08 Diabetes

SECTION 8

Diabetes 39.

Sulfonylureas in the Management of Type II Diabetes Mellitus Amit Varma

211

40.

Pioglitazone in the Management of T2DM Anil Kumar Virmani

216

41.

Usefulness of Ambulatory Glucose Profile (AGP) in Diabetes Care K Chaithanya Murthy, B Ramya, E Vidya, RM Anjana, V Mohan

220

42.

When Should I Use Newer Insulins?

Paturi Vishnupriya Rao

226

43.

DPP- 4 Inhibitors in the Management of Type 2 Diabetes Mellitus Balamurugan Ramanathan

231

44.

Preoperative Management of the Patient with Diabetes Sunil Gupta

238

45.

SGLT2- Inhibitors in the Management of Type 2 Diabetes Vinod Mittal

247

46.

In Hospital Management of Diabetes Mellitus Jothydev Kesavadev

252

47.

Practical Approach to a Patient whose First Time Random Blood Sugar is 208 mg/dl SV Madhu

257

48.

Practical Approach to Diabetic Foot Ulcer Yalamanchi Sadasiva Rao

262

49.

How to Start Statins in Diabetes R R Singh

265

C H A P T E R

39

Sulfonylureas in the Management of Type II Diabetes Mellitus Amit Varma

The sulfonylureas are the most frequently prescribed oral hypoglycemic agent along with metformin. Although the management of diabetes was attempted by the “experts” of the Pharaoah of Egypt 3500 years ago and

by Shushruta, the modern times efforts began only in the in the early 1900. In the year 1937, hypoglycemic activity of sulfur compounds was noted, and five years later, Michel Janbon noted hypoglycemia while using antibiotic para amino sulfonamide-isopropyl-thiodiaozole. Its secretogogue action was confirmed by Loubatieres in 1946 and tolbutamide was the first SU to be marketed in Germany in 19501-2.

CLASSIFICATION OF SULFONYLUREA

MECHANISM OF ACTION

4th Generation: This is a newer group which demonstrates sensitive, reversible and repeated manipulation of KATP channel state and beta cell activity with visible light, yielding optical control over insulin release. They therefore, offer selective targeting of KATP channels in pancreas and elsewhere. Hence, they are also called as ‘photo-switchable’ sulfonylureas. It is a light activated drug ,which is activated when exposed to a blue LED stuck to the skin.When the light is turned off the drug is deactivated ,allowing for a very specific control over insulin release and blood sugar level. It can be switched on for a short time when required after a meal as it targets drug activity to where it is needed in the pancreas.3

The mechanism of action of SU can be best understood by reviewing the insulin release by the beta cells. Blood glucose levels below 70 mg/dl triggers cascade of events enhancing protein translation and processing.

This results in the influx of glucose through glucose transporter (GLUT). The glycolysis cycle is thus initiated with the release of the ATP which in turn suppresses the activity of ATP sensitive K channels. This channel consist of two separate proteins: one is the binding site of OHA sulfonylurea (and also miglitide) and the other is inwardly rectifying K channel protein Kir6.2. Four SUR1 and four Kir6.2 subunit make up the K ATP channel. The binding of sulfonylureas to SUR1 results in closure of the K ATP channel, increased concentration of intracellular K and depolarization of beta cell membrane. Inhibition of K channels induces beta cell membrane depolarization, which opens voltage dependent Ca++ channels and stimulates insulin secretion. In short, sulfonylureas stimulate insulin release from pancreatic beta cells in glucose independent manner.

Glibenclamide and glimepiride, which contain both sulfonylurea and nonsulfonylurea moieties and block both SUR1- and SUR2-containing channels, are postulated to interact with both sites on SUR1, but only a single (benzamido-derivative) site on SUR2.

Currently, sulfonylureas are classified as first- and second-generation drugs, although there is no structural or functional basis for this classification. It is known that some sulfonylureas bind with high-affinity to SUR1, but not SUR2, whereas others interact with both types of SUR. It is therefore proposed that the classification of sulfonylureas, meglitinide derivatives, and structurally related compounds be changed to reflect the functional differences among these drugs, and that they be referred to instead as SUR1-specific and non-SUR1-specific.

1st generation

2nd generation:

Acetohexamide

Glibenclamide

Carbutemide

Gliburide

Chlorpropamide

Gliclazide

Glyclamide (tolhexamide) Tolbutamide 3 generationim rd

Glipizide 4th Generation JB253

Glimepiride

SUR SPECIFIC AND NON-SPECIFIC SULFONYLUREAS

As discussed earlier, SU stimulate insulin secretion by blocking the ATP sensitive potassium channels in the pancreatic beta cells. SU receptors are also present in other tissues besides pancreas. SUR-1 receptors are present in pancreatic beta cells, SUR 2A are present in cardiac muscles and SUR 2B in smooth muscles. The SU might act selectively or non-selectively on these receptors.

Gliclazide and tolbutamide blocks the beta cell SUR receptors (SUR 1) only while glibenclamide blocks all the three types of receptors with similar affinity. While the earlier generation SU are only sparingly used, the classification based on the SUR receptors would be more rationale. However, there appears to be no difference in mortality amongst SUR specific and non specific SU. 4

VARIABILITY IN SULFONYLUREA RESPONSEPHARMACOGENOMICS

SU have long been recognized as potent hypoglycemic agents capable of inducing hypoglycemia, especially the first generation. However, it has been observed that 10-20% of patients have less than 20 mg/dl reduction of fasting plasma glucose while 50-60% would have more

212

Table 1: Drug therapy of tye II DM Lifestyle changes are the foundation of any type 2 diabetes treatment program Monotherapy

Start with metformin (MET) If A1c target is not achieved after 3 months of monotherapy, proceed to Dual Therapy

Dual Therapy

MET + SU MET + TZD

DIABETES

MET + GLP-1 RA

contribute to sulfonylurea failure or variability in response may be summarized as-5 a.

polymorphisms in drug target genes (i.e., ATPbinding cassette, subfamily C, member 8 [ABCC8] and potassium inwardly-rectifying channel, subfamily J, member 11 [KCNJ11]) and diabetes risk genes (e.g., TCF7L2 and insulin receptor substrate [IRS-1]) have been associated with variability in sulfonylurea response in patients with Type 2 diabetes.

b.

ABCC8 encodes the regulatory subunit of the sulfonylurea receptor, and the ABCC8 Ser1369Ala polymorphism has been associated with differential response to sulfonylurea therapy in patients with Type 2 diabetes.

c.

KCNJ11 encodes Kir6.2, the pore subunit of the sulfonylurea receptor, and the KCNJ11 E23K polymorphism is associated with inter-individual variability in sulfonylurea response and adverse effects in patients with Type 2 diabetes.

d.

The KCNJ11 E23K and ABCC8 Ser1369Ala polymorphisms are in strong linkage disequilibrium. Recent data suggest that the K23/ Ala1369 risk haplotype confers increased sensitivity to gliclazidein vitro. This finding is primarily governed by the effects of the Ala1369 risk allele.

e.

TCF7L2 is a transcription factor in the WNT signaling pathway and it is a Type 2 diabetes risk gene.

Polymorphisms in TCF7L2 have been associated with differential response to sulfonylurea therapy in patients with Type 2 diabetes.

f.

IRS-1 is a signal transduction protein that mediates the metabolic effects of insulin. The IRS1Gly972Arg polymorphism is associated with an increased risk of Type 2 diabetes and an increased risk of secondary.

MET + DPP-4 inhibitor MET + SGLT2 inhibitor MET + basal insulin If A1c target is not achieved after 3 months of dual therapy, proceed to Triple Therapy Triple Therapy

MET + SU or TZD or DPP4 or GLP-1 or insulin TZD or SU or DPP4 or GLP-1 or insulin GLP1 or SU or TZD or insulin DPP4 or SU or TZD or insulin SGLT2 or SU or DPP4 or TZD or insulin Basal insulin + TZD or DPP-4 or GLP-1 If A1c target is not achieved after 3 months of triple therapy and patient (1) is on oral combination, move to injectable; (2) on GLP1, add basal insulin; or (3) on optimally titrated basal insulin, add GLP-1 or mealtime insulin. Refractory patients: consider adding TZD or SGLT2.

Combination injectable therapy

MET + Basal insulin + mealtime insulin or GLP-1

than 30 mg/dl reduction in the fasting glucose levels, but failed to achieved desired target. Diabetes Outcome Progression Trial (ADOPT) highlighted SU monotherapy failure and the inter-individual variability, it was largely attributed to declining beta cell function, long standing diabetes, high baseline blood sugar levels, high degree of insulin resistance and genetic polymorphism.

The advances in the genetic polymorphism which may

PLACE OF SULFONYLUREALS IN THE MANAGEMENT OF TYPE II DIABETES MELLITUS

Algorithm in the management of Type II Diabetes mellitusADA/EASD 2016 guidelines (Table 1)

The choice of pharmacotherapy in the management should be based upon the efficacy and experience with the drug, cost, potential side-effects, effect on the weight, co-morbidities, hypoglycemia risk and importantly, patient preferences. It is evident from the ADA/EASD guidelines of 2016 that SU are the preferred add-on drugs with metformin. As per the Indian Council of Medical Research guidelines also, sulfonylureas, alongside metformin, remains the mainstay of treatment of diabetes mellitus.6 The reason for their acceptance is a wide experience, their efficacy to lower blood sugar levels and HbA1c, low cost, fewer co-morbidities and large acceptance, especially in the developing countries. The newer generation SU, especially non-sulpher containing have fewer episodes of hypoglycemia and decrease microvascular risks. However, they are associated with

frequent and severe hypoglycemia than other insulin secretagogues in this class, including glipizide and glimepiride.

mild to moderate weight gain and may blunt myocardial ischemic preconditioning.7 An ideal candidate for starting sulfonylurea in Type II Diabetes mellitus would be one who still exhibit some beta cell function, diagnosed for less than 5 years and are willing to follow life style modification programs.

SU lower HbA1c significantly but increasing the dose does not result in further lowering of HbA112.

This reduction of HbA1c is superior to DPP4 inhibitors. Addition of TZD has fluctuating effect on HbA1c levels.

4.

There is no significant difference between DPP4 inhibitors and sulfonylureas when either is added to metformin monotherapy. However, there is a significant decrease in risk of hypoglycemia in patients using DPP4 inhibitors alone.13 However, it is observed that adding a DPP-4 inhibitor to metformin is associated with an increased, earlier requirement for treatment intensification compared to adding a SU or Thiozolindendione.

The secondary failure rate of SU is better than DPP4 inhibitors.14

5.

The calculated mortality risk for metformin associated lactic acidosis and glibenclamideassociated hypoglycaemia showed no significant differences.15

SULFONYLUREAS IN CHRONIC KIDNEY DISEASE

SU should be discontinued once the GFR falls below 45-60 ml/min. Such patients are at increased risk of hypoglycemia due to accumulation of its metabolites.

SULFONYUREAS AND PANCREATIC ‘BETA CELL EXHAUSTION’

Beta-cell exhaustion with the use of SU has been a concern with the use of secretogogues and the concept has largely governed the regimens of diabetes management. However, Nyback-Nakel A et al (2010) demonstrated inconsistent results supporting the concept, emphasizing that the decreased C-peptide levels are not due to long term use of sulfonylureas 8. ADOPT study also demonstrated similar beta cell function after 5 years in all treatment groups.

It is suggested that it is the metabolic hyperstimulation of persistent hyperglycemia (glucotoxicity) that is most damaging to the beta cells, rather than the hyperexcitability and hypersecretion produced by chronic use of sulfonylureas induced KATPchannel closure.

However, it is possible that chronic use of SU may induce refractoriness of beta cell responsiveness9.

6. Amongst other sulfonylureas, gliclazide is associated with better glycemic control, HbA1c and secondary failure rates.

7.

ADVANCE trial included subjected predominantly on SU as compared to ACCORD trial which included other classes of oral hypoglycemic medications. ADVANCE showed a comparatively better renal outcomes.

8.

Second generation SU are not associated with increased mortality after myocardial infarction as compared to other OHAs and insulin16.

EVIDENCES

1.

Glimipride maintains myocardial preconditioning while glibenclamide might prevent it10. Hence, glimipride is not associated with cardiovascular risk in comparison with the earlier generation sulfonylureas.

2. 3rd generation SU have a lower incidence of hypoglycemia as compared to other lower generation SU11. In the UK Prospective Diabetes Study (UKPDS), the rate of severe hypoglycemia was about 0.5% in the SU-treated group. A total of 11% of subjects taking chlorpropamide and 17.7% of people taking glyburide had more than one episode of hypoglycemia per year. Glyburide and chlorpropamide were associated with a severe hypoglycemia rate of 1.4 events and 1.0 events per year, respectively (in the intensively treated group of subjects), as compared with a 1.8 event rate in those taking insulin. In the A Diabetes Outcome Progression Trial (ADOPT), in which glyburide was compared with metformin and rosiglitazone as monotherapy, just under 30% of subjects randomized to SU treatment reported symptoms of minor hypoglycemia during the 5 years of study, yet only 0.6% experienced episodes of severe hypoglycemia. Not all SUs are, however, associated with such high rates of hypoglycemia.

Glyburide, which is very less frequently used these days is unequivocally associated with more

DIFFICULTIES AND POINTS TO PONDER17

1.

SUs have tendency to induce hypoglycemia due to its secretogogue effect. There is inverse correlation between HbA1c and patient reported hypoglycemia. However, the risk of hypoglycemia is less as compared to insulin and metformin combination. The incidence of hypoglycemia and hypoglycemia associated deaths are comparatively less as compared to insulin. Hypoglycemia caused by these agents appears not only to be dose related, but also correlates inversely with BMI.

2.

The rationale for associating SU use with adverse cardiac outcomes is based on the mechanism of action of these drugs—by binding to the SUR1 receptor on pancreatic β-cells and closure of the KATP channels occurs. This leads to a rise in intracellular calcium, which in turn results in insulin exocytosis. KATP channels are present in a number of other cells including cardiac myocytes, neurons, and smooth muscle cells. In theory, binding of SU to KATP channels in cardiomyocytes results in inhibition of the protective impact of ischemic

CHAPTER 39

3.

213

preconditioning, a phenomenon that causes worse cardiac outcomes following myocardial ischemia or infarction18.In the UKPDS trial, there was a nonsignificant 16% decrease in myocardial infarction rates in patients treated intensively with SUs at the end of the study but a significant 15% decrease in events in these subjects when evaluated 10 years after the end of the original study, despite the fact that they continued to take SUs and their metabolic control had been the same as the conventionally treated group within a year of completion of the original study. The ADOPT study failed to show any significant increase in cardiovascular events in the glyburide-treated cohort.

Sulfonylureas are not associated with increased risk of all-cause mortality, cardiovascular mortality, myocardial infarction or stroke.

DIABETES

214

3.

4.

Tolbutamide, like glyburide blocks increases in blood flow induced by diazoxide, a vasodilator, whose effects are mediated through the opening of ATP-sensitive potassium channels. Conversely, the sulfonylurea glimepiride did not exhibit this effect; furthermore, unlike glyburide, glimepiride does not block the improvements in chest pain and ST-segment depression that usually occur with a second balloon dilation during coronary artery angioplasty. Glicizide is another example of a sulfonylurea drug that appears to restrict its ATP-sensitive potassium channel activity to the pancreas19.

Weight gain, mainly is a result of their effect to increased insulin levels and thus utilization of glucose and other metabolic fuels. The weight gain is more so with the second generation SU. The incidence of weight gain is maximum with glibenclamide as compared to other agents in the class. It is attributed to reduction of glycosuria and increased calorie intake to prevent hypoglycemia.

However, Jil mamza et al (2016) observed a very small reduction in body weight with SU.

insulinase inhibition, regulation of free and bound insulin, inhibition of glucose output by the intact liver, and actions upon lipid, ketone, protein, and carbohydrate metabolism21.

11.

There is a growing interest in SUR-1 specific SUs. There is no evidence to suggest that SUR-1 specific and non specific SUs have differential effect on arterial distensibility, endothelial functions or vascular mechanisms in Type II diabetes mellitus22.

12.

Within class there is no difference in time for intensification with insulin or any third agent, whether it is glimepride, gliclazide or tolbutamide.

EXTRA-PANCREATIC EFFECTS OF SULFONYLUREAS23

1.

Reduces hepatic insulin clearance

2.

Inhibit glucagon secretion

3.

Enhances insulin sensitivity in the peripheral tissues

The sulfonylureas are the first oral hypoglycemic agents used, are efficacious both as mono therapy and in combination with a wide variety of agents. ADA/ EASD also recommend them as an important add-on to metformin. Besides, they are available at a lower cost which is an important consideration in the management of diabetes. They are safe and the concern regarding their cardiovascular safety is not convincingly proven.

Hypoglycemia produced by these agents needs caution, but it is much less with the newer agents.

REFERENCES

1.

Levine R: Sulfonylureas: background and development of the field. Diabetes Care 1984; 7 (Suppl. 1):3–7. MedlineWeb of ScienceGoogle Scholar

2.

Quianzon CCL,Cheikh I: History of current non-insulin medications for diabetes mellitus. J Community Hosp Intern Med Perspect. Published online 15 October 2012. (doi: 10.3402/jchimp.v2i3.19081

3.

Johannes Broichhagen, Matthias Schönberger, Simon C. Cork, James A. Frank, Piero Marchetti, Marco Bugliani, A. M. James Shapiro, Stefan Trapp, Guy A. Rutter, David J. Optical control of ​insulin release using a photoswitchable sulfonylurea Hodson & Dirk Trauner. http://www.nature. com/ncomms/2014/141014/ncomms6116/full/ncomms6116. html

4.

Evans JM, Ogston SA, Reimann F, Gribble FM, Morris AD, Pearson ER. No differences in mortality between users of pancreatic-specific and non-pancreatic-specific sulphonylureas: a cohort analysis. Diabetes Obes Metab 2008; 10:350-2. Epub 2007 Dec 17

5.

Cristina L Aquilante. Sulponylureas pharmacogenomics in type II DM. The influence of drug target and diabetis rick of polymorphisms. Expert Rev Cardiovascularther 2010; 8:359-72.

6.

S.Kalra, M.C.Deepak, P.Narang, V.Singh, M.G.Yuvraj, N.Agrawal. Usage pattern, Glycemic improvement, hypoglycemia and Body Mass Index with Sulfonylureas in real-life Clinical Practice. Results from OBSTACLR Hypoglycemia Study.

7.

Sulphonylureas pharmacogenomics in Type 2 diabetes: the

5. Headache 6.

Hypersensitivity in few individuals

7.

Safety not established in pregnancy as it may induce hypoglycemia in fetus and new born.

8.

Renal failure-increased risk of hypoglycemia.

However 3rd generation SU can be used in these situation.

9.

Fenofibrates or gemfibrozil is associated with increased risk of hypoglycemia in patients taking SU, especially glyburide.20 These classes of drugs are most commonly used in diabetics.

10. Sulfonylureas in vitro potentiate insulin action beyond the binding portion of the receptor— primarily at the level of insulin-stimulated glucose transport which is a pointer towards their extrapancreatic effects. The effects discussed include

influence of drug target and diabetes risk polymorphisms Christina L Aquilante : Expert Rev Cardiovasc Ther. 2010; 8:359–372.doi: 10.1586/erc.09.154http://www.ndei.org/ ADA-EASD-hyperglycemia-2012.aspx.html 8.

9.

Nyback-Nakell A, Bergstrom J, Adamson U, Lins PE, Landstedt-Hallin L. Decreasing postprandial C-peptide levels over time are not associated with long-term use of sulphonylurea: an observational study. Diabetes Metab 2010; 36:375–80.

10. Klepzig H et al. Sulfonylureas and ischemic preconditioning;a double blind, placebo controlled evaluation of glimipride and glibenclamide. Eur Heart J 1999; 20:439-16.

11. M.S. Rendell et al. Type II Diabetes management in older adults. Clinical Geriatrics 2004; 12:43-51.

12. J. A. Hirst & A. J. Farmer & A. Dyar & T. W. C. Lung & R. J. Stevens. Estimating the effect of sulfonylurea on HbA1c in diabetes: a systematic review and meta-analysis.

Diabetologia 2013; 56:973–984.

13. Naghmeh Foroutan PhD1,2Sergei Muratov, MPH1,2Mitchell Levine, MD. Safety and efficacy of dipeptidyl peptidase-4 inhibitors vs sulfonylurea in metformin-based combination therapy for type 2 diabetes mellitus: Systematic review and meta-analysis. Clin Invest Med 2016; 39:2.

14. Jil mamza, Rajnikant Mehta, R.Donley, I. Idris. Important differences in the durability of glycemic response among second line treatment options when added to metformin in type II Diabetes mellitus; a retrospective cohort study.

Annals of Medicine http://dx.doi.org/10.3109/07853890.201 6.1157263 15. Campbell IW. Metformin and the sulphonylureas: the comparative risk. Hormone and Metabolic Research.

Supplement Series [1985; 15:105-111].

17. Gerstein HC, Miller ME, Byington RP, Goff DC, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH, Probstfield JL, Simons-Morton DG, Friedewald WT. “Effects of intensive glucose lowering in type 2 diabetes”. The New England Journal of Medicine 2008; 358:2545–59.

18. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74:1124–1136.

19. Lee TM, Chou TF. Impairment of myocardial protection in type 2 diabetic patients. J Clin Endocrinol Metab 2003; 88:531-7.

20. Han X, Brensinger CM, Quinney SK, Bilker WB, Flockhart DA, Li L, Hennessy S. Pharmacoepidemiologic and in vitro evaluation of potential drug–drug interactions of sulfonylureas with fibrates and statins. Br J Clin Pharmacol 2014; 78:639-48. doi: 10.1111/bcp.12353.

21. Jerome M. Feldman, MD; Harold E. Lebovitz, MD. Appraisal of the Extrapancreatic Actions of Sulfonylureas.

Arch Intern Med 1969; 123:314-322. doi:10.1001/ archinte.1969.00300130096013.

22. P Dhindsa, Karl R. Davis, R. Dounnely. Comparison of micro and macro-vascular effects of glimepride and gliclazide in metformin treated patients with type 2 diabetes: a double blind cross-over study. Br J Clin Pharmacol 2003; 55:616-9.

23. Peter M. Thulé, Guillermo Umpierrez. Sulfonylureas: A New Look at Old Therapy Current DiabetesReports April 2014, 14:473 http://link.springer.com/article/10.1007/ s11892-014-0473-5.

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Remedi MS, Kurata HT, Scott A, et al. Secondary consequences of beta cell inexcitability: identification and prevention in a murine model of K(ATP)-induced neonatal diabetes mellitus. Cell Metabol 2009; 9:140–51.

16. Adelaide M. Arruda-Olson, MD, PhD, Richard K. Patch, III, MD, Cynthia L. Leibson, PhD, Adrian Vella, MD, Robert L. Frye, MD, Susan A. Weston, MS, Jill M. Killian, BS, and Véronique L. Roger, MD, MPH. Effect of SecondGeneration Sulfonylureas on Survival in Patients With Diabetes Mellitus After Myocardial Infarction. Mayo Clin Proc 2009; 84:28–33.

C H A P T E R

40

INTRODUCTION

The management of T2DM has undergone a paradigm shift after newer insights in its pathogenesis from the classical triumvariate to ominous octet to dirty dozen.

Cardio-vascular diseases remain the leading cause of morbidity and mortality in T2DM. It is now prudent to use anti-diabetic drugs with pleotropic effects and additional cardio-vascular risk reduction.

Pioglitazone, a thiazolidinedione, activates the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPAR-gamma agonist), thus increasing insulin sensitivity. It is cheap with a proven efficacy track record, addressing the core pathology of insulin resistance in both the adipose tissues & skeletal muscles.

This is very relevant, especially in the Indian population, as more than 80% of patients with pre-diabetes and T2DM have insulin resistance. Hence, insulin-sensitizing interventions should take priority over interventions that increase insulin secretion because of the potential benefit of cardiovascular risk reduction.1 Since its approval in India in 2002, it has undergone a roller-coaster ride with being on the verge of extinction [banned on June 18, 2013, by Indian Ministry of Health and Welfare, based on eight case reports of bladder cancer amongst pioglitazone users]2 to resurrection (Ban revoked on 31st July 2013, based on recommendation by the Drug Technical Advisory Board).

AFTER METFORMIN IS PIOGLITAZONE THE BEST ADD-ON DRUG IN THE INDIAN CONTEXT ?

Efficacy

It’s efficacy is comparable to the other oral anti-diabetic drugs. As monotherapy both metformin and pioglitazone have comparable glycemic effects, however pioglitazone increased insulin sensitivity more than metformin from week 4 through week 52, as assessed by QUICKI.3 As an insulin sensitizer, pioglitazone is superior to metformin.

In comparison to gliclazide, though HbA1c reduction was similar (0.79%), there was a greater reduction in fasting blood glucose (- 1.0 mmol/l vs – 0.7 mmol/l) with greater reductions in insulin levels and insulin resistance, and continuous decrease in fasting blood glucose over one year, which was not seen with gliclazide.4 Gliclazide is considered to be the safest and most prefered of the sulfonylureas, and pioglitazone has stood its ground in comparison.

As an add-on to patients uncontrolled with metformin

Pioglitazone in the Management of T2DM Anil Kumar Virmani

and sulfonylurea, pioglitazone (30 mg.) compared to sitagliptin (100 mg.), achieved comparable improvements in overall glycemic control, with greater reductions in fasting plasma glucose(35.7 vs 22.7 mg/dL),and a significant decrease in hs-CRP, albeit at a higher weight gain.5 Sitagliptin is cardio-vascular and weight neutral, whereas pioglitazone reduces cardio-vascular risk with comparable efficacy. The weight gain caused by pioglitazone can be taken care of by enforcing life-style modification, which remains an essential part of diabetes management.

In Indian patients, pioglitazone (15 mg) was found to significantly reduce HbA1c from mean 8.34 to 7.78%, FPG from mean 172.6 to 143.8 mg% and PPG from mean 222.9 to 204 mg% at the end of two years, and was safe & welltolerated.6 This observational study reflects the experience of most of the clinicians in our country.

Durability

Pioglitazone was found to be superior in achieving maximum reduction in HbA1c & FPG in the shortest time, with greater durability at end of four years in Japanese patients with T2DM, as compared to other oral glucoselowering drugs.7 In another retrospective cohort study in 20,070 patients, who were newly treated with a SU / DPP-4i / TZD, the risk of failure with dual therapy at one year was 15% with SU, 23% with DPP-4i, & 8% with TZD. Corresponding failure rates at 2 years were 26%, 38% & 12% respectively.

Adding a TZD to metformin was associated with a reduced hazard (aHR 0.45; 95% CI :0.41-0.50) and resulted in the most durable glycemic response.8 Pioglitazone proved to be superior to both sulfonylureas and DPP-4 inhibitors, as far as durability of glycemic response is concerned. It also proved to be superior to Sitagliptin in both durability and reducing HbA1c levels in drug-naïve patients.9 It also provides effective lowering of HbA1c by 0.5 – 1.5% and durable glycemic control in combination with other oral anti-diabetic drugs and insulin.10 In addition, it also resulted in 70% reduction in risk of developing T2DM in the ACT NOW study for prevention of diabetes.11

Addressing the Core Defect of Insulin resistance

Insulin resistance, which is seen in >80% of Indian patients (“The Thin Fat Indian”), manifests as endogenous glucose overproduction and reduced insulin mediated glucose uptake in both the adipose tissue and skeletal muscles. It

is a very strong independent predictor of cardiovascular events including myocardial infarction and stroke.12 Both metformin & pioglitazone increase insulin suppression of endogenous glucose production and fasting plasma glucose clearance, but only pioglitazone also improves insulin-mediated glucose uptake at all levels.13

Pleiotropic Effects

Unlike metformin, it reduces inflammatory cytokines like MMP-9, CRP, PAI-1, TNF-alpha, etc. and increases the vascular-protective adipokine - adiponectin levels as shown in the PIOCOMB Study.15 Pioglitazone provides consistent reductions in both systolic and diastolic blood pressure in the range of 3-5 mm at end of one year therapy.16 These effects translate into improved endothelial function, reduced carotid intima-media thickness, and improvements in stenosis after stent angioplasty as seen in various clinical trials. It also improves the circulating levels and functional activity of angiogenic endothelial progenitor cells, an independent predictor of CV events and death.17 Moreover, significant positive effects were seen in various organs and CV risk markers.

