsen the lipodystrophy associated with HIV infection. It is contraindicated in renal and hepatic diseases, and relatively contraindicated in tuberculosis, weight loss and cachexia, due to intolerability of this drug in these patients. When given to patients suffering from renal or hepatic dysfunction, metformin may lead to metformin-associated lactic acidosis (MALA). Therefore, metformin should be avoided in combination with stavudine, which also increases the risk of lactic acidosis.32 In such cases, abacavir, lamivudine and tenofovir may be used since they are least likely to cause elevation of lactate levels. Since, patients on metformin are at risk of developing lactic acidosis; they should be educated about its symptoms, including fatigue, weight loss, nausea, vomiting, hyperventilation, abdominal pain, dyspnea and arrhythmia. Thiazolidinediones are associated with a slight increase in subcutaneous fat which makes them the preferred drug class in patients with lipodystrophy.30 In HIVinfected individuals, poor responses to peroxisome proliferator-activated receptor-Îł agonists and fibrates have been reported.33 However, their wide usage is prevented due to the increase in cardiovascular morbidity, decrease in hematocrit and development of edema associated with them. The drugs are contraindicated in hepatic dysfunction and heart failure. These side effects contraindicate the usage of these drugs in patients with hepatic dysfunction and heart failure. Studies conducted on the safety and efficacy of ritonavir and nelfinavir used in HIV-infected individuals are limited. However, the frequent administration of various drugs in conjunction makes insulin a safer choice. Insulin secretagogues such as repaglinide, and sulfonylureas (glimepiride, gliclazide, glibenclamide) are safe and have a fast onset of action. However, they are not effective in patients with severe insulin resistance and are contraindicated in patients with ketonuria.29 15

review article Due to reasons previously mentioned, the reduction of inflammatory markers, such as TNF-a, ability to correct insulin deficiency and resistance, and no contraindications in cardiac, renal, hepatic or gastrointestinal dysfunctions make insulin the drug of choice for the management of diabetes in HIV.34 Since, modern insulin or insulin analogs are more predictable in action and cause less hypoglycemia, their use is encouraged by the American Association of Clinical Endocrinologists.35 Insulin therapy should be initiated at the outset, using basal bolus regime or premixed insulin. An average patient will need 1.0 U/kg/day of insulin initially, divided as 60% bolus and 40% basal insulin. In a few weeks, the requirement will come down to 0.5 U/kg/day, and may be met by 2-3 equal doses of premixed aspart/lispro.36 Usually, basal insulin alone is not sufficient to meet the insulin requirements in patients severely infected with HIV.29 Education of patients regarding the proper procedure of disposal of materials infected with their body fluids, such as needles, lancets and glucose strips should be emphasized. Since, the etiopathogenesis in the three groups of patients with diabetes and HIV is different, it implies that the management of these cases will also be different. It becomes important, therefore, to classify the patient before starting treatment. In patients with pre-existing diabetes, same therapy should be continued as before HIV infection. The patient should be educated regarding the possibility of worsening of their blood glucose levels and after HIV infection. The patient should be monitored for the blood glucose level and in case it worsens, the dose of the OAD should be increased, or a combination therapy should be ensued. Avoidance of PI should be considered in these patients. Those patients who are diagnosed at the time of onset of HIV infection should be managed according to their A1C levels. The drug of choice, as in the previous group, is metformin. If contraindicated, any other OAD may be used. If blood glucose levels are not stabilized with OADs, low-dose meglitinides or insulin may be used. Patients who develop diabetes after the start of HAART should be treated with OADs. Again, as in the previous groups, metformin is the first choice. However, insulin may also be used. In these patients, the PI in use may be switched to another drug within the same class. 16

Before antiretroviral drugs are switched to prevent hyperglycemia, the whole clinical picture should be considered so that the immunological benefit of the drugs is not lost. In cases where the current antiretroviral treatment is providing the best immunological benefits, the wiser clinical decision would be to continue the same drug and treat the hyperglycemia only. As previously mentioned, indinavir has been shown to cause the greatest hyperglycemia so, it should not be the first drug of choice, especially in patients with preexisting diabetes or risk factors for diabetes. Similar to the advice given to every diabetic, HIV-infected patients should also be advised to increase their physical activity, lose weight if they are overweight and follow a healthy diet. Suggested Improvements in National Programs The National AIDS Control Organization (NACO), working under the aegis of the Ministry of Health and Family Welfare, government of India, has created detailed, well-written guidelines for the management of HIV/AIDS. These include instructions for investigating patents with HIV as well. While NACO recognizes the risk of metabolic diseases, including lipodystrophy and diabetes mellitus, in patients with HIV, its recommendations for screening for these illnesses are surprisingly inadequate. A routine urinalysis is indicated at baseline, which may or may not detect glycosuria. Blood glucose estimation is not advised.37 An annual lipid profile is advised in patients on second line ART, but other tests such as blood glucose, glucose tolerance test (GTT) and HbA1C are not expected to be done. This approach leads to under diagnosis and under recognition of diabetes mellitus prior to, as well as after, onset of HIV. For care of diabetes, the NACO guidelines do not recommend and particular oral or injectable regime, leaving this choice to the discretion of the physician. This approach may lead to suboptimal treatment of glycemia, and in turn cause suboptimal management of HIV infection. The guidelines suggested by the United States government also cover screening and diagnosis of various metabolic diseases. The American guidelines38 suggest investigations including FBG at baseline, and Asian Journal of Diabetology, Vol. 13, No. 2

review article follow-up at intervals of 3-4 months during the first year of HAART. This frequency of testing, too, may not pick-up all patients with diabetes mellitus. Concerted efforts should be made by all professional bodies to make diabetes screening and management in HIV-infected patients more robust. Conclusions Current data shows that HIV and HAART may be responsible for causing hyperglycemia. In addition, with a high prevalence of diabetes among the general population as well, HIV-infected people are commonly seen with diabetes. HIV and diabetes are both chronic diseases that require significant pharmacotherapy and extensive lifestyle modifications. When they co-exist, much counseling is required to ensure patient compliance. The effective management of diabetes in HIV-infected patients requires an understanding of the glucose disturbances that are possible with HAART. Appropriate screening should be performed for glucose intolerance and prudent changes should be made in the HIV therapy. The choice should be based on the etiopathogenesis of the disease. The three groups of patients with co-existing diabetes and HIV require different method of management. However, any modification in the treatment should be balanced so that the immunological or viral benefits of HAART are not lost. References 1. Balasubramanyam A, Sekhar RV, Jahoor F, Jones PH, Pownall HJ. Pathophysiology of dyslipidemia and increased cardiovascular risk in HIV lipodystrophy: a model of ‘systemic steatosis’. Curr Opin Lipidol 2004;15(1):59-67. 2. Carr A, Samaras K, Burton S, Chisholm DJ, Law M, Freund J, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998;12(7): F51-8. 3. Spollett GR. Hyperglycemia in HIV/AIDS. Diabetes Spectrum 2006;19(3):163-6. 4. Ruxrungtham K, Brown T, Phanuphak P. HIV/AIDS in Asia. Lancet 2004;364(9428):69-82. 5. Estimated adult (15-49) HIV prevalence (%) for countries in 2009. Available at www.unaids.org/ documents/20101123_2010_HIV_Prevalence_Map_ em.pdf (Accessed on 4th March 2010). Asian Journal of Diabetology, Vol. 13, No. 2

