Abbas orabi.translating evidencePresentation Transcript
Translating evidence into patients’ benefits By: Abbas Oraby
Drugs in this classSulfonylureas were the first widely used oral anti-hyperglycaemicmedications. Many types of these pills have been marketed but not allremain available. • Acetohexamide • Glipizide • Chlorpropamide • Gliclazide • Glibenclamide (glyburide) • Tolbutamide • Gliquidone • Tolazamide • Glyclopyramide
MECHANISMS OF ACTION OF SUs
Insulin release• It involves 3 main steps : 1. Translocation of insulin granules. 2. Docking of insulin granules. 3. Fusion of insulin granules. 8
Microtubules form a network radiating from theperinuclear region outwords . The framework provides the mechanical pathway along which secretory granules move toward the exocytic sites close to the plasma membrane. It gives the way but not the force 10
Ca+ is essential for almost all stepsinvolved in insulin release, thus factorsincreasing intracellular Ca+ will augmentinsulin release.Mechanisms involved inincreasing intra-cytoplasmic Ca+ : Ca-influx from outside. Inhibition of Ca-reuptake by Ca++ Store intracellulas stores. x Increased Ca-sensitivity. 12
Increased intracellular Ca+ is essential for granules translocation and fusion hence release of insulin. ATP-sensitive Voltage-gate Ca Glucose K+ channel channel 6 GLUT2 X Fusion K retention 4 Glucose 3 Depolarization Ca+ 2Glucokinase 1 5 G-6-P ATP Translocation Each B-cell contains up to 500 Ca channels 13
Mechanisms of action cont.• The rise in intracellular calcium leads to increased fusion of insulin granules with the cell membrane, and therefore increased secretion of (pro)insulin.• There is some evidence that sulfonylureas also sensitize β-cells to glucose, that they limit glucose production in the liver, that they decrease lipolysis and decrease clearance of insulin by the liver.
Insulin Secretion (Glimepiride)Glimepiride binds to the 65 kDa subunit of the sulfonylureareceptor; glibenclamide binds to the 140 kDa subunit
Attributes of sulfonylureas How they work Enhance insulin secretion Expected HbA1c 1 to 2% reduction Adverse events Hypoglycemia* (but severe episodes are infrequent) Weight effects ~ 2 kg weight gain common when therapy initiated CV effects None substantiated by UKPDS or ADVANCE study* Substantially greater risk of hypoglycemia with chlorpropamide and glibenclamide (glyburide) than other second- generation sulfonylureas (gliclazide, glimepiride, glipizide) 17Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.
IDF Global Guideline for Type 2 Diabetes Diagnosis Lifestyle intervention then metformin HbA1c 6.5 % Add sulfonylurea HbA1c 6.5 % HbA1c 6.5 %*Alternatively, start Add thiazolidinedione* Add insulinthiazolidinedione beforesulfonylurea,and sulfonylurea later. HbA1c 7.5 % HbA1c 7.0 % Start insulin intensify insulin Meal-time + basal insulin + metformin ± thiazolidinedione IDF. Global Guideline for Type 2 Diabetes. 2005
ADA and EASD algorithm for the management of type 2 diabetes Tier 1: Well validated therapies Lifestyle and At Lifestyle and met + intensive diagnosis: met + basal insulin Lifestyle insulin + metformin Lifestyle and met + SUa Step 1 Step 2 Step 3 Tier 2: Less well validated therapies Lifestyle and met + pio Lifestyle and met No hypoglycaemia Oedema/CHF + pio + SUa Bone loss Lifestyle and met + GLP-1 agonistb Lifestyle and No hypoglycaemia Weight loss met + basal insulin Nausea/vomiting Reinforce lifestyle interventions every visit and check HbA1C every 3 months until HbA1C is <7% and then at least every 6 months. The interventions should be changed if HbA1C is ≥7%aSUs other than glybenclamide (glyburide) or chlorpropamide. bInsufficient clinical use to be confident regarding safety.Met=metformin; Pio=pioglitazone; SU=sulfonylureaNathan et al., Diabetes Care 2008 [Epub]