Clinical Trial Data

The PROactive trial, a prospective, randomized, doubleblind, secondary prevention study in 5,238 patients (50% with previous MI, 25% with previous stroke & 25% with previous peripheral arterial disease), showed that pioglitazone (45 mg) in addition to optimized care, significantly reduced CV death plus non-fatal MI & non-fatal stroke (HR 0.82 [95% CI 0.70-0.97]) in 3 years follow-up period. It reduced subsequent MI by 28%, acute coronary syndrome by 38% and second stroke by 48%.18 In the CHICAGO trial, pioglitazone decreased the progression of carotid intima-media thickness (surrogate marker for future CV events) in 462 patients, over 18 months compared with glimepiride.19 In the PERISCOPE (Pioglitazone effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) study, coronary intravascular ultrasonography in 360 patients with T2DM & CAD, showed a lower rate of progression of atherosclerosis in patients treated with pioglitazone as compared to glimepiride.20 In the DIABAMON project, a meta-analysis investigating the safety of glucose-lowering agents, showed that pioglitazone reduced the risk of CV events by 9% and MI by 10%, with no relation to heart failure.21 In the QUARTET studies, consistent lowering of albumincreatinine ratio (predictor of CKD and future CV events)

217

In a retrospective analysis of 5,290 diabetic patients on dialysis, there was a reduction of risk for all-cause mortality by 35% in patients on pioglitazone, which increased to 47% in patients who received pioglitazone without insulin.23 In a meta-analysis of 19 RCTs with pioglitazone, enrolling 16,390 patients with a study–drug treatment duration ranging from 4 months to 3.5 years, death, MI, or stroke occurred in 4.4% receiving pioglitazone and in 5.7% receiving control therapy (HR 0.82 [95% CI 0.72–0.94]; P = 0.005).24 In a recent trial (IRIS – Insulin Resistance Intervention after Stroke) in 3,876 patients with ischemic stroke or TIA, with no history of diabetes but presence of insulin resistance (HOMA-IR score >3.0), were treated with pioglitazone (45 mg./day) with a follow-up for 4.8 years. It decreased the risk of diabetes by 52% (HR 0.48, 95% CI 0.33-0.69, P>0.0001), while also reducing the risk of subsequent ischemic events, without any evidence of cancer risk.25 In a open cohort study in 469,688 patients with T2DM aged 25-84 years, between 1st April 2007 and 31st January 2015, for the risk of heart failure, cardiovascular disease and all cause mortality, compared to metformin monotherapy, the adjusted hazard ratio for pioglitazone was 0.74 (0.38 to 1.42) for heart failure, 1.03 (0.69-1.54) for cardiovascular disease and 1.38 (1.04-1.83) for all cause mortality, which was much more favourable as compared to sulfonylureas, insulin and gliptins . This study proves the safety and superiority of pioglitazone over other antidiabetic drugs.26

Safety Concerns

Risk of adverse events are weight gain, oedema, congestive heart failure, bone fractures, macular oedema and a possible link with bladder cancer.

Even though a weight gain of about 3-5 kg. has been seen in many studies, paradoxically, it was associated with an improved survival in a post hoc analysis of the PROactive population (HR per 1% weight gain : 0.96[0.92-1.00] P=0.037).27 Oedema, which has been seen in about 5% patients with monotherapy or in combination with other oral drugs, and in about 10% patients when combined with insulin, possibly due to decreased urine sodium excretion, increased plasma renin & aldosterone levels, increased vasodilation & vascular permeability, rarely leads to withdrawal of pioglitazone. Despite these adverse effects, the incidence of heart failure and mortality rates is less with pioglitazone. However, it should not be used in patients with heart failure (> NYHA 1), despite some benefits suggested by various outcome trials.28 Most studies have shown an increased risk of bone fractures with the glitazones especially in postmenopausal women, but the major evidence is from the use of rosiglitazone. A randomized control trial conducted

CHAPTER 40

Pioglitazone increases HDL-c, decreases LDL-particle size and non-HDL cholesterol, decreases fasting triglycerides & plasma free fatty acids, without having any effect on the total cholesterol and LDL-c, leading to favourable CV outcomes.14

was observed with pioglitazone, unlike with metformin or sulfonylurea.22

DIABETES

218

in 86 people with T2DM or IGT with pioglitazone 30 mg./ day for one year, did not show any significant changes in either bone mineral density or bone turnover.29 However, it is prudent to avoid pioglitazone in post-menopausal women and in those with low bone density.

giving us a therapeutic window of 5-7 years, to achieve early glycemic control and obtain the benefits of “Legacy Effect”. It is believed that in comparison to the western population, we are unable to compensate for insulin resistance with insulin secretion to the same extent.

Glitazones use have shown increased risk of Diabetic macular oedema, especially when combined with insulin, however the risk can be mitigated by the concurrent use of ACE inhibitors & aspirin.30 Regular eye check-up should be the norm in patients on pioglitazone.

More important is to know, when not to use this drug – in post-menopausal women & those with low bone density, in heart failure (> NYHA 1), in elderly patients > 75 years at risk of heart failure, and in patients with active bladder cancer or history of bladder cancer.

Diabetes, per se, has been associated with increased risk of various cancers of the liver, pancreas, ovary, colorectum, lung, bladder and breast (HR 1.25[95% CI 1.19-1.31].31 Interestingly, a recent study in > 60,000 patients with T2DM, showed that use of pioglitazone was associated with a significantly decreased risk of liver cancer (OR 0.83 [95% CI 0.72-0.95]), and colorectal cancer (adjusted OR 0.86 [ 95% CI 0.79-0.94].32

Like the intelligent use of any drug, it is prudent to be pharmaco-vigilant and judiciously select the patients.

Ofcourse, patient education about the benefit-risk ratio is of paramount importance. If, one wants a rose, then one should learn to accept the thorns along with it !

However, there have been number of conflicting studies regarding the link with bladder cancer, possibly because of flaws and inherent bias in most of the studies, which has been the major bone of contention. In a very recent large, pooled multipopulation analysis, data collated on 1.01 million persons over 5.9 million person-years showed 3248 cases of bladder cancer, with 117 exposed cases and a median follow-up of 4.0 to 7.4 years. After adjustment for age, calendar year, diabetes duration, smoking, no evidence for any association was found between cumulative exposure to pioglitazone and bladder cancer in men (RR 1.01; 95% CI 0.97-1.06) or in women (RR 1.04; 95% CI 0.97-1.11).33 In another study, conflicting data has been presented, with increased risk of bladder cancer with pioglitazone, in a population based cohort study (HR 1.63; 95% CI 1.222.19).34 In view of such conflicting data, one can assume that there may be a weak link with bladder cancer, and one has to remain vigilant about this adverse event.

Comments

Pioglitazone is a cheap and effective drug, and from the point of benefit-risk ratio, it has a confirmed cardiovascular risk protection with a dubious link to bladder cancer, with odds heavily favoring its use. Moreover, in a developing country like ours with more than 70 million diabetics, cost and affordability plays a significant role in long-term compliance.

It has not only proved its efficacy as compared to other oral drugs, but has also shown greater durability of glycemic response. Moreover, its pleotropic effects, of being lipid friendly and in reducing the inflammatory cytokines, gives it a distinct edge over other oral anti-diabetic drugs, No wonder, it is is still retained as a second-line option in all the guidelines (ADA/ EASD/ AACE/ IDF).

More so, in our scenario, where insulin resistance is the predominating culprit, pioglitazone would be the ideal drug along with metformin in the early stages of T2DM,

REFERENCES

1.

Haffner SM, Mykkanen L, Festa A, Burke JP, Stern MP, “Insulin-resistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive pre-diabetic subjects : implications for preventing coronary heart disease during the pre-diabetic state”. Circulation 2000; 101:975-980.

2.

Unnikrishnan R, Sundramoorthy C, Deshpande N, Sarvothaman R, Sahay RK, Mehtalia S et al, “Eight cases of bladder cancer in pioglitazone users from India”. J Assoc Physicians India 2012; 60-66.

3.

Roden M, Laakso M, Johns D, Widel M, Urguhart R, Richardson C, et al, “Long-term effects of pioglitazone and metformin on insulin sensitivity in patients with Type 2 diabetes mellitus”. Diabet Med 2005; 22:1101-6.

4.

Perriello G, Pampanelli S, Di Pietro C, Brunetti P, “Comparison of glycemic control over 1 year with pioglitazone or gliclazide in patients with Type 2 diabetes”.

Diabet Med 2006; 246-52.

5.

Liu SC, Chien KL, Wang CH, Chen WC, Leung CH, “Efficacy and safety of adding pioglitazone or sitagliptin to patients with type 2 diabetes insufficiently controlled with metformin and a sulfonylurea”. Endocr Pract 2013; 19:980-8.

6.

Balaji V, “Efficacy and safety of pioglitazone intype 2 diabetes in the Indian patients: Results of an observational study”. Indian J of Endocr and Metab 2013; 17:709-15.

7.

Stringer F, DeJongh J, Enya K, Koumura E, Danhof M, Kaku K, “Evaluation of the long-term durability and glycemic control of fasting plasma glucose and glycosylated hemoglobin in Japenese patients with type 2 diabetes mellitus”. Diabetes Technol Ther 2015; 17:215-23.

8.

Jil Mamza et al, “Important differences in the durability of glycemic response among second-line treatment options when added to metformin in type 2 diabetes : a retrospective cohort study”. Annals of Medicine, 10.3109/07853890.2016.1157263, pages 224-234, Published online : 16 Mar 2016.

9.

Russel-Jones D, Cuddihy RM, Hanefeld M et al, DURATION-4 Study Group, “Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naïve patients with type 2 diabetes (DURATION-4): a 26 week double blind study”. Diabetes Care 2012; 35:252-258.

10. Derosa G, “Efficacy and tolerability of pioglitazone in patients with type 2 diabetes mellitus : comparison with

other oral antihyperglycemic agents”. Drugs 2010; 70:19451961.

11. DeFronzo RA, Tripathy D, Schwenke DC et al, “ACT NOW Study. Pioglitazone for diabetes prevention in impaired glucose intolerance”. N Engl J Med 2011; 364:1104-1115.

12. Bonora E, Formentini G, Calcaterra F, Lombardi S, Marini F,Zenari L, et al, “HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabeteic subjects : prospective data from the Verona Diabetes Complications Study”. Diabetes Care 2002; 25:1135-41.

and Safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus : a double-blind, randomized trial.” J Clin Endocrinol Metab 2004; 89:6068-6076.

23. Brunelli SM, Thadhani R, Ikizler TA, Feldman HI. “Thiazolidinedione use is associated with better survival in haemodialysis patients with non-insulin dependent diabetes.” Kidney Int 2009; 75:961-968.

24. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. “ Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus : a meta-analysis of randomized trials.”

JAMA 2007; 298:1180-1188.

25. Silvio E, Inzucchi, Catherine M Viscoli, Lawrence H, Young Karen L Furie,Mark Gorman, Anne M Lovejoy, et al. “Pioglitazone Prevents Diabetes in Insulin-Resistant Patients with Cerebrovascular Disease”. Diabetes Care 2016 Jul 27, DOI: 10.2337/dc16-0798.

14. Van Wijik JP, de Koning EJ, Martens EP, Rabelink TJ. “Thiazolidinediones and blood lipids in type 2 diabetes”.

Arterioscler Thromb Vasc Biol 2003; 23:1744-1749.

26. Julia Hippisley-Cox, Carol Coupland. “Diabetes treatments and risk of heart failure, cardiovascular disease, and all cause mortality : cohort study in primary care”. BMJ 2016; 354:i3477.

16. Derosa G, Fogari E, Cicero AF, et al. “Blood pressure control and inflammatory markers in type 2 diabetes patients treated with pioglitazone or rosiglitazone and metformin”.

Hypertens Res 2007; 30:387-394.

17. Schernthaner G. “Pleiotropic effects of thiazolidinediones on traditional and non-traditional atherosclerotic risk factors”. Int J Clin Pract 2009; 63:912-929.

18. Dormandy JA, Charbonnel B, Eckland DJ, et al. “Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events):a randomized controlled trial”. Lancet 2005; 366:1279-1289.

19. Mazzone T, Meyer PM, Feinstein SB, et al. “Effect of pioglitazone compared with glimepiride on carotid intimamedia thickness in type 2 diabetes: a randomized trial.”

JAMA 2006; 296:2572-2581.

20. Nissen SE, Nicholls SJ, Wolski K, et al PERISCOPE Investigators. “Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes : the PERISCOPE randomized controlled trial.” JAMA 2008; 299:1561-1573.

21. Peter Boyle, Boniol M, Koechlin A,et al.”Safety of glucose lowering medication: The diabetes adverse event monitor(DIABAMON) project: II cardio-vascular disease.”

Diabetes 2013; 1405-P:A367.

22. Schernthaner G, Mathews DR, Charbonnel B, Hanefeld M, Brunetti P, Quartet [corrected] Studu Group. “Efficacy

27. Doehner W, Erdmann E, Cairns R, et al. “Inverse relation of body weight and weight change with mortality and morbidity in patients with type 2 diabetes and cardiovascular co-morbidity : an analysis of the PROactive study population”. Int J Cardiol 2012; 162:20-26.

28. Standl E, Schnell O, McGuire DK. “Heart Fialure Considerations of Antihyperglycemic Medications for Type 2 Diabetes”. Circulation Research 2016; 118:1830-43.

29. Andrew Grey, Mark Bolland, Sheryl Fenwick, Anne Horne, Grey gamble, Paul L Drury, et al. “The skeletal effects of pioglitazone in type 2 diabetes or impaired glucose tolerance : a randomized controlled trial”. European Journal of Endocrinology 2014; 170:255-62.

30. Idris I, Warren G, Donnelly R. “Association between thiazolidinedione treatment and risk of macular oedema among patients with type 2 diabetes”. Arch Intern Med 2012; 172:1005-11.

31. Emerging Risk Factors Collaboration, Seshasai SR, Kaptoge S, Thompson A, Di Anngelantonio E, Gao P, Sarwar N, et al. “Diabetes mellitus, fasting glucose, and risk of causespecific death”. N Eng J Med 2011; 364:829-41.

32. Chang CH, Lin JW, Wu LC, Lai MS, Chuang LM, Chan KA. “Association of thiazolidinediones with liver cancer and colorectal cancer in type 2 diabetes mellitus”. Hepatology 2012; 55:1462-1472.

33. Levin D, Bell S, Sund R, Hartikainen SA, Toumilehto J, Pukkala E, et al. “Pioglitazone and bladder cancer risk : a multipopulation pooled, cumulative exposure analysis”.

Diabetologia 2015; 58:493-504.

34. Marco Tuccori, Kristian B Filion, Hui Yin, Oriana H Yu,Robert W Platt, Laurent Azoulay. “Pioglitazone use and risk of bladder cancer : population based cohort study”.

BMJ 2016; 352:i1541.

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13. Natali A, Ferannini E, “Effects of metformin and thiazolidinediaones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes : a systematic review”. Diabetologia 2006; 49:43441.

15. Hanefeld M, Pfutzner A, Forst T, Kleine I, Fuchs W. “Doubleblind, randomized, multicentre, and active comparator controlled investigation of the effect of pioglitazone, metformin, and the combination of both on cardiovascular risk in patients with type 2 diabetes receiving stable basal insulin therapy : the PIOCOMB study. Cardiovasc Diabetol 2011; 10:65.

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Usefulness of Ambulatory Glucose Profile (AGP) in Diabetes Care

C H A P T E R

41

K Chaithanya Murthy, B Ramya, E Vidya, RM Anjana, V Mohan

ABSTRACT

Over the past decades, several newer technologies have been developed for monitoring blood glucose levels and diabetes control. These include newer glucometers that are plasma glucose calibrated, to Continuous Glucose Monitoring System (CGMS). The latest arrival in the Indian market is the Ambulatory Glucose Profile (AGP).

The AGP is helpful in studying the glycemic variability in patients with diabetes. AGP also helps in taking decisions to change diet, and diabetic medications to achieve smoother diabetic control. This article focuses on the use of AGP in various clinical situations in diabetes practice.

INTRODUCTION

The landmark Diabetes Control and Complications Trial (DCCT) showed that there is a direct correlation between the incidence of microvascular complications and glycated hemoglobin levels in type 1 diabetes.1 The United Kingdom Prospective Diabetes Study (UKPDS) showed the same in type 2 diabetes.2 However in the 1995 report by the DCCT research group,3 the authors showed that even at same level of HbA1c, the risk of progression of microvascular complications (especially retinopathy) was higher in the conventionally treated group compared to the intensively treated group.

This observation led to a hypothesis that there are metrics other than HbA1c that can quantify the risk of developing vascular complications of diabetes.4 Indeed this paved the way for the concept of ‘Glycemic Variability’.5

WHAT IS GLYCEMIC VARIABILITY ?

Glycemic variability (GV) can be defined as the swings in the blood glucose between the maximum (peak) and minimum (nadir). GV per se can contribute to the development of reactive oxygen species (ROS).6,7 There is also evidence to suggest that when human umbilical endothelial cells are subjected to fluctuations of blood glucose, there is an increased activity of protein kinase C.8 Thus, there could be an independent role of GV in the pathogenesis of vascular complications of diabetes.

Conversely, reduction in GV may help prevent the complications. However, as of now this is speculative, as randomized clinical trials are not available at this point of time.

DO WE NEED TO LOOK BEYOND HBA1C ?

The last couple of decades can be termed as the ‘Golden period of HbA1c’. Undoubtedly, HbA1c is the most important tool for accessing diabetes control and this

was rightly acknowledged by the American Diabetes Association (ADA) by including it in the diagnostic criteria for diabetes.9 However, there are other glycemic markers which can be used to assess short term and long term glycemic control in people with diabetes10,11 This is shown in Table 1.

Each of these markers has its own advantages and disadvantages. Of note, GV is a strong independent predictor of mortality in critically ill patients12

HOW DO WE MEASURE GLYCEMIC VARIABILITY ?

There are various indices which are used to measure glycemic variability13-16 and these are listed in Table 2.

1.

Self Monitoring of Blood Glucose (SMBG) :

One can measure glycemic variability by the checking the patients blood glucose over a day.

The data generated can be plotted in the form of a graph with the help of computer software or using a calculator. Various indices like mean, median, J index, Coefficient of variance or mean amplitude of glucose excursion (MAGE) can be estimated manually using SMBG or by using CGMS or AGP (as mentioned below).

The main limitations of SMBG include

•

The requirement of numerous needle pricks to test blood glucose which is difficult and painful to the patient.

•

Both the glucose peak or nadir cannot be assessed as the blood glucose is measured sporadically.

The above limitations underscore the need for a painless, easy to use, compact device for monitoring glucose levels continuously. This is where the CGM comes in.

2.

Continuous Glucose Monitoring (CGM) : A variety of devices have been used to continuously monitor glucose levels. CGM provides us with minute and a precise picture about the glycemic fluctuations of a patient on a day to day basis and helps in better management of diabetes. There are various devices approved by the FDA for CGM and these are summarized in Table 3.

The indications for doing CGMS are shown in Table 4.

3.

Ambulatory Glucose Profile (AGP)

Table 1: Markers Other than HBA1C to Assess Glycemic Control

Table 3: CGM Devices Approved By FDA

• Fasting plasma glucose

• Continuous Glucose Monitoring System (CGMS)

• Post prandial plasma glucose

• GlucoWatch G2 Biographer

• Glycated proteins like albumin

• Guardian Telemetered Glucose Monitoring system

• Fructosamine

• GlucoDay

• 1,5 Anhydroglucitol

• Pendra

• Measurement of Glycemic Variability (GV)

• FreeStyle Navigator Continuous Glucose Monitor

Table 2 : Glycemic variability indices

Table 4 : Indications for continuous glucose monitoring system • Patients with T1DM not meeting HbA1c targets or recurrent diabetic ketoacidosis

• Mean (average) ± standard deviation

• Patient with repeated hypoglycemic episodes or hypoglycemia unawareness

• J index • Coefficient of variance (CV)

• Subjects requiring better glycemic control while avoiding hypoglycemia

• Mean amplitude of glucose excursion (MAGE) • By one time measurement in serum : • 1,5-Anhydroglucitol

• Before or during pregnancy in women with T1DM or T2DM

• Glycated albumin/glycosylated hemoglobin ratio

• Need for improving brittle diabetes

Table 5 :. Differences between AGP and CGMS AGP

CGMS

1. Data available for 14 days

Data available for 3 days

2. Factory calibrated

Calibration for optimal accuracy 3-4 times/day is required

3. No alarms

Alarms for Hypo s and Hyper s

4. Sample patterns

Sample patterns

The concept of ‘AGP’ was the brain child of Dr.Roger Mazze17 from USA who in 1987, first put forth the idea by interpreting the glucose data.

440 glucose values from 69 subjects obtained with the help of reflectance meters containing memory chips were organized into 14-day periods and then reduced into a graphic depiction. These data were the first documented Ambulatory Glucose Profile (AGP) data in the world, and it was represented as the pattern of the 25th, 50th, and 75th percentiles of blood glucose values.17 From that point of time, numerous attempts have been made to interpret

the data in the form of AGP obtained from various devices. In 1987, AGP was initially used for representation of episodic SMBG. In 2001, it was applied to CGM. In 2013, it was applied to Flash Glucose monitoring system.

Freestyle Libre system was developed by Abbott Health care18 and is quite patient friendly and has come to be quite widely used. Table 5 shows the differences between AGP and CGMS.19,20

CHAPTER 41

Using Self monitoring of blood glucose (SMBG) or Continuous glucose monitoring system (CGMS) :

221

DIABETES

222

Fig. 1: Two weeks average summary of glucose readings Figure 1 shows the overall trends showing low readings in the night around 2 AM followed by a huge increase in glucose levels thereafter.

It can be seen in the Figures 1 & 2, that in the night and early morning, the blood sugars are going down almost every day followed by a rise in blood sugar going to hyperglycaemic levels. This is a classic demonstration of the so called ‘Somogyi Syndrome’ which the AGP helped to pick up.

Case 2: Use of AGP in Gestational Diabetes Mellitus A 30 year old primigravida was diagnosed with gestational diabetes mellitus (GDM) in the second trimester of pregnancy. Her fasting plasma glucose was 101 mg/dl and post randial plasma glucose was 166 mg/ dl and HbA1c, 7.1 %. She was started on tablet Metformin 500 mg once daily in the morning. AGP was initiated to monitor the glycemic control. AGP (Figure 4) showed gradual improvement in the post prandial spike with a few low sugar readings in the afternoon hours. Diet modification was done to reduce the hypoglycemic episodes. Thus, with the help of AGP, excellent glycemic control was achieved and also the hypoglycemic episodes were corrected.

Fig. 2 : Daily glucose summary

CLINICAL SCENARIOS FOR USE OF AGP

Case 1: Suspected Somogyi syndrome (Low sugar followed by high sugars) 58 year old Mr. X who is diagnosed to have diabetes at the age of 28. His HbA1c was not getting under control and he was admitted at our centre for glycemic control. He was on a basal bolus regimen of Insulin. His blood glucose levels were normal for persisting high fasting hyperglycemia.

During his stay in the hospital, his 3 AM blood glucose was checked with a glucometer which showed values in the range of 115 to 130 mg/dl. He never had symptoms of nocturnal hypoglycemia. He was advised AGP and his AGP profile is shown in Figures 1 & 2.

Case 3 : Use of AGP in early onset type 2 Diabetes Mellitus This is a case of 20 year old male patient with newly detected type 2 diabetes mellitus. His FPG was 352 mg/dl and PPPG was 433 mg/dl and HbA1c was 8.2%. He was started on Tab. Gliclazide and metformin combination in the morning and night along with basal insulin at night.

AGP was initiated to see the response of the treatment and to know the fluctuations in the blood glucose values.

Figures 5 & 6 show that by the end of the first week, there was significant improvement in the blood glucose values.

By the second week, almost near normal blood glucose levels were obtained.

Later a second AGP was installed.

Figures 7 & 8 present the second AGP results showing the excellent blood glucose targets were achieved with a

223

CHAPTER 41

Fig. 3: Two weeks average summary of glucose readings

Fig. 4 : Daily glucose summary

Fig. 6 : Daily glucose summary

Fig. 5: Two weeks average summary of glucose readings

DIABETES

224

Fig. 7: Two weeks average summary of glucose readings

Fig. 8: Daily glucose summary

Fig. 10: Daily glucose summary

Fig. 9: Two weeks average summary of glucose readings few hypoglycemic episodes. After two months, his blood glucose values were FPG 102 mg/dl and PPPG 142 mg/dl with a HbA1c - 5.6%. In this case, the AGP has helped us to analyse the glycemic control after initiation of treatment and the effect of early and aggressive treatment with insulin. As the patient started developing hypoglycemic

episodes, the insulin was stopped and later the dose of oral hypoglycemic agents was also reduced.

Case 4: AGP in type 1 Diabetes Mellitus This is a case of 15 year old girl with type 1 DM of 14 year duration. Her blood glucose values were FPG 262 mg/

dl and PPPG 476 mg/dl and HbA1c was 12.1%. She was started on Continuous Subcutaneous Insulin Infusion (CSII) pump with two basal doses and three pre meal bolus doses. AGP was initiated to know the pattern of her blood glucose values (Figures 9 & 10). With the titration of basal bolus doses, the blood glucose levels started settling and she started developing hypoglycemic episodes during the night and early morning hours. The night dose basal insulin was decreased accordingly. Thus AGP enabled us to detect the fluctuations in blood glucose levels and to adjust the doses accordingly.

REFERENCES

1.

DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin dependent diabetes mellitus.

N Engl J Med 1993; 329:977-86.

2.

UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS34). Lancet 1998; 352:854-65.

3.

DCCT Research Group. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes 1995; 44:968-83.

4. Hirsch IB, Brownlee M. Should minimal blood glucose variability become the gold standard of glycemic control? J Diabetes Complications 2005; 19:178-81.

5.

Glycemic Variability: How Do We Measure It and Why Is It Important? Diabetes Metab J 2015; 39:273-282

6.

Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414:813-820.

7.

Quagliaro L, Piconi L, Assalone R, Martinelli L, Motz E, Ceriello A. Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells. The role of Protein Kinase C and NAD(P) H- Oxidase activation. Diabetes 2003; 52:2795-2804.

Du X, Matsumura T, Edelstein D, Rossetti L, Zsengellér Z, Szabó C, Brownlee M. Inhibition of GAPDH activity by poly (ADP-ribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells. J Clin Invest. 2003; 112:1049-57.

9.

Classification and Diagnosis of Diabetes., American Diabetes Association Diabetes Care. 2016; 39:S13-S22.

225

10. Dungan KM. 1,5-anhydroglucitol (GlycoMark) as a marker of short-term glycemic control and glycemic excursions.

Expert Rev Mol Diagn 2008; 8:9-19 11. Takahashi S, Uchino H, Shimizu T, Kanazawa A, Tamura Y, Sakai K, Watada H, Hirose T, Kawamori R, Tanaka Y. Comparison of glycated albumin (GA) and glycated hemoglobin (HbA1c) in type 2 diabetic patients: usefulness of GA for evaluation of short-term changes in glycemic control. Endocr J 2007; 54:139-144 12. Glycemic variability: A strong independent predictor of mortality in critically ill patients. Krinsley JS. Crit Care Med 2008; 36:3008-3013.

13. Rodbard D. New and improved methods to characterize glycemic variability using continuous glucose monitoring.

Diabetes Technol Ther 2009; 11:551-65.

14. Service FJ. Glucose variability. Diabetes 2013; 62:1398-404.

15. DeVries JH. Glucose variability: where it is important and how to measure it. Diabetes 2013; 62:1405-8.

16. Rodbard D. Clinical interpretation of indices of quality of glycemic control and glycemic variability. Postgrad Med 2011; 123:107-18.

17. Mazze R, Lucido D, Langer O, et al. Ambulatory Glucose Profile: representation of verified self-monitored blood glucose data. Diabetes Care 1987; 10:111-17.

18. Hoss U, Budiman E, Liu H Christiansen H. Continuous Glucose Monitoring in the Subcutaneous Tissue over a 14Day Sensor Wear Period Diabetes. Sci Technol 2013; 7:12101219.

19. American Association of Clinical Endocrinologists (AACE) American College of Endocrinology (ACE) 2016 Outpatient Glucose Monitoring Consensus Statement. Endocrine Practice 2016; 21:231-261.