6. Lo YC, Chen MY, Sheng WH, Hsieh SM, Sun HY, Liu WC, et al. Risk factors for incident diabetes mellitus among HIV-infected patients receiving combination antiretroviral therapy in Taiwan: a case-control study. HIV Med 2009;10(5):302-9. 7. Samaras K, Wand H, Law M, Emery S, Cooper D, Carr A. Prevalence of metabolic syndrome in HIV-infected patients receiving highly active antiretroviral therapy using International Diabetes Foundation and Adult Treatment Panel III criteria: associations with insulin resistance, disturbed body fat compartmentalization, elevated C-reactive protein, and hypoadiponectinemia. Diabetes Care 2007;30(1):113‑9. 8. Calza L, Masetti G, Piergentili B, Trapani F, Cascavilla‑A, Manfredi R, et al. Prevalence of diabetes mellitus, hyperinsulinaemia and metabolic syndrome among 755 adult patients with HIV-1 infection. Int J STD AIDS 2011;22(1):43-5. 9. Takarabe D, Rokukawa Y, Takahashi Y, Goto A, Takaichi M, Okamoto M, et al. Autoimmune diabetes in HIV-infected patients on highly active antiretroviral therapy. J Clin Endocrinol Metab 2010;95(8):4056-60. 10. Dagogo-Jack S. HIV therapy and diabetes risk. Diabetes Care 2008;31(6):1267-8. 11. Negro F. Mechanisms of hepatitis C virus-related insulin resistance. Clin Res Hepatol Gastroenterol 2011 Feb. 24. [Epub ahead of print]. 12. Ryu JK, Lee SB, Hong SJ, Lee S. Association of chronic hepatitis C virus infection and diabetes mellitus in Korean patients. Korean J Intern Med 2001;16(1):18-23. 13. Soriano V, Barreiro P, Nunez M. Management of chronic hepatitis B and C in HIV-coinfected patients. J Antimicrob Chemother 2006;57(5):815-8. 14. Carpenter CC, Fischl MA, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, et al. Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS SocietyUSA Panel. JAMA 1997;277(24):1962-9. 15. Brown TT, Cole SR, Li X, Kingsley LA, Palella FJ, Riddler SA, et al. Antiretroviral therapy and the prevalence and incidence of diabetes in a multicenter AIDS cohort study. Arch Intern Med 2005;165(10):1179-84. 16. Martinez E, Conget I, Lozano L, Casamitjana R, Gatell JM. Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine. AIDS 1999;13(7):805-10. 17. Lee GA, Rao M, Grunfeld C. The effects of HIV protease inhibitors on carbohydrate and lipid metabolism. Curr Infect Dis Rep 2004;6:471-82.

review article 18. Justman JE, Benning L, Danoff A, Minkoff H, Levine A, Greenblatt RM, et al. Protease inhibitor use and the incidence of diabetes mellitus in a large cohort of HIV-infected women. J Acquir Immune Defic Syndr 2003;32(3):298-302.

28. Walli R, Herfort O, Michl G, Demant T, Jãger H, Dieterle C, et al. Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients. AIDS 1998;12(15):F167-73.

19. Noor MA, Seneviratne T, Aweeka FT, Lo JC, Schwarz JM, Mulligan K, et al. Indinavir acutely inhibits insulinstimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS 2002;16:(5)F1-F8.

29. Kalra S, Kalra B, Agrawal N, Unnikrishnan AG. Understanding diabetes in patients with HIV/AIDS. Diabetol Metab Syndr 2011;3(1):2.

20. Lee GA, Rao M, Mulligan K, Lo JC, Aweeka F, Schwarz JM, et al. Effects of ritonavir and amprenavir on insulin sensitivity in healthy volunteers. AIDS 2007;21(16):2183-90. 21. Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem 2000;275(27):20251-4. 22. Hertel J, Struthers H, Horj CB, Hruz PW. A structural basis for the acute effects of HIV protease inhibitors on GLUT4 intrinsic activity. J Biol Chem 2004; 279(52):55147-52. 23. Caron M, Auclair M, Vigouroux C, Glorian M, Forest C, Capeacu J. The HIV protease inhibitor indinavir impairs sterol regulatory elementbinding protein-1 intranuclear localization, inhibits preadipocyte differentiation and induces insulin resistance. Diabetes 2001;50(6):1378-88. 24. Fleischman A, Johnsen S, Systrom DM, Hrovat‑M, Farrar CT, Frontera WE, et al. Effects of a nucleoside reverse transcriptase inhibitor, stavudine, on glucose disposal and mitochondrial function in muscle of healthy adults. Am J Physiol Endocrinol Metab 2007;292(6):E1666-73. 25. Woerle HJ, Mariuz RR, Meyer C, Reichman‑RC, Popa EM, Dostou JM, et al. Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens. Diabetes 2003; 52(4):918-25. 26. Schutt M, Zhou J, Meier M, Klein HH. Long-term effects of HIV-1 protease inhibitors on insulin secretion and insulin signaling in INS-1 beta cells. J Endocrinol 2004;183(3):445-54. 27. Henry K, Rathgaber S, Sullivan C, McCabe K. Diabetes mellitus induced by megesterol acetate in patients with AIDS and cachexia. Ann Intern Med 1992;116(1):53-4.

30. Schambelan M, Benson CA, Carr A, Currier JS, Dubé MP, Gerber JG, et al; International AIDS Society USA. Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of an International AIDS SocietyUSA panel. J Acquir Immune Defic Syndr 2002;31(3): 257-75. 31. Agency for Healthcare Research and Quality: Clinician Summary Guide. Comparing oral medications for adults with type 2 diabetes. Rockville, Maryland: 2007; Agency for Healthcare Research of Quality. 32. Kohli R, Shevitz A, Gorbach S, Wanke C. A randomized placebo-controlled trial of metformin for the treatment of HIV lipodystrophy. HIV Med 2007;8(7):420-6. 33. Carr A, Workman C, Carey D, Rogers G, Martin A, Baker D, et al; Rosey Investigators. No effect of rosiglitazone for HIV-1 lipoatrophy: a randomised, double-blind, placebo-controlled trial. Lancet 2004; 363:429-38. 34. Rao PV. Persons with type 2 diabetes and co-morbid active tuberculosis should be treated with insulin. Int J Diab Dev Countries 1999;19:79-86. 35. Rodbard HW, Jelleinger PS, Davidson JA, Einhorn‑D, Garber AJ, Grunberger G, 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 control. Endocr Pract 2009;15(6):540-59. 36. Kalra S, Kalra B, Sharma A, Chhabra B. Dosage frequency of premixed aspart insulin: clinical correlates of three-dose. Diabetes 2008;57(Suppl 1):A570. 37. www.nacoonline.org/Quick_links/Publication/ Accessed on April 4.2011. 38. www.aidsinfo.nih.gov/guidelines/GuidelineDetail.aspx Accessed on April 4 2011.

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review article

Oral Agents in the Management of Postprandial Hyperglycemia Jitendra singh

aBstract We now have enough evidence which suggests that postprandial hyperglycemia (PPHG) is a contributing factor to the development of atherosclerosis. Traditionally, glycated hemoglobin (HbA1C) is the accepted standard for monitoring overall glycemic control with treatment and management strategies targeting fasting and preprandial glucose levels. However, postprandial glucose (PPG) levels also contribute to HbA1C and therefore optimization of glycemic control may also require targeting these values. In diabetes mellitus, the postprandial phase is characterized by a rapid and large increase in blood glucose levels and hence the possibility that postprandial â&#x20AC;&#x2DC;hyperglycemic spikesâ&#x20AC;&#x2122; may be relevant to the onset of cardiovascular complications has recently received much attention. Epidemiological studies and preliminary intervention studies have shown that PPHG is a direct and independent risk factor for cardiovascular disease (CVD). Most of the cardiovascular risk factors are modified in the postprandial phase in diabetic subjects and directly affected by an acute increase of glycemia. This alarmingly suggestive body of evidence for a harmful effect of PPHG on diabetes complications has been sufficient to influence guidelines from key professional scientific societies. Correcting PPHG may form part of the strategy for prevention and management of CVD as also other vasculopathies in diabetes. New therapeutic options that specifically target PPG levels may improve overall glycemic control and reduce the risk of micro- and macrovascular complications. While discussing the importance of detecting and managing PPHG and glycemic excursions, this article seeks to review new and emerging options for the purpose. Key words: Postprandial hyperglycemia, glycated hemoglobin, cardiovascular disease, fasting plasma glucose

iabetes is characterized by a high incidence of cardiovascular disease (CVD),1 and it has been demonstrated that poor control of hyperglycemia plays a significant role in the development of CVD in diabetes.2 Recently, there has been increasing evidence that the postprandial hyperglycemia (PPHG) is an important contributing factor to the development of atherosclerosis.3

In a recent meta-analysis,9 it was shown that improvement in glycemic control significantly reduced the incidence of macrovascular events in people with type 1 or type 2 diabetes. Although control of fasting hyperglycemia is important, it is usually insufficient to obtain optimal glycemic control. We now have enough evidence which suggests that reducing PPG excursions is as important or perhaps more important for achieving target HbA1C.

