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Glimepiride

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Glimepiride

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Glimepiride

  1. 1. Sulfonylureas in Type II DM Too Many Options, Too Little Clarity Dr. B. K. Iyer
  2. 2. Diabetes – Status Today Diabetes Reaching Epidemic proportion Monitoring difficulties/complications Economic Implications Prevalence of CAD in the diabetic population, i.e., major abnormalities in ECG, angina, or myocardial infarction (MI) is 2­4 times than observed in nondiabetics. Prevalence of CCF to which CAD and hypertension contribute, is increased 3- to 4-fold. Uusitupa M, Siitonen O, Aro A, Pyörälä K: Prevalence of coronary heart disease, left ventricular failure and hypertension in middle-aged, newly diagnosed type 2 (non-insulin-dependent) diabetic subjects. Diabetologia 28:22-27, 1985.
  3. 3. Diabetes – Roadmap of Today What we know What we may not know What we need to know What we need to do after knowing The different sulfonylureas and relative comparisons Effects of sulfonylureas on cardiac risk factors Aspects of using sulfonylureas in diabetic patients The right approach to the choice of sulfonylureas Today’s review
  4. 4. What Is Known?
  5. 5. Normal Glucose Regulation insulin Fats Muscle insulin pancreatic islet  cells Glucose absorbed from intestine GLUCOSE ABSORPTION GLUCOSE PRODUCTION PERIPHERAL GLUCOSE UPTAKE INSULIN SECRETION
  6. 6. OHAs Glucose Regulation Sulfonylureas Meglitinides Thiazolidinediones Metformin Thiazolidinediones  -Glucosidase Inhibitors Metformin Thiazolidinediones GLUCOSE ABSORPTION GLUCOSE PRODUCTION PERIPHERAL GLUCOSE UPTAKE INSULIN SECRETION
  7. 7. Second Generation sulfonylureas – what is known? Yes No No Yes Active metabolites 24 10-24 24 16-24 Duration of action 400 -1000 2.4 1-2 Glimepiride 50 -100 1 10 Glipizide 30 4 80 Gliclazide 150 -400 3 5 Glyburide [Glibenclamide] Relative potency Plasma Peak Equiv. Dose [mg.] Sulfonylurea
  8. 8. OHAs & Their Impact
  9. 9. Sulfonylureas – Mechanism Of Action sulfonylureas bind to a subunit of the ß-cell ATP-activated K channel complex (termed the sulfonylurea receptor) This binding reduces the rate of outward flow [efflux] of K+ ions across cell membrane & leads to closure of the channel Kruszynska Y, Olefsky JM. J Invest Med. 1996; 44:413-428. This depolarizes the membrane and triggers opening of voltage-sensitive Ca++ channels, leading to rapid influx of Ca Increased intracellular Ca++ causes an alteration in the cytoskeleton, This stimulates translocation of insulin-containing secretory granules to the plasma membrane and exocytotic release of insulin.
  10. 10. What May Be Unknown?
  11. 11. Sulfonylureas – what may be Unknown? What is ischaemic preconditioning of myocardium? What is its significance ? Various studies have provided excellent evidence that in diabetic patients, Sulfonylureas bind also to cardiovascular K ATP channels in the myocardium, although less well than to ß-cell K ATP channels chronic inhibition of the K ATP channel in the beta cells of the pancreas with oral sulfonylureas abolishes ischaemic preconditioning of myocardium.
  12. 12. Significance – ischaemic preconditioning of the myocardium <ul><li>This phenomenon has been shown experimentally to: </li></ul><ul><li>Limit anginal pain, </li></ul><ul><li>Minimize irreversible tissue injury, & </li></ul><ul><li>Protect myocardial function. </li></ul>ATP-dependent potassium (KATP) channels in: [1] vascular smooth muscle cells; and [2] myocardial cells have an important role in this process. How? A process by which transitory ischemia in the heart &quot;conditions&quot; the myocardium in a protective fashion, allowing greater tolerance of subsequent ischemia. significance What
  13. 13. Sulfonylureas – what may be Unknown? <ul><li>In the presence of heart muscle ischemia, intracellular ATP levels drop, opening the K+ channel and resulting in: </li></ul><ul><ul><li>decreased myocardial oxygen consumption and </li></ul></ul><ul><ul><li>vasodilatation. </li></ul></ul><ul><li>Pharmacological agents that open KATP channels have a protective effect similar to that of prior ischemia, </li></ul><ul><li>Agents closing the channels oppose preconditioning by ischemia. </li></ul>
  14. 14. Sulfonylureas – what may be Unknown? inhibit the opening of the potassium channel and promote closure interfere with the myocardial adaptive response Sulfonylureas could potentially disrupt this protective mechanism of ischaemic preconditioning by their presence and interaction with cardiovascular KATP. This could: This abolishing or opposing phenomenon might contribute to the increased cardiovascular mortality in sulfonylurea-treated diabetic patients
  15. 15. Sulfonylureas – What Is Unknown? Despite their comparable actions on the pancreatic beta-cell KATP channel, all sulfonylureas are not similar because they strongly differ in their ability to interfere with vascular or cardiac KATP channels A useful pharmacological approach would be to identify  -cell-specific sulfonylureas to avoid adverse effects: on the cardiac myocyte, as well as vasculature Why? Thus, what must be done?