20. DCCT/EDIC Research Group. Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the Diabetes Control Intervention and Complications and Pittsburgh Epidemiology of Diabetes Complications experience (1983–2005). Arch Intern Med 2009; 169:1307-16.

CHAPTER 41

SUMMARY

In conclusion, the Ambulatory Glucose Profile (AGP) is a very valuable clinical tool which has now come into routine clinical practice in diabetology. In our experience, the AGP can be used in a variety of clinical situations, type 1 diabetes, type 2 diabetes, gestational diabetes, suspected Somogyi Syndrome and many other conditions. The AGP is reasonably inexpensive and has become very popular in India. In our experience, this is one of the great boons to diabetologists in the management of diabetes.

8.

C H A P T E R

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When Should I Use Newer Insulins?

Paturi Vishnupriya Rao

KEYWORDS

Insulin analogues, newer insulins, hypoglycaemia, variability, flexibility

BACKGROUND

Diabetes is a major public-health problem that is globally reaching epidemic proportions, affecting 415 million people worldwide1. Insulins remain the cornerstone of treatment in type 1 diabetes and also in later stages of type 2 diabetes (T2D). If uncontrolled, diabetes can lead to a myriad of microvascular and macrovascular complications, culminating in premature death. Hence, compliance with therapy is important to prevent the adverse clinical effects of the disease2.

Since its discovery in 1921, insulin preparations have been continually evolving and improving. From animal insulins (bovine and porcine) to human insulin in the late 1940s, research was continuously ongoing due to an increased demand for the same. Further milestones

were the introduction of insulin analogues in the 1990s, initially rapid-acting followed by the long-acting basal analogues in 2000s. And now, we have reached the era wherein the possibility of oral insulin is not too far ahead in the future3.

During the past few decades many manipulations of the insulin molecule have been attempted, in an effort to provide an effective and safer treatment option for patients. The newer insulins have been formulated to allow for a closer replication of a normal insulin profile4.

Despite improvements in both basal and prandial insulin, a number of challenges still remain. Hypoglycemia remains the greatest challenge; it prevents many from achieving optimal glycaemic control, and nocturnal hypoglycemia is feared by many. Missed injections and mistimed injections also pose a problem for many, due to less flexible regimens. Table 1 gives the pharmacokinetics & pharmacodynamics of newer insulins.

Table 1: Key PK/PD data of available insulins in India5 Name

Type

Onset (min)

Peak (hrs)

Duration (hrs)

Human Insulins Regular Human Insulin (RHI)

Short-acting (Prandial)

30 – 60

2–3

5–8

Biphasic human insulin (BHI) 30/70

Premixed

30 – 60

Dual

10 – 16

Biphasic human insulin (BHI) 50/50

Premixed

30 – 60

Dual

10 – 16

Neutral Protamine Hagedorn (NPH)

Intermediate-acting (Basal)

120 – 240

4 – 10

10 – 16

Modern Insulins Aspart

Rapid-acting (Prandial)

5 – 15

0.5 – 1.5

<5

Lispro

Rapid-acting (Prandial)

5 – 15

0.5 – 1.5

<5

Glulisine

Rapid-acting (Prandial)

20

1.5

5.3

Biphasic Insulin Aspart (BIAsp) Premixed 30/70

5 – 15

Dual

10 – 16

Biphasic Insulin Aspart (BIAsp) Premixed 50/50

5 – 15

Dual

10 – 16

Lispro Mix 25/75

Premixed

5 – 15

Dual

10 – 16

Lispro Mix 50/50

Premixed

5 – 15

Dual

10 – 16

Glargine

Long-acting (Basal)

120 – 240

No pronounced peak

Up to 24

Detemir

Long-acting (Basal)

48 – 120

Degludec

Ultra Long-acting (Basal)

30 – 90

Peakless

> 42

Degludec/Aspart (IDegAsp)

Co-formulation

5 – 15

0.5 – 1.5

> 24

Up to 24

An ideal basal insulin would have a flat-time action profile with minimal day-to-day variability. A better rapid-acting insulin would further improve postprandial glucose levels as well as have a shorter time-action profile to avoid late hypoglycaemia, but long enough so that the between-meal glucose levels do not rise too high6.

LIMITATIONS OF CONVENTIONAL INSULINS3 Onset: delayed

•

Advised to inject 30 min before meals – makes the regimen less flexible.

•

Less insulin increase in early phase of glucose absorption à excessive rise in glucose at 1-2 hrs after meal.

• At 4-5 hrs after subcutaneous injection, inappropriate hyperinsulinemia à hypoglycaemia.

•

Defensive snacking, in between meals, to counter hypoglycaemia à weight gain.

•

Glycaemic variability.

•

Dose has a profound effect on time action profile.

WHEN CAN I USE NEWER INSULINS?

Newer insulin analogues can be used to advantage, in a subset of patients with diabetes.

Hypoglycaemia / Recurrent Hypoglycaemia /Hypoglycaemia Unawareness

Fear of hypoglycaemia and its associated risks of accident, coma, or death remains a major obstacle to the pursuit of good glycaemic control7. In general, all insulin analogues have shown lower rates of overall, major and nocturnal hypoglycaemia compared to human insulins.

Newer insulins have a distinct advantage in those patients who have experienced 1 or more hypoglycaemic episodes on their current regime and in those who have hypoglycaemia unawareness.

In a recently conducted study, 22% of Indian patients have deliberately not dosed their insulin as prescribed & 23% let blood glucose (BG) levels go higher to reduce their risk of nocturnal self-treated hypoglycaemia8.

The Cochrane review of rapid-acting insulin analogues vis-à-vis regular human insulin found a lower incidence of severe hypoglycaemic episodes. Individual trials have also reported lower rates of overall, major and nocturnal hypoglycaemia9. Similarly, the Cochrane review of the basal insulin analogues vis-à-vis NPH found significantly lower risks of nocturnal, symptomatic as well as severe hypoglycaemia with glargine and detemir10.

A pre-specified and planned meta-analysis of the phase 3 trials of insulin degludec vs. insulin glargine, showed a 38% reduction in nocturnal hypoglycemia overall in T2D, and 49% in insulin-naïve patients11. This was further corroborated by the SWITCH-2 trial, which showed 30% and 42% significant risk reduction of severe or BG confirmed symptomatic and nocturnal hypoglycaemia respectively12.

227

It is presumed that weight gain is an inevitable consequence of insulin therapy13.

With the advent of insulin analogues which have demonstrated lesser hypoglycaemic episodes, defensive in-between meal snacking is reduced which leads to less weight gain.

Various trials, with insulin degludec, have reported lesser dose required at the end of the trial, compared to its comparators, as reported in a meta-analysis of the phase 3 trials. Lesser insulin dose requirement would also translate into lesser weight gain14.

A meta‐analysis of trials of insulin detemir showed there was significantly less weight gain compared to insulin glargine, despite similar glycaemic control and risk of hypoglycaemia. This weight‐sparing effect appears to be unique to insulin detemir13.

Glycaemic Variability

Glycaemic variability predicts hypoglycaemia and has consistently been related to mortality even in non-diabetic patients. Day-to-day variability of insulin effects could have deleterious consequences and may hamper proper management15.

Insulin detemir and glargine have demonstrated 28% and 48% intra-patient variability, respectively, compared to the 68% with NPH16.

Insulin degludec has gone a step further and demonstrated 75% lesser intra-patient variability vis-àvis insulin glargine, both U100 and U30017. With U100, this was further corroborated in a Japanese study, using continuous glucose monitoring, which showed higher variability with insulin glargine with a significant amount of time spent in hyperglycemia18.

With a flatter and more predictable action profile, the requirement of SMBG also reduces, which is an advantage for those who have difficulties in performing frequent SMBG.

Flexible Timing of Administration

Flexibility of an insulin regime or preparation can be defined as their ability to be injected at variable times, with variable injection‑meal time gaps19.

All insulin analogues offer the advantage of meal time flexibility, i.e. can be taken at the beginning of the meal or even upto 15 mins of starting the meal, as opposed to conventional insulins which need to be injected 30 min before start of the meal2.

The Indian cohort of the GAPP (Global Attitudes of Patients and Physicians in Insulin Therapy) study has reported that 2-in-5 patients had missed a dose of basal insulin within the last 30 days8.

Glargine can be injected at any time of the day, at the same time each day. Insulin degludec can be injected at any time of the day, without regards to the previous

CHAPTER 42

•

Less Weight Gain

228

Table 2: Newer insulins in the pipeline Basal Insulin

Prandial Insulin Available outside India

Glargine U300

Insulin PH20

Degludec U200

Linjeta

Inhaled insulin (Afrezza)

Faster acting insulin aspart

DIABETES

injection timing, provided an 8 h gap is maintained, and upto 40h should a dose be missed19.

Special Situations

• Pregnancy

Given the importance of excellent glycaemic control in pregnancy and the problem of hypoglycaemia, insulin analogues may offer potential benefits in pregnant women with diabetes.

Amongst the rapid-acting analogues, insulin lispro and aspart are safe in pregnancy and may improve post-prandial glycaemic control.

Insulin detemir has shown improved fasting glucose compared to NPH, without an increased incidence of hypoglycaemia20.

All these 3 insulins are approved and are classified as Category B drugs for use in pregnancy.

• Elderly

Recurrent hypoglycaemia is common in older people with diabetes. It is less recognized and usually under-reported. Hypoglycaemia is associated with significant morbidities, more so in the elderly, as it can lead to both physical and cognitive dysfunction21.

If insulin therapy is required, then this subset of patients may benefit from the newer insulins, as they have reports of significantly lesser hypoglycaemic episodes, especially nocturnal hypoglycaemia.

• Children

Insulin analogues have a distinct advantage in children. They offer meal-time flexibility (this is not only effective for good glycaemic control but also helps combat erratic children behaviour, for children who are reluctant to eat) and reduced rates of hypoglycaemia22.

Amongst the rapid-acting analogues, insulin aspart can be used for children >2 years, lispro for >3 years and glulisine for >6 years. Amongst the basal analogues, insulin glargine can be used for children > 2 years and detemir for > 1 year.

Intensification

At some point after initiation of therapy with basal insulin, it will no longer be enough and increasing the basal dose alone will be inadequate. At that point,

addition of mealtime coverage will be needed to address the postprandial levels23.

Conventionally, after basal failure the options to intensify therapy are by adding a shot of prandial insulin to the largest meal or switching to premixed insulin.

At this point, IDegAsp offers the convenience of a “basalplus” regimen, in a single device.

IDegAsp is a novel co-formulation of basal insulin degludec (IDeg) and rapid-acting insulin aspart (IAsp) (ratio 70% IDeg: / 30% IAsp), available as a single subcutaneous injection.

The clinical trial program of IDegAsp has demonstrated comparable glycaemic efficacy and similar hypoglycaemia rates compared with standard basal–bolus treatment, with fewer shots and two different insulins in the same device.

In comparison to premixed analogues, IDegAsp provided effective reduction in HbA1c comparable with BIAsp30, with superior reductions in FPG levels24. A subsequent combined analysis has also demonstrated lower overall rates of confirmed and severe hypoglycaemia, and a significantly lower rate of nocturnal hypoglycaemia, with twice-daily IDegAsp vis-à-vis BIAsp3025.

EXAMPLES OF PATIENT PROFILES WHO MAY BENEFIT FROM NEWER INSULINS19

•

Persons with erratic meal timings

•

Persons with irregular exercise schedules

•

Those who have a busy lifestyle, who cannot inject at the same time every day

•

Those who depend on others for assistance in insulin injection

•

Those who cannot monitor blood glucose frequently

•

Shift workers

•

Those who travel frequently, warranting a change in time zone.

FUTURE INSULINS AND DELIVERY SYSTEMS (TABLES 2 & 3)

Continued progress in the field of newer insulins is on as well with research extending to developing other routes of insulin administration.

The concept of a smart insulin involves an insulin that would be responsive to the existing plasma glucose levels and would work more effectively when glucose levels are high and less effectively when glucose levels are lower5.

Continuous Subcutaneous Insulin Infusion (CSII) is emerging as the gold standard akin to the artificial pancreas. Steady progress is being made towards this, which will ultimately be a fully automated, closed-loop, glucose control system comprising a continuous glucose monitor, an insulin pump, and a controller. Although glycaemic efficacies in CSII are similar, safety data show lower pump occlusion rates with insulin aspart (9.2%) compared with lispro (15.7%) and glulisine (40.9%)27.

229

Table 3: Alternative routes of insulin administration26,27 Advantage

Disadvantage

Pulmonary/ Inhaled

• High permeability • Large surface area • Rich vasculature • Lack of mucociliary clearance • Immunotolerance

• Low bioavailability (9 – 22%) • Variation in absorption • Large quantity insulin required • Cannot be used by smokers.

• Mild to moderate cough, shortness of breath, sore throat, dry mouth

Oral

• Easy and convenient • Patient compliance • Easily accessible route

• Low bioavailability (1%) • Proteolytic degradation in GIT. • First-pass hepatic metabolism • Large quantity insulin required • High resistance by intestinal epithelial barriers

Transdermal

• Large surface area • Micro-needle approach increases insulin permeability.

• Can use iontophoresis & sonophoresis techniques

• Skin is impermeable • Variability in dosing

Nasal

-Large absorptive surface -High vascularity

• Low bioavailability (8-15%) • Degraded by proteolytic enzymes • Nasal irritation • Nasal tolerance • High rates of treatment failure • Mucociliary clearance • Inconsistent absorption

Ocular

• Fast systemic absorption • No first-pass hepatic metabolism

• Low bioavailability • Local irritation

Rectal

• Avoids local enzymatic degradation • Local adverse reactions • Insulin enters systemic circulation via the • Low and variable levels of absorption lymphatic system.

• Local irritation • No first-pass hepatic metabolism

Buccal

• No first-pass hepatic metabolism • Good accessibility • Drug is in direct mucosal contact, • Avoids acidic pH of stomach • Large surface for absorption • High vascularity • Quite robust • Improved compliance

• No first-pass hepatic metabolism • Good accessibility • Drug is in direct mucosal contact, • Avoids acidic pH of stomach • Large surface for absorption • High vascularity • Quite robust • Improved compliance

Patch Pad25

• Ease of use, accuracy • Predictability • Ability to calculate bolus insulin doses based on user-input

• Temporary unavailability of a controller device • Pump size (form factor) • Adhesive intolerance • Poor adherence

For many patients, administering insulin by subcutaneous injection seems like a daunting therapy option.

Consequently, research is being undertaken on alternative methods for administering insulin. An ideal route for insulin delivery should have the ability to provide effective and predictable lowering of blood glucose level.

Continuous subcutaneous insulin infusion (CSII), popularly known as the ‘insulin pump’ provides a precise and controlled rate of insulin delivery to diabetic patients who would normally need multiple daily injections to regulate blood glucose levels. The main benefit of insulin pump therapy is the flexible and accurate basal and bolus

CHAPTER 42

Route

230

dosing to meet patient’s individual insulin requirements while reducing the risk of severe hypoglycaemia.

SUMMARY

DIABETES

The advent of newer long-acting analogues with more physiological basal profile holds promise, as does the new co-formulation with the convenience of a “basalplus” regime in a single device. Additionally, it has be to kept in mind, that human insulins may have a modestly higher projected cost as the impact of hypoglycaemia is not accounted for.

Newer insulins, although expensive, offer some distinct advantages over existing ones. They reduce the rates of hypoglycaemia (especially nocturnal hypoglycaemia), have lower levels of postprandial glucose excursions (for the rapid acting analogues), better patient adherence, greater quality of life, and higher satisfaction with treatment. They offer flexibility in daily dosing and have the added advantage of reduced glycaemic variability.

REFERENCES

1.

International Diabetes Federation. IDF Diabetes Atlas, 7th edn. Brussels, Belgium: International Diabetes Federation, 2015. http://www.diabetesatlas.org

2.

Kaur J, Badyal DK. Newer insulins. JK Science 2008; 10:10711.

3.

Tibaldi JM. Evolution of Insulin Development: Focus on Key Parameters. Adv Ther 2012; 29:590–619

4.

Cahn A, Miccoli R, Dardano A,Del Prato S. New forms of insulin and insulin therapies for the treatment of type 2 diabetes. Lancet Diabetes Endocrinol 2015; 3:638–52

5.

Unnikrishnan AG, Singh AK, Modi KD, Saboo B, Garcha SC, Rao PV. Review of Clinical Profile of IDegAsp. J Assoc Physicians India 2015; 63:15-20

6.

Woo VC. New Insulins and New Aspects in Insulin Delivery. Can J Diabetes 2015; 39:335-43

7.

Hartmann I. Insulin Analogs: Impact on Treatment Success, Satisfaction, Quality of Life, and Adherence. Clin Med Res 2008; 6:54–67

8.

Global Attitudes of Patients and Physicians in Insulin Therapy Survey. Data on file. Novo Nordisk A/S.

9.

Siebenhofer A, Plank J, Berghold A, Jeitler K, Horvath K, Narath M, et al. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus.

Cochrane Database Syst Rev 2006; (2):CD003287.

10. Horvath K, Jeitler K, Berghold A, Ebrahim SH, Gratzer TW, Plank J, et al. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev 2007; (2):CD005613.

11. Ratner RE, Gough SC, Mathieu C, Del Prato S, Bode B, Mersebach H, et al. Hypoglycaemia risk with insulin degludec compared with insulin glargine in type 2 and type 1 diabetes: a pre-planned meta-analysis of phase 3 trials. Diabetes Obes Metab 2013; 15:175-84 12. Wysham C, Bhargava A, Chaykin L, de la Rosa R, Handelsman Y, Troelsen LN. SWITCH 2: reduced hypoglycemia with insulin degludec (IDeg) versus insulin glargine (IGlar), both U100, in patients with T2D at high

risk of hypoglycemia: a randomized, double-blind, crossover trial. Poster session presented at: ADA, 76th Scientific Session of the, American Diabetes Association; 2016 Jun 10-14; New Orleans, Louisiana.

13. Russell-Jones D, Danne T, Hermansen K, Niswender K, Robertson K, Thalange N, et al. Weight-sparing effect of insulin detemir: a consequence of central nervous systemmediated reduced energy intake? Diabetes Obes Metab 2015; 17:919-27 14. Vora J, Christensen T, Rana A, Bain SC. Insulin Degludec Versus Insulin Glargine in Type 1 and Type 2 Diabetes Mellitus: A Meta-Analysis of Endpoints in Phase 3a Trials.

Diabetes Ther 2014; 5:435–46.

15. Hans DeVries JH. Glucose Variability: Where It Is Important and How to Measure It. Diabetes 2013; 62:1405-8.

16. Heise T, Nosek L, Rønn BB, Endahl L, Heinemann L, Kapitza C, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes 2004; 53:1614-20.

17. Heise T, Hermanski L, Nosek L, Feldman A, Rasmussen S, Haahr H. Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes. Diabetes Obes Metab 2012; 14:859-64.

18. Hamasaki H, Nakayama T, Yamaguchi A, Moriyama S, Katsuyama H, Kakei M, et al. Comparison of Glycemic Variability by Using Insulin Glargine and Insulin Degludec in Japanese Patients With Type 1 Diabetes, Monitored by Continuous Glucose Monitoring: A Preliminary Report. J Endocrinol Metab 2013; 3:138-46 19. Kalra S, Gupta Y, Unnikrishnan AG. Flexibility in insulin prescription. Indian J Endocr Metab 2016; 20:408-11.

20. Lambert K, Holt RI. The use of insulin analogues in pregnancy. Diabetes Obes Metab 2013; 15:888-900.

21. Abdelhafiz AH, Rodríguez-Mañas L, Morley JE, Sinclair AJ. Hypoglycemia in older people - a less well recognized risk factor for frailty. Aging Dis 2015; 6:156-67.

22. Danne T, Bangstad H-J, Deeb L, Jarosz-Chobot P, Mungaie L, Saboo B, et al. Insulin treatment in children and adolescents with diabetes. Pediatric Diabetes 2014; 15:115–34 23. Garber AJ. Insulin intensification strategies in type 2 diabetes: when one injection is no longer sufficient. Diabetes Obes Metab 2009; 11:14-8.

24. Atkin S, Javed Z, Fulcher G. Insulin degludec and insulin aspart: novel insulins for the management of diabetes mellitus. Ther Adv Chronic Dis 2015; 6:375–88.

25. Christiansen JS, Niskanen L, Rasmussen S, Johansen T, Fulcher G. Lower rates of hypoglycemia during maintenance treatment with insulin degludec/insulin aspart versus biphasic insulin aspart 30: a combined analysis of two Phase 3a studies in type 2 diabetes. J Diabetes 2016; 8:720-8.

26. Kumria R et al. Emerging trends in insulin delivery. Journal of Diabetology, 2011; 2:1 27. Anhalt H, Bohannon NJV. Insulin Patch Pumps: Their Development and Future in Closed-Loop Systems. Diabetes Technol Ther 2010; 12:S51–8.

C H A P T E R

43

DPP- 4 Inhibitors in the Management of Type 2 Diabetes Mellitus

KEY WORDS

Antihyperglycemic drug, Clinical trial, Diabetes, DPP-4 inhibitor, Glucagon Like Peptide -1 and Incretin

INTRODUCTION, HISTORY AND EVOLUTION OF INCRETINS

Dipeptidyl peptidase-4 (DPP- 4) inhibitors or Gliptins are a class of antihyperglycemic agents used in treatment of type 2 diabetes mellitus (T2DM). They reversibly inhibit DPP- 4, a serine protease enzyme which degrades incretins like Glucose dependent Insulinotropic polypeptide (GIP) and Glucogan like peptide 1 (GLP-1) from intestine.

Hence biological active levels of Incretins are increased that control the levels of fasting and postprandial glucose concentration within minutes through its pleotropic mechanism.1 Incretins stimulates insulin secretion and suppresses glucagon in a glucose dependant manner along with decreased hepatic glucose production and gastric emptying. Although metformin is preferred for T2DM, insulin, sulfonylureas and thiazolidinediones are recommended as second line drugs to optimize glycemic

Balamurugan Ramanathan

control.2 Nevertheless, intensive use of these therapies, they were associated with multiple risk factors like hypoglycemia, bone fracture, weight gain, cardiovascular, renal and other comorbities. This led to a new modality of treatment like incretin based therapy with specific interest on DPP-4 inhibitors. Table 1 gives the historical perspective of incretins.

Glucagon-like peptide -1 Receptor (GLP-1R) agonists and DPP IV inhibitors were the two classes of incretin based therapies approved for T2DM. They either promote weight loss (GLP-1 Receptor agonist) or do not affect body weight (DPP –IV inhibitor) and cause no risk of hypoglycemia. Hence Incretin based therapy offers a good treatment option for T2DM.3

DPP IV INHIBITORS ADDRESSING THE KEY PATHOGENIC DEFECT IN T2DM

The key pathological defects in type 2 diabetes occurs due to impaired insulin secretion through progressive

Table 1: Historical perspectives of Incretins and Evolution of Incretin based therapy Year

Development

1902

Mechanism of Pancreatic Secretion by William M Bayliss, Ernest H Starling

1932

La Barre et al coined the term Incretine (Incretin) and defined its effect

1964

Incretin effect (Significant Insulin release on oral ingestion than Intravenous injection) demonstrated through radio Immunoassay by Elrick et al, Mcintyre et al.

1966

DPP –4 enzyme first described

1970

GIP discovered

1973

GIP demonstrated

1985

GLP 1demonstrated

1995

GIP & GLP 1 were demonstrated to be degraded by DPP-4 enzyme

2002

GLP 1 – Exendin -4 extracted

2005

Exenatide introduced

2006

Sitagliptin introduced for the use of T2DM

2007

Vildagliptin

2009

Saxagliptin

2010

Alogliptin

2011

Linagliptin

Recent GLP 1 R agonist

Liraglutide (2010), Albiglutide(2014), dulaglutide (2014) Taspiglutide semaglutide are under investigation

Recent DPP IV inhibitors

Anagliptin,Gemigliptin, Teneligliptin in 2012; Evogliptin, Omarigliptin and Trelagliptin in 2015.

DPP-4: Dipeptidylpeptidase-4, GIP: Glucose dependent Insulinotropic polypeptide, GLP-1: Glucagon-like peptide -1, T2DM: Type 2 Diabetes Mellitus.

DIABETES

232

Table 2: Comparison of action of DPP-4 inhibitors and GLP-1 receptor agonists Action

DPP-4 inhibitors

GLP-1 receptor agonists

Insulin secretion

Increased

Increased

Glucagon Secretion

Decreased

Decreased

PPPG

Reduced

Reduced

Appetite

No effect

Suppressed

Satiety

No effect

Induced

Gastrointestinal adverse effects

Rare to none

Often Nausea

Gastric emptying

No effect

Slowed

Body weight

Neutral

Reduced

DPP-4: Dipeptidylpeptidase-4, GLP-1: Glucagon-like peptide -1

deterioration of pancreatic β-cell function and increased insulin resistance in peripheral tissues (in both liver & skeletal muscle) which results in elevated fasting and postprandial glucose levels leading to hyperglycemia.4 Dysregulation in the incretin effect characterized by reduced GLP-1 secretion and impaired responsiveness to GIP is another major defect in T2DM. Glucagon-like peptide 1 and GIP are intestinal incretin hormones released in response to food ingestion. GLP1, secreted from intestinal L cells, is an incretin derived from the transcriptional product of the proglucagon gene.

GIP is derived from K cells, a 153-amino acid proprotein encoded by the GIP gene and circulates as a biologically active 42-amino acid peptide. Both GLP-1 and GIP enhance meal-related insulin secretion and promote glucose tolerance, a phenomenon called ‘incretin effect’.5 Besides insulin secretion enhancement via cAMP-dependent signalling pathways, GLP-1 also suppress glucagon secretion from pancreatic alpha cell in highly glucosedependent manner, and glucagon secretion is inhibited under hyperglycaemic conditions and even increased under hypoglycaemia. In addition GLP-1 regulates glucose homeostasis through its beneficial effects such as slowing of gastric emptying which decreases the entry of glucose into the circulation after meals, a reduction in appetite, and earlier induction of satiety, leading to weight reduction. GLP-1 also promotes beta-cell regeneration and reduces beta-cell apoptosis, which provide hope for preservation of beta-cell functions in T2DM patients.

However upon secretion, GLP-1 and GIP are rapidly degraded and inactivated by dipeptidyl peptidase 4 (DPP-4) enzyme (also known as CD26), a 110-kDa trans membrane glycoprotein constitutively expressed as a dimer on epithelial cells of the liver, hepatocytes, kidney and intestinal tissues, as well as in some endothelial cells, fibroblasts and lymphocytes. Endogenously released GLP-1 has a short biological half-life of 1.5–5 min and the serum half-life of GIP is 5–7 min. In order to prevent degradation of endogenously released GLP-1 and

GIP, and to extend their half-life, led to the proposal of development of DPP-4 inhibitors.

DPP-4 INHIBITORS (INCRETIN ENHANCERS) VERSUS GLP-1 RECEPTOR AGONISTS (INCRETIN MIMETICS)

GLP-1 receptor agonists and DPP-4 inhibitors has been compared head-to-head in few long-term clinical trial, it is difficult to identify the patient population most likely to respond optimally to these two groups of drugs.6 DPP IV inhibitors are small molecular weight drugs generally well tolerated and are effective orally. When used either as monotherapy or in combination with metformin, sulphonylureas or a combination of both, they are relatively easy to use and can be used in elderly, frail or vulnerable, renal and hepatic impairment patients. They are also associated with lower rates of hypoglycemia , reduction in HbA1c levels (0.6 to 0.7 %), and have also been shown to be weight neutral. Because they do not cause hypoglycaemia, they do not require dose titration and can be taken at any time of day, independently of meal times. They are also generally free of drug– drug interactions and can mostly be used with other medications without the need for dose adjustment of either agent. Neither the pharmacokinetic profiles of nor exposure to other commonly used medications, including drugs which alter the activity of the CYP system [e.g. ketoconazole, rifampicin (rifampin) and ritonavir] or the P-glycoprotein transporter (e.g. cyclosporine) are affected in a clinically relevant manner by DPP-4 inhibitors. DPP-4 inhibitors may, therefore, be useful in conditions such as tuberculosis or HIV, which often present with diabetes as a side effect of the disease.

In contrast Incretin mimetics or GLP1 R agonists are peptide based drugs administered as subcutaneous injection to avoid degradation by gastrointestinal hormones. Compared to DPP IV inhibitor they are more effective in reducing HbA1c levels due to its increased concentration (6 to 10 fold) after injection. GLP-1 receptor agonists are associated with high rates of nausea due to gastric slowing, causes significant weight loss, especially in very obese patients, whereas DPP-4 inhibitors are weight neutral agents.

