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Shedding the lights on SUs Translating evidence into patients’ benefits

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Sulfonylureas were discovered by the french chemist Marcel Janbon and co-workers during World War II …

Sulfonylureas were discovered by the french chemist Marcel Janbon and co-workers during World War II
, who were studying sulfonamide antibiotics and discovered that the compound sulfonylurea induced hypoglycemia in animals.

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  • Normally, after meals, glucose concentrations increase in the blood, tissues, and pancreatic b-cells. Increased intracellular glucose concentrations result in the increased production of adenosine triphosphate (ATP) in b-cells, which is followed by closure of ATP-dependent potassium (KATP) channels (Campbell, 1998). This results in cell membrane depolarization and the opening of voltage-sensitive calcium channels. The subsequent increase in intracellular calcium induces insulin secretion. Sulfonylureas exert their stimulant effect on insulin secretion by binding to and blocking KATP channels in b-cells membranes, thereby simulating the effects of glucose in eliciting insulin release.
  • Therapeutic actions of metformin: correcting the pathophysiology of type 2 diabetes Impaired insulin secretion and insulin resistance and are the two key endocrine defects of type 2 diabetes. Normally, insulin acts not only to promote peripheral glucose uptake and utilisation, but also to suppress the endogenous generation of glucose production by the liver. Both of these actions of insulin are blunted in an insulin-resistant individual. Indeed, elevated hepatic glucose production is an important factor in the hyperglycaemia characteristic of type 2 diabetes. Metformin counters insulin resistance in liver and muscle, and these actions underpin the antihyperglycaemic actions of this agent. It should also be noted that restoring a state of normoglycaemia reduces the toxic effects of glucose on the pancreas, and this leads to improvements in  -cell function and insulin secretion.
  • Key Points Sulfonylureas lower glycemia by enhancing insulin secretion. They appear to have an effect similar to metformin, lowering HbA 1c by approximately 1.5%. The major adverse side effect with sulfonylureas is hypoglycemia, but severe episodes, characterized by need for assistance, coma, or seizure, are infrequent. Several of the newer sulfonylureas have a relatively lower risk for hypoglycemia. Weight gain of 2 kg is common with the initiation of sulfonylurea therapy. This may have an adverse impact on cardiovascular risk, although it has not been established. Sulfonylurea therapy was implicated as a potential cause of increased cardiovascular mortality in the University Group Diabetes Program (UGDP). However, these concerns were not substantiated by the UKPDS. Reference: Nathan DM et al . Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006;29(8):1963-72.
  • ADA-EASD Consensus Algorithm for T2DM The ADA/EASD algorithm’s goal is to achieve and maintain HbA1c levels of <7%. The well-validated core therapies represent the preferred route. Tier 1: well-validated therapies Step 1: lifestyle intervention and metformin Lifestyle interventions remain an underlying theme for the management of type 2 diabetes mellitus; however as most individuals fail to achieve goals with lifestyle intervention alone, metformin should be initiated concurrently at diagnosis. Step 2: additional medications If lifestyle intervention and maximal tolerated doses of metformin fail to sustain goals, another medication should be added within 2–3 months of the initiation of therapy or at any time when HbA1C goal is not achieved. The consensus is to choose either insulin or a sulfonylurea (SU). Step 3: further adjustments If lifestyle, metformin, and a basal insulin or SU do not result in glycaemic control, start or intensify insulin therapy: insulin secretagogues (SUs or glinides) should be discontinued, or tapered and then discontinued, since they are not considered synergistic with insulin. Tier 2: less-well validated therapies In selected clinical settings, the second tier algorithm may be considered. When hypoglycaemia is particularly undesirable, the addition of exenatide or pioglitazone may be considered (rosiglitazone is not recommended). If weight loss is a major issue and HbA1c is close to target (<8.0%), exenatide is an option. If these interventions are not effective in achieving target HbA1c, or are not tolerated, addition of an SU could be considered. Alternatively, tier 2 interventions should be stopped and basal insulin started. Reference Nathan et al. Management of Hyperglycemia in Type 2 Diabetes Mellitus: A Consensus Algorithm for the Initiation and Adjustment of Therapy. Diabetes Care 2008 [Epub].
  • 1 In extrapancreatic tissues, sulfonylureas promote the synthesis of glucose transporters (Jacobs, Hayes, & Lockwood, 1989), improving insulin sensitivity by potentiating glucose transport in adipose tissue and glycogen synthesis in skeletal muscle (Groop, 1992).