Unique Dual Mode of Action Action on insulin Action on insulin secretion resistance 1 Glimepiride ► ► Conventional Sulfonylureas1 ► - Glinides1,2 ► - Biguanides1,3-5 - ► Glitazones1,6 - ►1MedicalManagement of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139; 2Goldberg 1998, et al. Diabetes Care21:1897-1903; 3Bell & Hadden. Endocrinol Metab Clin 1997;26:523-37; 4De Fronzo, et al. N Engl J Med 1995;333:541-9; 5Bailey & Turner. N Engl J Med1996;334:574-9; 6Henry. Endocrinol Metab Clin 1997;26:553-73
2nd Action: Extra-Pancreatic The extrapancreatic effect of Glimepiride Rate limiting step for glucose utilization is glucose uptake via GLUT4 transporter Glimepride↑ translocation of GLUT4 transporters from low-density microsomes to plasma membrane of insulin-resistant fat and muscle cells Glimepiride appears to ↑ peripheral glucose uptake and to mimic the action of insulin27 Müller & Wied. Diabetes. 1993;42: 1852-1867
Glimepiride Controls Glycemia with Less Insulin Secretion • For an equivalent glycemic effect, Glimepiride induces a lower secretion of insulin Mean variation of insulin and Mean ratio between increased level of glycemia over a 36-h period insulin and reduced glycemia Sulfonylureas tested in fasted male beagle dogs 3 to determine ratios ofInsulinemia 2 Ratio mean plasma insulin release/ blood glucose(U/mL) 1 decrease 0.20 n=16 0 Glimepiride Glibenclamide Gliclazide Glipizide 0.15 0 n=13 0.10 5 n=14variation (%) 10 0.05 n=16Glycemic 15 0.00 20 Glibenclamide Glipizide Gliclazide Glimepiride 28 Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37
Glimepiride Beneficial Effect on Adiponectin Levels • Glimepiride increases plasma adiponectin levels whilst achieving control of glycemia Evolution of adiponectin and HbA1c levels during 12 weeks of Glimepiride treatment 11 9 concentration (g/mL) 10 10.2 Plasma adiponectin 9 8 HbA1c (%) A study in 17 elderly patients with type 2 8 diabetes who were 8.2 treated with Glimepiride for 12 weeks. 7 7 7.5 6.6 6.9 6 6.5 5 6 Baseline 4 weeks 8 weeks 12 weeks Plasma adiponectin HbA1c (%)29 Tsunekawa T, et al. Diabetes Care 2003; 26(2); 285-289
GLIMEPIRIDE IS MORE THAN ANINSULIN SECRETAGUGE !!!
Glimepiride : Efficacy Proven in Monotherapy Tight glycemic control (HbA1c<7.2%) Glimepride : decreased FPG by 46 was achieved in 69% of Glimepiride patients mg/dL more and 2-hour PPG by 72 mg/dL and 32% of placebo patients more than placebo (p<0.001) Change from baseline to week 22 Change from baseline to week 22 in in median HbA1c median FPG and 2-hour PPG Prospective, Baseline HbA1c randomized, double- blind, placebo- FPG PPG 9.1% 8.9% controlled, dose- 0 titration study. T2DM n=117 n=118 n=108 n=101 Δ in glucose concentration (mg/dL) 0 patients received -1% Glimepiride (n=123) or Δ in median HbA1c (%) -1 placebo (n=126) for a -20 -13 -2.4%# 10-week dose-titration period and then the -40 -31 -2 optimal dose (1 to 8 7.9% mg) for 12 weeks. -60 54% of patients on -59* -3 active treatment -80 received <4 mg/day Glimepiride -4 6.7% -100 HbA1c at Endpoint -120 -117* *p<0.001 vs placebo -140 Glimepiride PlaceboSchade DS et al. J Clin Pharmacol 1998;38:636-51 31
Safety: Hypoglycemia vs Glibenclamide Significantly lower incidence of severe hypoglycemic events with Glimepiride vs glibenclamide (0.86 vs 5.6/1000 person-years) Incidence of severe* hypoglycemic events according to treatment 6 # Episodes/1000 person-years Prospective, population- based, 4-year study to6.5x compare frequency of 4 severe hypoglycemia inless patients with T2DMrisk of 5.6 treated with Glimepiride (estimatedhypo n=1768) versus glibenclamide 2 (estimated n=1721) 0.86 0 Glimepiride Glibenclamide *Defined as requiring IV glucose or glucagon Holstein A et al. Diabetes Met Res Rev 2001; 17:467-73
CARDIAC SAFETY ?!!!