The main patient-perceived difference between DPP4 inhibitors and GLP-1R agonists is likely to be their mode of administration and convenient once-daily oral dosing that promote patient adherence and improve health outcomes.7, 8 Although it is believed that patients generally oppose injectable therapies, evidence suggests that this is not always the case, especially if the injectable therapy has greater efficacy. A comparison of the actions of the DPP-4 inhibitors and GLP-1 receptor agonists in patients with T2DM is provided in Table 2.

DPP-4 INHIBITORS

Dipeptidyl peptidase-4 inhibitors can be broadly divided into peptidomimetics (i.e., sitagliptin, gemigliptin, teneligliptin, vildagliptin, saxagliptin, and anagliptin) and non-peptidomimetics (i.e., alogliptin and linagliptin).

Both are competitive reversible inhibitors of the DPP-4

Alogliptin Approval 2010 date Peptidomimetic Pharmacodynamics IC50 for 7 DPP-4 inhibition (nmol/L) DPP-4 >14000 selectivity (vs DPP-8 and 9) % Inhibition 75-93 of plasma DPP-4 activity 3-4 Fold increase in active GLP1 level Reduction in HbA1C (%) Pharmacokinetics Oral bio100 availability (%) Volume of 417 distribution (Vd, L) 20 Fraction bound to plasma proteins (%) Half-life 21.1 (hr) Renal 63.3-76 excretion (%) >70

2-3

>80

1.8-2.8

17-21 63.4

4.37

73.2

73

>10000

27728, 23373

59000, 100000

<10

70

5

75

2.2-3.8

151

368-918

120-184

75

0.5-1.2

1.5-2

>70

390, 77

0.5

+

29.5

1

6.31

3.8

-

+

Evogliptin Gemigliptin Linagliptin Omarigliptin Saxagliptin 2015 2012 2011 2015 2009

+

Anagliptin 2012

75-87

8-14

38

198

71-88

2

>80

4777, 10926

18

+

3.5

135, 8

0.9-1.8

703, 1460

84-85 70.5 9.3

2.8 85

58-83 106.8 77.6-82.2

16-20 35.8

2-3

>80

+

+

Sitagliptin Teneligliptin Trelagliptin Vildagliptin 2006 2012 2015 2007

CHAPTER 43

Table 3: Comparison of different properties of available DPP-IV inhibitors

233

No

No

22.6

2-4.5

In 1990s kinetic properties and substrate specificity of DPP-4 enzyme inhibitors were studied which provided knowledge for the basis of DPP – 4 inhibitor concept and was used in developing several DPP – 4 inhibitors which were identified in drug discovery programmes based on structure-activity profiling.

Cyp3A4, Cyp2C8

No

Cyp3A4

Hydroxylated metabolite (50% activity of parent drug)

Cyp3A4, Cyp2D6, FMO1, FMO3

79 24

40.9

13-21 22

33.3

DPP-4 inhibitors differ widely in their chemistry and pharmacokinetic, pharmacodynamic clinical characteristic and safety profiles.9 (Shown in Table -3) Sitagliptin was the first member of DPP-4 inhibitors launched in 2006, with new drugs continuing to be approved (Anagliptin,Gemigliptin, Teneligliptin in 2012; Evogliptin, Omarigliptin and Trelagliptin in 2015), and the class is now an established therapy. Intense research activities towards these inhibitors have resulted in seventeen gliptins. Out of these, eleven DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, anagliptin, teneligliptin, trelagliptin, omarigliptin, evogliptin, and gemigliptin) are currently approved for clinical use in various countries while others are advancing into pre-registration/phase 3 and looking forward for approval. DPP-4 inhibitors are widely used in various combination regimens because of their robust efficacy, good tolerability, and overall favorable safety profiles.10

No No M-I (3% of parent drug activity; M-II not active) Active metabolites

Cyp3A4 Unknown Cyp3A4, Cyp2D6

90 50 95

90

26 10-13

Approval date Faecal excretion (%) % Excreted unchanged Metabolism

Anagliptin 2012

85

CURRENT STATUS OF CARDIOVASCULAR SAFETY OF DPP IV INHIBITORS

27.1

Sitagliptin Teneligliptin Trelagliptin Vildagliptin 2006 2012 2015 2007 Evogliptin Gemigliptin Linagliptin Omarigliptin Saxagliptin 2015 2012 2011 2015 2009

substrate acting extracellularly.

Alogliptin 2010

Table 3: Comparison of different properties of available DPP-IV inhibitors is given in table

DIABETES

234

The effects of glucose-lowering agents on the incidence of cardiovascular AEs have been extensively debated in recent years so that the cardiovascular safety and potential protection of antidiabetic agents is currently a major issue. T2DM is associated with increased risk of micro and macrovascular complication leading to increased athero-thrombotic events which results in cardiovascular morbidity and mortality. DPP-4 inhibitors may increase the circulating numbers of bone-marrow derived stem cells that repair injured vascular endothelial cells, this phenomenon led to investigation of clinical trials.11 Currently DPP-4 inhibitors are the first antihyperglycemic agent which undergoes comprehensive investigation of clinical trials for assessing its cardiovascular safety.

DPP-4 inhibitors control blood pressure via regulation of natriuresis independent of its glucose reduction action, especially in individuals with salt-sensitive hypertension.

A recent study provided the first evidence for a complex interactive hemodynamic effect of DPP-4 and angiotensinconverting enzyme (ACE) inhibition in humans.DPP4 inhibitors (Sitagliptin) reduced postprandial plasma levels of triglyceride rich lipoproteins of both intestinal and hepatic origin. This effect is most likely mediated by increasing incretin hormone levels, reducing circulating plasma free fatty acid concentrations and improving insulin sensitivity and B-cell function. Reductions in hsCRP, soluble vascular cell adhesion molecule and microalbuminuria have also been observed with the use of gliptins.12 In T2DM, microalbuminuria is not only

considered as a marker of early nephropathy, but also as a marker of widespread endothelial dysfunction. Therefore, disappearance of microalbuminuria, when possible, may also reflect improvement of endothelial function with DPP-4 inhibitors reducing macrovascular disease as well.

Results of a recent meta-analysis of 18 trial has shown that overall use of DPP-4 inhibitors was associated with a lower risk of adverse CV effects [risk ratio (RR) = 0.48, 95% CI = 0.31–0.75, p = 0.001] and a lower risk of nonfatal myocardial infarction or acute coronary syndrome (RR = 0.40, 95% CI = 0.18–0.88, p = 0.02) compared to placebo or other oral hypoglycemic agents.13

of hypoglycemia and also weight neutrality. The efficacy and safety of DPP-4 inhibitors in elderly patients with T2DM have been demonstrated in RCTs with sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin.16, 17 Renal impairment

With reduced glomerular filtration rate (GFR), toxicity of the oral drugs increases as the drugs tend to accumulate in the body. Except linagliptin every gliptin dose has to be reduced in case of moderate to severe renal impairment (RI) (Table 4).

Sitagliptin has shown reduction of HbA1c in case of moderate/severe RI and in end-stage renal disease (ESRD) patients who are undergoing dialysis. It can also be given after kidney transplant and reduces albuminuria. Saxagliptin dose has to be reduced to half in moderate-severe RI. Trial results shows after 52 weeks the reduction in HbA1c was greater with saxagliptin than with placebo in the subgroups of patients with moderate and severe RI, but not in the subgroup with ESRD on hemodialysis. In pooled analysis, it has been found that vildagliptin is also safe and effective in case of mild/moderate RI. No dose adjustment is necessary for linagliptin.18

3.

Hepatic impairment

Only mild changes in pharmacokinetic characteristics of sitagliptin, vildagliptin, saxagliptin, linagliptin and alogliptin were observed in patients with different degrees of hepatic impairment, presumably without major clinical relevance. No significant changes in liver enzymes were reported with DPP-4 inhibitors alone or in combination with various other glucoselowering agents, in clinical trials up to 2 years.

Warning against a potential risk of hepatotoxicity of alogliptin has been reported by the FDA but overall the set of available data from RCTs and reallife condition provides reassurance and if present the risk of liver injury appears very low. Except vildagliptin, all the gliptins are recommended in case of hepatic insufficiency.

DIFFERENT CLINICAL TRIAL PROGRAMMES OF DPP IV INHIBITORS

Following concerns about the uncertainty regarding the cardiovascular profile of glucose lowering agents regulatory agencies in both Europe and the United States issued guidance requesting the assessment of cardiovascular safety of new antidiabetic medications during the early stages of their marketing authorization.

Some of the trials which is ongoing or completed to assess the safety outcome of DPP IV inhibitors are “The EXAMINE (NCT00968708; Alogliptin), CARMELINA (NCT01897532; Linagliptin), OMNEON (NCT01703208; Omarigliptin), SAVOR-TIMI (NCT01107886; Saxagliptin) and TECOS (NCT00790205; Sitagliptin) trials compare DPP-4 inhibition against placebo and CAROLINA (NCT01243424; Linagliptin) with glimepiride as the active comparator”.9 Trial results of DPP-IV inhibitors shows neutral effect on all cause and cardiovascular mortality, acute coronary syndrome, stroke and less risk of heart failure. SAVOR-TIMI-53 and EXAMINE trials had a composite primary outcome of CV death, nonfatal MI, and nonfatal stroke. HF hospitalization was an adjudicated secondary outcome for SAVOR-TIMI-53 & EXAMINE. The CAROLINA study, a large prospective cardiovascular safety trial comparing linagliptin with glimepiride may be expected to shed further light on cardiovascular safety for which the results are expected in 2018.14

CAN DPP-4 INHIBITORS BE USED IN COMORBID CONDITIONS ?

Patients with type 2 diabetes mellitus frequently have comorbidities (elderly, renal and hepatic impairment patients) that complicate the management of their disease.15 The particular decision to use antidiabetic agent is based on risk and benefits of each treatment decision in light of the patient’s glycaemic control, cardiovascular status, efficacy, cost, effects on weight, comorbidities and patient preferences.

1.

Elderly people

Age is not a co-morbid disease condition per se but usually a constellation that increases the likelihood of comorbid diseases. In elderly patients with T2DM, reductions in HbA1c after treatment with a DPP-4 inhibitor were not significantly different from those in younger patients and the use of DPP-4 inhibitors was associated with a low risk

SAFETY OF DPP-IV INHIBITORS

All oral glucose-lowering agents have some adverse effects: gastrointestinal intolerance and risk of lactic acidosis with metformin, allergic reactions and severe hypoglycemia with sulfonylureas, bone fractures, fluid retention and heart failure (and possibly bladder cancer for pioglitazone) for thiazolidinediones and increased risk of mycotic genital infections and urinary tract infections associated with SGLT-2 inhibitors. Commonly reported adverse reactions in clinical trials were nasopharyngitis, upper respiratory tract infection, hypersensitivity and headache.19 Pancreatitis has been reported with use of DPP-4 inhibitors and warnings exist on all labels – specifically, they should not be prescribed to patients with a history of pancreatitis. Treatment should be discontinued if signs and symptoms arise, and in this

CHAPTER 43

2.

235

236

Table 4: Use of Different DPP-I inhibitors based on renal and hepatic impairment DPP-IV Inhibitor

Vidagliptin

Renal impairment Mild (Crcl >50ml/min) Moderate (Crcl >30 <50 ml/min) Severe- (Crcl <30ml/min) 50 mg â&#x20AC;&#x201C; moderate - OD 25 mg â&#x20AC;&#x201C; severe - OD 50 mg â&#x20AC;&#x201C; Moderate & Severe - OD

Hepatic impairment

Renal & Liver Use with other drugs function (Dose reduction with sulphonyl monitoring urea & Insulin)

Yes

Yes

-

No

Yes

2.5 mg OD

Yes

Yes

Yes

Yes

Linagliptin

12.5 mg â&#x20AC;&#x201C;moderate-OD 6.25 mg â&#x20AC;&#x201C;severe-OD Yes

Dose reduction (50mg once daily) when used with sulphonylurea Dose reduction (2.5mg once daily) when used with strong CYP3A4/5 inhibitors (e.g. ketoconazole, ritonavir) -

Saxaglitpin

Alogliptin

Yes

No

Gemigliptin

Yes with caution

Presently not recommended

Teneligliptin

Yes

Yes with care

DIABETES

Sitagliptin

regard, it is important to educate patients on the signs and symptoms of pancreatitis. Therapy should not be resumed if pancreatitis is confirmed. Hypoglycemia is infrequent and severe hypoglycemia is rare when using DPP-4 inhibitors.

CURRENT PLACE OF DPP IV INHIBITORS IN THE MANAGEMENT OF TYPE II DM

In clinical trials, all available DPP-4 inhibitors have been shown to improve glycemic control, with clinically meaningful reductions in HbA1c. Furthermore, they are well tolerated, are associated with a low risk of hypoglycemia, and have a favorable weight profile. As evidence accumulates for their effectiveness, the DPP4 inhibitors have been incorporated into numerous guidelines available for the management of patients with T2DM. A consensus statement and algorithm issued by the American Association of Clinical Endocrinologists (AACE) in 2016 describes several options for monotherapy and variations of combination therapy. The DPP-4 inhibitors are placed among monotherapy options for patients with an entry level HbA1c of < 7.5%. As with American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) recommendations, metformin is recommended as the first-line choice where not contraindicated. The AACE algorithm also places DPP-4 inhibitors as an option for the second component of initial dual or triple therapy in patients with entry HbA1c levels of â&#x2030;Ľ7.5% or â&#x2030;Ľ9%, respectively. The DPP-4 inhibitors may also be considered as the first component of dual or triple therapy for patients for whom metformin is contraindicated. The detailed AACE guidelines issued in 2016 noted that DPP-4 inhibitors, along with metformin, sulfonylureas, glinides, and thiazolidinediones, are all

No

Efficacy may be reduced if used with CYP3A4 inducer (e.g. rifampin) May require dose reduction when used with drugs which alter CYP3A4 activity -

approved for use in combination with insulin.

RATIONALE OF COMBININGÂ DPP IV INHIBITORS WITH METFORMIN OR SGLT2 INHIBITORS

The progressive deterioration of đ?&#x203A;˝-cell function in T2DM often necessitates the use of combination therapy in order for individuals to reach their glycaemic goals; however, the use of anti-hyperglycaemic agents in combination may lead to an increase in the risk of adverse events, including weight gain and hypoglycaemia, which occur with sulphonylureas and thiazolidinediones.20, 21 The rationale for combining metformin with DPP-4 inhibitors is its complimentary mechanism of action, metformin acts primarily by reducing hepatic glucose output and improving insulin sensitivity in liver and muscle whereas DPP-4 inhibitors act by increasing GLP1 levels and thereby stimulating insulin secretion and inhibiting glucagon secretion. The two strategies therefore have the potential to improve different mechanisms, which are defective in type 2 diabetes and therefore an additive or synergistic action when used in combination is anticipated. In addition, metformin has been shown to increase GLP-1 levels and DPP-4 inhibition to some extent which would be a potential for an additional synergistic action with DPP-4 inhibitors. Another important information is that when combined metformin and DPP4 inhibitor their pharmacokinetic properties remain unchanged which further indicates the feasibility of the combination.22 In contrary to DPP-4 inhibitors, Sdium-glucose cotransporters-2 (SGLT 2) inhibitors (canagliflozin, dapagliflozin and empagliflozin) acts completely by different mechanism;23 They reduces reabsorption of

CONCLUSION

DPP-4 inhibitors have become potential therapeutic agent for the treatment of T2DM. Overall, the DPP-4 inhibitors appear to be very well tolerated, with fewer side effects, do not inherently cause hypoglycaemia, they are weight neutral with decreased cardiovascular risk and generally not different to other antidiabetic agents. They are preferable agents in certain patients, including vulnerable individuals or those with occupational/social activities where avoidance of hypoglycaemia is important.

Medication costs clearly influence drug of choice in some geographic regions (due to economics and/or healthcare provider systems), but this may become less relevant in the future, when generic DPP-4 inhibitors may be readily available. Ultimately, the decision of which drug to use should take into account differences, both within and between drug classes, and be made according to the individual patient needs.

REFERENCES

1.

2.

3.

4.

5.

6.

7.

Gallwitz B. The evolving place of incretin-based therapies in type 2 diabetes. Pediatr Nephrol 2010; 25:1207-17.

Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. Consensus statement by the american association of clinical endocrinologists and american college of endocrinology on the comprehensive type 2 diabetes management algorithm-2015 executive summary. Endocrine Practice 2015; 21:1403-14.

Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB. Incretin-Based Therapies for the Treatment of Type 2 Diabetes: Evaluation of the Risks and Benefits. Diabetes Care 2010; 33:428-33.

Leahy JL. Pathogenesis of type 2 diabetes mellitus. Archives of Medical Research 2005; 36:197-209.

Kazafeos K. Incretin effect: GLP-1, GIP, DPP4. Diabetes Research and Clinical Practice 2011; 93:S32-6.

Nisal K, Kela R, Khunti K, Davies MJ. Comparison of efficacy between incretin-based therapies for type 2 diabetes mellitus. BMC Medicine 2012; 10:152.

Brunton S. GLP-1 receptor agonists vs. DPP-4 inhibitors

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

for type 2 diabetes: is one approach more successful or preferable than the other? International Journal of Clinical Practice 2014; 68:557-67.

Brown DX, Evans M. Choosing between GLP-1 receptor agonists and DPP-4 inhibitors: a pharmacological perspective. Journal of Nutrition and Metabolism 2012; 2012.

Deacon CF, Lebovitz HE. Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas. Diabetes Obes Metab 2016; 18:333-47.

Deacon CF. Dipeptidyl peptidaseâ&#x20AC;?4 inhibitors in the treatment of type 2 diabetes: a comparative review.

Diabetes, Obesity and Metabolism 2011; 13:7-18.

Scheen AJ. Safety of dipeptidyl peptidase-4 inhibitors for treating type 2 diabetes. Expert Opinion on Drug Safety 2015; 14:505-24.

Scheen AJ. A review of gliptins in 2011. Expert opinion on Pharmacotherapy 2012; 13:81-99.

Patil HR, Al Badarin FJ, Al Shami HA, Bhatti SK, Lavie CJ, Bell DS, et al. Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. The American Journal of Cardiology 2012; 110:826-33.

Wu S, Hopper I, Skiba M, Krum H. Dipeptidyl peptidase-4 inhibitors and cardiovascular outcomes: meta-analysis of randomized clinical trials with 55,141 participants.

Cardiovascular Therapeutics 2014; 32:147-58.

Hollander PA, Kushner P. Type 2 diabetes comorbidities and treatment challenges: rationale for DPP-4 inhibitors.

Postgraduate Medicine 2010; 122:71-80.

Chen C, Yu Q, Zhang S, Yang P, Wang C-Y. Assessing the efficacy and safety of combined DPP-4 inhibitor and insulin treatment in patients with type 2 diabetes: a meta-analysis.

International Journal of Clinical and Experimental Pathology 2015; 8:14141-50.

Schernthaner G, Barnett AH, Patel S, Hehnke U, von Eynatten M, Woerle HJ. Safety and efficacy of the dipeptidyl peptidase-4 inhibitor linagliptin in elderly patients with type 2 diabetes: a comprehensive analysis of data from 1331 individuals aged >/= 65 years. Diabetes Obes Metab 2014; 16:1078-86.

Arjona Ferreira JC, Marre M, Barzilai N, Guo H, Golm GT, Sisk CM, et al. Efficacy and safety of sitagliptin versus glipizide in patients with type 2 diabetes and moderateto-severe chronic renal insufficiency. Diabetes Care 2013; 36:1067-73.

Karagiannis T, Boura P, Tsapas A. Safety of dipeptidyl peptidase 4 inhibitors: a perspective review. Therapeutic Advances in Drug Safety 2014; 5:138-46.

Charbonnel B, Schweizer A, Dejager S. Combination therapy with DPP-4 inhibitors and insulin in patients with type 2 diabetes mellitus: what is the evidence? Hospital Practice (1995). 2013; 41:93-107.

Liu Y, Hong T. Combination therapy of dipeptidyl peptidase-4 inhibitors and metformin in type 2 diabetes: rationale and evidence. Diabetes Obes Metab 2014; 16:111-7.

Ahren B. Novel combination treatment of type 2 diabetes DPP-4 inhibition + metformin. Vascular Health and Risk Management 2008; 4:383-94.

Sharma MD. Potential for combination of dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors for the treatment of type 2 diabetes. Diabetes Obes Metab 2015; 17:616-21.

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CHAPTER 43

glucose from the glomerular filtrate independant of insulin and induce excretion of glucose into the urine (i.e.

Glycosuria). In response to glycosuria, SGLT2 inhibitors enhance glucagon secretion, which may in turn increase glucose production in the liver and elevates blood glucose levels. Although this effect helps reduce the risk for hypoglycemia, it may contribute to an increase in blood glucose levels. However, this effect is counteracted by combining it with DPP-4 inhibitor and possibly further reduce blood glucose levels. In addition to improvements in glycemic control, SGLT2 inhibitors provide other effects such as weight loss and moderate reductions in systolic blood pressure. The combination of DPP-4 inhibitors and SGLT2 inhibitors also has the potential to exert beneficial effects on the kidney. Both classes have been reported to lower urinary albumin excretion, a risk factor for renal disease. In addition, drugâ&#x20AC;&#x201C;drug interactions of these inhibitors had no clinically relevant effect on the pharmacokinetics of either agent; therefore can be coadministered without dose adjustments.

C H A P T E R

44

Preoperative Management of the Patient with Diabetes

KEY WORDS

Diabetes, Surgery, Perioperative management, Insulin, Hyperglycemia in ICU

INTRODUCTION

Hyperglycemia has shown strong association with worse outcomes in critically ill hospitalized patients.1 Hyperglycemia in patients following stroke have poor functional recovery and higher mortality.2 Critically ill patients with high blood glucose, who had myocardial infarction are more likely to have congestive heart failure, cardiogenic shock or death during hospitalization.3 Perioperative hyperglycemia in surgical patients, increases the risk of postoperative mortality, and cardiovascular, respiratory, neurologic, and infectious morbidity.4 Hyperglycemia increases morbidity and increased length of stay, irrespective of admission specialty, which increases the inpatient costs. This is a particular problem in surgical patients where the excess bed days were estimated to be 45% greater than for people with diabetes admitted to medical wards.5 The peri-operative mortality rate is reported to be up to 50% higher than that of the non-diabetic population.6 Hyperglycemia might be due to pre-existing diabetes or it might get first detected just on admission. While hospitals often have standard protocols in place to manage those known to have diabetes, these previously known diabetics are just a fraction of those at risk for abnormal inpatient glycemic control. The other dysglycemic patients, especially undiagnosed diabetes and those with stress-induced hyperglycemia (SIH), may be unexpected, unrecognized, difficult to differentiate from each other in the inpatient setting, and not well understood, present a big challenge in perioperative care.

INPATIENT HYPERGLYCEMIA: DEFINITIONS

The American Diabetes Association (ADA) classifies three categories of inpatient dysglycemia.7 The first category is being those with a known case of diabetes. May be type 1 DM, type 2 DM, pre-existing IFG (Impaired fasting glucose) and IGT (Impaired Glucose Tolerance) or a case of GDM. The second category, unrecognized diabetes, includes patients with inpatient hyperglycemia which persists even after discharge. However, because inpatient blood glucose values should not be used routinely to make a diagnosis of diabetes, this population is difficult to define accurately in the acute care setting.

Hemoglobin A1c (HbA1c) is a suitable screening test for diabetes8 may simplify the inpatient diagnosis of diabetes if drawn preoperatively. The third category, hospitalrelated hyperglycemia, or stress-induced hyperglycemia (SIH), defines patients with inpatient hyperglycemia

Sunil Gupta

that normalizes when the counter- regulatory hormone surge and excessive pro-inflammatory state abate. Stress hyperglycemia seem to be different than hyperglycemia secondary to diabetes, in that it confers an increased risk of mortality. Rady and colleagues have shown higher mortality in patients without diabetes requiring insulin versus patients with known diabetes (10% vs 6%) in a retrospective single institution intensive care unit (ICU), despite lower average glucose values in the group without diabetes.9 In their retrospective cohort, Egi et all have found that hyperglycemia was associated with increased mortality in patients without diabetes, but not in patients with known diabetes, suggesting that high blood glucose in this group may represent a different pathophysiology and natural history than in patients with known diabetes.10 Current recommendations for glycemic control do not differentiate patients with diabetes from those with hyperglycemia attributable to stress, but it is not known currently whether glycemic targets should, in fact, be the same.12 Unfortunately, very little is currently known about SIH in general, including its natural history and risk for developing overt diabetes mellitus in the future.

(Figure 1)

WHY IS MANAGEMENT OF DIABETES IMPORTANT IN THE SURGICAL SETTING?

On average, diabetics require more hospitalizations, longer durations of stay, and cost more to manage than non-diabetics. The estimated cost of managing known diabetes in 2012 was $245 billion, a 41% increase from the 2007 estimate, with the largest percentage (43% of the total medical cost) being spent on inpatient hospital care.13 Furthermore, diabetics undergo certain procedures and surgeries more commonly than non-diabetics and have higher morbidity and mortality when acutely compromised or ill.14 Surgical procedures may result in various metabolic consequences, which can alter normal glucose homeostasis. The resulting hyperglycemia is a risk factor for postoperative sepsis,15 endothelial dysfunction16 cerebral ischemia17 and impaired wound healing.18 Moreover, the stress response may trigger diabetic ketoacidosis19 (DKA) or hyperglycemic hyperosmolar syndrome20 (HHS) during surgery or postoperatively.

Nevertheless, new data suggests that meticulous control of blood glucose in patients undergoing major surgeries, like cardiac21 and orthopedic22 procedures may minimize the above-mentioned negative sequel and promote better outcomes.

239

CHAPTER 44

Fig. 1: Relationship of In-hospital Hyperglycemia11

HOW DOES SURGERY AFFECTS METABOLISM (FIGURE 2)

The surgery-associated trauma results in increased production of stress hormones, cortisol and catecholamine, which reduce the insulin sensitivity, while heightened sympathetic activity reduces insulin secretion.

Simultaneously there is increase in growth hormone and glucagon secretion also.23 Amongst diabetics, insulin production is already marginalized; the metabolic changes that occur during surgery cause a marked catabolic state.

Changes in normal metabolic patterns due to surgery trigger gluconeogenesis, glycogenolysis, proteolysis, lipolysis, and ketogenesis eventually resulting in hyperglycemia and ketosis.24

PRE-OPERATIVE ASSESSMENT

Preoperative identification of patients with DM, or those at risk for perioperative dysglycaemia, provides a potential opportunity to reduce morbidity and mortality. Early identification facilitates timely intervention and allows arrangement of appropriate perioperative and long-term follow-up.26 In any hyperglycemic inpatient who did not have a prior diagnosis of diabetes but with fasting glucose ≥100 mg/dl or random glucose ≥180 mg/dl, we should get HbA1c done to determine the presence or absence of preexisting diabetes. HbA1c values >5.7% is suggestive of prediabetes, while HbA1c of >6.5 endorsed the diagnosis of diabetes. Given the implication of undiagnosed diabetes on poor wound healing, every effort should be made to establish the diagnosis prior to discharge. Such patients should be considered high risks for and should also receive appropriate ambulatory follow-up.

PREOPERATIVE EVALUATION

In elective surgical procedures, potential problems should be identified, corrected, and stabilized before surgery.

Preoperative evaluation includes assessment of metabolic control and any diabetes-associated complications, including cardiovascular disease, autonomic neuropathy, and nephropathy, which could affect the surgical outcome.

Asymptomatic cardiac ischemia occurs relatively often in patients with diabetes.27 The presence of cardiovascular risk factors should prompt a thorough evaluation.

At minimum, resting electrocardiography should be

performed, but a stress test is often justified if there is suspicion for cardiovascular disease. Cardiac autonomic neuropathy may predispose patients to perioperative hypotension,28 so the presence of resting tachycardia, orthostatic hypotension, peripheral neuropathy, and loss of normal respiratory heart rate variability should be sought. Serum creatinine levels should be measured, but they are not a sensitive indicator of early renal dysfunction, which is usually advanced before an elevation in creatinine develops. Kidney function can be estimated by using eGFR formulas but, if a high index of suspicion for renal impairment exists, a measured creatinine level from a 24- hour urine collection is the best gauge of renal function. Diabetic patients with proteinuria or abnormal creatinine clearance have a greater risk of developing acute renal failure.