  16. 16. How Does This Finding Advance Our Knowledge? Initiating / Continuance of long term oral pharmacotherapy Effects on fasting / Postprandial hyperglycaemia concern for benefits beyond the obvious concern for weight gain and hypo-glycaemia Expectations from sulfonylureas Rational Choice of Oral Antihyperglycaemic Agents, By Subhankar Chowdhury, Nilanjan Sengupta- JIMA, Vol. 100, No. 2, February 2002.
  17. 17. What Needs to Be Known?
  18. 18. Diabetic Patients and Complications <ul><li>Diabetic patients have an increased level of blood glucose, but most also have secondary effects from the diabetes, such as </li></ul><ul><ul><li>poor circulation, </li></ul></ul><ul><ul><li>platelet adhesion and aggregation, </li></ul></ul><ul><ul><li>excess free radicals, </li></ul></ul><ul><ul><li>shortage of antioxidants, </li></ul></ul><ul><ul><li>heart disease, cataracts and liver and kidney problems. </li></ul></ul><ul><li>Most of these are caused, at least in part, by excess glucose which can be toxic to cells in several ways, 2 of which are the formation of advanced glycation end products (AGE) and free radicals - both contributing to diabetic complications. </li></ul>Free Radicals in Biology and Medcine, J. R. Pffafly, Spring 2001.
  19. 19. Choosing the Right sulfonylurea <ul><li>Is it different in safety or adverse events? </li></ul><ul><li>Does it differ in the progression or occurrence of clinically relevant outcomes? </li></ul><ul><li>Is it superior in ability to influence HbA1C levels? </li></ul><ul><li>Is it able to influence other diabetic risk factors? </li></ul>
  20. 20. Criteria for An Ideal sulfonylurea <ul><li>Has to be more specific to the pancreas than to other tissues, especially the myocardium. </li></ul><ul><li>Has a rapid as well as longer duration of action, </li></ul><ul><li>Has extra pancreatic effects beyond insulin secretion for glucose-decreasing activity. </li></ul><ul><li>Has effects on both phases of insulin secretion </li></ul><ul><li>Has a once-a-day dosage convenience. </li></ul><ul><li>Has beneficial effects on adiponectin. </li></ul><ul><li>Has low potential for weight gain </li></ul><ul><li>Has low incidence of hypoglycaemia </li></ul>
  21. 21. Is there such a sulfonylurea? Yes! GLIMEPIRIDE
  22. 22. Glimepiride - Introduction <ul><li>Second-generation sulfonylurea, more specific to pancreas than other tissues, especially myocardium. </li></ul><ul><li>More rapid onset as well as longer duration of action, </li></ul><ul><li>stimulating less insulin secretion in comparison with glibenclamide, but despite that, it has been shown to have higher glucose-decreasing activity. </li></ul><ul><li>{HOW & WHY} </li></ul>
  23. 23. Glimepiride - Pharmacokinetics <ul><li>Completely absorbed and Tmax < 3 hours. </li></ul><ul><li>Half-life of 5-8 hours. </li></ul><ul><li>Completely metabolised - Main metabolite also has some antidiabetic effect, so, overall, the hypoglycaemic action of a single dose lasts for 24 hours. </li></ul><ul><li>Most of the metabolites are excreted in the urine, so the drug is contraindicated in patients with severe impairment of renal or hepatic function. </li></ul>
  24. 24. Glimepiride – Side Effects <ul><li>Side effects are few and most are mild occuring in 1-2% of the patients. Some of the common side effects are- </li></ul><ul><ul><li>gastrointestinal problems (nausea, diarrhea, pain, constipation), </li></ul></ul><ul><ul><li>dermatological disturbances (rash, flushing, erythema), </li></ul></ul><ul><ul><li>lightheadedness, headaches and dizziness </li></ul></ul><ul><ul><li>One of the important problems to watch for is hypoglycemia. </li></ul></ul><ul><li>Many drugs may interact and affect the hypoglycaemic action of glimepiride. </li></ul>
  25. 25. Glimepiride – Availability and Dosage <ul><li>Glimepiride is available as 2 mg tablets and usually taken before breakfast. </li></ul><ul><li>Can cause hypoglycaemia, particularly in the first month of treatment. The maximum dose is 8 mg daily. </li></ul>Begin with 1 mg daily Increase by 1 mg every 1-2 weeks Most patients controlled with a dose of 4 mg or less. Divide dose If higher doses are needed Individual Dose to be titrated based on blood glucose levels
  26. 26. Glimepiride - Summary of Benefits <ul><li>Glimepiride offers benefits that makes it unique / dependable. </li></ul>Specific site binding Action on both Insulin phases Extrapancreatic actions Activity duration & dosage convenience Good safety profile Benefits beyond the obvious