Although preprandial and fasting plasma glucose (FPG) concentrations have been considered the primary measures of daily glucose control, postprandial glucose (PPG) levels are equally important.4 PPHG has been associated with cardiovascular morbidity and mortality even when glycated hemoglobin (HbA1C) values are in the nondiabetic range5-7 whereas elevated FPG concentrations are not independently associated with increased CVD risk.3,8

Postprandial Hyperglycemia and CVD: Epidemiological Evidences

Professor and Head Division of Diabetes and Endocrinology Postgraduate, Dept. of Medicine Government Medical College, Jammu Address for correspondence Dr Jitendra Singh 169/3, Trikuta Nagar, Jammu - 180 012

Asian Journal of Diabetology, Vol. 13, No. 2

Data from epidemiological studies have identified PPHG as an independent have risk factor for CVD in patients with or without diagnosed diabetes, suggesting that PPHG may be a better predictor of risk than is FPG or HbA1C alone (Table 1). It has been demonstrated that PPHG, but not FPG, is a significant predictor of subsequent myocardial infarction (MI) and death in patients with newly diagnosed type 2 diabetes.6 Also, studies have shown that the reductions in carotid intima-media thickness (CIMT) have been linked to changes in postprandial but not fasting hyperglycemia or 19

review article Table 1. Summary of Epidemiological Studies Diabetes Intervention Study6 Hoorn Study

2-h plasma glucose levels better predictor of mortality than HbA1C

Honolulu Heart Program11 Chicago Heart Study

Postprandial hyperglycemia but not fasting glucose is associated with CHD

1-h glucose predicts coronary heart disease 2-h postchallenge glucose predicts all-cause mortality

DECODE13

High 2-h plasma blood glucose is associated with an increased risk of death, independent of fasting plasma glucose levels

Coutinho et al14

2-h glucose is associated with CHD

Whitehall Study, Paris Prospective Study and Helsinki Policemen Study15

2-h plasma blood glucose predicts all-cause and CHD mortality

Islington Diabetes Survey16

2-h postchallenge glucose better predictor of CHD than HbA1C

CHD = Coronary heart disease.

HbA1C,17 and PPHG has been associated with the development of diabetic nephropathy and retinopathy.18,19 Results from The United Kingdom Prospective Diabetes Study (UKPDS), the Diabetes Control and Complications Trial (DCCT), the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and the Action in Diabetes and Vascular Disease (ADVANCE) demonstrate that intensive glycemic control early in the course of diabetes is important in achieving cardiovascular (CV) benefit and provide guidance in terms of stratification of patientsâ&#x20AC;&#x2122; target glycemic control.20 Postprandial Hyperglycemia - Management International organizations such as the American Diabetes Association and the International Diabetes Federation now accept that postmeal hyperglycemia is harmful and should be taken care of. The aims of therapy are as follows: Two-hour postmeal plasma glucose should not exceed 7.8 mmol/l (140 mg/dl) as long as there is no hypoglycemia. This could be done by self-monitoring of blood glucose (SMBG) since it is currently the most practical method for monitoring postmeal glycemia. Efficacy of treatment regimens should be monitored as frequently as needed to guide therapy toward achieving targeted postmeal plasma glucose levels.21 It is therefore, recommended that treatment strategies to lower postmeal plasma glucose in people with postmeal hyperglycemia, should be implemented. A variety of both nonpharmacologic and pharmacologic therapies should be considered to target postmeal plasma 20

glucose. Also, besides diabetes control, physicians must address other modifying factors of CVD, including blood pressure, hyperlipidemia, obesity, smoking cessation, regular exercise and healthy diet.21 Benefits of Treatment of Postprandial Hyperglycemia As yet, no completed studies have specifically examined the effect of controlling PPHG on macrovascular disease. However, there is some evidence which supports using therapies that target PPHG. A meta-analysis by Hanefeld et al revealed significant positive trend in risk reduction for all selected CV event categories with treatment with alphaglucosidase inhibitor (AGI) that specifically reduces PPHG by delaying the breakdown of disaccharides and polysaccharides into glucose in the upper small intestine. These findings are consistent with findings from the STOP-NIDDM trial,22 which showed that treating people with impaired glucose tolerance (IGT) with AGI (acarbose) is associated with a significant reduction in the risk of CVD and hypertension. Options for Managing Postprandial Hyperglycemia The Role of Diet and Exercise

Dietary counseling, regular physical exercise and weight loss have been recommended for all patients with diabetes.23-25 SMBG may help patients understand how food choices and exercise affect their blood glucose levels.26 The total amount and nature (composition, portion size, preparation method, consumption and digestion rate) of the carbohydrates in our diet are all important determinants of PPG levels and low Asian Journal of Diabetology, Vol. 13, No. 2

review article carbohydrate/low glycemic index diets can reduce PPHG, at least in the short-term.26-29 SMBG around meals or following exercise may be the best way to determine how certain foods or habits affect blood glucose levels.30 Oral Agents for Managing Postprandial Hyperglycemia

Although many agents improve overall glycemic control, including PPG levels, several pharmacological therapies specifically target PPHG. The choice of drugs should always take the efficacy for the patient, safety and cost-benefit aspects into account. Table 2 gives a brief description of the mechanism(s) of action of the commercially available therapies. Alpha-glucosidase Inhibitors

AGIs are safe and effective agents since they lower only PPHG and do not produce hypoglycemia when administered as a single drug. They may better be termed as antihyperglycemic drugs rather than hypoglycemic drugs. Although other drugs for PPHG are also available, AGI alone have a promising safety profile. They inhibit a-glucosidase enzyme in the upper gut, decrease breakdown of complex carbohydrates and delay its final absorption. Although the main effect of AGIs is to decrease PPHG in patients with type 2 diabetes, their use also results in a slight decrease in fasting glucose concentrations. This change is probably attributable to an overall improvement in glycemic control and reduction of glucose toxicity. They are effective as monotherapy or in combination

with other antidiabetic agents, particularly if the diet contains at least 50% carbohydrate. Overall, the use of AGIs results in the improvement of glycemia, lipidemia and insulin action.31 The AGIs inhibit the conversion of oligosaccharides into monosaccharides at the intestinal brush border and thereby decrease the rise in plasma glucose concentrations after ingestion of complex carbohydrates.31 As a result, oligosaccharides are partially broken down in the upper gut, move into the middle and lower guts where they are degraded and undergo bacterial fermentation and produce short-chain fatty acids, methane, carbon dioxide, hydrogen gas, etc., all of which lead to abdominal distension and flatulence.31 To avoid such side effects of AGIs, treatment should be started with low dosage, sugar, sweets, laxatives should be avoided and patient should take more of complex carbohydrates like rice, bread, vegetables, etc. Three drugs are available in this class - acarbose, meglitol and voglibose. Their mechanisms of action are same except for the selectivity on the oligosaccharidase enzymes. Acarbose inhibits pancreatic amylase, glucoamylase, maltase, sucrase and dextrinase, and has got minimal effect on isomaltase and no effect on lactose. Voglibose inhibits majority of these enzymes with no action on amylase. Meglitol, largely inhibits isomaltase (in contrast to acarbose) and has no effect on amylase (like voglibose). Acarbose is not substantially absorbed

Table 2. Mode of Action of Antidiabetic Agents of Different Classes with their Primary Target Mode of action

Class

Primary target

Improve insulin concentration

Sulfonylureas Benzoic acid derivatives Amino acid derivatives

Fasting plasma glucose Postprandial glucose Postprandial glucose

Enhance insulin sensitivity

Biguanides Thiazolidinediones Îą-glucosidase inhibitors

Fasting plasma glucose Fasting plasma glucose Postprandial glucose

Amylin analogs

Postprandial glucose

Decrease intestinal breakdown of complex carbohydrates Reduce gastric emptying rates; reduce postprandial glucagon secretion; promote hepatic glycogen storage

Improve glucose-dependent insulin secretion; enhance glucose GLP-1 analogs disposal, lipogenesis and glycogen synthesis; decrease gastric DPP-4 inhibitors motility and slow gastric emptying

Postprandial glucose Postprandial glucose Postprandial glucose

Insulin-like actions

Postprandial glucose

Rapid-acting insulin analogs

GLP-1 = Glucagon-like peptide-1; DPP-4 = Dipeptidyl peptidase-4.