STANDARDS FOR PERIOPERATIVE CARE INCLUDE THE FOLLOWING:26

1.

Target glucose range for the peri-operative period should be 80–180 mg/dL.

2.

Preoperative risk assessment for patients at high risk for ischemic heart disease and those with autonomic neuropathy or renal failure.

3.

The morning of surgery, hold any oral hypoglycemic agents and give half of NPH dose or full doses of a long-acting analog or pump basal insulin.

4.

Monitor blood glucose every 4–6 h while NPO and give short-acting insulin as needed.

A review found that tight perioperative glycemic control did not improve outcomes and was associated with more hypoglycemia29 therefore, in general, tighter glycemic targets than mentioned above are not advised.

PERIOPERATIVE MANAGEMENT

Transition from tight to reasonable glucose control: Van den Berghe and colleagues in 2001 published their single-centered prospective randomized study of 1548 surgical ICU patients and have reported a lower risk of blood stream infections, renal failure, blood transfusions, critical illness polyneuropathy, shorter requirement for mechanical ventilation, and a 30% decrease in mortality,

Impaired chemotaxis and phagocytosis ↑ expression of adhesion molecules ↓ complement function

240

↓ vasodilation

DIABETES

impaired nitric oxide generation

Anesthesia

Metabolic Stress Critical Illness

↓Insulin secretion & ↑ Insulin resistance

Perioperative Hyperglycemi a

↑Inflammation, vulnerability to infection multi-organ system dysfunction

↑Counter regulatory Hormones

↓Gluconeogenesis &

↑ Glucose utilization Fig. 2: How Surgery affects Metabolism?25

which was reduced in patients given an insulin infusion to control blood glucose to 80–110 mg/dl compared to 180–200 mg/dl, most of whom had recent cardiac surgery.

This is also referred as “tight” glucose control. The results from this investigation were met with great enthusiasm, and tight glucose control became the standard of care in many institutions.30 However, a meta- analysis of 29 randomized controlled trials found no difference in mortality between “tight” glucose control (<110 mg/dL) and “moderately tight” (<150 mg/dL) control.31 Importantly the largest prospective multinational, multidisciplinary Normoglycemia in Intensive Care Evaluation and Survival PRE-OPERATIVE Using Glucose AlgorithmASSESSMENT: Regulation (NICE-SUGAR) trial in 6104 ICU patients reported increased mortality in patients randomized to achieve a blood glucose level of 81–108 mg/dl versus <180 mg/dl.32 Thereafter, updated, comprehensive recommendations for inpatient glycemic control were issued by the American Association of Clinical Endocrinologists (AACE) and the ADA. They emphasize the need for “reasonable, achievable, and safe” glycemic goals and recommended in- hospital intensive care unit targets to 140–180 mg/dl and have suggested 100–180 mg/dl as a guideline for general care medical and surgical wards.33

SHOULD SURGERY BE DELAYED TO OPTIMIZE HEMOGLOBIN A1C OR ACUTE HYPERGLYCEMIA?

It is also unclear whether shorter term improvement in glucose control (hours to days) could improve perioperative outcomes. Observational evidence shows that patients with acutely elevated preoperative glucose

fare worse than those with normoglycemia,34 although there have been no randomized, prospective trials to date investigating whether acute preoperative glycemic correction carries any benefit. At this time, it seems prudent to control blood glucose to a reasonable level preoperatively, but recommendations for exact targets cannot be made. In addition, a delay in surgery is not practical for many patients requiring urgent or emergent procedures. At this point, glycemic correction of elevated HbA1c prior to elective surgery is not recommended.

HOW TO MINIMIZE THE RISKS OF EMERGENCY SURGERY IN PATIENTS WITH DIABETES

•

Metabolic status: immediate measurement of plasma glucose, pH, creatinine, BUN, electrolytes

•

Volume status: check for orthostasis, elevated BUN and/or creatinine, urine output

•

Cardiac status: ECG

•

Delay surgery if possible until metabolic control and volume status are stabilized.

•

Maximize glucose, electrolyte, and acid-base status.

Insulin and glucose infusions.

•

Saline infusion if volume is depleted, depending on renal function and cardiac status.

•

Potassium infusion if renal function is normal and serum potassium is normal or low. Bicarbonate infusion only in patients with severe acidosis

WHAT PHARMACOLOGIC AGENTS ARE RECOMMENDED?

ORAL ANTI-DIABETIC DRUGS

Preoperatively, oral hypoglycemic agents, especially sulfonylurea and meglitinide, have potential for producing hypoglycemia during fasting prior to surgery.

In addition, the long half-life of many of these drugs makes titration in the setting of rapidly changing clinical parameters difficult. Thus, oral antidiabetic drugs should be continued up to the night prior to surgery, then held on the morning of surgery, with consideration of the fact that stopping antidiabetic therapy too early may compromise glucose control. Maintenance of preoperative glucose concentrations of 140 to 180 mg/dL or less is a reasonable goal. Oral drugs should not be restarted, until the patient has resumed adequate and regular oral intake. Until adequate oral intake occurs, short- or medium duration insulin may be used to treat hyperglycemia until oral antihyperglycemic drugs can be restarted. Insulin therapy allows an improved ability to titrate to changing glucose concentrations compared with oral hypoglycemic agents. Sulfonylurea agents should be held for 24 hours prior to elective surgery because of the risk of adverse effects resulting from closure of the cardiac KATP channels, which may increase the risk for myocardial ischemic injury by blocking an intrinsic mechanism of cardioprotection, termed “ischemic preconditioning”. Ischemic preconditioning provides myocardial protection by the application of brief episodes of ischemia, which renders the myocardium more resistant to injury.36 Because the meglitinides (nateglinide, repaglinide), act by a similar mechanism involving closure of the KATP channels, it is recommended that these drugs should also be held for 24 hours prior to surgery.

Chemically metformin has similarities to its predecessor, phenformin, which was associated with high risk of lactic acidosis and approximately 50% mortality37 thus, concern has been raised of the possibility of life-threatening lactic acidosis occurring with metformin. In addition, surgical patients are already at increased risk for lactic acidosis because of predisposing conditions, including renal insufficiency, congestive heart failure, hypoxemia and hypovolemia. Perioperative metformin-associated lactic acidosis has been reported;38 thus it is recommended that metformin to be discontinued for 24 hours or more prior to surgery. Metformin may be restarted following surgery after adequate oral intake has resumed. Metformin should

241

INSULIN THERAPY

Insulin is the drug of choice for most of the patients subjected for surgery, especially during any major surgical procedures. The best protocol is basal-bolus regimen.

Use of insulin analogues (Rapid acting: Aspart, Lispro, Glulisine and Long acting: Glargine, detemir) is preferred over regular & NPH insulin. Endocrine society clinical practice have given the most simplified recommendations as below: Example of a basal bolus insulin regimen for the management of non-critically ill patients with type 2 diabetes41 A.

Basal insulin orders: Discontinue oral diabetes drugs and non-insulin injectable diabetes medications upon hospital admission. Starting insulin: calculate the total daily dose as follows:

•

0.2 to 0.3 U/kg of body weight in patients: aged >70 yr and/or e-GFR less than 60 ml/min.

•

0.4 U/kg body weight/day for patients not meeting criteria above & have BG of 140–200 mg/dl.

•

0.5 U/kg body weight/day for patients not meeting the criteria above & have BG 201–400 mg/dl.

•

Distribute total calculated dose as approximately 50% basal insulin and 50% nutritional insulin.

•

Give basal insulin once (glargine/detemir) or twice (detemir/NPH) daily, at same time each day.

•

Give rapid-acting (prandial) insulin in three equally divided doses before each meal. Hold prandial insulin if patient is not able to eat.

•

Adjust insulin dose(s) according to the results of bedside BG measurements.

B.

Supplemental (correction) rapid-acting insulin analog or regular insulin.

SUPPLEMENTAL INSULIN ORDERS

•

If a patient is able and expected to eat all or most of his/her meals, give regular or rapid-acting insulin before each meal and at bedtime following the “Usual” column (Section C below).

•

If a patient is not able to eat, give regular insulin every 6 h (6–12–6–12) or rapid-acting insulin every 4 to 6 h following the “Sensitive” column (Section C below).

•

Supplemental insulin adjustment.

•

If fasting and premeal plasma glucose are persistently above 140 mg/dl in the absence of

CHAPTER 44

Insulin remains the standard of care for inpatient glycemic control. In the ICUs, insulin infusions are the preferred, as the half-life of intravenous insulin is in minutes, allowing for rapid titration in the setting of changing clinical status.

Insulin infusions are also useful on general care wards, allowing rapid titration at a time when steroids may taper, the counter regulatory hormone surge declines, and diet is advanced. However, because insulin infusion is labor-intensive, and is not available on many general care units, subcutaneous insulin, including basal, bolus, and correction, is the recommended alternative to using correction regimens alone. As a general rule, correction or “sliding scale” insulin should not be used as a single modality.35

not be restarted in patients with renal insufficiency, hepatic impairment, or heart failure because of the increased risk of metabolic acidosis.39 Oral agents have class-specific limitations for inpatient use and, except for the most stable general care patients approaching discharge, should not be used routinely. An elevated preoperative HbA1c can provide information that a significant adjustment in preoperative medication may be needed at discharge, including continuing of inpatient insulin for patients that were first placed on it in the hospital.11

242

Table 1: Perioperative blood glucose management in patients with diabetes undergoing ambulatory surgery40 • Determine level of glycemic control • Discontinue metformin prior to surgery in patients with renal dysfunction and who will receive IV contrast • Avoid oral agents and noninsulin injectables the day of surgery • Base perioperative use of insulin on safety concerns and maintenance of adequate glucose control • Use basal (long intermediate-acting or continuous SQ rapid acting)- prandial/supplemental (short or rapid acting) insulin

DIABETES

• Avoid alterations of long acting basal insulin (glargine or detemir) the day before surgery unless there is report of hypoglycemia and in patients on diet restriction preoperatively. The day of surgery, may use 75% to 100% of daily long – acting insulin dose.

• Reduce evening dose of intermediate – acting insulin(NPH) the day before surgery to 75%. The day of the surgery use 50% to 75% of morning dose.

• Withhold prandial insulin while patient is fasting • Consider the level of preoperative glycemic control when planning for preoperative insulin use • Postpone surgery in patient with significant dehydration ketosis and hyperosmolar nonketotic states • Consider presence of comorbidities and potential risks of surgical complication in chronically poorly controlled patient • Maintain intraoperative blood glucose levels between 100 to 180mg/dl • Consider using rapid -acting insulin over regular insulin in the postoperative period • Favor SQ administration of insulin to achieve and maintain target glucose level rather that IV insulin in ambulatory patients undergoing short procedures. IV insulin is the most favorable treatment for patient undergoing long procedures.

• Avoid respective doses of subcutaneously administered insulin to prevent insulin “stacking” • Consider perioperative use of insulin for insulin naïve patients with significant hypoglycemia if able to monitor blood glucose level at home.

• Schedule patients with diabetes as the first case of the day when possible to minimize disruption of their routine.

• Request patients to bring their insulin and hypoglycemia treatment to the facility • Instruct adequate preoperative hydration and administer at adequate intraoperative crystalloid infusion provide that there are on contraindications • Obtain blood glucose level on the patient arrival before surgery the before discharge home • Monitor intraoperative blood glucose 1-2 h depending upon the duration of the procedure and type of insulin used • Corroborate significantly low glucose levels with central laboratory tests. May treat first or while waiting for results to avoid adverse sequelae in patient with altered consciousness under anesthesia • Suspect , prevent, identify, and manage hypoglycemia promptly • Observe patient in and ambulatory facility until hypoglycemia from perioperatively administrate insulin is excluded.

• Provide clear and consistent instructions regarding plans to return to preoperative antidiabetic regime and management of potential hypoglycemia • Instruct patient to travel with hypoglycemia treatment to and from the surgical facility hypoglycemia, increase insulin scale of insulin from the insulin-sensitive to the usual or from the usual to the insulin-resistant column.

•

If a patient develops hypoglycemia BG <70 mg/dl, decrease regular or rapid-acting insulin from the insulin-resistant to the usual column or from the usual to the insulin-sensitive column.

C.

Supplemental insulin scale (Table 2)41

The numbers in each column of Section C indicate the number of units of regular or rapid-acting insulin analogs

per dose. “Supplemental” dose is to be added to the scheduled insulin dose. Give half of supplemental insulin dose at bedtime. If a patient is able and expected to eat all or most of his/her meals, supplemental insulin will be administered before each meal following the “Usual” column dose. Start at insulin-sensitive column in patients who are not eating, elderly patients, and those with impaired renal function. Start at insulin- resistant column in patients receiving corticosteroids and those treated with more than 80 U/d before admission.

Approaches to insulin therapy during Enteral Nutrition (EN)41

Continuous EN: Administer basal insulin once (glargine, detemir) or twice (detemir/NPH) a day in combination with a short- or rapid- acting insulin analog in divided doses every 4 h (lispro, aspart, glulisine) to 6 h (regular insulin).

CYCLED FEEDING

•

Administer basal insulin (glargine, detemir, or NPH) in combination with short- or rapid-acting insulin analog at the time of initiation of EN.

BG (mg/dl)

Insulin-sensitive Usual Insulin-resistant

>141-180

2

4

6

181-220

4

6

8

221-260

6

8

10

261-300

8

10

12

301-350

10

12

14

351-400

12

14

16

>400

14

16

18

Repeat the dose of rapid-acting insulin (lispro, aspart, glulisine) at 4-h intervals or short-acting (regular) insulin at 6-h intervals for the duration of the EN. It is preferable to give the last dose of rapid-acting insulin approximately 4 h before and regular insulin 6 h before discontinuation of the EN.

243

Bolus feeding: Administer short-acting regular or rapidacting insulin analog (lispro, aspart, glulisine) before each bolus administration of EN.

BEDSIDE BLOOD GLUCOSE MONITORING

Bedside point of care (POC) blood glucose (BG) monitoring guides insulin dosing. In the patient receiving nutrition, glucose monitoring should be performed before meals to match food ingestion. In the patient not receiving nutrition, BG monitoring is advised every 4–6 h.42 More frequent BG testing ranging from every 30 min to every 2 h is required for patients receiving intravenous insulin. Safety standards should be established for BG monitoring that prohibit the sharing of finger- stick lancing devices, lancets, needles, and pens to reduce the risk of transmission of blood-borne diseases.

Limitations in the Hospital Setting: POC meters have limitations for measuring BG. Although the U.S. Food

Table 3: Insulin dosing for enteral/parenteral feedings41 Situation

Basal

Bolus

Continuous enteral feedings

Glargine q.d. or NPH/detemir b.i.d.

SQ rapid-acting correction every 4 hours

Bolus enteral feedings

Continue prior basal; if none, consider 10 SQ rapid-acting insulin with each bolus units NPH or glargine insulin to TPN IV feeding to cover the bolus feeding and to bottle correct for hyperglycemia

Parenteral feedings

Regular insulin to TPN IV bottle

Rapid-acting insulin SQ every 4 hours to correct for hyperglycemia

IV, intravenous; SQ, subcutaneous; TPN, total parenteral nutrition.

Table 4: Intravenous Insulin Infusion protocol44 Variable Rate Intravenous Insulin Infusion Mix 100 U short-acting insulin in 100 mL normal saline (1 U = 1 mL) Start insulin infusion at 0.5 to 1 U per hour {0.5 to 1 mL per hour)* Start a separate infusion of 5 percent dextrose in water at 100 to 125 mL per hour Monitor b’ood glucose hourly (every two hours when stable) and adjust insulin infusion rate according to the following algorithm: Blood glucose level, mg per dL Action (mmol per L)† Below 70 (30.89)

Turn off insulin infusion for 30 minutes, recheck blood glucose level. If blood glucose level is still below 70, give 10 g glucose and recheck blood glucose evel every 30 minutes until the level is above 100 (5.56), then restart infusion and decrease rate by 1 U per hour.

71 to120 (3.94 to 6.67)

Decrease insulin infusion rate by 1 U per hour

121 to 180 (6.72 to 10.0)

Continue insulin infusion as is

181 to 250 (10.1 to 13.89)

Increase insulin infusion rate by 2 U per hour

251 to 300 (13.94 to 16.67)

Increase insulin infusion rate by 3 U per hour

301 to 350 (16.72 to 19.4)

Increase insulin infusion rate by 4 U per hour

351 to 400 (19.5 to 22.2)

Increase infusion rate by 5 U per hour

Above 400 (22.2)

Increase insulin infusion rate by 6 U per hour

*—Glucose infusion rate can also be increased if tendency toward hypoglycemia persists. †—Target blood glucose range is 120 to 180 mg per dL (6.67 to 10 mmol per L).

CHAPTER 44

Table 2: Supplemental insulin scale

•

DIABETES

244

Table 5: Summary45 Broad management goals across the perioperative timeline. Overall goals: (i) reduce patient morbidity & mortality, (ii) avoid clinically significant hyper- or hypoglycemia, (iii) maintain acid/base, electrolyte, & fluid balance, (iv) prevent ketoacidosis, (v) Achieve blood glucose target less than 180 mg/dL in critical patients and less than 140 mg/dL in stable patients.

Preoperative management key points

Intraoperative management key points

Postoperative management key points

i. Verify target blood glucose concentration with frequent glucose monitoring

i. Aim to maintain intraoperative glucose levels between 140 and 170 mg/dL

i. Target postoperative glycemic range between 140 and 180 mg/ dL

ii. Use insulin therapy to maintain glycemic goals

ii. Physicians must take length of surgery into account when determining an intraoperative glucose management strategy

ii. In the event a patient is hypoglycemic after surgery, begin a dextrose infusion at approximately 5-10 g/hour

iii. For minor surgery, preoperative glucose protocols may be continued

iii. Ensure basal insulin levels are met, especially in type 1 diabetic patients

iii. Discontinue biguanides, alpha glucosidase inhibitors, thiazolidinediones, sulfonylureas, and GLP-1 agonists

iv. Consider cancelling iv. IV insulin infusion is being nonemergency procedures if promoted as a more efficient patient presents with metabolic method of glycemic control for longer or more complex abnormalities (DKA, HHS, etc.) surgeries or glucose reading above 400-500 mg/dL

iv. Postprandial insulin requirements should be tailored according to the mode in which the patient is receiving nutrition v. Supplemental insulin can be used to combat hyperglycemia and restore blood glucose values back to target range

Please note that the information presented in this table has been referenced in the text. and Drug Administration (FDA) has standards for blood glucose meters used by lay persons, there have been questions about the appropriateness of these criteria, especially in the hospital and for lower BG readings.43 Significant discrepancies between capillary, venous, and arterial plasma samples have been observed in patients with low or high hemoglobin concentrations and with hypoperfusion. Any glucose result that does not correlate with the patient’s clinical status should be confirmed through conventional laboratory glucose tests. The FDA established a separate category for POC glucose meters for use in health care settings and has released a draft on in- hospital use with stricter standards. Before choosing a device, consider the device’s approval status and accuracy.

Recheck BG and repeat treatment every 15 min until glucose level is at least 80 mg/dl.

CONCLUSION

Perioperative management of hyperglycemia is more an art than clinical science. Glucose homeostasis at various circumstances remains highly variable and unpredictable.

Intravenous insulin infusion is suppose to be the best, but is expensive and often cumbersome. Moreover, infusion might not be necessary for all surgical cases. Clinical acumen plays a vital role for achieving the set glycemic and other targets during pre, intra and postoperative period of a diabetic person subjected for any surgery.

REFERENCES

1.

HYPOGLYCEMIA MANAGEMENT PROTOCOL:

41

For treatment of BG below 70 mg/dl:

In a patient who is alert and able to eat and drink, administer 15–20 g of rapid-acting carbohydrate such as 15–30 g glucose 4–6 ounces orange or apple juice, 6 ounces “regular” sugar sweetened soda or 8 ounces skim milk.

2.

3.

In an alert and awake patient who is NPO or unable to swallow, administer 20 ml dextrose 50% solution IV and start IV dextrose 5% in water at 100 ml/h.

In a patient with an altered level of consciousness, administer 25 ml dextrose 50% (1/2 amp) and start IV dextrose 5% in water at 100 ml/h.

In a patient with an altered level of consciousness and no available iv access, give glucagon 1 mg IM. Limit, two times.

4.

5.

Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345:1359–67. [PubMed: 11794168] Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress Hyperglycemia and Prognosis of Stroke in Nondiabetic and Diabetic Patients: A Systematic Overview.

Stroke 2001; 32:2426–32. 2001. [PubMed: 11588337] Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet 2000; 355:773–8.

[PubMed: 10711923] Duncan AE, Abd-Elsayed A, Maheshwari A, Xu M, Soltesz E, Koch CG. Role of intraoperative and postoperative blood glucose concentrations in predicting outcomes after cardiac surgery. Anesthesiology 2010; 112:860–71. [PubMed: 20216389] Moghissi ES, Korytkowski MT et all. American Association of Clinical Endocrinologists and American Diabetes

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H.U. Rehmanand K. Mohammed,â&#x20AC;&#x153;Perioperative management of diabetic patients,â&#x20AC;? Current Surgery 2003; 60:607â&#x20AC;&#x201C;611.

Angela K. M. Lipshutz, Michael A. Gropper, Perioperative Glycemic Control An Evidence-based Review, Anesthesiology 2009; 110:408 â&#x20AC;&#x201C;21 Diabetes Care in the Hospital, Standards of medical care in Diabetes 2016, Diabetes Care 2016; 39:S99â&#x20AC;&#x201C;S104 | DOI: 10.2337/dc16-S016 Burgos LG, Ebert TJ, Asiddao C, Turner LA, Pattison CZ, Wang-Cheng R, et al. Increased intraoperative cardiovascular morbidity in diabetics with autonomic neuropathy. Anesthesiology 1989; 70:591-7.

Escalante DA, Kim DK, Garber AJ. Atherosclerotic cardiovascular disease. In: DeFronzo RA, ed. Current therapy of diabetes mellitus. St. Louis: Mosby, 1998:176-82.

Buchleitner AM, MartÄąnez-Alonso M, Herna Ě ndez M, Sola` I, Mauricio D. Perioperative glycaemic control for diabetic patients undergoing surgery. Cochrane Database Syst Rev 2012; 9:CD007315.

Van den Berghe G, Wouters P, Weekers F. et all. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345:1359-67.

Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-analysis.

JAMA 2008; 300:933â&#x20AC;&#x201C;44. [PubMed: 18728267] NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V,et all. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360:1283-97.

Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D, Hellman R, Hirsch IB, Inzucchi SE, Ismail-Beigi F, Kirkman MS, Umpierrez GE; American Association of Clinical Endocrinologists; American Diabetes Association.

American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Endocr Practice 2009;15:353-69.

Noordzij PG, Boersma E, Schreiner F, et all, Increased preoperative glucose levels are associated with perioperative mortality in patients undergoing noncardiac, nonvascular surgery. Eur J Endocrinol 2007; 156:137-42.

Fahy BG, Sheehy AM, Coursin DB. Glucose control in the intensive care unit. Crit Care Med 2009; 37:1769-76.

Gu W, Pagel PS, Warltier DC, Kersten JR. Modifying cardiovascular risk in diabetes mellitus. Anesthesiology 2003; 98:774â&#x20AC;&#x201C;9. [PubMed: 12606925] Bailey CJ, Turner RC. Drug therapy: Metformin. N Engl J Med 1996; 334:574â&#x20AC;&#x201C;9. [PubMed: 8569826] Mears SC, Lipsett PA et all. Metformin-associated lactic acidosis after elective cervical spine fusion. Spine 2002; 27:E482â&#x20AC;&#x201C;E4. [PubMed: 12436007] Andra E. Duncan, Hyperglycemia and Perioperative Glucose Management Curr Pharm Des 2012; 18:6195â&#x20AC;&#x201C;6203.

Ariana Pichardo-Lowden & Robert A. Gabbay, Management of Hyperglycemia During the Perioperative Period, Curr Diab Rep (2012) 12:108â&#x20AC;&#x201C;118 DOI 10.1007/ s11892-011-0239-2 Guillermo E. Umpierrez, Richard Hellman, Mary T. Korytkowski, Mikhail Kosiborod, Gregory A. Maynard, Victor M. Montori, Jane J. Seley, and Greet Van den Berghe,

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Frisch A, Chandra P, Smiley D, Peng L, Rizzo M, Gatcliffe Cetal. Prevalence and clinical outcome of hyperglycemia in the perioperative period in non cardiac surgery. Diabetes Care 2010; 33:1783-8.

Clement S, Braithwaite SS, Magee MF, Ahmann A, Smith EP, Schafer RG, Hirsch IB; American Diabetes Association Diabetes in Hospitals Writing Committee. Management of diabetes and hyperglycemia in hospitals. Diabetes Care 2004; 27:553-91.

The International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009; 32:1327-34.

Rady MY, Johnson DJ, Patel BM, Larson JS, Helmers RA. Influence of individual characteristics on outcome of glycemic control in intensive care unit patients with or without diabetes mellitus. Mayo Clin Proc 2005; 80:1558-67.

Egi M, Bellomo R, Stachowski E, French CJ, Hart GK, Hegarty C, Bailey M. Blood glucose concentration and outcome of critical illness: the impact of diabetes. Crit Care Med 2008; 3:2249-55.

Ann M. Sheehy, Robert A. Gabbay J Diabetes Sci Technol Vol 3, Issue 6, November 2009. .Dungan KM, Braithwaite SS, Preiser J. Stress hyperglycemia. Lancet 2009; 373: 1798-807 American Diabetes Association, â&#x20AC;&#x153;Economic costs of diabetes in the U.S. in 2012â&#x20AC;? Diabetes Care 2013; 36:1033â&#x20AC;&#x201C; 1046.

G. Angelini, J. T. Ketzler, and D. B. Coursin, â&#x20AC;&#x153;Perioperative care of the diabetic patient,â&#x20AC;? ASA Refresher Courses in Anesthesiology 2001; 29:1â&#x20AC;&#x201C;9.

E. J. Rayfield, M. J. Ault, et al, â&#x20AC;&#x153;Infection and diabetes: the case for glucose control,â&#x20AC;? The American Journal of Medicine 1982; 72:439â&#x20AC;&#x201C;450.

A.Hempel, C.Maasch, U.Heintzeetal, â&#x20AC;&#x153;High glucose concentrations increase endothelial cell permeability via activation of protein kinase Cđ?&#x203A;ź,â&#x20AC;? Circulation Research 1997; 81:363â&#x20AC;&#x201C; 371.

W. A. Pulsinelli, D. E. Levy, et al, â&#x20AC;&#x153;Increased damage after ischemic stroke in patients with hyperglycemia with or without established diabetes mellitus,â&#x20AC;? The American Journal of Medicine 1983; 74:540â&#x20AC;&#x201C;544.

J. F. McMurry Jr., Wound healing with diabetes mellitus.

Better glucose control for better wound healing in diabetes, The Surgical Clinics of North America 1984; 64:769â&#x20AC;&#x201C;778.

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W. I. Brenner, Z. Lansky, R. M. Engelman, and W. M. Stahl, â&#x20AC;&#x153;Hyperosomolar coma in surgical patients: an iatrogenic dis- ease of increasing incidence,â&#x20AC;? Annals of Surgery 1973; 178:651â&#x20AC;&#x201C;654.

G. A. Lee, S. Wyatt, D. Topliss, K. Z. et al, â&#x20AC;&#x153;A study of a pre-operative intervention in patients with diabetes undergoing cardiac surgery,â&#x20AC;? Collegian 2014; 21:287â&#x20AC;&#x201C;293. . D.K.Wukich,â&#x20AC;&#x153;Diabetes and its negative impact on outcomes in orthopaedic surgery,â&#x20AC;? World Journal of Orthopedics 2015; 6:331â&#x20AC;&#x201C;339.

M. R. Werb, B. Zinman, S. J. Teasdale et al, â&#x20AC;&#x153;Hormonal and metabolic responses during coronary artery bypass

DIABETES

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Management of Hyperglycemia in Hospitalized Patients in Non-Critical Care Setting: An Endocrine Society Clinical Practice Guideline, J Clin Endocrinol Metab 2012: 97:16–38.

42. Moghissi ES, Korytkowski MT, DiNardo M, et al.; American Association of Clinical Endocrinologists; American Diabetes Association. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care 2009; 32:1119–1131.

