Smart Approach to Post Prandial Glycemic Peaks Glimepiride

Smart Approach to Post Prandial Glycemic Peaks : Glimepiride, Metformin & Voglibose Combination in T 2 DM Dr. Mohammed Riyaz M. D (Medicine), Masters in Endocrinology(UK) Chief Endocrinologist & Medical Director (EDSC)

Flow of contents ü Type 2 diabetes population requiring stringent glycemic control ü Triple drug combination in the management of type 2 diabetes mellitus ü Postprandial hyperglycemia and glycemic variability ü Role of alfa glucosidase inhibitors in triple drug combination ü Amaryl MV: A triple drug combination of glimepiride, metformin and voglibose

Introduction ü Prevalence of diabetes mellitus is rising world over, so the related burden of mortality and morbidity 1 ü Diabetes and its complications are also associated with significant economic burden 1 ü Glycemic control reduces complications of diabetes 1 ü The United Kingdom Prospective Diabetes Study (UKPDS) of patients with type 2 diabetes showed that, intensive glycemic control results in a 25% reduction of microvascular complications 2 1. Expert Opin. Drug Metab. Toxicol. (2010) 6(2): 225 -235 2. Lancet 1998; 352(9131): 837 -53

Triple drug therapy in the management of type 2 diabetes mellitus Lifestyle changes Entry Hb. A 1 c <7. 5% >9% with no symptoms Oral monotherapy Oral dual or triple therapy Hb. A 1 c >6. 5% in 3 months Endocrine practice. May/June 2013; 19; suppl 2: 1 -48 If goal not achieved in 3 months with dual therapy: Triple therapy

Metformin: A first line agent for type 2 diabetes Parameter Efficacy Risk of hypoglycemia Effect on body weight Costs Metformin High Low Neutral/weight loss Low Metformin, if not contraindicated and if tolerated, is the preferred initial pharmacological agent for type 2 diabetes American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetesd 2015. Diabetes Care 2015; 38(Suppl. 1): S 41–S 48

Combination therapy for type 2 diabetes Metformin or Sulfonylurea + or Thiozolidinedione or DPP 4 inhibitor or SGLT 2 inhibitor or GLP-1 receptor agonist Insulin (basal) Each new class of noninsulin agents added to initial therapy lowers Hb. A 1 c around 0. 9– 1. 1%. American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetesd 2015. Diabetes Care 2015; 38(Suppl. 1): S 41–S 48

SU + Metformin : Effective combination for t 2 dm Metformin üIncreases insulin secretion üExtensive experience + Sulfonylurea üReduces microvascular risk (UKPDS) üEconomical American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetesd 2015. Diabetes Care 2015; 38(Suppl. 1): S 41–S 48 W h rat at i ion s th ale e ?

Glimepiride: a Preferred Sulfonylurea Improves the relative insulin secretory deficit Minimal hypoglycemia & weight gain High on efficacy: Upto 2. 5% Hb. A 1 c Reduction Pleiotropic Benefits (antioxidative, antiinflammat ory, angiogenic properties) Expert Opin. Drug Metab. Toxicol. (2010) 6(2): 225 -235; J Assoc Physicians India. 2004 Jun; 52: 459 -63. Cardiovascular Diabetology 2014, 13: 15

Glimepiride is Different from Other Sulfonylureas Among interventions to preserve or “rejuvenate” β-cells, is the induction of β -cell “rest” by selective activation of ATP-sensitive K+ (KATP) channels. Most Sulphonylureas Glimepiride used at an optimum dose, causes no β-cell hyperfunction (reduced β-cell exhaustion) & no hyperinsulinemia due to its unique binding characteristics.

Comparison of Extrapancreatic Action of Glimepiride and Other Sulfonylureas Glimepiride has greatest extrapancreatic activity among sulfonylureas Mean increase in plasma insulin (PI) and mean % decrease in blood glucose (BG) over 6 hours after single dose PI/BG ratio Sulfonylurea Glimepiride® 0. 03 (n=16) Glibenclamide 0. 16 (n=16) Gliclazide 0. 07 (n=14) Glipizide 0. 11 (n=13) 0 5 10 15 20 Mean plasma insulin increase (µU/ml) PI Mean blood glucose decrease (%) BG Müller G et al. Diabetes Res Clin Pract 1995; 28 (suppl): S 115 -S 137 Sulfonylureas tested in fasted male beagle dogs to determine ratios of mean plasma insulin release/ blood glucose decrease

Glimepiride and CV safety Glimepiride is superior to other Sulfonylureas in terms of reducing the risk of macrovascular diseases, despite achieving the same glycemic control. H. Onuma et al. / Journal of Diabetes Mellitus 4 (2014) 33 -37