Asian Journal of Diabetology, Vol. 13, No. 2

review article from the gastrointestinal tract, whereas miglitol is absorbed rapidly and excreted by the kidneys. Acarbose, however, is metabolized by bacterial action in the colon, and its metabolites are absorbed, conjugated and excreted in bile. Rare cases of cholestatic jaundice have been reported. The beneficial effect of AGIs is moderate in people consuming a typical Western diet; they are most effective when the diet contains large amounts of complex carbohydrates, as is typical of many Asian diets. When used as monotherapy the risk of hypoglycemia with AGIs is minimal but hypoglycemia may occur when AGIs are used in combination with insulin secretagogues or insulin therapy. When hypoglycemia does occur, it must be treated with glucose as digestion and absorption of sucrose and complex carbohydrates are inhibited by these drugs.31 It has been demonstrated that combination of different AGIs with other oral antidiabetic agents significantly and synergistically improve the PPG level. Miglitol, the first pseudomonosaccharide AGI, can be combined effectively with metformin therapy to give significantly greater reductions in HbA1C and postprandial plasma glucose levels than metformin alone, with a good safety profile, in patients in whom type 2 diabetes is insufficiently controlled by diet alone. Miglitol and metformin may act synergistically to confer this additional glycemic control, especially on postprandial plasma glucose peaks and may thereby help to reduce the risk of microvascular and macrovascular diabetic complications.32

In clinical trials, DPP-4 inhibitors are found to be as effective as metformin and sulfonylureas. Because the effects of GLP-1 on insulin and glucagon secretion are glucose-dependent, there is insignificant risk of hypoglycemia when it is used as monotherapy or in combination with metformin or a thiazolidinedione (TZD). The currently available DPP-4 inhibitors, sitagliptin and saxagliptin, are conveniently administered once-daily. Since, elimination of sitagliptin is mostly renal, its dosage must be reduced for patients with moderate or severe renal insufficiency. Saxagliptin is likewise primarily excreted by the kidneys but is also subject to hepatic metabolism; its dosage must be reduced only in subjects with severe renal insufficiency.31

Amylin Analogs

Glinides

Human amylin is a 37-amino acid glucoregulatory peptide that is normally cosecreted by the b cells with insulin. Pramlintide, which is commercially available, is a synthetic analog of human amylin that restores the natural effects of amylin on glucose metabolism by decelerating gastric emptying, lowering plasma glucagon and increasing satiety, thereby blunting PPHG.33,34

Glinides have a mechanism of action similar to sulfonylureas, but have a much shorter metabolic half-life. They stimulate a rapid but short-lived release of insulin from pancreatic b cells that lasts one or two hours. When taken at mealtimes, these agents attenuate PPG excursions and decrease the risk of hypoglycemia during the late postprandial phase because less insulin is secreted several hours after the meal. Nateglinide and repaglinide are the two glinides which are commercially available.35

Dipeptidyl Peptidase-4 Inhibitors

Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) decrease the metabolism of the incretin hormones, glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide, by inhibition of the DPP-4 enzyme, 22

which removes the two end-terminal amino acids and causes rapid inactivation of these gastrointestinal hormones. Active GLP-1 and gastric inhibitory polypeptide plasma levels are increased approximately 2-fold after meal ingestion. This results in increased first-phase insulin secretion, suppression of glucagon secretion in the postprandial state and improved suppression of hepatic glucose production and peripheral glucose uptake and metabolism. Hepatic glucose production is also decreased in the fasting state; the result is lower FPG concentrations. Thus, the DPP-4 inhibitors decrease both FPG and PPG.31 Examples of the commercially available DPP-4 inhibitors are vildagliptin, sitagliptin and saxagliptin.

Metformin

Metformin is a biguanide that improves the effectiveness of insulin in suppressing excess hepatic glucose Asian Journal of Diabetology, Vol. 13, No. 2

review article production, in both the fasting and the postprandial state. Although major effect is on liver, other tissues are also involved in the mechanism. How exactly metformin acts on this tissues is not clear, but it is certainly due to the modulation of plasma membrane and AMP kinase-dependent activity. Metformin appears to inhibit DPP-4 enzyme activity by 80% at 4-6 hours after dosing, compared with reduction of 40% with placebo. This effect may contribute to positively improve PPG level if metformin is combined with GLP-1 analogs or DPP-4 inhibitors like gliptins.36 Thiazolidinediones

TZDs are effective insulin-sensitizing agents. These agents increase the insulin sensitivity of skeletal muscle, adipose tissue and, to a lesser extent, the liver, resulting in increased insulin-stimulated glucose uptake and metabolism and improved insulinmediated suppression of hepatic glucose production.37 When used as monotherapy or in combination with other antidiabetic agents (including insulin), TZDs are effective in decreasing both FPG and PPG concentrations. When used as monotherapy, they do not cause hypoglycemia. When TZDs are used with insulin secretagogues or insulin, however, hypoglycemia can occur. The major side effect of the TZDs is weight gain, due to both increased adipose tissue mass and fluid retention.37 Summary Traditionally, diabetes management has focused on HbA1C for long-term glycemic control and FPG for day-to-day monitoring. PPHG is now increasingly recognized as an important risk factor for CVD in patients with diabetes or prediabetes. PPG concentrations may be elevated in patients who are seemingly well-controlled with diet, exercise and medical therapy even though with normal FPG and HbA1C values. SMBG may complement information provided by HbA1C as it provides information on glucose excursions in response to daily events, meals, medications, exercise and illness. To realize the full potential of SMBG, patients must be educated on how and when to monitor and what steps to take in response to high or low blood glucose levels. New and emerging Asian Journal of Diabetology, Vol. 13, No. 2

medications specifically target PPHG in patients experiencing postprandial glycemic excursions. The combination of improved detection-cum-monitoring of PPHG and effective medication to address it may help establish optimal glycemic control thus reducing the risk of microvascular and macrovascular complications of diabetes. References 1. Kannel WB, McGee DL. Diabetes and cardiovascular diseases. The Framingham study. JAMA 1979;241(19):2035‑8. 2. Laakso M. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes 1999;48(5):937-42. 3. Bonora E, Muggeo M. Postprandial blood glucose as a risk factor for cardiovascular disease in Type II diabetes: the epidemiological evidence. Diabetologia 2001;44(12):2107‑14. Review. 4. Abrahamson MJ. Optimal glycemic control in type 2 diabetes mellitus: fasting and postprandial glucose in context. Arch Intern Med 2004;164(5):486-91. 5. Temelkova-Kurktschiev TS, Koehler C, Henkel E, Leonhardt W, Fuecker K, Hanefeld M. Postchallenge plasma glucose and glycemic spikes are more strongly associated with atherosclerosis than fasting glucose or HbA1c level. Diabetes Care 2000;23(12):1830-4. 6. Hanefeld M, Fischer S, Julius U, Schuzle J, Schwanebeck U, Schmechel H, et al. Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up. Diabetologia 1996;39(12):1577-83. 7. Lowe LP, Liu K, Greenland P, Metzger BE, Dyer AR, Stamler J. Diabetes, asymptomatic hyperglycemia, and 22-year mortality in black and white men. The Chicago Heart Association Detection Project in Industry Study. Diabetes Care 1997;20(2):163-9. 8. Ceriello A, Hanefeld M, Leiter L, Monnier L, Moses‑A, Owens D, et al. Postprandial glucose regulation and diabetic complications. Arch Intern Med 2004;164(19):2090-5. 9. Stettler C, Allemann S, Jüni P, Cull CA, Holman RR, Egger M, et al. Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: meta-analysis of randomized trials. Am Heart J 2006;152(1):27-38. 10. de Vegt F, Dekker JM, Ruhè HG, Stehouwer CD, Nipels G, Bouter LM, et al. Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study. Diabetologia 1999;42(8):926‑31.