  27. 27. Glimepiride Impact on Phases of Insulin Secretion <ul><li>Glimepiride improves both first and second phases of insulin secretion in type 2 diabetes </li></ul><ul><li>Following a meal, there is a steep increase in insulin secretion called the First-phase insulin secretion that represents the release of mature secretory granules present close to the ß-cell plasma membrane </li></ul>Glimepiride improves first-phase insulin secretion, which plays an important role in reducing postprandial hyperglycemia. Pharmacotherapy, 2004;24(5):606-620). Sulfonylurea treatment of type 2 diabetes mellitus: Focus on glimepiride by Mary T. Korytkowski
  28. 28. Glimepiride Impact on Phases of Insulin Secretion <ul><li>In between meals when glucose concentration is low, there is parallel low insulin concentration and this lower insulin concentration with glimepiride explains the lower incidence of hypo-glycemia as compared to glibenclamide. </li></ul>Diabetes care,  Vol.25, No. 9, Sept, 2002, by Mary Korytkowski Second-phase insulin secretion corresponds both to the release of stored secretory granules and to the de novo synthesis of insulin.
  29. 29. Glimepiride - Comparison With Glipizide <ul><li>In comparative trials, it has been noticed that glimepiride was as effective in lowering glucose levels as glyburide and glipizide, but glimepiride was associated with </li></ul><ul><ul><li>a reduced likelihood of hypoglycemia and </li></ul></ul><ul><ul><li>a smaller increase in fasting insulin and C-peptide levels than glyburide, and </li></ul></ul><ul><ul><li>a more rapid lowering of fasting plasma glucose levels than glipizide. </li></ul></ul>Pharmacotherapy, 2004;24(5):606-620). Sulfonylurea treatment of type 2 diabetes mellitus: Focus on glimepiride by Mary T. Korytkowski
  30. 30. Glimepiride- Comparison with Glibenclamide <ul><li>Various studies have shown that glimepiride maintains myocardial preconditioning, while glibenclamide might prevent it. </li></ul><ul><ul><li>Eur Heart J. 1999 Mar;20(6):439-46, Sulfonylureas and ischaemic preconditioning; a double-blind, placebo-controlled evaluation of glimepiride and glibenclamide by Klepzig H et al. </li></ul></ul><ul><ul><li>Horm Metab Res. 1996 Sep;28(9):496-507, Cardiovascular effects of conventional sulfonylureas and glimepiride by Geisen K et al . </li></ul></ul><ul><li>Lower incidence of hypoglycemia occurs with glimepiride than with glyburide. </li></ul><ul><ul><li>Horm Metab Res. 1996 Sep;28(9):426-9, Clinical evaluation of glimepiride versus glyburide in NIDDM in a double-blind comparative study. Glimepiride / Glyburide Research Group by Dills DG, Schneider J., Department of Medicine, University of Wisconsin, Madison, USA. </li></ul></ul><ul><ul><li>Diabetes Metab Res Rev. 2001 Nov-Dec;17(6):467-73, Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide by Holstein A, Plaschke A, Egberts EH.1st Department of Medicine, Klinikum Lippe-Detmold, Detmold, Germany. </li></ul></ul>
  31. 31. Glimepiride- Hypoglycaemia <ul><li>Glimepiride appears to be associated with a lower incidence of severe hypoglycemia than glyburide in older patients with diabetes. </li></ul><ul><ul><li>Clinical Geriatrics; 2004,12[5]:43-51, Type 2 Diabetes Management in Older Adults, M. S. Rendell. </li></ul></ul><ul><li>Lower incidence of hypoglycemia occurs with glimepiride than with glyburide. </li></ul><ul><ul><li>Horm Metab Res. 1996 Sep;28(9):426-9, Clinical evaluation of glimepiride versus glyburide in NIDDM in a double-blind comparative study. Glimepiride / Glyburide Research Group by Dills DG, Schneider J., Department of Medicine, University of Wisconsin, Madison, USA. </li></ul></ul><ul><ul><li>Diabetes Metab Res Rev. 2001 Nov-Dec;17(6):467-73, Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide by Holstein A, Plaschke A, Egberts EH.1st Department of Medicine, Klinikum Lippe-Detmold, Detmold, Germany. </li></ul></ul>
  32. 32. Glimepiride - Study in Obese / Non-obese <ul><li>Studies have shown that no intrinsic difference is observed in the oral clearance of glimepiride in obese patients compared with non-obese patients. </li></ul><ul><li>Given that the dosage is titrated to achieve optimal fasting glucose levels, no special dose consideration is required for the use of glimepiride in the treatment of obese patients with type 2 diabetes. </li></ul>Ann Pharmacother. 2004 Jan;38(1):30-5, Glimepiride pharmacokinetics in obese versus non-obese diabetic patients by Shukla UA, Chi EM, Lehr KH.