  • Purpose: To summarize the English-language literature on the benefits and harms of oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, meglitinides, and -glucosidase inhibitors) in the treatment of adults with type 2 diabetes mellitus. Study Selection: 216 controlled trials and cohort studies and 2 systematic reviews that addressed benefits and harms of oral diabetes drug classes available in the United States. Figure shows the comparative effects of oral diabetes agents on hemoglobin A1c. Thiazolidinediones, second-generation sulfonylureas, and metformin produced similar reductions in hemoglobin A1c levels when used as monotherapy (absolute reduction, about 1 percentage point). Repaglinide produced similar reductions in hemoglobin A1c levels compared with sulfonylureas. Combination therapies had additive effects, producing an absolute reduction in hemoglobin A1c levels of about 1 percentage point more than monotherapy. Conclusions: Compared with newer, more expensive agents (thiazolidinediones, -glucosidase inhibitors, and meglitinides), older agents (second-generation sulfonylureas and metformin) have similar or superior effects on glycemic control, lipids, and other intermediate end points. Large, long-term comparative studies are needed to determine the comparative effects of oral diabetes agents on hard clinical end points.
  • Cross-reference to Safety Section: The improved glycemic control is accompanied by a significantly reduced risk of hypoglycemia – see slide entitled “Safety: Hypoglycemia vs Insulin” for details.
  • The reasons for the differences noted in hypoglycemia rate in this study are probably multifactorial. One factor is thought to be related to the differences in receptor binding between the two medications. Glimepiride has a considerably lower binding affinity to the  -cell receptor and a higher exchange rate, associating with its receptor (65 kDa protein on the pancreatic sulfonylurea receptor in the cell membrane) 2 to 3 times faster than glyburide (which binds to 140 kDa protein) and dissociating about 8 to 9 times faster than glibenclamide. Additionally, glibenclamide accumulates after long-term use. Taken together, these factors can lead to a high risk of severe hypoglycemia. Furthermore, for the same blood-glucose lowering effect, glimepiride stimulates the secretion of smaller amounts of insulin than glibenclamide, both when fasting and postprandially. This ability to suppress endogenous insulin production between meals (and during exercise) is clearly different from glibenclamide and presumably lessens the risk of hypoglycemia. Holstein et al. Diabetologia 2000;43:A40.
  • Glimepiride May Offer Cardiovascular Advantages Compared With Other Sulfonylurea Drugs The onset of ischemia causes the opening of the cardiovascular ATP-sensitive potassium (K ATP ) channels, a mechanism that plays a role in protecting the myocardium; this process is called ischemic preconditioning. It has been suggested that classical sulfonylureas such as g libenclamide have adverse effects on the cardiovascular system , mainly because they abolish the cardioprotective responses of the K ATP channel opening, presumably by inhibiting mitochondrial K ATP channel opening in cardiac myocytes. Unlike glibenclamide , data from animal and human studies show glimepiride does not block the beneficial effects of mitochondrial K ATP channel opening in cardiac tissue. This may have implications for the treatment of T2DM patients who are typically at increased cardiovascular complications vs. non-diabetic subjects.
  • The decrease in chest pain scores in the control non diabetic group is suggestive of IP. A similar decrease was observed in the Amaryl group but not in the glibenclamide group of non-diabetic subjects Similar results were observed in the group of diabetic patients receiving long-term SU treatment. However, when glibenclamide-treated patients also received nicorandil (K-ATP channel activator), chest pain scores were significantly lower at first and second inflations vs glibenclamide alone.
  • After 12 weeks with Glimepiride treatment, significant reductions were observed in fasting blood glucose (FBG) and 2-h postprandial BG(PBG), HbA1C (from 8.60 3.10 to 7.10 1.60%) and HOMA-IR (from 4.11 0.85 to 2.42 0.91%). The level of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) were significantly decreased, whereas that of high-density lipoprotein (HDL) was increased markedly with statistical significance. In addition, there was an obvious improvement in t-PA activity (from 0.225 0.11 to 0.457 0.177 IU/ml); whereas the PAI-1 activity was decreased significantly (from 0.898 0.168 to 0.533 0.215 AU/ml). No significant changes were observed in plasma lipoprotein profiles and plasminogen activity in Glibenclamide receiving group.
  • 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.

Transcript

  • 1. Translating evidence into patients’ benefits By: Abbas Oraby
  • 2. HistorySulfonylureas were discovered by the french chemist MarcelJanbon and co-workers during World War II , who were studying sulfonamide antibiotics anddiscovered that the compound sulfonylurea induced hypoglycemia in animals.