review article 11. Donahue RP, Abbott RD, Reed DM, Yano K. Postchallenge glucose concentration and coronary heart disease in men of Japanese ancestry. Honolulu Heart Program. Diabetes 1987;36(6):689-92. 12. Lowe LP, Liu K, Greenland P, Metzger BE, Dyer AR, Stamler J. Diabetes, asymptomatic hyperglycemia, and 22-year mortality in black and white men. The Chicago Heart Association Detection Project in Industry Study. Diabetes Care 1997;20(2):163-9. 13. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative analysis of Diagnostic criteria in Europe. Lancet 1999;354(9179):617-21. 14. Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events: a metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 1999;22(2):233-40. 15. Balkau B, Shipley M, Jarrett RJ, Pyörälä K, Pyörälä M, Forhan A, et al. High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. 20-year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study. Diabetes Care 1998;21(3):360-7. 16. Jackson CA, Yudkin JS, Forrest RD. A comparison of the relationships of the glucose tolerance test and the glycated haemoglobin assay with diabetic vascular disease in the community. The Islington Diabetes Survey. Diabetes Res Clin Pract 1992;17(2):111-23. 17. Esposito K, Giugliano D, Nappo F, Marfella R. Campanian Postprandial Hyperglycemia Study Group. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Circulation 2004;110(2):214-9. 18. Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Longterm results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000;23(Suppl 2):B21-9. 19. Shiraiwa T, Kaneto H, Miyatsuka T, Kato K, Yamamoto K, Kawashima A, et al. Postprandial hyperglycemia is a better predictor of the progression of diabetic retinopathy than HbA1c in Japanese type 2 diabetic patients. Diabetes Care 2005;28(11):2806-7.

Diabetes Federation guidelines. Diabetes Care 2009; 32(Suppl 2):S322-5. 22. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA 2003;290(4):486-94. 23. International Diabetes Federation Clinical Guidelines Task Force. Global guideline for type 2 diabetes. Brussels: International Diabetes Federation; 2005. 24. American Diabetes Association. Standards of medical care in diabetes - 2006. Diabetes Care 2006; 29(Suppl 1):S4-42. 25. Canadian Diabetes Association; Dietitians of Canada; Diabète Québec; Ordre professionnel des diététistes du Québec. Recommendations for nutrition best practice in the management of gestational diabetes mellitus. Executive summary (1). Can J Diet Pract Res 2006;67(4):206-8. 26. Mayfield J, Havas S, for the AAFP Panel on SelfMonitoring of Blood Glucose. Self-control: A Physician’s Guide to Blood Glucose Monitoring in the Management of Diabetes. An American Family Physician Monograph. Available at: http://www.aafp.org/online/ en/home/publications/otherpubs/afpmonographs/ smbgmonograph.html. Accessed February 14, 2005. 27. Franz MJ. Carbohydrate and diabetes: is the source or the amount of more importance? Curr Diab Rep 2001;1(2):177-86. 28. Arora SK, McFarlane SI. The case for low carbohydrate diets in diabetes management. Nutr Metab (Lond) 2005;2:16. 29. Beebe CA. Self blood glucose monitoring: an adjunct to dietary and insulin management of the patient with diabetes. J Am Diet Assoc 1987;87(1):61-5. 30. Ceriello A, Garber AJ, Hirsch IB, Jovanovic L, Kruger DF. Postprandial glycemic control. Achieving goals in type 2 diabetes. Medical Crossfire 2005;6:4-18. 31. Rendell MS, Jovanovic L. Targeting postprandial hyperglycemia. Metabolism 2006;55(9):1263-81.

20. Fava S. Role of PPHG in cardiovascular disease. Expert Rev Cardiovasc Ther 2008;6(6):859-72.

32. Chiasson JL, Naditch L; Miglitol Canadian University Investigator Group. The synergistic effect of miglitol plus metformin combination therapy in the treatment of type 2 diabetes. Diabetes Care 2001;24(6):989-94.

21. Gallwitz B. Implications of postprandial glucose and weight control in people with type 2 diabetes: understanding and implementing the International

33. Weyer C, Maggs DG, Young AA, Kolterman OG. Amylin replacement with pramlintide as an adjunct to insulin therapy in type 1 and type 2 diabetes mellitus: Asian Journal of Diabetology, Vol. 13, No. 2

review article a physiological approach toward improved metabolic control. Curr Pharma Des 2001;7(14):1353-73. 34. Samsom M, Szarka LA, Camilleri M, Vella A, Zinsmeister AR, Riza RA. Pramlintide, an amylin analog, selectively delays gastric emptying: potential role of vagal inhibition. Am J Physiol Gastrointest Liver Physiol 2000;278(6): G946-51. 35. Wolffenbutel BH, Nijst L, Sels JP, Menheere PP, MĂźller PG, Kruseman AC. Effects of a new oral

hypoglycaemic agent, repaglinide, on metabolic control in sulphonylurea-treated patients with NIDDM. Eur J Clin Pharmacol 1993;45(2):113-6. 36. Lindsay JR, Duffy NA, McKillop AM, Adrill J, Oâ&#x20AC;&#x2122;Harte FP, Flatt PR, et al. Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes. Diabet Med 2005;22(5):654-7. 37. Hurel SJ, Mohan V. Clinical decision making: managing postprandial hyperglycemia. J Assoc Physicians India. 2006;54:871-6.

Cover Picture

Post-Meal Glucose Insulin Resistance

Fasting Glucose

Insulin Secretion

-30

-10

Years of Diabetes

Natural History of Diabetes Mellitus

Asian Journal of Diabetology, Vol. 13, No. 2

The cover picture depicts the natural history of diabetes mellitus. Day 0 is the day of diagnosis. In the natural history, both fasting and postprandial glucose start rising years before the clinical presentation. Hyperinsulinemia and insulin resistance (IR) also start to increase before the clinical presentation. This underscores the importance of pre-clinical diagnosis of diabetes known as impaired fasting glucose (IFG). Once the clinical diagnosis is established, the insulin levels go on decreasing leading to increasing dose of OHAs and insulin. There is gradual increase in the fasting and postprandial glucose levels, which correlates with the fall in insulin secretion. The IR normally stays at a plateau once the clinical presentation starts.

clinical study

Glucose Tolerance in Nondiabetic Patients after First Attack of Acute Myocardial Infarction and its Outcome Ajay s Dabhi*, M Vadivelan*, sR Rathava*

aBstract Aims: To find out the incidence of impaired glucose tolerance (IGT) and frank diabetes mellitus (DM) in patients of acute myocardial infarction (AMI) and to study the natural history of IGT in relation to AMI. Study Design: A cross-sectional study was done in 60 patients of AMI in whom oral glucose tolerance test (OGTT) was performed after admission. Those with normal glucose tolerance on admission and till discharge were taken in the study. Material and Methods: The study was conducted at the intensive coronary care unit (ICCU) of Shri Sayajirao General (SSG) Hospital, Vadodara, Gujarat. The study was conducted over a period of 7-month in 60 patients of AMI. Results: The present study revealed that cardiovascular complications related to AMI were more common in patients with abnormal glucose tolerance. Conclusion: Glucometabolic abnormalities in nondiabetic patients with acute coronary events have an influence on in-hospital and short-term cardiovascular morbidity as well as mortality. Key words: Impaired glucose tolerance, acute myocardial infarction

espite impressive strides in the diagnosis and management of myocardial infarction, it still continues to be a major public health problem worldwide. Cardiovascular disease is a major cause of death in diabetic patients.1 Although diabetes mellitus (DM) has emerged as a major risk factor for coronary artery disease (CAD)related morbidity and mortality, recently, it has been suggested that impaired glucose tolerance (IGT) is also an independent risk factor.2 IGT is a dysglycemic state, which is the intermediate state between normal glycemic state and DM.3 Asymptomatic hyperglycemia is a significant public health problem and confers an increased cardiovascular risk, independent of other classical cardiovascular risk factors. In patients with IGT, cardiovascular risk is equal and in some cases, even higher than in those diagnosed to have diabetes.4 Aims of Study  To find out the incidence of IGT and frank DM in patients of acute myocardial infarction (AMI) *Assistant Professor, Dept. of Medicine Medical College and SSG Hospital, Vadodara Address for correspondence Dr Ajay S Dabhi 38, Alkanagar, Near Priyalaxmi Mill Old Alembic Road, Vadodara - 390 003, Gujarat E-mail: dr_ajay_44@yahoo.co.in

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in 3-month follow-up period who, after first attack of AMI, were normoglycemic on admission and till discharge. To evaluate the relationship between plasma glucose level on admission and its outcome (in-hospital and short-term) in patients with AMI without previously known DM. To evaluate IGT as an independent cardiovascular risk factor in AMI. To study the natural history of IGT in relation to AMI and to compare the outcome in patients after 3-month follow-up.