  33. 33. Glimepiride and Weight Gain <ul><li>Body weight gain with glimepiride treatment is less frequent in elderly patients with type 2 DM than in non-elderly patients with the disease. </li></ul><ul><li>Such study results together with the recent increase in the number of obese elderly patients with diabetes suggest that glimepiride is recommended for treatment of type 2 diabetes in this age group. </li></ul><ul><ul><li>Long-term treatment of type 2 diabetes mellitus with glimepiride is weight neutral: A meta-analysis, Diabetes Research and Clinical Practice, September 2000, vol. 50, no. 1001,   pp. 47-47(1) by Bugos C.; Austin M.; Atherton T.; Viereck C. </li></ul></ul><ul><ul><li>Less frequent body weight gain in elderly type 2 diabetic patients treated with glimepiride, Inoue K.et al, Geriatrics and Gerontology International,   March 2003, vol. 3, no. 1,   pp. 56-59(4). </li></ul></ul>
  34. 34. Glimepiride and Weight Gain <ul><li>Prof Rosak has performed 7 studies with glimepiride over different treatment periods and has shown that there is also little or no increase in body weight. </li></ul><ul><li>In all of the studies, he said, there was an average weight reduction of 1.3% </li></ul><ul><ul><li>Diabetes Obes Metab. 2004 Mar;6(2):114-9, Prevention of weight gain in type 2 diabetes requiring insulin treatment by de Boer H, Jansen M, Koerts J, Verschoor L., Department of Internal Medicine, Ziekenhuis Rijnstate Arnhem, Arnhem, The Netherlands. </li></ul></ul>
  35. 35. Glimepiride and The GUIDE Study <ul><li>The European GUIDE study is the first large-scale double-blind, 27-week, parallel-group design, head-to-head comparison of 2 sulphonylureas designed for once-daily administration used under conditions of everyday clinical practice. </li></ul><ul><li>845 type 2 diabetic patients were randomized to either gliclazide modified release (MR) 30-120 mg daily or glimepiride 1-6 mg daily as monotherapy or in combination with their current treatment (metformin or an alpha-glucosidase inhibitor). </li></ul>GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. Eur J Clin Invest. 2004 Aug;34(8):535-42, Schernthaner G, et al, Rudolfstiftung Hospital, Vienna, Austria.
  36. 36. Glimepiride and The GUIDE Study <ul><li>HbA1c decreased similarly in both groups from 8.4% to 7.2% on gliclazide MR and from 8.2% to 7.2% on glimepiride. </li></ul><ul><li>Approximately 50% of the patients achieved HbA1c levels less than 7%, and 25% less than 6.5%. </li></ul><ul><li>This study showed that gliclazide MR is only as effective as glimepiride, either as monotherapy or in combination. </li></ul>GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. Eur J Clin Invest. 2004 Aug;34(8):535-42, Schernthaner G, et al, Rudolfstiftung Hospital, Vienna, Austria.