Comparison : Glimepiride vs DPP 4 Inhibitors Efficacy: ∆A 1 c(minus) Glimepiride DPP 4 Inhibitors 25 -30%* 8 -12%* More or equal† Less or equal† Cost Less More Cost Efficacy More Less Hypoglycemia ++‡ CVD Decreased# +‡ No Change¶ *from Baseline in Premarketing trials † 2 -6 mg Glimepiride vs Maximum DPP 4 Inhibitors ‡Severe, Rare with both #MI in UKPDS, ADOPT, ADVANCE, BARI trials[Diabetes Care, 2015; 38(1): 166] ¶ Increased CHF [Clin Ther, 2014; 36(12): 20729, Curr. Treat. Options. Cardiovasc. Med, 2014; 16(12): 353]

• Glimepiride doses (1 -3 mg) vs max doses of DPP 4 I • All efficacy variables – reduction in Hb. A 1 c, % patients reaching Hb. A 1 c<7 & FPG reduction are consistently favourable to glimepiride • Weight variations ( ~2 kg) not significantly different • Serious adverse events not significantly different • Greater effectiveness with glimepiride compared to DPP 4 I and offers potential advantages in management Int J Clin Pract. 2015 Feb 16

Controlling glucose triad Long term average glucose level Hb. A 1 c Glucose triad Peak glucose level Int J Cur Res Rev, Aug 2013; 05; 16: 20 -26 Postpra ndial glucose Fasting plasma glucose Basal glucose level

Postprandial hyperglycemia results in oxidative stress through different mechanisms Postprandial hyperglycemia ü Protein nitration üPARP activation and ↑ of NAD+ ü↑NFK-B activation ü↑ GAPDH activity üLDL oxidation European Review for Medical and Pharmacological Sciences 2005; 9: 191 -208 üOverloaded mitochondrial metabolism üAutoxidation üEarly or reversible glycation üincreased carbonylic stress Oxidative stress

Postprandial hyperglycemia: ADA-2015 ü Elevated post challenge (two hour glucose tolerance test ) glucose values are associated with increased cardiovascular risk independent of fasting plasma glucose ü Endothelial function is negatively affected American Diabetes Association. Glycemic targets. Sec. 6. In Standards of Medical Care in Diabetesd 2015. Diabetes Care 2015; 38(Suppl. 1): S 33–S 40

Glycemic pentad in the management of diabetes Hb. A 1 c Quality of life Glycemic pentad Glycemic variability Fasting blood glucose Postprandial blood glucose Glycemic pentad should to be considered in diabetes management Indian J Endocrinol Metab. 2013 Jul-Aug; 17(4): 611– 619

Typical Indian Foods are rich in Carbohydrates and may result in High PPG levels üTraditional Asian Indian diets are carbohydrate-rich üSometimes even up to 80% percent of the macronutrient composition comes from carbohydrate üHigh glucose load leads to higher prandial glycemic excursion JAPI Nov 2010; 58: 665

Triple Combination therapy for type 2 diabetes Metformin + Sulfonylurea s ti ha W the ale? n tio üNo hypoglycemia + ra üReduces postprandial glucose excursions Alfa glucosidase inhibitor üNon-systemic üReduced CV events (? ) American Diabetes Association. Approaches to glycemic treatment. Sec. 7. In Standards of Medical Care in Diabetesd 2015. Diabetes Care 2015; 38(Suppl. 1): S 41–S 48

Alfa (α) glucosidase inhibitors • α-glucosidase inhibitors are oral drugs used in the management of type 2 diabetes mellitus with postprandial hyperglycemia • Prevent digestion and absorption of carbohydrates by inhibiting the terminal step of carbohydrate digestion at the brush border of the intestinal epithelium • Carbohydrate absorption is shifted more distally in the intestine and therefore delayed Int J Med Res. 2011; 1(2): 121 -129

AGIs reduce absorption of carbohydrates With AGIs Without AGIs Red ca M r ab boh ore so yd rp ra tio te n uc del ed an d a car boh yed abs ydra orp t tion e Jejunum Ileum Carbohydrates Carbohydrate absorption Jejunum Ileum without AGIs with AGIs Carbohydrate absorption Duodenum Jejunum Ileum

Place of AGIs in therapy to control PPG At the diagnosis when PPG is high Start with AGI – alternative to metformin Patients uncontrolled on metformin monotherapy with high PPG Add AGI if PPG is high with monotherapy Patients uncontrolled on dual therapy with PPG Start with AGI – if PPG is high on dual therapy