43. Boyd JC, Bruns DE. Quality specifications for glucose meters: assessment by simulation modeling of errors in insulin dose. Clin Chem 2001; 47:209–214.

44. Jennifer B. Marks, Perioperative Management Of Diabetes, American Family Physician 2003; 67:93-100 45. Sivakumar Sudhakaran and Salim R. Surani, Guidelines for Perioperative Management of the Diabetic Patient, Surgery Research and Practice Volume 2015, Article ID 284063, 8 pages http://dx.doi.org/10.1155/2015/284063

C H A P T E R

45

SGLT2- Inhibitors in the Management of Type 2 Diabetes

INTRODUCTION

T2DM individuals manifest a 2-3 times greater risk of CV events compared to non-diabetics, and CV mortality is responsible for ~70% of total mortality. In T2DM patients without MI, risk of CV death is similar to individuals without diabetes with prior MI.1 Although hyperglycemia is a strong risk factor for microvascular complications, it is a weak risk factor for CV disease (CVD), and interventional studies focused on reducing plasma glucose in T2DM have only a minor effect to reduce CV risk.2-5 Furthermore, it takes many years to observe the CV benefit associated with improved glycemic control.6,7 Most T2DM individuals manifest insulin resistance (metabolic syndrome), which is associated with multiple metabolic abnormalities, i.e., obesity, dyslipidemia, and hypertension, all of which are CV risk factors. The molecular mechanisms responsible for insulin resistance directly contribute to the pathogenesis of atherosclerosis, independent of the associated metabolic abnormalities.8 Thus, obese individuals without diabetes with the insulin resistance syndrome manifest a similarly increased risk for CVD compared with T2DM patients, supporting the concept that hyperglycemia is not a major determinant for the development of CVD in T2DM. Consequently, lowering blood pressure and improving lipid profile have a greater effect to reduce CVD risk than lowering plasma glucose concentration in T2DM.9 Therefore, it is not surprising that antidiabetes agents, e.g. sulfonylureas,10 insulin,11 and DPP4-inhibitors (12-14), that lower plasma glucose without affecting other metabolic abnormalities associated with the insulin resistance syndrome have little beneficial effect to lower CVD risk in T2DM, especially when these agents are started late in the natural history of T2DM and atherosclerosis. Conversely, pioglitazone, which improves insulin sensitivity and multiple components of insulin resistance syndrome, i.e., blood pressure and lipids, exerts a favorable effect on CVD risk in T2DM individuals, independent of its glucose-lowering action.15 In the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive), pioglitazone lowered the main secondary end point (CV death, nonfatal MI, and stroke) by 16% (P = 0.025).15 While SGLT2-inhibitors can exert a beneficial effect on CV risk by having favorable effects on weight and blood pressure, and also other favorable hemodynamic effects.16

MECHANISM OF ACTION OF SGLT2-INHIBITORS

Sodium-GLucose co Transporter 2 (SGLT2) inhibitors have a unique mechanism of action, which is independent

Vinod Mittal

of insulin secretion and insulin action.16 By inhibiting SGLT2 receptors in the renal proximal tubule, they lower plasma glucose by producing glucosuria. This unique mechanism of action, in addition to lowering plasma glucose, also corrects a number of metabolic and hemodynamic abnormalities that are risk factors for CVD. Urinary glucose loss produces negative caloric balance, resulting in a weight loss of 2–3 kg. Approximately twothirds of the weight loss is fat, with subcutaneous and mesenteric fat loss contributing equally to the reduction in total body fat.17 SGLT2 inhibition decreases sodium reabsorption in the proximal tubule and exerts diuretic/natriuretic effect.

SGLT2 inhibition also promotes urinary sodium excretion by causing osmotic diuresis. The result is a modest decrease in extracellular volume of ~5–10%. This natriuretic effect, combined with the more long-term reduction in body weight, contributes, in part, to decreases in systolic/ diastolic blood pressure (4–5/1–2 mmHg), which is observed with all SGLT2 inhibitors.17 Blood pressure reduction is not accompanied by an increase in heart rate and is independent of background antihypertensive therapy, suggesting that SGLT2 inhibition might reduce sympathetic tone or influence other hormonal factors that contribute to decreased blood pressure without increasing heart rate.

SGLT2 inhibitors cause a small increase in plasma LDL and HDL cholesterol and a decrease in plasma triglycerides;18 LDL/HDL cholesterol ratio remains unchanged. The mechanism by which SGLT2 inhibitors cause these changes in lipid profile remains unknown. Weight loss can explain, in part, the decrease in triglycerides and increase in HDL cholesterol. The mechanism(s) responsible for increased LDL cholesterol and clinical significance of this increase requires further study.

T2DM individuals manifest moderate-to-severe insulin resistance. It has been suggested that insulin resistance per se contributes to the pathogenesis of atherosclerosis, independent of accompanying metabolic abnormalities, i.e., obesity, dyslipidemia, or hypertension. Thus, improving insulin sensitivity would be anticipated to reduce CV risk. Two weeks of dapagliflozin treatment improved whole-body insulin-mediated glucose uptake by 20–25%, measured with the euglycemic insulin clamp.16 Because of the beneficial cardiometabolic/hemodynamic profile associated with SGLT2 inhibitor therapy, one might expect that this class of drugs would lower CVD risk in

248

in Diabetes (ACCORD) study,4 Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study,5 and Veterans Affairs Diabetes Trial (VADT).6 Second, the difference in HbA1c between empagliflozin and placebo groups was modest: 0.45% at 90 weeks and 0.28% at 204 weeks. Third, it took ~10 years in UKPDS7 and VADT8 to demonstrate a small (~10%), though significant, reduction in CV events by tight glycemic control, while the effect of empagliflozin on CV mortality was evident at 3 months and well established at 6 months.

T2DM, independent of its glucose-lowering effect. Thus, the EMPA-REG OUTCOME study, which was required

by U.S. Food and Drug Administration to establish CV safety, was powered not only for noninferiority compared to placebo but also for superiority.19

DIABETES

EMPA-REG OUTCOME STUDY

The EMPA-REG OUTCOME study19 is the first study to provide evidence that an antidiabetes agent decreases CV events. In 7,020 T2DM patients with established CVD, empagliflozin significantly reduced (hazard ratio [HR] 0.86 [95% CI 0.74–0.99], P = 0.04) the primary major adverse cardiac event (MACE) outcome (CV death, nonfatal MI, nonfatal stroke). However, several outcomes were surprising. First, the primary outcome was driven by decreased CV mortality and a striking disconnect between the three MACE components was observed: 1) for nonfatal MI, HR (0.87) decreased slightly but not significantly (P = 0.22); 2) for stroke, HR (1.24) increased slightly but not significantly (P = 0.22); and 3), and for CV death, HR (0.62) decreased significantly by 38% (P = 0.001). Second, unlike other interventions that reduce CV risk, e.g., lowering LDL cholesterol and blood pressure, separation between empagliflozin and placebo curves occurred very early (3 months), thus reduction in the primary outcome was evident 3 months after starting empagliflozin. Third, the beneficial effect of empagliflozin on mortality and hospitalization for heart failure widened progressively over the 3.1 years of treatment. Fourth, both empagliflozin doses (10 and 25 mg) had a similar effect on outcome measures with no dose-response relationship.

3.

Weight Loss: Glucosuria (~ 70 gm/day) produced

by SGLT2 inhibitors, causes caloric loss (~ 280 Cals/ day) and a decrease in body weight. In the EMPAREG OUTCOME study, empagliflozin-treated subjects lost ~2 kg. Although possible, it is unlikely that this small amount of weight loss contributed to the reduction in CV mortality that was observed within 2–3 months after the start of empagliflozin.

4.

Effect on Blood Pressure? Most of the participants in the EMPA-REG OUTCOME study were hypertensive and >90% received antihypertensive therapy, starting blood pressure was well controlled (135/77 mmHg). The decrease in systolic/diastolic blood pressure in the EMPA-REG OUTCOME study was ~5/2 mmHg, and was maintained throughout the 3.1-year study duration. Such a decrease in blood pressure could contribute to the reduction in CV events in the EMPA-REG OUTCOME study. However, in studies that examined the effect of blood pressure reduction on CV events, the decrease became evident only after 1 year.

Moreover, lowering blood pressure generally has a greater impact on stroke reduction than on other cardiac events. In the EMPA-REG OUTCOME study there was a small, albeit non-significant, increase in nonfatal stroke. Thus, it is unlikely that the decrease in CV events in empagliflozin treated individuals can be explained solely by the decrease in brachial artery blood pressure. However, reduction in brachial artery blood pressure may underestimate central aortic pressure and provides no information about aortic stiffness, both of which are independent predictors of CV mortality and LV function. Also empagliflozin caused a 5/2 mmHg decrease in systolic/diastolic blood pressure without any increase in heart rate. This is consistent with the action of the drug to reduce sympathetic tone, which could have favorable effects on CV mortality. But further studies are needed to examine the effect of SGLT2 inhibitor therapy on the sympathetic nervous system.

5.

Effect to Slow Atherosclerosis? Empagliflozintreated subjects experienced ~2 kg weight loss, 2 mg% increase in HDL cholesterol, and 5 mmHg decrease in systolic blood pressure compared with placebo-treated subjects. These benefits

POSSIBLE MECHANISMS FOR CARDIO-RENAL BENEFITS

1.

Metabolic Actions: Inhibition of renal SGLT2 in T2DM exerts multiple metabolic effects (e.g., reduced HbA1c, weight loss, increase in fat oxidation, and increase in glucagon secretion) that can affect cardiac function and potentially influence CV mortality. Reduction in CV death without decrease in MI or stroke suggests that the beneficial effect of empagliflozin is to improve survival among patients experiencing a CV event rather than to slow the atherosclerotic process and prevent atherosclerotic events, i.e. MI and stroke.

Reduction in CV death (5.9 to 3.6%, P < 0.001) was observed across all diagnostic categories (sudden death, 1.6 to 1.1%; worsening heart failure, 0.8 to 0.2%; acute MI, 0.5 to 0.3%; stroke, 0.5 to 0.3%; other CV death, 2.4 to 1.6%). The latter category includes deaths not explained by other known causes. The majority of such cases result from acute MI and arrhythmias, and this category is not as diagnostically sound as the others.19

2.

Glycemic Control: It is unlikely that empagliflozin reduced mortality in the EMPA-REG OUTCOME study by improving glucose control. First, hyperglycemia is weak risk factor for CVD. Intensive glycemic control failed to decrease CV events in the UK Prospective Diabetes Study (UKPDS),3 Action to Control Cardiovascular Risk

would be expected to slow the atherosclerotic process and reduce nonfatal CV events. However, nonfatal CV events (MI and stroke) were not affected by empagliflozin.19 It is possible that the study duration was too short to observe the impact of these metabolic/hemodynamic effects on atherosclerosis-related events or that the antiatherosclerotic effect of empagliflozin may have been obscured by the advanced atherosclerotic condition of the participants. It is also possible that the increase in plasma LDL, although small, negated some beneficial effect of empagliflozin on CV risk factors.

7.

8.

Effect on Glucagon: SGLT2 is expressed in pancreatic α-cells and plays an important role in regulating glucagon secretion.20 Dapagliflozin and empagliflozin cause a small increase in plasma glucagon in T2DM patients (Figure 1). In experimental animals, glucagon receptor activation exerts a detrimental effect on myocardial function, and glucagon infusion in humans has no effect on left ventricular (LV) function. Thus, it is unlikely that an increase in plasma glucagon contributed to reduced CV mortality or hospitalization for heart failure by empagliflozin.

Effect on Uric Acid: SGLT2 inhibitors promote uric acid excretion and reduce the plasma uric acid concentration by ~0.7% mg/dL. Increased uric acid levels long have been associated with increased CVD,21 but a causal link remains controversial.

However, accumulating evidence in both humans and animals indicates that elevated plasma uric acid levels can cause hypertension, vascular damage, and impaired renal function. Although unlikely to explain the early reduction in CV mortality, the potential benefits of uric acid reduction to reduce blood pressure and prevent vascular damage may play a role in the progressive late separation in the mortality curves between empagliflozin and placebo. The reduction in plasma uric acid concentration also may contribute to the impressive slowing of diabetic nephropathy observed in the EMPA-REG Renal study.20 Change in Plasma Electrolyte Concentration: There is a negative sodium balance in the first 2–3 days after starting the drug without a change in plasma sodium concentration. What remains to be established is whether sodium redistribution between the intra- and extracellular compartments may have occurred as a result of the natriuretic effect of the drug. Preclinical studies also have reported heart tissue remodeling22 after the administration of SGLT2 inhibitors in association with a marked reduction of interstitial fibrosis.

The latter, however, requires time and is unlikely to explain the early deviation of curves for CV mortality and heart failure hospitalization. No consistent changes in plasma potassium, chloride,

Fig. 1: Schematic representation of the possible metabolic and hemodynamic mechanisms via which empagliflozin reduced CV mortality and hospitalization for heart failure in the EMPA-REG OUTCOME study. bicarbonate, or calcium concentrations have been reported with SGLT2 inhibitors. Small increases in serum phosphate (3–5%) and magnesium (7– 9%) have been reported with SGLT2 inhibitors.

It is unlikely that such a small increase in serum phosphate could affect myocardial function, and serum magnesium correlates poorly with tissue magnesium levels.

9.

Shift in Fuel Metabolism: SGLT2 inhibitors shift whole-body metabolism from glucose to fat oxidation27,28 (Figure 1). and the end product of fatty acid oxidation is acetyl CoA, which either can enter the tricarboxylic acid cycle or be converted to Beta-OH Butyrate, which is a more efficient fuel (Super fuel) than fatty acids28 (Figure 3). The rise in plasma ketone concentration is small (0.3–0.6 meq/L) and does not lead to ketosis. The heart avidly extracts and consumes Beta-OH Butyrate, resulting in improved cardiac muscle efficiency.

This mechanism appears to be the most important and plausible in explaining the Cardio-renal benefits of empagliflozin. Further physiological and imaging studies will be required to examine whether the preferential oxidation of ketones by the heart27 provides an energetic benefit to the failing myocardium.

10.

Direct Effect of the Drug: SGLT2 is not expressed in cardiac myocytes, but SGLT1 is present in myocardial tissue. Thus partial SGLT1 inhibition by empagliflozin could affect cardiac function.

However, half-maximal effective concentration for SGLT1 inhibition by empagliflozin is 8.3 μmol/L, which is ~2,600-fold greater than for SGLT2, and the peak plasma empagliflozin concentration following the administration of 10 and 25 mg/day doses is only ~500 and ~800 nmol/L. Moreover, most of the circulating drug is bound to plasma proteins and free drug concentration is much lower. Therefore, the expected plasma-free

CHAPTER 45

6.

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empagliflozin concentration in the EMPA-REG OUTCOME study would be very low, and it is very unlikely that the low circulating free empagliflozin level could have any effect on SGLT1 function.

Further, if SGLT1 were inhibited by empagliflozin, myocardial function would be expected to decline, not improve. In short, direct myocardial effects by empagliflozin are unlikely to explain the beneficial effect of the drug on CV mortality.

DIABETES

IS IT A CLASS EFFECT?

There are no significant differences in glucose lowering, body weight loss, and blood pressure reduction among the individual SGLT2 inhibitors. Using the Archimedes model, it has been predicted that, over a period of 20 years, patients with diabetes treated with dapagliflozin would experience a relative reduction of MI, stroke, CV death, and all-cause death. However, only well-designed CV intervention trials will provide a true answer to the question. The CANagliflozin cardioVascular Assessment Study (CANVAS),26 is going to be completed in 2017 and DECLARE TIMI 58 study, going to be completed in 2019. These ongoing studies would examine the effect of canagliflozin and dapagliflozin, respectively, on CV outcomes, may help clarify whether the effect of empagliflozin19 to reduce CV events is a class effect or represents a specific pharmacological effect of empagliflozin. It is impossible at this time to determine whether other SGLT2 inhibitors will exert similar reductions in CV death and CHF hospitalization.

Populations with diabetes in CANVAS and DECLARE differ significantly from those in the EMPA-REG OUTCOME study. Approximately 60-70% of patients in CANVAS and ~40% in DECLARE had a prior CV event and the remaining participants qualified based on CV risk factor profile. Moreover, the sample size (4,339 patients) in CANVAS is relatively small compared with the EMPA-REG OUTCOME study. As the beneficial CV effects of empagliflozin most likely are mediated via its hemodynamic/volume depletion actions, one might expect other members of this class to have similar beneficial effects on CV events. However, because of different selection criteria in CANVAS and DECLARE, it is possible that a beneficial effect of canagliflozin and dapagliflozin to reduce CV mortality and CHF may not be observed even though the beneficial hemodynamic (and metabolic) effects of all three SGLT2 inhibitors are similar.

ADVERSE EFFECTS

The most common adverse effect seen with SGLT2 inhibitors is an increase in infections of the genitourinary tract as well as female genital mycotic infections. These genitourinary infections are generally mild and can be managed conservatively. Dapagliflozin causes other side effects such as dehydration (probably because of polyuria) while canagliflozin is associated with polydipsia, constipation, nausea as well as polyuria. An imbalance in the frequency of bladder cancer was observed in clinical trials with dapagliflozin. Hence, dapagliflozin should

not be prescribed to patients with active bladder cancer or with a history of bladder cancer. With empagliflozin, headaches were a common adverse event.

The US FDA issued a drug safety communication in May 2015 that warned patients and healthcare professionals about the tendency of SGLT2 inhibitors to cause ketoacidosis. A review of the FDA Adverse Event Reporting System (FAERS) database showed that there were 73 cases of ketoacidosis from March, 2013 to May, 2015 in patients with type 1 and type 2 diabetes who were being treated with SGLT2 inhibitors. The communication also said that a review of the FAERS database from March 2013 to October 2014 also identified 19 cases of urosepsis and pyelonephritis that originated as urinary tract infections]. All the adverse effects are very uncommon and can be avoided by proper selection of the patient.

FUTURE PERSPECTIVE

SGLT2-inhibitors exert multiple hemodynamic (reduction in plasma volume and decrease in blood pressure) and metabolic benefits (decreases in HbA1c, body weight, and an increase in HDL cholesterol), The results of the EMPAREG OUTCOME study suggest that the beneficial effect of empagliflozin to lower CV mortality in T2DM patients most likely results from its hemodynamic rather than its metabolic effects, it is intriguing to examine the impact of the drug specifically in subjects with and without diabetes with reduced LV function (e.g., post-MI) and in subjects with existing CHF. At present the beneficial effect of empagliflozin on CV mortality and CHF hospitalization in these patient populations is likely to be quite robust, which may change the paradigm in the management of type 2 diabetes. Additional physiological and imaging studies are required to further examine this possibility.

REFERENCES

1.

Di Angelantonio E, Kaptoge S, Wormser D, et al.; Emerging Risk Factors Collaboration. Association of cardiometabolic multimorbidity with mortality. JAMA 2015; 314:52–60.

2.

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

3.

Gerstein HC, Miller ME, Byington RP, et al.; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358:2545–2559.

4.

Patel A, MacMahon S, Chalmers J, et al.; ADVANCE Collaborative Group.Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358:2560–2572.

5.

Duckworth W, Abraira C, Moritz T, et al.; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360:129–139.

6.

Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359:1577–1589.

7.

Hayward RA, Reaven PD, Wiitala WL, et al.; VADT

Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 372:2197–2206.

18. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014; 124:499–508.

8.

DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia 2010; 53:1270–1287.

9.

Obunai K, Jani S, Dangas GD. Cardiovascular morbidity and mortality of the metabolic syndrome. Med Clin North Am 2007; 91:1169–1184.

19. Zinman B, Wanner C, Lachin JM, et al.; EMPA-REG OUTCOME Investigators.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373:2117–2128.

10. Sattar N. Revisiting the links between glycaemia, diabetes and cardiovascular disease. Diabetologia 2013; 56:686–695.

12. Scirica BM, Bhatt DL, Braunwald E, et al.; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013; 369:1317–1326.

13. White WB, Cannon CP, Heller SR, et al.; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013; 369:1327– 1335.

14. Green JB, Bethel MA, Armstrong PW, et al.; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015; 373:232–242.

15. Dormandy JA, Charbonnel B, Eckland DJ, et al.; PROactive Investigators.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; 366:1279–1289.

16. Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes.Diabetes Obes Metab 2013; 15:853–862.

17. Abdul-Ghani MA, Norton L, DeFronzo RA. Renal sodiumglucose cotransporter inhibition in the management of type 2 diabetes mellitus. Am J Physiol Renal Physiol 2015; 309: F889–F900.

20. Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med 2015; 21:512–517.

21. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811–1821.

22. Levelt E, Mahmod M, Piechnik SK, et al. Relationship between left ventricular structural and metabolic remodeling in type 2 diabetes. Diabetes 2016;65:44–52.

23. Cherney DZ, Perkins BA, Soleymanlou N, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol 2014; 13:28.

24. Heise T, Seman L, Macha S, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus. Diabetes Ther 2013; 4:331–345.

25. Muskiet MH, van Raalte DH, van Bommel E, Smits MM, Tonneijck L. Understanding EMPA-REG OUTCOME. Lancet Diabetes Endocrinol 2015; 3:928–929.

26. Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)- a randomized placebocontrolled trial. Am Heart J 2013; 1 66:217–223.

27. Ele Ferrannini, MichaelMark, and Eric Mayoux- CV Protection in the EMPA-REG OUTCOME Trial: A“Thrifty Substrate” Hypothesis Diabetes Care 2016; 39:1108–1114.

28. Sunder Mudaliar, Sindura Alloju, and Robert R. Henry - Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis. Diabetes Care 2016; 39:1115– 1122.

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11. Gerstein HC, Bosch J, Dagenais GR, et al.; ORIGIN Trial Investigators. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012; 367:319–328.

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In Hospital Management of Diabetes Mellitus

INTRODUCTION

Diabetes and its complications are a major cause of hospitalizations. Number of diabetes related deaths in India was estimated to be 1.02 million.1 Various co-morbidities associated with diabetes such as dyslipidemia, hypertension, chronic kidney disease, cardiovascular disease, chronic obstructive pulmonary disease (COPD), nonalcoholic fatty liver disease, lower extremity amputations, obesity, infections, depression, etc. make patients susceptible to frequent hospitalizations.

The presence of comorbidities can further complicate the diabetes treatment. For instance, patients who need to be treated with steroids for pneumonia or COPD have to be shifted to insulin regimen from oral agents. The occurrence of hyperglycemic and hypoglycemic episodes might also lead to serious events including death2,3 and hence the major hospital goals for an individual with diabetes should definitely consist of reducing or preventing these fluctuations aiding in an effective disease management.

Individuals of high risk groups should be identified soon after hospitalization and properly monitored to ensure adequate treatment as well as to avoid complications.4 Special attention must be taken to minimize the disruption of the metabolic state, prevent an untoward result, and return the patient to a stable glycemic balance as quickly as possible. The stress from acute illness raises the chances for hyperglycaemia whereas; illness related anorexia or need of fasting for certain procedures often culminates in hypoglycemia. This makes the glycemic status of the patient highly unpredictable and thus the glycemic targets must be carefully set and reviewed frequently so as facilitate timely therapeutic decisons.

HYPERGLYCEMIA

Umpierrez et al reported that hyperglycaemia was present in 38% of patients at the time of hospitalisation and that one-third of these patients had no known history of diabetes before the admission.5 In patients with diabetes, missing an insulin injection or oral hypoglycaemic agent; or ingesting large quantities of carbohydrates, low physical activities etc. can all trigger hyperglycaemic events.

Acute illness leads to various physiological changes (e.g. increases in circulating concentrations of stress hormones) or therapeutic choices (e.g. glucocorticoid use) that can exacerbate hyperglycaemia. This, in turn, causes physiological changes that can exacerbate acute illness, such as decreased immune function and increased oxidative stress. This leads to a vicious cycle of worsening illness and poor glucose control.6 Infections and fever are known to activate medulla and cortex to produce

Jothydev Kesavadev epinephrine and cortisol subsequently resulting in severe hyperglycaemia. Moreover, elevations in blood glucose (BG) support infectious process and thereby slow down the healing process. To control such exacerbations, antidiabetic medications should be appropriately modified in subjects with diabetes in case of infections.7

Hyperglycaemia goals in hospitalised patients

The studies on tight glycemic control (TGC) by intensive insulin therapy brought out special interests in hyperglycemia management in hospitalised patients. In the Leuven proof-of-concept studies, the BG levels were kept tightly between 80 and 110 mg/dl. This approach, decreased mortality and morbidity in surgical critically ill patients and morbidity in medical critically ill patients.8,9 Several International guidelines incorporated these results, and intensive care units (ICU) started implementing TGC. However, data from the Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study,10 contradicted and overrode the Leuven Trials and demonstrated increased mortality among medical and surgical ICU patients who received TGC. As a result, TGC in the ICU to a goal <110 mg/dL is no longer recommended.

The American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) consensus statement, recommend that insulin therapy should be initiated for treatment of persistent hyperglycemia, starting at a threshold of no greater than 180 mg/dL. Once insulin therapy is started, a target glucose range of 140–180 mg/dL should be set for the majority of critically ill patients and non-critically ill patients. More stringent goals, such as 110–140 mg/dL should be considered for selected critically ill patients, as long as this can be achieved without significant hypoglycaemia. (2). ADA recommended glycemic goals for hyperglycemia treatment is given in Table 1.

Managing hyperglycaemia in hospitalised patients

In most instances in the hospital setting, insulin is the preferred treatment for glycemic control.2 Oral antihyperglycemic agents are not suitable due to difficulty in titrating their dose to meet fluctuating blood glucose levels, associated co-morbid conditions like hepatic and renal impairment, and most importantly the need for quick achievement of target blood sugar levels.12 However, in certain circumstances, it may be appropriate to continue well-controlled patients (who are eating, and in whom no change in their medical condition or nutritional intake is anticipated) on their prior out-patient oral regimen. It

Tabel 1: ADA recommended glycemic targets for hyperglycemia treatment in a hospital setting11 ICU

Non-ICU

Initiate insulin therapy for A glucose target between persistent 140-180 mg/dL, (between 7.8 and 10.0 mmol/L) is hyperglycemia (glucose recommended. >180 mg/dl [10

is often also reasonable to resume oral agents in some patients when preparing for hospital discharge.13 If a patient was previously eating but is unable to eat after the evening meal in order to prepare for a procedure the next morning, oral hypoglycaemic drugs should be omitted on the day of procedure (surgical or diagnostic).

If procedures are arranged as early in the day as possible, anti-hyperglycemic therapy and food intake can then be shifted to later in the day.

Basal plus correction insulin regimen/ Basal–bolus subcutaneous insulin injections for noncritical care setting

Administration of subcutaneous insulin injections should align with meals and bedtime or every 4–6 h if no meals or if continuous enteral/ parenteral therapy is used.2 For patients with poor oral intake or those who are taking nothing by mouth (NPO), a basal plus correction insulin regimen is the preferred treatment.17 An insulin regimen with basal, nutritional, and correction components (basal– bolus) can be chosen for patients with good nutritional intake.13 BG should be monitored immediately before meals and if oral intake is poor, it is safer to administer the short-acting insulin after meals or to count the carbohydrates and cover the amount ingested. Basal– bolus treatment has been found to improve glycaemic control as well as reduce hospital complications than SSI in general surgery patients with T2DM.18

The common themes in the insulin infusion protocols are the use of regular insulin for continuous insulin infusion and a basal/bolus subcutaneous insulin regimen including a long-acting insulin analog (insulin degludec, glargine or detemir) and prandial and correctional doses of a rapidacting insulin (insulin aspart, glulisine, or lispro).