Material and Methods In this prospective, cross-sectional study, 60 patients presenting with clinical features of AMI admitted to the intensive coronary care unit (ICCU) of Sri Sayajirao General Hospital, Vadodara, Gujarat were taken as the study group. Oral glucose tolerance test (OGTT) was performed in all patients and those with normal glucose tolerance on admission and till discharge were included in the study group. Inclusion Criteria

Adults below the age of 65 years who presented within 24 hours of AMI for the first time and with random Asian Journal of Diabetology, Vol. 13, No. 2

clinical study blood sugar (RBS) level <180 mg/dl were included in the study sample.

In patients with ST elevation MI, 35 (59%) patients had anterior wall MI (Table 2).

Exclusion Criteria

Table 3 shows that glucose tolerance in all patients of study sample was normal till discharge.

Patients with DM, systemic arterial hypertension, ischemic heart disease and those with history of gestational diabetes mellitus, cerebrovascular accident, peripheral vascular disease, structural heart disease, chronic liver and kidney disease were excluded from the study.

At the end of 3-month follow-up, 40 patients (67%)Group A had normal glucose tolerance while 14 patients (23%) - Group B1 had IGT and six patients (10%) - Group B2 had frank DM (Table 4).

RBS was estimated on admission and fasting blood sugar (FBS) was estimated on the second day after admission and on discharge. OGTT was carried out according to WHO guidelines under controlled conditions after an overnight fast.

Table 2. ECG Findings in Study Sample

Impaired fasting glucose was defined as venous plasma glucose level in the range of 110-125 mg/dl while IGT was defined as venous plasma glucose level in the range of 140-199 mg/dl (2 hours after glucose load). Each patient was evaluated with OGTT (FBS and PG2BS), electrocardiogram (ECG) and echocardiogram at 3-month follow-up.

Right ventricle MI

Patients (%) ST elevation MI Anterior wall MI

35 (59%)

Inferior wall MI

14 (23%)

Total

3 (5%) 52 (87%)

Non-ST elevation MI Subendocardial MI

2 (3%)

ST segment depression

4 (7%)

Fresh left bundle-branch block

2 (3%)

Total

8 (13%)

Results Total 60 indoor patients admitted to ICCU with AMI satisfying the inclusion criteria were selected for the study. The age of patients ranged from 35 to 65 years. Majority of patients were in the age group of 56-65 years (65%) indicating more prevalence of AMI in elderly people. Out of 60 patients in the study group, 40 were males (67%) and 20 were females (33%) (Table 1).

Table 3. RBS and OGTT Results in Study Sample

The AMI patients were further divided into subgroups on the basis of ECG findings.

On discharge FBS (mg/dl)

93 ± 12

ST elevation MI was seen in 52 (87%) patients and non-ST elevation MI was seen in eight (13%) patients.

PG2BS (mg/dl)

104 ± 8

Variable

Values

On admission RBS (mg/dl)

121 ± 57

On 2nd day of admission FBS (mg/dl)

97 ± 8

PG2BS (mg/dl)

117 ± 18

(In study, cut-off value of RBS <180 mg/dl)

Table 1. Age and Sex Distribution of Patients with Myocardial Infarction

Table 4. Division of Study Sample-based on Glucose Tolerance at the End of 3-month Follow-up

Age (years)

Group

Sex

Total (%)

Male (%)

Female (%)

35-45

5 (8%)

1 (2%)

6 (10%)

46-55

9 (15%)

6 (10%)

15 (25%)

56-65

26 (44%)

13 (21%)

39 (65%)

Total

40 (67%)

20 (33%)

60 (100%)

Asian Journal of Diabetology, Vol. 13, No. 2

Patients (%)

40 (67%)

14 (23%)

6 (10%)

Total

60 (100%)

clinical study Table 5. Comparison of Segment Motion Abnormality in Both Groups

Table 6. Comparison of Left Ventricle Ejection Fraction (LVEF) in Both Groups

segment motion abnormality

LVEf (%)

group A (%) group B (%)

Total (%)

group A (%)

group B (%)

Total (%)

>50 (normal)

10 (25%)

6 (30%)

16 (27%)

41-50

21 (53%)

8 (40%)

29 (48%)

On admission

On admission Normokinesia

10 (25%)

6 (30%)

16 (27%)

Hypokinesia

21 (53%)

8 (40%)

29 (48%)

Akinesia

5 (12%)

3 (15%)

8 (13%)

31-40

5 (12%)

3 (15%)

8 (13%)

Paradoxical movement

4 (10%)

3 (15%)

7 (12%)

<30

4 (10%)

3 (15%)

7 (12%)

On follow-up

On follow-up Normokinesia

6 (15%)

1 (5%)

7 (12%)

>50 (normal)

6 (15%)

1 (5%)

7 (12%)

Hypokinesia

15 (38%)

8 (40%)

23 (38%)

41-50

15 (38%)

8 (40%)

23 (38%)

Akinesia

10 (25%)

5 (25%)

15 (25%)

31-40

10 (25%)

5 (25%)

15 (25%)

Paradoxical movement

9 (22%)

6 (30%)

15 (25%) <30

9 (22%)

6 (30%)

15 (25%)

On admission

Group A

On follow-up

Group B

Group A

Group B

40%

60%

35% 50%

40%

% of involved patients

30%

20%

25% 20% 15% 10%

10% 5% 0% >50%

41-50%

31-40%

<30%

LVEF (%)

0% >50%

41-50%

31-40%

<30%

LVEF (%)

figure 1. Comparison of left ventricle ejection fraction in both groups.

Table 5 shows segment motion abnormality in AMI on 2-D echo done at the time of admission and on follow-up. Worsening of involved segment was noticed more in Group B as compared to Group A on 2-D echo.

Out of 36 patients who developed cardiovascular complications related to AMI, 95% patients were having abnormal glucose tolerance (IGT and frank DM). Among complications, patients developed congestive heart failure, cardiogenic shock and arrhythmias (Table 7).

Table 6 and Figure 1 shows progression to poor cardiac pump function in Group B as compared to Group A on 2-D echo at 3-month follow-up.

Table 8 shows that death due to cardiac cause was more in Group B than Group A. Cause of death was congestive heart failure in all patients. Asian Journal of Diabetology, Vol. 13, No. 2

clinical study Table 7. Comparison of Both Groups for Complicated MI Acute MI

Group A (%)

Group B (%)

Total (%)

Complicated

17 (43%)

19 (95%)

36 (60%)

Uncomplicated

23 (57%)

1 (5%)

24 (40%)

Total

40 (100%)

20 (100%)

60 (100%)



Table 8. Comparison of Both Groups for MI-related Mortality Acute MI Alive

Group A (%)

Group B (%)

Total (%)

39 (98%)

16 (80%)

55 (91%)

Death

1 (2%)

4 (20%)

5 (9%)

Total

40 (100%)

20 (100%)

60 (100%) 