  • 3. History Janbon convinced a medicalcolleague, August Loubatieres, totry it on his diabetic patients. The drug triggered a fall in these patients blood sugars. Experiments by Loubatieres and others, with animals and with isolated pancreas, later revealed that the sulfonylurea stimulated pancreas cells to release insulin.
  • 4. History Sulfonylureas were the first widely used oral anti- hyperglycaemic medications. Many types of these pills havebeen marketed but not all remain available. Until 1995, sulfonylureas were the only class of medications available for the treatment of patients with type 2 diabetes besides insulin.
  • 5. Drugs in this classSulfonylureas were the first widely used oral anti-hyperglycaemicmedications. Many types of these pills have been marketed but not allremain available.
  • 6. MECHANISMS OF ACTION OF SUs
  • 7. Insulin release• It involves 3 main steps : 1. Translocation of insulin granules. 2. Docking of insulin granules. 3. Fusion of insulin granules. 8
  • 8. Translocation of insulin granules• Two essential components of the cytoskeletal elements : 1. Microtubules (formed of tubulin subunits). 2. Microfilaments (Actin + Myosin). 9
  • 9. 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
  • 10. The motive force to propel granules along themicrotubules is provided by the interaction between : Filamentous Phosphorylated actin + myosin ATP Ca+ Granule transport It gives the force but not the way 11
  • 11. 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
  • 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
  • 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.
  • 14. Insulin Secretion (Glimepiride)Glimepiride binds to the 65 kDa subunit of the sulfonylurea receptor; glibenclamide binds to the 140 kDa subunit
  • 15. Therapeutic actions Pancreas Sulfonylurea + Impaired glimepiride Insulin secretion Insulin – resistance Increased Decreased glucose glucose production Hyperglycaemia uptakeLiver Muscle Metformin 16
  • 16. 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.
  • 17. 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
  • 18. 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%SUs other than glybenclamide (glyburide) or chlorpropamide. bInsufficient clinical use to be confident regarding safety.aMet=metformin; Pio=pioglitazone; SU=sulfonylureaNathan et al., Diabetes Care 2008 [Epub]
  • 19. Type 2 Diabetes is a Dual Problem Schematic Representation of the Natural Progression of Type 2 Diabetes INSULIN RESISTANCE FPG/PPG HbA1c↑ INSULIN SECRETION Normal IGT Type 2 Adapted from Type 2 Diabetes BASICS. Minneapolis, MN: International Diabetes Center; 2000
  • 20. Glimepiride : Dual Mechanism for Dual Problem INSULIN RESISTANCE FPG / PPG HbA1C INSULIN SECRETION Normal IGT Type 2Graphic interpretation based on: 24Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37; Massi-Benedetti M. Clin Ther 2003; 25(3): 799-816
  • 21. Unique Dual Mode of Action Action on insulin Action on insulin secretion resistance Glimepiride1 ► ► Conventional Sulfonylureas1 ► - Glinides1,2 ► - Biguanides1,3-5 - ► Glitazones1,6 - ►1 Medical Management 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
  • 22. Acting on Both Phases of Insulin Secretion GlimepirideThe only sulfonylurea to treat fasting and postprandial hyperglycemia First and second phase insulin secretion before and after treatment with Glimepiride p=0.02 100 Incremental plasma insulin Euglycemic and hyperglycemic clamp studies in 11 obese patients with T2DM with good glycemic p=0.04 + Glimepiride control before and after 50 4 months treatment with Glimepiride to assess effect of (pmol/L) +Glimepiride Glimepiride on insulin secretion 0 First Phase Second Phase Insulin secretion Before treatment After Glimepiride treatmentKorytkowski M et al. Diabetes Care 2002; 25(9):1607-11.
  • 23. 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
  • 24. 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(µU/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
  • 25. 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 (µg/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
  • 26. GLIMEPIRIDE IS MORE THAN ANINSULIN SECRETAGUGE !!!
  • 27. 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 -1% patients received 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
  • 28. Adding sulfonylurea to metformin is particularly effective in lowering HbA1c Drug 1 more beneficial Drug 1 less beneficial Drug 1 Glyb vs. other SU TZD vs. SU TZD vs. Met Repag vs. SU SU vs. Met SU vs. Acarbose Met + TZD vs. Met SU + TZD vs. SU Met + SU vs. Met Met + SU vs. SUGlyb: glyburide -1.5 -1.0 -0.5 0 0.5TZD: thiazolidinedioneRepag: repaglinide Weighted mean difference inSU: sulfonylurea HbA1c Value, %Met: metformin 32Bolen S, et al. Ann Intern Med 2007;147:386-399.