Insulin therapy in Type 1 Diabetes- Patients who have a known history of T1DM are insulin deficient and hence, dosing insulin based solely on premeal glucose levels does not account for basal insulin requirements or calorie intake, increasing both hypoglycemia and hyperglycemia risks and potentially leading to diabetic ketoacidosis (DKA). Typically basal insulin dosing schemes are based on body weight, with some evidence that patients with renal insufficiency should be treated with lower doses.19

Sliding scale insulin therapy

Insulin therapy in patients using insulin pumps

Insulin therapy

The widespread use of the Sliding Scale Insulin (SSI) administration began during the era of urine glucose testing and it increased after the introduction of rapid capillary blood glucose testing in the last two to three decades. At the present, the sole use of SSI in the inpatient hospital setting is strongly discouraged.2 In most SSI therapy regimens, BG is measured about four times a day (every 5 to 6 hours, or before meals and at bedtime) and accordingly insulin (mostly rapid acting) is administered. However, there are few data to support its benefit and some evidence of potential harm when the “sliding scale” is applied in a rote fashion, that is, when all patients receive the same orders. In fact, when the sole form of insulin administered is rapid acting insulin every four to six hours without underlying provision of basal insulin, they are associated with an increased rate of hyperglycemic episodes.14

Continuous intravenous insulin infusions (CIVII) for critical care setting

CIVII is the best method for achieving glycemic targets in

Continuous Subcutaneous Insulin Infusion (CSII) or Insulin Pump Therapy (IPT) when compared to other conventional insulin delivery methods provides the advantage of achieving better glycaemic control, minimising glucose variability and thereby, preventing or reducing the risk of microvascular and macrovascular complications in patients with diabetes. A cross-sectional survey conducted among T2DM patients demonstrated that IPT brought out significant improvement in their quality of life. The attitude and behaviour of these individuals were also found to be very positive and promising.20 Patients on IPT do not necessarily discontinue this form of therapy during hospitalization. However, to ensure a collaborative relationship between the hospital staff and the patient and to ensure patient safety, hospitals should have clear policies and procedures in place to guide the continued use of IPT in the inpatient setting.21 During admission, patients must be assessed for their physical and mental competency to continue the use of their insulin pumps. The patient should also have adequate insulin pump supplies. If the patient cannot

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Hospitalised patients who are clinically stable For most patients, target a and has a prior history of glucose level between 140- successful tight glycemic 180 mg/dl. control target for BG <140 mg/dL (7.8 mmol/L) More stringent goals (110-140 mg/dl) may be Less stringent targets may appropriate for selected be appropriate in patients patients, if achievable with severe comorbidities without significant risk for hypoglycemia mmol/l])

a critical care setting and should be done with validated protocols so as to allow for predefined adjustments in the infusion rate, accounting for glycaemic fluctuations and insulin dose.2,15 With CIVII, frequent BG monitoring should be done to minimize the occurrence of hypoglycemia and to achieve optimal glucose control. Regular human insulin is commonly used for IV infusion and a recent study has shown that rapid acting insulin analog can also be effective, well tolerated option for managing inpatient hyperglycemia.16

254

competently demonstrate and/or describe the abovementioned actions, insulin pump therapy should be discontinued and the patient placed on a subcutaneous insulin regimen or CIVII.22

DIABETES

Transition from intravenous to subcutaneous insulin therapy

A transition protocol is recommended for discontinuing intravenous insulin in order to reduce morbidity and costs of care.23 To maintain adequate levels of insulin, it is necessary to administer subcutaneously short/ rapidacting insulin 1–2 h before or intermediate or longacting insulin 2–3 h before discontinuation of the CIVII. For the transitional process, subcutaneous insulin with appropriate duration of action may be administered as a single dose or repeatedly to maintain basal effect until the time of day when the choice of insulin or analog preferred for basal effect normally would be provided.3 Converting to basal insulin at 60–80% of the daily infusion dose has been shown to be effective.11

PREVENTING HYPOGLYCEMIA

Hypoglycemia, especially in insulin-treated patients, is the leading limiting factor in the glycemic management of patients with diabetes.3 In a retrospective cohort study done by Jothydev et al, a telemedicine (DTMS®) based follow-up and multidisciplinary care accompanied by self-monitoring of blood glucose was proven beneficial in the intensive treatment of T2DM. Compared to the traditional healthcare approach, DTMS® aided patients in achieving glycaemic targets without any serious symptomatic hypoglycaemia or other co-morbidities and also reduced the frequency of their hospital visits.24 Hypoglycemia in hospitalized patients has been defined as blood glucose, 70 mg/dL and in cases of severe hypoglycemia as, 40 mg/dL.25 In the hospital, multiple additional risk factors for hypoglycemia are present, even among patients who are neither “brittle” nor tightly controlled. Patients with or without diabetes may experience hypoglycemia in the hospital, in association with factors such as altered nutritional state, heart failure, renal or liver disease, malignancy, infection, or sepsis.26,27 Iatrogenic hypoglycemia can also be triggered by sudden reduction of corticosteroid dose, altered ability of the patient to report symptoms, and reduced oral intake, emesis, new NPO status, inappropriate timing of shortacting insulin in relation to meals, reduced infusion rate of intravenous dextrose, and unexpected interruption of oral, enteral, or parenteral feedings. Under-prescribing anti-hyperglycemic therapy than the advisable range is not always fully protective against such causes of hypoglycemia. Standardized treatment protocols to address mild, moderate and severe hypoglycaemia should be implemented in hospitals and healthcare team should be educated about factors that increase the risk of hypoglycaemia.22 Common preventable sources of iatrogenic hypoglycemia are improper prescribing of hypoglycemic medications, inappropriate management of the first episode of hypoglycemia, and nutrition–insulin mismatch, often related to an unexpected interruption of nutrition. A study of “bundled” preventative therapies

including proactive surveillance of glycemic outliers and an interdisciplinary data-driven approach to glycemic management showed that hypoglycemic episodes in the hospital could be prevented.28

MANAGEMENT OF DIABETIC EMERGENCIES

Diabetic ketoacidosis (DKA) and Hyperglycemic Hyperosmolar Nonketotic syndrome (HHNS, otherwise called Hyperosmolar hyperglycemic state (HHS) or Hyperosmolar Hyperglycemic Nonketotic Coma (HHNC)) are diabetic emergencies with overlapping features. With insulin deficiency, hyperglycemia causes urinary losses of water and electrolytes (sodium, potassium, chloride) and the resultant extracellular fluid volume (ECFV) depletion.

Potassium is shifted out of cells, and ketoacidosis occurs as a result of elevated glucagon levels and absolute insulin deficiency (in the case of T1DM) or high catecholamine levels suppressing insulin release (in the case of T2DM).

In DKA, ketoacidosis is prominent, while in HHNS, the main features are ECFV depletion and hyperosmolarity.29 DKA is a commonly confronted by T1DM patients and also occasionally occurs in T2DM patients who are completely or almost insulin deficient. DKA can occur with infection, steroid treatment, stress etc. but recurrent DKA is often due to omitted insulin doses. Classic symptoms include polyuria, polydipsia and polyphagia with weight loss. Classic signs are Kussmaul’s respiration (labored breathing) and dehydration. Diagnosis is confirmed with an elevated BG level and initial screens should include electrolytes (basic/ comprehensive metabolic panel) and perhaps arterial blood gas. BG levels can vary from >126 mg dl to more than 3000 mg/dl. Sodium potassium levels, pH, bicarbonate levels and anion gap and serum creatinine levels are of significance for understanding the state of acidosis and hydration.7 HHNS is most often seen in individuals (mostly older than 60 yrs and rarely in children) with T2DM or in those who have no previous diagnosis of diabetes. The cause of this condition is relative insulin deficiency sufficient to produce hyperglycemia but not severe to allow ketonemia. The person may have classic signs of diabetes (polyuria, polydipsia and weight loss) but no or little ketonemia or ketonuria. Distinguishing features of this condition are marked serum hyperosmolarity, very high BG (900-3000 mg/dL), frequent hypernatremia, severe dehydration and hypokalemia, coma not associated with ketosis or acidosis.7 The therapeutic goals of DKA and HHNS management include restoration of volume status, correction of hyperglycemia and ketoacidosis (in DKA), correction of electrolyte abnormalities, treatment of precipitating factors, and prevention of the complications of DKA and HHNS.30 Lesser insulin is required for HHNS than DKA since the patient is not ketotic, but fluid requirements are higher due to extreme hyperosmolarity. Patients are usually older, and may have renal insufficiency and/ or congestive heart failure. Fluid administration must be done carefully to prevent fluid overload and nephrology

and cardiology service might be required.7 A suggested protocol for the management of DKA and HHNS.31

CONCLUSION

REFERENCES

1.

IDF Diabetes Atlas. Brussels, Belgium: International Diabetes Federation, 2015.

2.

Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D, Hellman R, Hirsch IB, et al. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care 2009; 32:1119-31.

3.

Clement S, Braithwaite SS, Magee MF, Ahmann A, Smith EP, Schafer RG, et al. Management of diabetes and hyperglycemia in hospitals. Diabetes Care 2004; 27:553-91.

4.

Umpierrez GE, Hellman R, Korytkowski MT, Kosiborod M, Maynard GA, Montori VM, et al. Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism 2012; 97:16-38.

5.

Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. Hyperglycemia: an independent marker of inhospital mortality in patients with undiagnosed diabetes.

The Journal of Clinical Endocrinology & Metabolism 2002; 87:978-82.

6.

Inzucchi SE. Management of hyperglycemia in the hospital setting. N Engl J Med 2006; 355:1903-11.

7.

Dr. Diana W. Guthrie PDBCADMCDEF, Dr. Richard A. Guthrie MDF. Management of Diabetes Mellitus: A Guide to the Pattern Approach, Sixth Edition: Springer Publishing Company; 2008.

8.

Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001; 345:1359-67.

9.

Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, et al. Intensive insulin therapy in the medical ICU. N Engl J Med 2006; 354:449-61.

10. Investigators N-SS. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 2009:128397.

11. Diabetes Care in the Hospital. Diabetes Care. 2016; 39(Supplement 1):S99-S104.

12. Bhoraskar A. Inpatient management of diabetes mellitus. J Assoc Physicians India 2011; 59:29-31.

13. Maynard G, Wesorick DH, O’Malley C, Inzucchi SE, Force SoHMGCT. Subcutaneous insulin order sets and protocols:

255

14. Queale WS, Seidler AJ, Brancati FL. Glycemic control and sliding scale insulin use in medical inpatients with diabetes mellitus. Arch Intern Med 1997; 157:545-52.

15. Umpierrez G, Cardona S, Pasquel F, Jacobs S, Peng L, Unigwe M, et al. Randomized controlled trial of intensive versus conservative glucose control in patients undergoing coronary artery bypass graft surgery: GLUCO-CABG trial.

Diabetes Care 2015; 38:1665-72.

16. Udwadia F, Bhattacharyya A, Seshiah V, Kumar Sethi B, Kumar S, Kumar Subbanna P, et al. Intravenous insulin aspart in a hospital setting: results from an observational study examining patient outcomes and physician preferences. Diabetes Management 2012; 2:103-10.

17. Umpierrez GE, Smiley D, Hermayer K, Khan A, Olson DE, Newton C, et al. Randomized study comparing a basalbolus with a basal plus correction insulin regimen for the hospital management of medical and surgical patients with type 2 diabetes. Diabetes Care 2013; 36:2169-74.

18. Umpierrez GE, Smiley D, Jacobs S, Peng L, Temponi A, Mulligan P, et al. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery).

Diabetes Care 2011; 34:256-61.

19. Baldwin D, Zander J, Munoz C, Raghu P, DeLange-Hudec S, Lee H, et al. A randomized trial of two weight-based doses of insulin glargine and glulisine in hospitalized subjects with type 2 diabetes and renal insufficiency.

Diabetes Care 2012; 35:1970-4.

20. Kesavadev J, Shankar A, Pillai P, Saboo B, Joshi S, Krishnan G, et al. CSII as an Alternative Therapeutic Strategy for Managing Type 2 diabetes: Adding the Indian Experience to a Global Perspective. Current diabetes reviews. 2015.

21. Bailon R, Partlow B, Miller-Cage V, Boyle M, Castro J, Bourgeois P, et al. Continuous subcutaneous insulin infusion (insulin pump) therapy can be safely used in the hospital in select patients. Endocrine Practice 2009; 15:24-9.

22. Houlden R, Capes S, Clement M, Miller D. In-hospital Management of Diabetes. Canadian Journal of Diabetes 37:S77-S81.

23. Schmeltz LR, DeSantis AJ, Thiyagarajan V, Schmidt K, O’Shea-Mahler E, Johnson D, et al. Reduction of surgical mortality and morbidity in diabetic patients undergoing cardiac surgery with a combined intravenous and subcutaneous insulin glucose management strategy.

Diabetes Care 2007; 30:823-8.

24. Kesavadev J, Shankar A, Pillai PBS, Krishnan G, Jothydev S. Cost-effective use of telemedicine and self-monitoring of blood glucose via Diabetes Tele Management System (DTMS) to achieve target glycosylated hemoglobin values without serious symptomatic hypoglycemia in 1,000 subjects with type 2 diabetes mellitus—A retrospective study. Diabetes Technology & Therapeutics 2012; 14:772-6.

25. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 2013; 36:1384-95.

26. Shilo S, Berezovsky S, Friedlander Y, Sonnenblick M. Hypoglycemia in hospitalized nondiabetic older patients.

J Am Geriatr Soc 1998; 46:978-82.

CHAPTER 46

Patients with diabetes meet with frequent hospitalizations for diabetes related or unrelated complications. Owing to highly unstable glycemic control seen in these individuals (because of stress of the illness or procedure, changes in diet and physical activities etc.), they deserve best possible hospital care. Sliding scale insulin protocols should be totally discouraged and doctors and supporting staff irrespective of the speciality of care should have the basic understanding of the duration of action and frequency of commonly used insulin preparations. The glycemic targets should be individualised considering the severity of illness and risk benefit ratio. Though tight metabolic control may be beneficial in a subgroup, the occurrence of hypoglycemia could be fatal in the critically ill.

effective design and implementation strategies. J Hosp Med 2008; 3(5 Suppl):29-41.

256

27. Fischer KF, Lees JA, Newman JH. Hypoglycemia in hospitalized patients. N Engl J Med 1986; 315:1245-50.

28. Maynard G, Kulasa K, Ramos P, Childers D, Clay B, Sebasky M, et al. Impact of a hypoglycemia reduction bundle and a systems approach to inpatient glycemic management.

Endocrine Practice 2014; 21:355-67.

DIABETES

29. Goguen J, Gilbert J. Hyperglycemic emergencies in adults.

Canadian Journal of Diabetes 2013; 37 (suppl 1):S1-S212.

30. Lupsa BC, Inzucchi SE. Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic Syndrome.

Endocrine Emergencies: Springer; 2014. p. 15-31.

31. Kitabchi AE, Umpierrez GE, Murphy MB, Kreisberg RA. Hyperglycemic Crises in Adult Patients With Diabetes.

A consensus statement from the American Diabetes Association. 2006; 29:2739-48.

C H A P T E R

47

Practical Approach to a Patient whose First Time Random Blood Sugar is 208 mg/dl SV Madhu

When a patient is first seen with a random blood sugar value of 208 mg/dl several clinical issues arise and several questions need to be answered. These include : 1.

Does the patient have diabetes mellitus or stress hyperglycaemia ?

2.

How do we confirm the diagnosis of diabetes mellitus?

3.

What is the type of diabetes mellitus?

4.

Does the patient have any of the long term complications of diabetes Mellitus?

5.

Does the patient have any other comorbidity?

6.

What are the management Issues in this patient?

a.

Glycaemic management – what should be the approach?

b.

Management of complications and comorbidities Approach ?

7.

How should I monitor this patient ?

DOES THE PATIENT HAVE DIABETES MELLITUS OR STRESS HYPERGLYCAEMIA ?

Hyperglycaemia is often transient and can be secondary to minor or major stress – stress hyperglycaemia or due to other factors. Hence it is absolutely essential to rule out these cases of transient hyperglycaemia before labelling the patient as a diabetic. Many times the cause of stress is obvious such as a major infection, an acute coronary event or stroke etc. but sometimes this is not apparent and we need to confirm the transient nature of hyperglycaemia by further testing. In a case scenario like this we should ask for a repeat blood glucose and a glycated haemoglobin estimation. The best way to measure blood glucose here is by a fasting plasma glucose and a 2hour plasma glucose measured after 75 oral glucose. This will not only confirm the hyperglycaemia but also help make a reliable diagnosis of diabetes mellitus. HbA1C will indicate the relatively long term nature of the hyprglycaemia that has lasted at least 3 months which would rule out any acute stress hyperglycaemia.

HOW DO WE CONFIRM THE DIAGNOSIS OF DIABETES MELLITUS?

A diagnosis of diabetes mellitus is confirmed by

measuring fasting plasma glucose and a 2 hour plasma glucose measured after 75 oral glucose.

Diabetes can be diagnosed on any of the following criteria1: •

Fasting plasma glucose (FPG) ≥ 126mg/dl* or

•

Oral glucose tolerance test (OGTT) using 75 gms of anhydrous glucose with FPG ≥ 126 mg/dl and/or 2 hour plasma glucose ≥ 200 mg/dl or

•

Glycated haemoglobin (HbA1c) ≥ 6.5% ** or

•

Random plasma glucose ≥ 200mg/dl in the presence of classical diabetes symptoms

•

Asymptomatic individuals with a single abnormal test should have the test repeated to confirm the diagnosis unless the result is unequivocally abnormal.

WHAT IS THE TYPE OF DIABETES MELLITUS?

Once a diagnosis of diabetes mellitus is confirmed the next question is to determine the type of diabetes : •

Type 2 Diabetes Mellitus

•

Type 1 Diabetes Mellitus

•

Secondary Diabetes

•

MODY

If the patient is obese (BMI >) or is centrally obese (Waist > in males and in females), has clinical markers of insulin resistance such as acanthosis nigricans, skin tags , has a strong family history of Diabetes mellitus, and has presented with an insidious onset of hyperglycaemia or is diagnosed incidentally the patient is likely to be suffering from type 2 diabetes mellitus.

If the patient has a normal weight and waist ,has no family history of diabetes, and has presented with a recent onset of osmotic symptoms or diabetic ketoacidosis the likely diagnosis is type 1 diabetes mellitus.

If the patient has other features of other illness such as thyrotoxicosis, cushings syndrome or chronic pancreatitis or has been on any diabetogenic drug the likely diagnosis is secondary diabetes.

If the patient has a strong 3 generation history of diabetes, is nonobese, and is not ketotis prone he could be a case of MODY.

258

DOES THE PATIENT HAVE ANY OF THE LONG TERM COMPLICATIONS OF DIABETES MELLITUS?

The patient should be thoroughly examined for any evidence of neuropathy particularly for any abnormalities of ankle jerk and vibration sense and peripheral vascular disease. He should also undergo a fundus examination for evidence of diabetic retinopathy and a urine albumin/ creatinine ratio for evidence of nephropathy.

foods with high amounts of added sugars, fats or alcohol.

•

Limited care •

DOES THE PATIENT HAVE ANY OTHER COMORBIDITY?

DIABETES

Provide advice on the use of foods in the prevention and management of hypoglycaemia where appropriate.

Nutritional counselling may be provided by someone with training in nutrition therapy, but not necessarily a credentialed dietician (nutritionist)

One should also look for associated hypertension clinically, evidence of CAD by electrocardiography and dyslipidaemia by measuring serum lipids.

Lifestyle Management1

WHAT ARE THE MANAGEMENT ISSUES IN THIS PATIENT?

•

Offer lifestyle advice to all people with type 2 diabetes around the time of diagnosis.

Diet therapy1

•

Review and reinforce lifestyle modification yearly and at the time of any treatment change or if feasible at every visit.

•

Review and provide ongoing counselling and assessment yearly as a routine, or more often as required or requested, and when changes in medication are made.

•

Advise people with type 2 diabetes that lifestyle modification, by changing patterns of eating and physical activity, can be effective in controlling many of the adverse risk factors found in the condition.

•

Introduce physical activity gradually, based on the individual’s willingness and ability, and setting individualised and specific goals.

•

A total of 60 min of physical activity is recommended every day for healthy Indians in view of the high predisposition to develop T2DM and CAD.

-

at least 30 min of moderate-intensity aerobic activity.

-

15 min of work-related activity.

-

15 min of muscle-strengthening exercises (at least 3 times / week).

Recommended care

Glycaemic management – what should be the approach1?

Recommended care •

High-carbohydrate diets with relatively large amounts of unrefined carbohydrate and fibre such as legumes, unprocessed vegetables and fruits are recommended. Brown rice is preferred to polished white rice.

•

Protein intake equivalent to at least 15% of daily total calories is recommended.

•

Intake of non-nutritive artificial sweeteners in moderate amounts may be considered

•

Combining foods with high and low glycaemic indices, such as adding fibre-rich foods to a meal or snack, improves the glycaemic and lipaemic profiles.

•

Cardio-protective diet should include:

-

More: leafy vegetables, vegetable salads, coarse grains, sprouted grams, spices and all other foods, which are rich in fibre and antioxidants.

-

Moderate amounts of: low fat milk and milk products, vegetable oils with monounsaturated fatty acids (MUFA) and poluunsaturated fatty acids (PUFA), flesh foods (fish, chicken without skin, white of the egg) and artificial sweeteners.

•

Avoid: Alcohol, sugar, saturated fats and foods that are refined, processed, salt-rich, cholesterol-rich and deep-fried, polished rice, high fructose corn syrup.

In the absence of contraindications, encourage resistance training three times per week.

•

Provide guidance for adjusting medications (insulin) and/or adding carbohydrate for physical activity.

-

Total dietary salt intake should be reduced (< 5 g/ day) in population at high risk of hypertension.

•

•

Provide access to a dietician (nutritionist) or other health-care professionals trained in the principles of nutrition, at or around the time of diagnosis offering an initial consultation with follow-up sessions as required, individually or in groups.

Yogic practices lead to improvement in glycaemic control, reduction in BP, correction of dyslipidaemia, reduction of insulin resistance and correction of hyperinsulinemia, with elimination of stress

•

Yogic practices can be combined with other forms of physical activity when it should be done for 30min every day while for those individuals not having other forms of physical activity, it is recommended

-

•

Individualise advice on food/meals to match needs, preferences, and culture.

•

Advise on reducing energy intake and control of

that yogic practices are carried out for 45-60 min to achieve the metabolic benefits.

Limited care The principles and content of lifestyle management are as for recommended care.

•

Encourage increased duration and frequency of physical activity (where needed), up to 30-45 minutes on all days of the week, or an accumulation of at least 150 minutes per week of moderateintensity aerobic activity (50-70% of maximum heart rate).

•

AGIs and gliptins are weight neutral and so can be used as third line of agents.

•

The last option for such kind of patients should be SU’s, insulin or glitazones since they are having weight gain properties.

CKD •

Gliptins as add on therapy with metformin are good choices. Few of the gliptins need dose adjustment as per eGFR while vildagliptin needs dose adjustment in hepatic insufficiency. Linagliptin does not require any dose adjustment in renal disease.

•

Repaglinide is another agent which may be used across all stages of renal insufficiency. Similarly glitazones may be used in CKD, however, one has to careful about fluid retention.

•

Short acting sulfonylureas glipizide and gliclazide may also be used across renal insufficiency, however hypoglycemia is a huge limiting factor. AGIs may be used in patients with mild to moderate renal disease.

•

Insulin may be used in any stages of renal insufficiency and is the best agent for this purpose.

Targets for glycaemic control1 Target values for glucose control for HbA1c and capillary/ plasma glucose are as follows: • HbA1c < 7% •

FPG < 115mg/dl

•

PPPG < 160mg/dl

Individualizing therapy1 ABCD (EFGH) approach for diabetes management Choice of any anti-diabetic agent should take into account the patient’s general health status and associated medical disorders. This patient centric approach may be referred to as the ABCD (EFGH) approach for diabetes management.

As shown in the figure, for any T2DM patient first line of therapy should be metformin unless not tolerated or contraindicated.

Duration of diabetes •

As results of recent trials have suggested to utilize an aggressive approach in cases where duration of diabetes is less than 5 years, SU or glinide, as an add on therapy to metformin, will be the best choices, being very potent agents. Addition of glitazones may be useful at this stage.

•

GLP-1 RA may score over gliptins for this indication as they are more efficacious than gliptins. Gliptins may be an option for 2nd add on agent & SGLT2 inhibitors may also be useful as second add on agent due to their insulin independent action

•

AGIs are last choices due to their moderate efficacy.

Age •

eGFR adjusted doses of gliptins may be a suitable addition to metformin for elderly patients in whom one will like to avoid hypoglycemia and weight gain.

•

Agents belonging to AGI could also be an important choice in elderly patient. These agents have moderate efficacy but minimal side effects.

•

In elderly males, glitazones may be a safer alternative in patients with preserved cardiac function. However, postmenopausal females must be spared for its use because of high predisposition to osteoporosis.

•

SUs, GLP-1RA, SGLT-2 inhibitors or glinides should emerge as last choice since there are adverse effects of these agents in this age group.

BMI •

GLP-1 RA seems to be the best add on therapy for those having high BMI. This group of medications have highest weight reducing property in addition to the excellent efficacy. SGLT-2 inhibitors also have a weight reduction property.The medicines in this group have an additional advantage of excellent tolerance and can be given orally as compared to GLP-1 RA. However their glycemic efficacy seems

259

Established CVD •

In patients with established CVD, DPP-4 inhibitors may be preferred agents after pioglitazone, SGLT2 inhibitors and AGIs because of low risk of hypoglycaemia.

•

GLP-1 analgoues may be good suitable alternative for patients who are overweight or obese. AGIs may be preferred in patients with postprandial hyperglycaemia.

•

Pioglitazone has also been shown in different studies to reduce CVD risk.

•

Recent data fromEMPA-REG study has shown that SGLT inhibitors reduce CV risk and CV mortality, and may be preferred.

CHAPTER 47

•

to be less than that of GLP-1 RA. The experience with this group of agents is less than that with GLP-1 RA.

RSSDI Diabetic Therapeutic Wheel1

DIABETES

260

LMT-Lifestyle management therapy Su – Sulfonyl Urea

From Innermost to Outermost A  Age = Advancing Age B  BMI = Increasing BMI Lesser Options availablee

C  CKD = Advancing CKD D  Duration of Diabetes = Increasing Duration E  Established CVD = Low CVD risk to Established CVD Risk F  Finance = Adequate to Limited

Wider options available

G  Glycemic Status = Worsening glycemic control H  Hypoglycemia = Hypoglycemia concern

Su* - Preferably Glimiperide or Gliclazide SuS – Short acting Sulfonyl ureas I – Insulin Ic – Conventional Insulins Ia – Insulin Analogues IaS – Short Acting Insulin analogues D – DPP4 inhibitors D-L – Linagliptin P – Pioglitazone P* - Pioglitazone if EF > 40% Sg – SGLT2 Inhibitors A – Alphaglucosidase Inhibitors G – GLP Analogues Gl – Glinides

RSSDI Diabetic Therapeutic Wheel1 Financial concern •

Cost of therapy also plays an essential role considering that treatment needs to be continued lifelong.

•

SUs should be first choice with metformin by considering its cost, then after AGI’s or glitazone should be used at next therapy level; in the next level the therapeutic option should be glinides or insulin.

•

High cost will prevent the use of insulin analogues, gliptins, SGLT-2 inhibitors and GLP-1 RA in most of the patients.

When you see a patient in your clinic

•

Prescribe lifestyle intervention to all and metformin to most patients as mentioned in the inner core of the wheel (white and light blue rings)

•

Then identify the 2/3 most important concerns / factors (from ABCDEFGH)that you feel should influence your choice of antidiabetic agent eg. Age / CKD / finance etc.

•

Identify the best choices available to you from the outer rings of the wheel (Orange and red)

•

Further fine tune your choices if more concerns exist in a given patient and reach a rational final choice in an ‘individualised approach’

Glycemic status •

Good glycemic control of patients is directly correlated with efficacy of any anti-diabetic agent.

•

Insulin followed by GLP-1RA, SUs and glitazones have highest efficacy in terms of reducing HbA1c.

•

Gliptins, SGLT2 inhibitors or AGIs should be considered as add on therapy if these agents are not able to achieve glycemic targets.

Hypoglycemia concern •

•

•

Hypoglycemia is the biggest hurdle that any medical fraternity is facing during treatment course of diabetes.

In patients with history of hypoglycemia or for those at high risk of hypoglycemia, GLP-1RA or gliptins should be considered as first choice with. Other options include SGLT-2 inhibitors, glitazones, and AGIs. Last option for such patients should be either glinides, SUs or insulin since there are high chances of hypoglycaemia with these agents.

How to use the RSSDI Diabetic Therapeutic Wheel ?

•

RSSDI therapeutic wheel is designed to be a simple user friendly approach to decide the appropriate antidiabetic agent to be used in Type 2 diabetes mellitus

Management of complications and comorbidities - Approach ?

Management of all the complications as well as comorbidities is as important as managing glycaemia in diabetes and should be undertaken along established lines.

In conclusion, there are several clinical issues that need to be focussed on when a patient presents with a high random blood sugar value and the treating physician should adopt a systematic and practical approach to address these issues to provide appropriate management and care.