Glimepiride Beneficial Effect on Cardiovascular Risk FactorsGlimepiride significantly reduces cardiovascular risk markers Reductions metabolic parameters after 12 months of treatment with Glimepiride Lp(a) PAI-1 Hcy mg/dL (ng/mL) (mol/L) 0 Randomized, double- Change from baseline -5 blind study in which patients with type 2 -10 diabetes were treated -15 -21.4† with Glimepiride (n=62)or repaglinide -20 ng/mL (n=62) for 12 months. -25 -30 -39.7* -40.1* -35 mg/dL mol/L -40 -45 Lp(a) = Lipoprotein A PAI-1 = plasminogen activator inhibitor-1 *p<0.01; †p<0.05 vs baseline Hcy = homocysteine De Rosa, et al. Clin Ther 2003; 25(2); 472-484
Cardiovascular Safety: Ischemic Preconditioning Unlike glibenclamide, Glimepiride does not block the beneficial cardioprotective effect of ischemic preconditioning Mean ST segment depression during balloon occlusion according to treatment p = 0.049 p = 0.01 p = NS 100 % change in mean ST shift Double-blind, randomized, placebo-controlled trial in 45 patients with stable coronary artery disease. 50 Mean ST segment shift (mV) after repetitive balloon dilatation was measured to compare the effects of Glimepiride 0 glibenclamide and Placebo Glimepiride(n=15) Glibenclamide placebo on ischemic (n=15) (n=15) preconditioning. Baseline After drug administration Klepzig et al. Eur Heart J 1999;20:439-446
Safety: All-Cause Mortality In combination with metformin, Glimepiride is associated with lower all-cause mortality than other sulfonylureas with less selectivity for β-cell receptors Kaplan-Meier survival analysis 1.0 Glimepiride or gliclazide Retrospective, observational cohort Repaglinide study in T2D 0.9 Cumulative survival outpatients. A total of 696 patients received insulin secretagogues in combination with 0.8 biguanides. A Kaplan- Glibenclamide Meier survival analysis was conducted in patients treated with Yearly mortality metformin in 0.7 Glimepiride 0.4% combination with Gliclazide 2.1%* glibenclamide, gliclazide, repaglinide Repaglinide 3.1%* or Glimepiride . Glibenclamide 8.7%** 0.6 Time * P < 0.05 vs Glimepiride 0 10.0 20.0 30.0 40.0 (months) **P <0.01 vs all comparatorsMonami M, et al. Diabetes Metab Res Rev 2006; 22(6): 477-482
GLIMEPIRIDE IN 2010A NON-STOPPING WEALTH OF EVIDENCE
2010 2010Xu dan-yan et al. diabetes research and clinical practice 88(2010 ) 71–75
Research Design and methods 2010• Objective: – To investigate the effects of Glimepiride on blood glucose in patients with newly diagnosed type 2 diabetes mellitus (T2DM) in connection with plasma lipoproteins and plasminogen activity.• Methods – A total of 565 T2DM patients received Glimepiride (n = 333) or Glibenclamide (n = 232) for 12 weeks. The level of blood glucose (BG), glycated hemoglobin (HbA1C), the insulin resistance (IR) state, plasma lipoproteins, tissue- type plasminogen activator (t-PA) and plasminogen activator inhibitor type I (PAI-1) were observed before and after a 12 weeks of treatment. Xu dan-yan et al. diabetes research and clinical practice 88(2010 ) 71–75
Results Cont. 2010Conclusion: Glimepiride can rapidly andstably improve glycemic control andlipoprotein metabolism, significantlyalleviate insulin resistance and enhancefibrinolytic activity. Xu dan-yan et al. diabetes research and clinical practice 88(2010 ) 71–75
2010 2010Pantalone K. M. et al. DIABETES CARE(33)-6, 2010, 1224 - 29
Research Design and methods 2010• Objective: The purpose of this study is to assess the relationship of individual sulfonylureas and the risk of overall mortality in a large cohort of patients with type 2 diabetes.• Methods: A retrospective cohort study , 11,141 patients with type 2 diabetes (4,279 initiators of monotherapy with glyburide, 4,325 initiators of monotherapy with glipizide, and 2,537 initiators of monotherapy with glimepiride), ≥ 18 years of age, with and without a history of coronary artery disease (CAD), and not on insulin or a non-insulin injectable at baseline. The patients were followed for mortality Pantalone K. M. et al. DIABETES CARE(33)-6, 2010, 1224 - 29
Results 2010 • No statistically significant difference in the risk of overall mortality was observed among these agents in the entire cohort, But• evidence of a trend towards an increased overall mortality risk with glyburide vs. glimepiride (HR 1.36; CI 0.96-1.91) and glipizide vs. glimepiride (HR 1.39; 95% CI 0.99-1.96), in those with documented CAD was found. Pantalone K. M. et al. DIABETES CARE(33)-6, 2010, 1224 - 29
Mortality Risk with Sulfonylurea Monotherapy 2010 Conclusion: The results did not identify an increased mortality risk among the individual sulfonylureas but did suggest that glimepiride may be the preferred sulfonylurea in those with underlying CAD. Pantalone K. M. et al. DIABETES CARE(33)-6, 2010, 1224 - 29
Conclusion Glimepiride the 3rd generation SU: – Unique dual mode of action – Fast and sustained blood glucose lowering effect – Ideal for combination with insulin and/or other oral antidiabetic agents – Benefits beyond blood glucose-lowering – Clinically proven safety profile – Glimepiride and Metformine in fixed dose combination presentation offer a synergistic combination serving the efficacy and safety objectives needed in the management of T2DM and Described in ADA/EASD Guidelines.61