Discussion Acute myocardial infarction is the commonest cause of cardiovascular disability in developed countries and the leading cause of morbidity and mortality in developing countries.5 Cardiovascular relative risk increases 2-4 folds in patients with diabetes as compared to the nondiabetic population.6 Stress hyperglycemia is usually associated with AMI and quite a large number of patients developed IGT or frank DM in due course after AMI.7 The risk of congestive heart failure is also increased in patients with stress hyperglycemia. Elevated glycosylated hemoglobin (HbA1C) in nondiabetic patients is a risk factor for one year mortality after AMI. Hyperglycemia in AMI is a transient phenomenon that is induced by acute stress which increases the level of cortisol and catecholamines in blood. HbA1C is the most powerful indicator of high blood glucose on admission. It is a marker of acute stress and also reflects the prevailing disturbed glucometabolic state.8 Patients with AMI with IGT and frank DM are at increased risk of in-hospital and short-term morbidity as well as mortality. Few possible mechanisms may explain this observation.9  Hyperglycemia is a reflection of relative insulin deficiency which is associated with increased lipolysis and excess circulating free fatty acids (FFAs). This effect is exaggerated in cases of acute stress such as MI. FFAs are toxic to ischemic myocardium and may lead to damaged cardiac cell membranes, calcium overload and arrhythmias. Asian Journal of Diabetology, Vol. 13, No. 2

High concentration of FFAs during MI increases myocardial contractility. Insulin deficiency also limits the ability of cardiac muscle to take up glucose for anaerobic metabolism. Hyperglycemia may precipitate an osmotic diuresis, resulting in volume depletion that may interfere with Frank-Starling mechanism which is an important compensatory mechanism for the failing left ventricle. Reflex adaptation to hemodynamic stress secondary to infarction may be impaired by autonomic dysfunction which is common in diabetics. Also, diabetics have extensive CAD that limits the availability of collateral blood flow to the infarct zone.10 IGT may be a marker of more extensive cardiac damage in AMI, which may lead to greater rise in stress hormones (promoting glycogenolysis and hyperglycemia) and may also increase the risk of congestive heart failure and mortality.

Limitations  This cross-sectional, comparative study was conducted with only 60 patients of AMI and hence, could not derive information regarding boundaries of abnormal glucose tolerance. Larger samples are needed to decide the cut-off values of abnormal glucose tolerance.  In our study, 3-month follow-up was done, but long-term follow-up studies are needed to find out future development of overt DM in patients with IGT as well as long-term prognosis.  Measurement of stress markers like circulating catecholamines and cortisol would be needed to exclude influence of stress hyperglycemia in glucometabolic abnormalities which was not done in our study. Conclusion Patients with AMI who were found to have IGT and frank DM on screening with OGTT on follow-up had a high incidence of cardiovascular morbidity especially dyskinesia of involved segment, pump failure, arrhythmias and recurrent cardiac events as well as mortality. Thus, glucometabolic abnormalities in nondiabetic patients with acute coronary events have an influence on cardiovascular morbidity (in-hospital and short-term) as well as mortality. 29

clinical study IGT confers an increased cardiovascular risk in acute ischemic event, even in the absence of other classic coronary risk factors. Hence, OGTT should be included in the armamentarium in patients with AMI to detect at high cardiovascular risk individuals.

5. Stubbs PJ, Alaghband-Zadeh J, Laycock JF, Collinson PO, Carter GD, Noble MI. Significance of an index of insulin resistance on admission in non-diabetic patients with acute coronary syndromes. Heart 1999;82(4): 443-7.

References

6. Braunwald E. Acute myocardial infarction. In: Braunwald’s Heart Disease. 8th edition, Lippy P, et al. (Eds.), Saunders Philadelphia 2008.

1. Joron GE, Laryea E, Jaeger D, Macdonald L. Cause of death in 1144 patients with diabetes mellitus: an autopsy study. CMAJ 1986;134(7):759-64.

7. Mizock BA. Alteration in carbohydrate metabolism during stress: a review of the literature. Am J Med 1995;98(1):75-84.

2. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycemia and increased risk of death after myocardial infarction in patients with and without diabetes. Lancet 2000;355(9206):773-8.

8. Oswald GA, Smith CC, Betteridge DJ, Yudkin JS. Determinants and importance of stress hyperglycemia in non-diabetic patients with myocardial infarction. Br Med J (Clin Res Ed) 1986;293:917-22.

3. American Diabetic Association. Consensus development conference on insulin resistance. Diabetes Care 1998; 21(2):310-4.

9. Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H. Coronary heart disease risk and impaired glucose tolerance. The Whitehall study. Lancet 1980; 28(1):1373‑6.

4. Norhammer A, Rydén L, Mamberg K. Admission plasma glucose. Independent risk factor for long-term prognosis after myocardial infarction, even in non-diabetic patients. Diabetes Care 1999;22(11):1827-31.

10. Tavani A, Bertuzzi M, Gallus S, Negri E, La Vecchia G. Diabetes mellitus as a contributor to risk of acute myocardial infarction. J Clin Epidemiol 2002; 55(11):1082-7.

Asian Journal of Diabetology, Vol. 13, No. 2

emedinews section

From eMedinewS Novel Antifibrotic Agent may Benefit Diabetic Nephropathy Diabetic nephropathy may not just slow but may actually improve with the novel antifibrotic agent pirfenidone Esbriet, according to a preliminary study in the Journal of the American Society of Nephrology. Antifibrotic may Slow Diabetic Nephropathy Diabetic nephropathy may not just slow but may actually improve with the novel antifibrotic agent pirfenidone, researchers found in a preliminary study. Kidney function continued to drop in diabetic kidney disease patients without treatment, but rose significantly with a low-dose of pirfenidone over one year, Kumar Sharma, MD, of the University of California San Diego and VA Medical Center in La Jolla, Calif., and colleagues reported online in the Journal of the American Society of Nephrology. (Source: Medpage) Low Vitamin D Levels may Double Diabetes Risk Low vitamin D levels may increase the risk of developing diabetes, according to a study in the journal Diabetes Care.

cognitive behavioral therapy over the phone, followed by nine monthly booster sessions, which included a walking program. Low Serum Amylase Levels may Indicate Increased Risk for Metabolic Syndrome, Diabetes People with low serum amylase levels have an increased risk for cardiometabolic conditions, such as the metabolic syndrome and diabetes, according to a study in the journal Cardiovascular Diabetology. Poor Sleep Quality Associated with Poorer Control of Type 2 Diabetes People with diabetes who sleep poorly have higher blood glucose levels and a more difficult time controlling their disease, according to a study published in the May issue of the journal Diabetes Care. Stress may Predict Development of Impaired Glucose Metabolism in Normoglycemic Individuals Perceived stress and stressful life events predict the development of impaired glucose metabolism over five years in previously normoglycemic individuals, according to results from the Australian Diabetes, Obesity, and Lifestyle study (AusDiab).

Ketogenic Diet Alone may Reverse Diabetic Nephropathy, Study in Mice Suggests

Pediatric Update

A study in the journal PLoS ONE of mice suggest that consumption of a ketogenic diet may be sufficient to reverse the symptoms of diabetic nephropathy.

Even mild elevations in fasting blood sugar values during childhood predict a risk for developing type 2 diabetes mellitus. In the Bogalusa heart study, children with fasting blood sugar values in the upper half of the normal range (between 86 and 99 mg/dl (4.8 - 5.5 mmol/l) have 2.1 times the risk for developing diabetes during adulthood, and 3.4 times the risk for developing prediabetes, independent of the child’s weight status (Arch Pediatr Adolesc Med 2010;164:124).

Treating Depression may Augment Diabetes Patients’ Overall Health Treating diabetes patients’ depression boosts their overall health, according to study in the journal Medical Care, which included 145 people with type 2 diabetes and depression who received a yearlong depression intervention that included 12 weeks of Asian Journal of Diabetology, Vol. 13, No. 2

fasting Blood sugar

–Dr Neelam Mohan, Director Pediatric Gastroenterology, Hepatology and Liver Transplantation, Medanta - The Medicity

emedinews section Obesity Update International Diabetes Federation (IDF) Study Highlights 



People with obesity often struggle not only with health and physical consequences but also with discrimination at work, socially and in the healthcare system. Bariatric surgery is associated with significant health benefits in severely obese patients with type 2 diabetes. Benefits are gained through weight reduction, improved glycemic control, reduced hypertension, and improved health-related quality-of-life. A 2009 Cochrane systematic review concluded that bariatric surgery was more effective than conventional treatment of weight loss in patients with Class I obesity (BMI >30 kg/m2) as well as those with severe obesity. The Swedish Obese Subjects study demonstrated prevention and remission of type 2 diabetes in 2,037 patients with type 2 diabetes and severe obesity who had bariatric surgery compared with control subjects. A randomized trial specifically focused on treatment of type 2 diabetes showed a remission of 73% for patients who underwent bariatric surgery versus 13% in control participants who received a comprehensive management program. Bariatric surgery should be considered an accepted option in those with type 2 diabetes and a BMI of 35 kg/m2 or higher. Surgery should be considered an alternative

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treatment option in patients with a BMI of between 30 and 35 kg/m2 when type 2 diabetes cannot be adequately controlled by an optimal medical regimen, especially in the presence of other cardiovascular risk factors. The morbidity and mortality risks associated with bariatric surgery are low and are similar to wellaccepted procedures such as elective gallbladder or gallstone surgery. Bariatric surgery in severely obese patients is associated with a reduced mortality risk.