REFERENCES

1.

Madhu SV, Saboo B, Makkar BM, Reddy GC, Jana J, Panda JK et al. RSSDI Clinical Practice Recommendations for Management of Type 2 Diabetes Mellitus. IJDDC 2015; 35:1-71.

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CHAPTER 47

•

Practical Approach to Diabetic Foot Ulcer

C H A P T E R

48

Yalamanchi Sadasiva Rao

Foot ulceration is a dreaded complication of diabetes that often results in diminished quality of life. By â&#x20AC;&#x2DC;A rule of 15â&#x20AC;&#x2122; 15% of people develop an ulcer, 15% of ulcers will develop osteomyelitis and 15% ulcers result in amputation. 85% amputations result from non-healing ulcer. Approximately half of amputated patients will have contralateral amputations within 3 years and half will die within 5 years.

Every 20 seconds, a limb is lost due to diabetes, and one million limb amputations occur yearly worldwide. In our country, one lakh legs are amputated every year and the commonest cause of amputation is infected neuropathic foot which in a majority of cases is preventable.

Every break in the skin in diabetic foot is a portal of entry for bacteria and has the potential for disaster. Many patients go for amputation following a trivial lesion. A diabetic foot lesion should never be considered as trivial until it is healed and has remained healed for at least a month.

The underlying cause of diabetic foot ulcer will have a significant bearing on the clinical management and must be determined before care plan is put into place. So in most patients peripheral neuropathy and peripheral arterial disease play a central role. The diabetic foot ulcers are commonly classified as 1. Neuropathic, 2. Ischaemic, 3. neuro ischaemic.

Neuro ischemia is a combined effect of diabetic neuropathy and ischaemia. Where by macro vascular disease and in some instances micro vascular dysfunction, impair perfusion in a diabetic foot.

NEUROPATHIC ULCER

Neuropathic ulcer is usually painless and common site is the apex of the toe, which when associated with a claw toe deformity, develop callus on a plantar pressure site and there in breaks down.

Callus also forms over the dorsal aspect of the toes due to the constriction pressure of footwear on the flexed interphalangeal joint and also on the planter aspect of prominent metatarsal heads. Failure to remove the callus leads to ulceration.

Ulcers on the plantar aspect of the heel are usually caused by acute trauma, particularly treading on foreign bodies.

On initial observation the neuropathic ulcer may seem shallow but it is always important to probe an ulcer as this may reveal hidden depths and also demonstrate a sinus down to bone suggesting osteomyelitis.

NEUROISCHAEMIC ULCER

Ulceration in the neuroischaemic foot usually occurs on the margins of the foot.

The first sign of neuroischaemic ulceration is a red mark which blisters and then develops into shallow ulcer with a base of sparse pale granulations or yellowish closely adherent slough. In ischaemia there is a hallow of erythema around the ulcer.

Although ulcers occur on the medial surface of the first metatarsophalangeal joint and over the lateral aspect of the 5th metatarsophalangeal joint. The commonest sites are the apices of the toes and beneath any toe nails if allowed to become overly thick.

Feature

Neuropathic

Ischaemic

Neuroischaemic

Sensation

Sensory loss

Painful

Degree of sensory loss

Callus/necrosis

Callus present and often thick

Necrosis common

Minimal callus prone to necrosis

Wound bed

Pink and granulating surrounded by callus

Pale and sloughy with poor granulation

Poor granulation

Foot temperature and pulses

Warm with bounding pulses

Cool and absent pulses

Cool with absent pulses

Other

Dry skin and fissuring

Delayed healing

High risk of infection

Typical location

Weight-bearing areas of Tips of toes, nail edges the foot, such as metatarsal and between the toes and heads, the heel and over lateral boarders of the foot the dorsum of clawed toes

Margins of the foot and toes

Prevalence (based on 35)

35%

50%

15%

Key points

Wagner

Assesses ulcer depth along with Well established presence of gangrene and loss of Does not fully address infection perfusion using six grades(0-5) and ischaemia

Wagner 1981

University of Texas (Armstrong)

Assesses ulcer depth, presence of infection and presence of signs of lower-extremity ischaemia sing a matrix of four grades combined with four stages

Well established

Lavery et al 1996

Describes the presence of infection and ischaemia better than wagner and may help in predicting the outcome of the DHU

Armstrong et al 1998

PEDIS

Assesses Perfusion, Extent (size), Depth (tissue loss), Infection and sensation (neuropathy) using four grades (1-4)

Developed by IWGDF

Lipsky e al 2012

Assesses Site, Ischaemia, Neuropathy, Bacterial infection and Depth Uses a scoring system to help predict outcomes and enable comparisons between different settings and countires

Simplified version of the S(AD) SAD classification system includes ulcer site as data suggests this might be an important determinant of outcome

SINBAD

Pros/Cons

References

User-friendly (clear definitations, few categories) for practitioners with a lower level of experience with diabetic foot management Ince et al 2008

SPECIAL CATEGORIES OF ULCERS

A physical examination should determine:

1.

Is the wound predominantly neuropathic, ischaemic or neuroischaemic?

These include

2.

Decubitus heel ulcers caused by unrelieved pressure.

If ischaemic, is there critical limb ischaemia?

Ulcers of Charcot osteoarthropathy associated with rocker bottom deformity, medial convexity and hind foot deformity.

Are there any musculoskeletal deformities?

3.

Ulcers over the Achilles tendon

What is the colour/status of the wound bed?

4.

Puncture wounds caused by standing on sharp objects

---Black (necrosis)

5.

Traumatic wounds, including burns

Is there any exposed bone?

6.

Artefactual ulcers caused deliberately by patients

Is there any necrosis or gangrene?

7.

Iatrogenic ulcers caused by tape, tight bandage

8.

Malignant ulcers

Is the wound infected? If so, are there systemic signs and symptoms of infection (such as fevers, chills, rigors, metabolic instability and confusion)?

CLASSIFICATION OF DIABETIC FOOT ULCERS

Classification systems grade ulcers according to the presence an extent of various physical characters such as size, depth and location. They can help in the planning and monitoring of treatment and predicting outcome and also research and audit.

EXAMINATION OF THE ULCERS

Patients with diabetic foot ulcer need to be assessed in order to identify intrinsic and extrinsic factors. This should encompass full patient history including medication, comorbidities in diabetes status we should also take into consideration the history of the wound previous DFU or amputations and any symptoms suggestive of neuropathy or peripheral vascular disease.

What is the size/depth/location of the wound?

---Yellow, red, pink

Is there any malodour?

Is there local pain?

Is there any exudate? What is the level of production (high, moderate, low, none), colour and consistency of exudate, and is it purulent?

What is the status of the wound edge (callus, maceration, erythema, oedema, undermining)?

MANAGEMENT

In the management the aim is to heel ulcers with in the first 6 weeks of their development. This is the time for aggressive management and is a window of opportunity that should be taken seriously. All diabetic foot ulcers should be referred for multi-disciplinary care without

263

CHAPTER 48

Classification systems

264

delay so that the opportunity of early heeling is not wasted. The ulcer is a pivotal event on the road to amputation, and the diabetic patient with an ulcer on the foot is at great risk of infection, gangrene and loss of the leg. Because it is difficult to predict which ulcers do well and which will end in catastrophic. So it is important essential to organize optimal care of all ulcers.

4.

6.

Refer for vascular assessment if clinically significant limb ischaemia is suspected.

GLOBAL WOUND CARE PLAN

7.

Diagnosing of diabetes (+/- peripheral sensory neuropathy)

Offer patient education on how to self-manage and when to raise concerns.

Development of vascular disease.

AIM: Prevent the development of a DFU

1.

Implement DFU prevention care plan that includes treatment of co-morbidities, good glycaemic control and pressure offloading

AIM: Prevent ischaemia

1.

Ensure early referral to vascular specialist for arterial reconstruction to improve blood flow in patients with an ischaemic or neuroischaemic ulcer

DIABETES

A.

Review offloading device and ensure footwear accommodates dressing

5. Optimize glycemic management.

control

for

diabetes

complications associated with

2.

Annually perform general foot examination:

-

Use 10mg monofilament to assess sensory status

2.

Optimize diabetes control.

-

Inspection of the feet for deformities

B.

Ulcer becomes infected.

-

Inspection of footwear for wear and tear and foreign objects that may traumatize foot

AIM: Prevent life-or limb-threatening complications

1.

AIM: Prevent life-or limb-threatening complications

-

Maintain skin hydration (consider emollient therapy) for skin health

2.

-

Offer patient education on checking feet for trauma

For superficial (mild) infections-treat with systemic antibiotics and consider topical antimicrobials in selected cases.

3.

For deep (moderate or severe) infectionsâ&#x20AC;&#x201D;treat with appropriately selected empiric systemic antibiotics, modified by the results of culture and sensitivity reports

4.

Offload pressure correctly and optimize glycaemic control for diabetes management.

Consider therapy directed at biofilm in wounds that are slow to heal.

3. Ensure regular review and provide patient education

Development of DFU

AIM: Treat the ulcer and prevent infection

1.

Determine cause of ulcer.

2.

Agree treatment aims with patient and implement would care plan:

5.

-

Debride and regularly cleanse the wound

-

Take appropriate tissue samples for culture if infection is suspected.

ACTIVE MANAGEMENT OF THE ULCER AND COMORBIDITIES SHOULD AIM TO PREVENT AMPUTATION

-

Select dressings to maintain moist wound environment and manage exudate effectively.

1.

Implement skin and wound care plan to manage surgical wound and optimize healing.

3.

Initiate antibiotic treatment if infection suspected and consider topical antimicrobial therapy if increased bio burden is suspected.

2.

Review regularly and implement prevention care plan to reduce risk of recurrence or further DFU on contralateral limb.

Where amputation is not avoidable:

How to Start Statins in Diabetes

C H A P T E R

49

R R Singh

INTRODUCTION

Diabetes and cardiovascular diseases are major cause of illness and death world wide. Elevated blood cholesterol levels, specifically the low density lipoprotein {LDL} cholesterol is associated with a higher risk of myocardial infarction, stroke, and heart failure.

Diabetes is a significant cardiovascular risk factor (conferring a three time absolute adjusted risk of CVD death). Furthermore, in individuals with diabetes, a log linear relationship exists between cholesterol levels and CVD regardless of the baseline LDL. Thus, it is assumed, that regardless of the baseline cholesterol level, reducing the LDL will reduce the occurrence of CVD. This led to a number of primary cardiovascular prevention trials using statin therapy as the principal intervention. It has been clearly shown (and thus clearly incorporated into the ADA guidelines) that diabetic individuals with other risk factors should indeed be treated with a statin.

Diabetes mellitus (DM) is rapidly expanding pandemic (Figure 1) as per IDF (international Diabetes Federation) 2013 there are 382 million people suffering of (DM) all over the world and there will be an increase of 55% by year 2035. (Table 1) Thus the figure will be around 592 million.

(Figure 2) Africa will have an increase 109 %, Europe will have a rise of 22.4 %. when we see these figures in India we will find more than 100 million DM patients by 2035 (68% increase vs 2013). 2 new countries i.e. Turkey & Pakistan will also appear in top ten list. (Table 2) India is home to the second largest number of adults living with diabetes worldwide At least 72% of persons with diabetes have concomitant dyslipidemia worldwide. But, In India, almost all diabetics have dyslipidemia Prevalence of Dyslipidemia (%) in Male T2 DM is 85.5 % & in Female T2DM is 97.8 % Iitâ&#x20AC;&#x2122;s an alarming sign and is to be treated earliest possible as incidence of CAD is 3-5 times higher in DM pts.

Diabetes: A Global Emergency Estimated number of people with diabetes worldwide and per region in 2015 and 2040 (20-79 years)

North America and Caribbean 2015 44.3 million 2040 60.5 million

World 2015 415 million 2040 642 million

Europe 59.8 million 2040 71.1 million 2015

Middle East and North Africa 2015 35.4 million 2040 72.1 million

South and Central America 2015 29.6 million 2040 48.8 million

Africa 14.2 million 2040 34.2 million

Western PaciďŹ c 153.2 million 2040 214.8 million 2015

South East Asia 2015 78.3 million 2040 140.2 million

2015

Fig. 1: Diabetes: A Global Emergency

HOW TO REDUCE RISK FACTORS?

WHAT ARE STATINS & THERE ROLE

i.

Life-style management

ii.

Blood sugar control

iii.

Weight reduction in obese, by diet/excercise/drugs/ surgery.

iv.

Management of hypertension.

v.

Cessation of smoking

vi.

Less alcohol consumption

vii.

Lipid therapy which reduces long term damage to circulation

DIABETES

266

WORLD

592 M ä 55% people living with diabetes in 2035

WORLD

382 M

Statins are 3-Hydroxy-3-methyl glutaryl coA reductase inhibitors & cholesterol lowering drugs.

•

They have complex relationship with diabetes (DM) & are basic focus of healthcare debate..

•

Statins do reduce incidence of MI, stroke & also minimize risk of neuropathy,nephropathy&retino pathy.

We all know that 80 % of cholesterol (TC) is made by liver and 20 % is what, we get from the diet. Statins slow the action of HMG CoA reductase, which plays key role in manufacture of Cholesterol.They block a critical step in production of LDL. and also reduce inflammation and promote health of the lining of endothelium.

Table 1: Estimated Increase in Diabetes Countrywise Country/ territory

2013 (Millions)

Country/ territory

2035 (Millions)

AFR ä 109.1%

China

98.4

China

142.7

MENA ä 96.2%

India

65.1

India

109.0

United States of America

24.4

United States of America

29.7

Brazil

11.9

Brazil

19.2

Russian Federation

10.9

Mexico

15.7

NAC ä 37.3% EUR ä 22.4%

Mexico

8.7

Indonesia

14.1

Indonesia

8.5

Egypt

13.1

Germany

7.6

Pakistan

12.8

Egypt

7.5

Turkey

11.8

Japan

7.2

Russian Federation

11.2

SEA ä 70.6% SACA ä 59.8% WP ä 46%

2013

•

2035

Fig. 2: Estimated Increase in Diabetes Globally AFR: Africa, MENA: Middle East and North Africa, SACA: South and Central America, WP: Western Pacific, NAC: North America and Caribbean, SEA: South east Asia

Table 2: Comparison of Increase in People with Diabetes in 2015 with 2040 2015 Rank

Country/Territory Number of People with Diabetes

2040 Rank

Country/Territory Number of People with Diabetes

1

China

109.6 million (99.6-133.4)

1

China

150.7 million (138.0-179.4)

2

India

69.2 million (56.2-84.8)

2

India

123.5 million (99.1-150.3)

3

United States of America

29.3 million (27.6-30.9)

3

United States of America

35.1 million (33.0-37.2)

4

Brazil

14.3 million (12.9-15.8)

4

Brazil

23.3 million (21.0-25.9)

5

Russian Federation

12.1 million (6.2-17.0)

5

Mexico

20.6 million (11.4-24.7)

6

Mexico

11.5 million (6.2-13.7)

6

Indonesia

16.2 million (14.3-17.7)

7

Indonesia

10.0 million (8.7-10.9)

7

Egypt

15.1 million (7.3-17.3)

8

Egypt

7.8 million (3.8-9.0)

8

Pakistan

14.4 million (10.6-20.4)

9

Japan

7.2 million (6.1-9.6)

9

Bangladesh

13.6 million (10.7-24.6)

10

Bangladesh

7.1 million (5.3-12.0)

10

Russian Federation

12.4 million (6.4-17.1)

International Diabetes Federation. IDF Diabetes Atlas, 7th edn. Brussels, Belgium. International Diabetes Federation. 2015 http:// www.diabetesatlas.org

267

Inhibition of the Cholesterol Biosynthetic Pathway Squalene synthase Farnesyl pyrophosphate

Dolichol Squalene

Farnesyltransferase

Cholesterol

E, E, EGeranylgeranyl pyrophosphate

Farnesylated proteins

Geranylgeranylated proteins

Ubiquinones

Fig. 3: Inhibition of the Cholesterol Biosynthetic Pathway The reduction in hepatic cholesterol synthesis lowers intracellular cholesterol, which stimulates upregulation of the LDL receptor and increases uptake of non-HDL particles from the systemic circulation. (Figure 3) Statin therapy in DM is advocated (regardless of baseline LDL-C) a.

b.

When age is more than 40 yrs with micro/ macrovascular disease or DM of more than 15 yrs duration with age 40 yearsÂą, then it warrants lipid therapy(based on the 2012 Canadian Cardiovascular Society lipid guidelines).

Among women with childbearing potential, statins should only be used in the presence of proper preconception counseling & reliable contraception.

Statins are to be stopped prior to conception.

Commonly used statins are atorvastatin, rosuvastatin, pitavastatin, simvastatin, pravastatin, fluvastatin.

Statins definitely lower lipids and reduces risk of CVA, CAD. Second- line agents are to be used if LDL-C target not reached with statin. We have to add bile acid sequestrants, cholesterol absorption inhibitors, fibrates or nicotinic acid/niacin. (Table 3) Statin Therapy Should be concomitant with Lifestyle Therapy.

In the form of a.

b.

Smoking cessation

Energy-restricted diet

Table 3: Therapies to Lower LDL-C Class

Drug(s)

3-Hydroxy-3-Methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors [Statins]

Simvastatin Atorvastatin Rosuvastatin Lovastatin Pitavastatin Fluvastatin

Bile acid sequestrants

Cholestyramine Colesevelam Colestipol

Cholesterol absorption inhibitor

Ezetimibe

Nicotinic acid

Niacin

Dietary Adjuncts

Soluble fiber Soy protein Stanol esters

i.

Low cholesterol

ii.

Low saturated and trans fatty acids

iii.

Low refined carbohydrates

iv.

Include viscous fibres, plant sterols, nuts, soy proteins

v.

Alcohol in moderation, if necessary

vi.

Physical activity (20-40 mts vigorous exercise, 5-7 days a week)

If triglycerides are more than 10.0 mmol/Lâ&#x20AC;Ś (180 mg %), fibrates are to be used to reduce the risk of pancreatitis

CHAPTER 49

HMG-CoA Reductase HMGMevalonate CoA

268

DIABETES

Table 4: Major secondary prevention studies on statin Name

Study Drug Vs Comparator

Patients

Primary End Point

Duration

Results

CARE

Pravastatin 40 mg Vs Post-MI 4159 Placebo

Non-Fatal MI or CAD Death

5 yrs

24% risk reduction by pravastatin

Lipid

Pravastatin 40 mg Vs 9000 patients with CAD mortality Placebo Unstable angina / MI

6.1 yrs

24% risk reduction by pravastatin

Prove IT TIMI 22

Atorvastatin 80 mg 4000 patients with Vs Pravastatin 40 mg ACS

Death, MI, Stroke, CABG/PCI

2 yrs

16% risk reduction by atorvastatin 80 mg

TNT

Atorvastatin 80 mg Vs 10 mg

10000 patients with Stable CAD, high LDL

MI, Stroke, Death

4.9 yrs

22% risk reduction by 80 mg Vs 10 mg atorvastatin

MIRACL

Atorvastatin 80 mg Vs Placebo

3000 patients with ACS (unstable angina/MI)

Death MI, resuscitated cardiac arrest, rehospitalisation for CAD

16 weeks

16% risk reduction by atorvastatin 80 mg

SPARCL

Atorvastatin 80 mg Vs Placebo

4700 patients with TIA/Stroke

Fatal/nonfatal stroke

5 yrs

16% risk reduction by atorvastatin 80 mg

Table 5: Drug Interactions with Statins Statin

Contra-indicated or to be avoided with

Caution required

Dose limited

Atorvastatin

Cyclosporine, Tipranavir + Lopinavir + Ritonavir, Ritonavir Telaprevir Digoxin, Niacin

Upto 20 mg:/day: Saquinavir / Darunavir / Fosamprenavir + Ritonavir, Clarithromycin, itraconazole Upto 40 mg/day: Boceprevir (Hepatitis C), Nelfinavir, Fenofibrate

Rosuvastatin

Gemfibrozil

Upto 5 mg/day: Cyclosporin Upto 10 mg/day: Gemfibrozil, Lopinavir or Atazanavir + Ritonavir

Coumarin Anticoagulants, Niacin, Fenofibrate

one has to optimize glycemic control and should not forget implementation of lifestyle management in form of weight reduction in obese, optimal dietary strategies and permission of alcohol in moderate quantity.

Certain dietary adjunts are also effective in reducing LDL-C they a include dietary soluble fiber, soy protein, stanol esters they reduce LDL-C 5-15 %.

Dietary soluble fiber, stanol esters are recommended in dose of 2-6 gms / day while soy protein is required 2030gms / day in diet.

Atorvastatin dose response relationship in primary hypercholesterolemia is also very interesting. As we increase dose of atorvastatin from 10 mg to 80 mg / day, LDL-C fall is observed 30 -60 % after 6 wks. We should also have a Iook on vascular protection check list i.e.

ABCDE A.

A1C – optimal glycemic control (usually ≤ 7%)

B.

BP – optimal blood pressure control (<130/80)

C.

Cholesterol – LDL ≤ 2.0 mmol/L if decided to treat

D.

Drugs to protect the heart (regardless of baseline BP or LDL)

A - ACEi or ARB | S – Statin | A – ASA if indicated

E.

Exercise / Eating healthily – regular physical activity, achieve and maintain healthy body weight.

There are two famous studies which recommend effect of statin in primary prevention in DM. They are CARDS (Collaborative Atorvastatin Diabetes Study) & HPS (Heart Protection Study). (Table 4) CARDS was performed in 2838 no. of patients with age group of 40-75 years. They had no history of CVD. These T2DM patients were having one or more risk factors in form of retinopathy, albuminuria, hypertension, smoking.

Intervention was done with atorvastatin 10 mg vs placebo.

Significant results were observed in acute coronary events, coronary revascularisation (CABG), stroke and in acute cardiovascular disease event. the benefits were seen regardless of age, sex, or whether the cholesterol level was high or low. The trial’s success meant, it was halted two years early.

HPS (study) was carried in 10269 pts vs 10267 pts. (placebo gp). Simvastatin40 mg/ day was given and beneficial effect among patients with DM were observed.

And both studies incidence of MI & Stroke were less as compared to control i.e. placebo group. CARDS showed reduction of events (MI 37 %, Stroke 48 %) while HPS results showed 33% reduction in MI & Stroke events.

Itâ&#x20AC;&#x2122;s not necessary that all DM patient have the same risk factors e.g. they may be normal weight individual, non smokers. While the studies show that statins are effective across the board. Their role starts even at less than 40 years age in young adults with T2DM.

RECOMMENDATIONS

Statins should be recommended as a part of treatment to reduce lipids & complications in DM pts. with addition of exercise, sensible eating, avoidance of excessive alcohol and good blood pressure control.

1.

Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels, for diabetic patients with overt cardiovascular disease (CVD) level of evidence as described in the ADA evidencegrading system the primary goal is an LDL cholesterol <100 mg/dl (<2.6 mmol/l) a lower LDL cholesterol goal of 70 mg/dl (1.8 mmol/l), using a high dose of a statin, is an option and without CVD who are over the age of 40 years and have one or more other CVD risk factor. The primary goal is an LDL cholesterol <100 mg/dl (<2.6 mmol/l)

2.

For lower-risk patients than those specified above (e.g., without overt CVD and under the age of 40 years), statin therapy should be considered in addition to lifestyle therapy if LDL cholesterol remains >100 mg/dl or in individuals with multiple CVD risk factors.

3.

If drug-treated patients do not reach the above targets on maximal tolerated statin therapy, a reduction in LDL cholesterol of >40% from baseline is an alternative therapeutic goal.

4.

Combination therapy using statins and other lipidlowering agents may be considered to achieve lipid targets but has not been evaluated in outcome studies for either CVD outcomes or safety.

5.

Statin therapy is contraindicated in pregnancy.

PRIMARY PREVENTION: IS THERE A DIABETIC INDIVIDUAL WHO SHOULD NOT GET A STATIN?

Diabetes is a significant cardiovascular risk factor

(conferring a three time absolute adjusted risk of CVD death). Furthermore, in individuals with diabetes, a log linear relationship exists between cholesterol levels and CVD regardless of the baseline LDL. Thus, it was assumed, that regardless of the baseline cholesterol level, reducing the LDL will reduce the occurrence of CVD. This led to a number of primary cardiovascular prevention trials using statin therapy as the principal intervention.

It has been clearly shown (and thus clearly incorporated into the ADA guidelines) that diabetic individuals with other risk factors should indeed be treated with a statin.

Yet only a few studies have included diabetic individuals without other CVD risk factors. In the Heart Protection Study (HPS), 5,963 individuals with diabetes were randomized to 40 mg simvastatin or placebo regardless of their baseline LDL or prior vascular disease status. A significant 22% reduction in the first event rate of major vascular outcomes (first major coronary event, stroke, or revascularization) was note. Based on the HPS data, an evaluation of the cost-effectiveness of lifetime simvastatin treatment found it to be cost saving even in patients as young as 35 years or with a 5-year risk of major vascular events as low as 5% (considered moderate CVD risk).

These criteria include almost all of the diabetic individuals, including individuals with type 1 diabetes over the age of 30 years and individuals with type 2 diabetes over the age of 32 years for men and 38 years for women.

SECONDARY PREVENTION: HOW LOW SHOULD WE GO?

In patients with overt CVD, the guidelines state an optional goal LDL of 70 mg%. This recommendation is based on several recently published trials that examined the effect of aggressive LDL lowering therapy (i.e., high dose statin therapy) in high risk populations of patients.

In the PROVE-IT TIMI 22 trial, 4,162 patients 10 days after an acute coronary syndrome (acute ST-segment elevation myocardial infarction [STEMI], nonâ&#x20AC;&#x201C;STsegment elevation myocardial infarction [NSTEMI], or high-risk unstable angina) were randomized to standard 40 mg pravastatin treatment or high dose/aggressive 80 mg atorvastatin treatment. Patients were followed for 18 to 36 months and achieved an average LDL cholesterol level of 62 mg% in the atorvastatin group and 95 mg% in the pravastatin group. In the aggressive therapy group versus the control group, a significant 16% reduction in the primary end point (a composite of death from any cause, myocardial infarction, unstable angina requiring re-hospitalization, revascularization and stroke) was noted. 18% of the ~1,600 patients in each treatment arm suffered from diabetes and showed similar risk reduction to that of the general cohort. A post hoc analysis of the PROVE-IT TIMI 22 trial data revealed a reduction not only in LDL cholesterol but also in CRP levels. This reduction in CRP was significantly associated with a reduction in cardiovascular events irrespective of the associated LDL reduction.

CONCLUSIONS & SUMMARY

Both in primary prevention and in the very-high-risk patients, it seems that statins reduce major cardiovascular

269

CHAPTER 49

On one hand statin therapy is quite useful in DM patients.

They may increase risk of new DM. Various studies like HPS, ASCOT, CORONA, JUPITER showed risk of development of new DM by 10-13 %. Other side-effects of statin are occassional headache, abdominal pain, skin rashes, rarely memory problems which are reversible after dose adjustment / discontinuation if necessary.

In few cases of DM patients on statin therapy elevated hepatic transaminases have been observed but it is dose dependent phenomenon and is usually reversible. There is some incidence of myalgias (15.4%), myositis (0.9% ) & rhabdomyolysis (0.2%). Side-effects are observed with high doses of atorvastatin (80 mg / day) for more than 6 wks, If these patient are later put on low doses i.e. 5-10 mg of atorvastatin / day, there is regression in symptoms and SGOT,PT levels reach to normal.

DIABETES

270

events irrespective (at least in part) of the baseline and post-therapy LDL levels achieved. Should statins be generally prescribed in a fixed-dose manner? We would not go so far as to suggest that, but indeed, in the diabetic individual whose LDL cholesterol is seemingly within normal limits, this should be considered. The indication for statin therapy in diabetic individuals should not rely solely on LDL levels but on the inherent cardiovascular risk that accompanies this disease (even if goal LDL levels are met).

We believe that the standards of care for individuals with diabetes should mirror the evidence. Replacing a fixed-dose statin trial scheme with a treat-to-target LDL guideline is controversial. This inherent problem of the current guidelines should be amended. Evidence based on “hard” outcome trials of statin use should guide our treatment goals and considerations, not epidemiologic or extrapolated LDL-based data.

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13. American Diabetes Association. Standards of medical care in diabetes: 2008. Diabetes Care 2008; 31:S12-S54.

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