  • 29. Glimepiride + Metformin Combination vs Monotherapy Superior glycemic control with metformin + Glimepiride Evolution in FBG over time according to treatment 225 209 mg/dl Metformin Mean FBG (mg/dL) 200 Prospective, Glimepiride 207 mg/dl multicenter, randomized, double- blind, double-dummy 175 parallel group study of 372 T2DM patients Metformin + Glimepiride inadequately controlled by metformin 850 mg 150 tid. Patients received 158 mg/dl metformin, Glimepiride or both for 20 weeks. 125 0 3 6 9 12 15 18 20 Titration Maintenance Treatment Duration (wk) Glimepiride Metformin Metformin + G;imepiride33 Charpentier G et al. Diabet Med. 2001;18:828-34
  • 30. Efficacy: Glimepiride + Metformin Combination vs Pioglitazone + Metformin Glimepiride + metformin provides faster glycemic control than pioglitazone + metformin Change in HbA1c over time Glimepiride + Metformin (n = 96) Pioglitazone + Metformin (n = 107) 9 Open-label, 8.5 randomized, forced-Mean HbA1C (%) titration study in 203 8 * adults with poorly controlled T2D (HbA1c 7.5 * 7.5-10%)on metformin monotherapy. * Glimepirideor 7 pioglitazone, titrated to maximum doses, 6.5 was added to metformin therapy and patients were 6 followed for 26 0 6 12 20 26 weeks. Time (Weeks) *p<0.05 vs metformin + pioglitazone Adapted from Umpierrez G, et al. Curr Med Res Opin 2006; 22(4): 751-759
  • 31. Efficacy: Glimepiride + Gliptin Combination • Combining sitagliptin with Glimepiride improves glycemic control1 Difference in LSM change from baseline in HbA1c relative to placebo Baseline HbA1c 8.4% 8.3% Randomized, 0 placebo-controlled -0.1 study in 441 patients with T2D poorly -0.2 controlled by Glimepiride + sitagliptin Glimepiride or -0.3 ∆ in HbA1c (%) glimepiride + -0.4 Glimepiride + metformin (HbA1c -0.5 -0.57* metformin + sitagliptin ≥7.5% and ≤10.5%). In addition to their -0.6 usual therapy, -0.7 patients received -0.89* sitagliptin 100mg or -0.8 placebo for 24 -0.9 weeks. -1 *p<0.001 vs placebo Hermansen K, et al. Diabetes Obes Metab 2007; 9: 733-745 1 The EU’s Committee for Medicinal Products for Humans (CHMP) recently recommended that sitagliptin be approved for use in combination with a sulfonylurea and for triple therapy in combination with metformin + sulfonylurea2 2 European Medicines Agency, 15 Nov 2007: Available at http://emea.europa.eu/pdfs/human/opinion/Januvia_53120907en.pdf
  • 32. Efficacy: Glimepiride + Insulin Analog Combination • Superior glycemic control with insulin glargine + Glimepiride + metformin vs 70/30 insulin as initial therapy Adjusted mean decrease in HbA1c at week 24 according to treatment All patients (n=371) Elderly patients (n=130) 24-week, multinational Baseline HbA1c 8.85 8.83 8.8 8.9 open, parallel group 0 Insulin clinical study. Insulin- -0.2 glargine naïve T2DM subjects (n=371) with poor -0.4 + glycemic control on OAD ∆ in HbA1c (%) Glimepiride (sulfonylurea + -0.6 metformin) were + metformin -0.8 randomized to once-daily morning insulin glargine -1 + Glimepiride and -1.2 -1.31 70/30 insulin metformin (glargine + -1.4 OAD) or to 30% regular/ -1.4 70% human NPH insulin -1.64* (70/30) twice daily -1.6 7.49 without OADs 7.4 -1.8 -1.9† -2 7.15 HbA1c at endpoint 7.0 *p=0.0003; †p=0.003 vs 70/30 insulin36 Janka HU et al. Diabetes Care. 2005; 28: 254-259; Janka HU, et al. J Am Geriatr Soc 2007; 55: 182-188
  • 33. SAFETY ?!!!