Management of Obesity in Diabetics

The goal of the management of type 2 diabetes is glucose control at a level that prevents the sugar in the blood from damaging organs including the kidneys. Lifestyle modifications including adequate physical activity, nutrition therapy, and antidiabetic drugs form the cornerstones of diabetes management.  The goals of lifestyle modifications and nutrition therapy are to achieve and maintain optimal metabolic status with respect to the levels of blood glucose, lipids and blood pressure to prevent and treat complications of diabetes. When weight reduction by lifestyle modifications is not adequate, weight loss drugs can be considered.  When considering pharmacotherapy, weight loss drugs should always be used in concert with diet regulation, exercise and behavior modifications.  Pharmacotherapy in combination with diet and lifestyle modifications is much more efficacious in inducing weight loss as compared to drugs alone. –Dr Parveen Bhatia and Dr Pulkit Nandwani

An Inspirational Story Expect the Best

A little girl walked daily to and from school. Though the weather this particular morning was questionable and clouds were forming, she made her trek to the elementary school. As the afternoon progressed, the winds whipped up, along with thunder and lightning. The child’s mother, concerned that her daughter would be frightened and possibly harmed by the storm got into her car and drove along the route to her child’s school. As she did so, she saw her little daughter walking along happily but at each

flash of lightning the child would stop, look up and smile. Stopping the car, the mother called to the child to get in with her. As they drove toward school, the girl continued to turn toward each lightning flash and smile. The Mother asked, ‘What are you doing?’ The child answered, ‘Well, I must do this, God keeps taking pictures of me.’ –Dr Prachi Garg

Asian Journal of Diabetology, Vol. 13, No. 2

practice guidelines

Updated Recommendations on Daily Aspirin Use in Patients with Diabetes

ersons with diabetes mellitus have two to four times the risk of cardiovascular events compared with persons of the same age and sex who do not have the disease. Coronary heart disease (CHD) is responsible for more than two-thirds of deaths in persons with diabetes who are older than 65 years. Although aspirin has been proven to reduce cardiovascular morbidity and mortality rates in highrisk patients with myocardial infarction or stroke, its benefit is unclear in patients without a history of cardiovascular events. In 2007, the American Diabetes Association and American Heart Association recommended aspirin therapy (75 to 162 mg daily) for primary prevention in patients with diabetes who had increased CHD risk (e.g., older than 40 years, smoking, family history of cardiovascular disease). Since these recommendations were published, new evidence has raised questions about the effectiveness of this strategy. The U.S. Preventive Services Task Force recently recommended that physicians encourage aspirin use in men 45 to 79 years of age and in women 55 to 79 years of age, regardless of whether they have diabetes. To address the uncertainties about aspirin use in persons with diabetes, experts from the American Diabetes Association, American Heart Association, and American College of Cardiology Foundation reviewed the current evidence and updated the 2007 recommendations. The group organized its recommendations around the following questions:  What is the evidence for aspirin in preventing initial cardiovascular events in patients with diabetes?  How can the conflicting results of various primary prevention trials be reconciled?  What are the risks of aspirin therapy, and are these risks similar for patients with diabetes compared with those for patients without the disease?  What is the recommended dosage?  How should the potential benefits and risks of Source: Adapted from Am Fam Physician. 2010;82(12):1559-1563..

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aspirin therapy be integrated to determine which patients should take aspirin daily for the primary prevention of cardiovascular events? The current evidence on aspirin therapy for prevention of cardiovascular disease includes three trials conducted in patients with diabetes, and six trials containing subgroups of patients with diabetes. None of these trials provides definitive results, so the group performed a meta-analysis to reconcile the available data. Data from subgroups of patients with diabetes from the six trials were included in a previous meta-analysis by the Antithrombotic Trialists’ Collaboration. These were combined with data from the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes study, the Prevention of Progression of Arterial Disease and Diabetes trial, and the Early Treatment of Diabetic Retinopathy Study. A random-effects model showed that aspirin use is associated with nonsignificant decreases in the risk of CHD events (relative risk [RR] = 0.91; 95% confidence interval [CI], 0.79 to 1.05) and of stroke (RR = 0.85; 95% CI, 0.66 to 1.11). The results of the diabetes-specific analyses are consistent with the findings of the previous metaanalysis, and suggest that aspirin use likely reduces the risk of cardiovascular disease to a modest degree in patients with diabetes. Adverse effects of aspirin therapy include intracranial bleeding (hemorrhagic stroke) and extracranial bleeding (mainly gastrointestinal [GI]). Several cardiovascular risk factors also increase the risk of extracranial bleeding, which suggests that persons at higher risk of CHD events are also at higher risk of aspirinrelated adverse effects. Current evidence supports the use of proton pump inhibitors to decrease the risk of recurrent aspirin-related GI bleeding. However, routine use of these agents may not be cost-effective, and it is not clear whether they should be recommended for primary prevention of GI bleeding. The optimal dosage of aspirin for prevention of CHD events is not clear. The average daily dosage used in primary prevention trials that included persons with 37

practice guidelines diabetes ranged from 50 to 650 mg. The risk reductions achieved with low dosages (75 to 162 mg per day) seem to be similar to those obtained with higher dosages. Although platelets from patients with diabetes have altered function, it is not clear whether this affects the recommended dosage of aspirin for cardioprotection. There are alternate pathways for platelet activation and aggregation that are independent of thromboxane A2 and are therefore not sensitive to the effects of aspirin. The evidence is insufficient to empirically recommend higher dosages of aspirin for patients with diabetes. In adults with cardiovascular risk greater than 1 percent per year, the number of CHD events prevented will be approximately equal to or greater than the number of bleeding events induced, although these events (myocardial infarction, stroke, and GI bleeding) do not have equal effects on long-term health. Recommendations

Low-dose aspirin therapy is reasonable in adults with diabetes and no history of vascular disease, whose 10-year risk of CHD events is greater than 10 percent, and who are not at increased risk of bleeding (i.e., no history of GI bleeding or peptic ulcer disease, and no concurrent use of other medications that increase bleeding risk). Adults with diabetes who are at increased risk of CHD events include most men

older than 50 years and women older than 60 years who have at least one additional major risk factor (i.e., smoking, hypertension, dyslipidemia, albuminuria, or family history of premature cardiovascular disease). Aspirin should not be recommended in adults with diabetes who are at low risk of cardiovascular events (men younger than 50 years and women younger than 60 years with no additional major risk factors). The potential adverse effects from bleeding offset the potential benefits in these patients. Low-dose aspirin therapy may be considered for patients with diabetes who are at intermediate risk of CHD events (younger patients with at least one risk factor, older patients with no risk factors, or patients with a 10-year risk of 5 to 10 percent). These recommendations depend on the accurate assessment of CHD risk. Not all patients with diabetes are at high risk, and the use of a risk prediction tool is essential. There are several Web-based tools available, such as the UK Prospective Diabetes Study Risk Engine (http://www.dtu.ox.ac.uk/riskengine/index.php)â&#x20AC;&#x2018;and the Atherosclerosis Risk in Communities CHD Risk Calculatorâ&#x20AC;&#x2018;(http://www.aricnews.net/riskcalc/html/ RC1.html). Risk should be reassessed periodically, because patients may acquire additional risk factors over time. n

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