Place of alfa glucosidase inhibitors in the management of type 2 diabetes Lifestyle measures Usual approach At each step, if not to target (generally Hb. A 1 c ‹ 7. 0 %) Alternative approach Consider first line Metformin SU or AGI Consider second line SU Consider third line or Basal/premix insulin Consider fourth line Basal + meal time insulin International Diabetes Federation ; 2012 Clinical Guidelines or Metformin (if not used first line) or AGI/DPP-4 inhibitor or TZD Basal/pre-mix insulin (later basal + meal time) AGI/DPP-4 inhibitor or TZD

Voglibose ü Competitive α glucosidase inhibitor (α-GIs) discovered in 1981 and available for treatment of DM in Japan since 19941 ü Inhibitory activity on maltose and sucrose is 190 -270 times higher than acarbose and 100 times higher than miglitol 1 ü Specifically targets postprandial hyperglycemia, with little or no risk of hypoglycemia 2 ü Negligible renal excretion 2 ü Can be used as monotherapy or in combination with other antidiabetic agents 2 ü Mobilize endogenous pool of insulinotropic GLP-1; inhibits overwork of pancreatic beta-cells and has insulin-sparing effect 2 1. Journal of Clinical and Diagnostic Research. 2013 Dec, Vol-7(12): 3023 -3027 2. Expert Opin. Pharmacother. 2014; 15(8): 1181 -1190

Voglibose: Reduces oxidative stress and hyperlipidemia In obese type 2 diabetes patients, voglibose reduces Oxidative stress generation Soluble intercellular adhesion molecule PPG and hyperlipidemia Satoh N, Shimatsu A. Metabolism. 2006 Jun; 55(6): 786 -93.

Triple drug combination with voglibose for controlling PPH Patients uncontrolled on dual therapy (like Met+SU) and who have post-prandial hyperglycemia.

Non-compliance: A significant challenge in type 2 diabetes üA study of 600 type 2 diabetes patients üOnly 16. 6% patients were adherent to prescribed anti-diabetic drugs 85. 00% 90. 00% 80. 00% 71. 60% % of patients 70. 00% 60. 80% 60. 00% 50. 00% 40. 00% 30. 00% 20. 00% 18. 30% 10. 00% Did you ever forget to take Were you careless at times When you felt better, did Sometimes, if you felt worse your medication? about taking your you sometimes stop taking when you took medicine did medication? your medication? you stop taking it? JIACM 2014; 15(1): 26 -9

Need of fixed dose combination ü Non-adherence was highly significantly (p < 0. 001) associated with frequent dosing and multiple drugs 1 ü More than half of patients desired less number frequency of medications 1 Reduced pill burden Increased adherence Different strengths of FDCs • Better adherence • Better glycemic control • Reduced disease management cost • Dosing flexibility Fixed-dose combination decreases the risk of medication noncompliance and can translate into better clinical outcomes 2 JIACM 2014; 15(1): 26 -9 Am J Med. 2007 Aug; 120(8): 713 -9 Adv Ther 2012; Jan 29 (1): 1 -13

Dosing of three individual agents • Glimepiride – After oral administration, glimepiride is rapidly absorbed, and bioavailability is practically 100% and is essentially unaffected by food 1 – Glimepiride may be taken before or after meal with similar results. 2 • Metformin – Recommended and approved for use with meals. 3 • Voglibose – Usual starting dose is 0. 2 mg three times daily with meals. 4. 1. xpert Opin. Drug Metab. Toxicol. (2010) 6(2): 225 -235) 2. Vascular Health and Risk Management 2012: 8 463– 472 3. Metformin Prescribing information 4. Expert Opin. Pharmacother. (2014) 15(8))

Amaryl MV ü Indication – As third line treatment of Type II diabetes mellitus in adult patients when diet, exercise and the single agents and second line therapy with two drugs do not result in adequate glycemic control ü Dosage & Administration – Usual recommended dose for adults: 1 tablet of Amaryl MV twice a day before meals. Additionally, voglibose tablets may be taken before the remaining meal, as prescribed by the physician. ü Available as – Amaryl® MV 1 mg : Each uncoated bilayered tablet contains Metformin hydrochloride IP 500 mg (in sustained release form) + Glimepiride IP 1 mg + Voglibose IP 0. 2 mg – Amaryl® MV 2 mg : Each uncoated bilayered tablet contains Metformin hydrochloride IP 500 mg (in sustained release form) + Glimepiride IP 2 mg + Voglibose IP 0. 2 mg

Summary ü Control of glucose triad (Hb. A 1 c, fasting blood glucose level and postprandial blood glucose level) is important in reducing complications of diabetes mellitus ü Combination of glimepiride, metformin and voglibose controls glucose triad and is well tolerated ü Fixed dose combination of drugs from different classes helps in better control of glycemia and offers advantages of convenience, and potential for improved compliance