  • 34. 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
  • 35. Safety: Weight• Reduction in glycemia with Glimepiride is accompanied by significant and stable weight loss Mean intra-individual changes from baseline in body weight and HbA1c Months of treatment 4 12 18 0 Open, uncontrolled, Change from baseline observational study. 1770 T2DM patients -1 -1.4* were enrolled and 284 -1.5* were followed-up for 1.5 -1.7* years. Patients -1.9* received 0.5 to > 4 mg -2 Glimepiride once daily. Baseline HbA1c: 8.4%; -2.9† -3.0‡ body weight: 79.8kg -3 Body weight (kg) HbA1c (%) *p<0.0001; †p<0.05; ‡p<0.005 vs baseline Weitgasser R et al. Diabetes Res Clin Pract 2003; 61: 13-19
  • 36. Safety: Weight • The higher the BMI, the greater the weight loss Change in body weight after 2 months of treatment with Glimepiride according to baseline BMI BMI at baseline 0.5 <20 ≥19 to <25 ≥25 - <30 ≥30 0.2 0 Weight loss (kg) -0.4 -0.5 -1.0 -1.4 -1.5 -2.0 -2.2 -2.5Scholz GH, et al. Clin Drug Invest 2001; 21: 597-604
  • 37. CARDIAC SAFETY ?!!!
  • 38. University Group Diabetes Program• Study Design Randomized Clinical Trial 1000 Patients with Type 2 Diabetes Assigned to Diet, Insulin or Sulphonylureas Primary Outcomes – Cardiovascular Events
  • 39. University Group Diabetes ProgramStudy TerminatedIncreased Risk of Cardiovascular Mortality p < 0.05
  • 40. 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) (µmol/L) 0 Randomized, double- -5 Change from baseline 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 -35 -39.7* -40.1* mg/dL µmol/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
  • 41. 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. Mean 50 ST segment shift (mV) after repetitive balloon dilatation was measured to compare the effects of Glimepiride glibenclamide and 0 placebo on ischemic Placebo Glimepiride(n=15) Glibenclamide preconditioning. (n=15) (n=15) Baseline After drug administration Klepzig et al. Eur Heart J 1999;20:439-446
  • 42. Cardiovascular Safety: Ischemic Preconditioning • Glimepiride maintains KATP channel-dependent peripheral vasodilation, unlike glibenclamide Mean (SEM) % change in forearm blood flow in response to intra-arterial infusion with 2.25 mg/min/dL diazoxide *p value compared with placebo 900 % change in forearm blood flow *p = NS The effects on forearm blood flow of co- 700 administration of diazoxide + Glimepiride or *p < 0.01 glibenclamide were 500 assessed in healthy males volunteers (n = 12 per group). 300 100 Placebo Glimepiride Placebo Glibenclamide n=12 2.5 µg/min/dL n=12 0.33 µg/min/dL (n=12) (n=12) Bijlstra PJ et al. Diabetologia. 1996;39:1083-1090
  • 43. Cardiovascular Safety: Ischemic Preconditioning Glimepiride maintains and glibenclamide blunts the anti-anginal effect of ischemic preconditioning Mean (SD) chest pain scores during angioplasty Non-diabetic Diabetic group group Myocardial responses were assessed Glib + Glimepiri following coronary Control Glib Glimepiri Glib Glimepiri Nic de + Nic angioplasty in (n=7) (n=6) de (n=7) (n=6) de (n=5) (n=6) (n= 6) diabetic and non- diabetic subjects Inflation 1 5.9 5.2 6.2 5.8 6.2 3.2 4.4 receiving Glimepiride (2 mg or usual dose) ± 0.9 ± 1.5 ± 0.8 ± 0.8 ± 0.8 ± 0.8† ± 1.5 or glibenclamide (10 mg or usual dose). Inflation 2 2.4 5.3 3.2 5.5 3.4 2.7 4.0 ± 0.5* ± 1.5 ± 0.8* ± 1.5 ± 0.9* ± 0.8† ± 1.2 *p<0.05 v. inflation 1 within same group. † p<0.05 vs Glib group alone at same time. Glib = glibenclamide; Nic = nicorandil. Lee TM, Chou TF. J Clin Endocrinol Metab. 2003;88:531-537
  • 44. 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 outpatients. A total of Cumulative survival 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
  • 45. GLIMEPIRIDE IN 2010A NON-STOPPING WEALTH OF EVIDENCE
  • 46. 2010 2010Xu dan-yan et al. diabetes research and clinical practice 88(2010 ) 71–75
  • 47. 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
  • 48. 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
  • 49. 2010 2010Pantalone K. M. et al. DIABETES CARE(33)-6, 2010, 1224 - 29
  • 50. 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
  • 51. 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
  • 52. 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
  • 53. 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