  37. 37. Glimepiride Vs. Metformin - A Study <ul><li>One multicentre, randomised, controlled, open, parallel group study compared glimepiride with metformin in which 164 patients with T2DM were randomized to 81 patients (aged 56+/-10 yr) receiving glimepiride (3+/-1 mg/d)and 83 patients (aged 58+/-9 yr) receiving metformin (2500+/-500 mg/d). </li></ul><ul><li>Metabolic parameters were measured after 6 and 12 months of treatment. </li></ul>Metabolic variations with oral antidiabetic drugs in patients with Type 2 diabetes: comparison between glimepiride and metformin, Diabetes Nutr Metab. 2004 Jun;17(3):143-50 by Derosa G, Franzetti I, Gadaleta G, Ciccarelli L, Fogari R. Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy. giuderosa@tin.it
  38. 38. Glimepiride Vs. Metformin - A Study <ul><li>Both lowered PAI-1 at 12 months and significantly improved levels of glycosylated haemoglobin, FBS and PPBG after 6 and 12 months. </li></ul><ul><li>Metformin significantly lowered fasting plasma insulin and postprandial plasma insulin. </li></ul><ul><li>Glimepiride significantly lowered lipoprotein(a) [Lp(a)] and homocysteine levels (HCT) at 6 and 12 months. </li></ul>Metabolic variations with oral antidiabetic drugs in patients with Type 2 diabetes: comparison between glimepiride and metformin, Diabetes Nutr Metab. 2004 Jun;17(3):143-50 by Derosa G, Franzetti I, Gadaleta G, Ciccarelli L, Fogari R. Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy. giuderosa@tin.it
  39. 39. Glimepiride – Lower Insulin Secretion <ul><li>Glimepiride is unique in comparison with conventional sulfonylureas such as glibenclamide, glipizide, and gliclazide in that the ability to stimulate insulin secretion is lower but yet, the glucose-lowering efficacy is similar. </li></ul><ul><li>Studies in dogs show that a lower ratio of total plasma insulin to total blood glucose occur after oral glimepiride than other sulfonylureas. </li></ul><ul><li>This low ratio suggests that the drug has greater insulin-independent effects on blood glucose than other sulfonylureas. </li></ul>
  40. 40. Glimepiride – Lower Insulin Secretion <ul><li>Why and How does this occur? </li></ul><ul><li>Glimepiride is hypothesized to have greater extrapancreatic effect, such as improvement in insulin resistance. </li></ul><ul><li>In older patients with type 2 diabetes, glimepiride appears to exert significant hypoglycemic effects through reductions in insulin resistance, according to a study from Japan. </li></ul>Glimepiride Provides Surprising Improvements in Insulin Resistance by Charles D. Ponte American Pharmaceutical Association, Drug Infoline, March 2003, Vol. 4, No. 3
  41. 41. Glimepiride – Effects on Insulin Resistance <ul><li>This study done on a total of 19 men and 10 women with type 2 diabetes showed that during 12 weeks of glimepiride treatment, several indicators improved significantly compared with those for patients who remained on glyburide, including </li></ul><ul><ul><li>HbA1C, </li></ul></ul><ul><ul><li>FBG and PPG, </li></ul></ul><ul><ul><li>metabolic rate of glucose clearance, </li></ul></ul><ul><ul><li>Body mass indices and plasma lipid profiles. </li></ul></ul><ul><ul><li>A hyperinsulinemic-euglycemic clamp experiment conducted in 6 of the patients, showed that glimepiride’s mechanism of action may be similar to that of thiazolidinediones </li></ul></ul>Glimepiride Provides Surprising Improvements in Insulin Resistance by Charles D. Ponte, American Pharmaceutical Association, Drug Infoline, March 2003, Vol. 4, No. 3
  42. 42. Glimepiride – Extra Pancreatic Effects <ul><li>Studies have shown that glimepiride is a safe and effective oral antidiabetic agent that lowers blood glucose effectively without much effect on fasting insulin levels and body weight. </li></ul><ul><li>Patients treated with glimepiride show significantly reduced FPG, HbA1c and 2-hour PPG. </li></ul><ul><li>However, fasting insulin levels and body weight do not change significantly. </li></ul><ul><li>Therefore, with less body weight gain and lower risk of hypoglycemia, glimepiride is a better sulfonylurea for Type 2 diabetes. </li></ul>The Effect of Glimepiride on Glycemic Control and Fasting Insulin Levels By TING-TING SEE1 at al, Journal of Food and Drug Analysis, Vol. 11, No. 1, 2003, Pages 1-3
  43. 43. Glimepiride – Extra Pancreatic Effects <ul><li>Glimepiride has an extrapancreatic effect on glucose metabolism and thereby </li></ul><ul><ul><li>improves peripheral glucose uptake and </li></ul></ul><ul><ul><li>decreases endogenous glucose production. </li></ul></ul><ul><li>This postulate is based on circumstantial evidence from human and animal in vivo experiments and in vitro data. </li></ul><ul><li>This characteristic may be due to a direct effect on the expression of intra-cellular glucose transporters, such as Glut-1 & Glut-4. </li></ul>Diabetes Care, November,2002.
  44. 44. Glimepiride – Extra Pancreatic Effects <ul><li>Successful Glimepiride treatment not only decreases levels of plasma glucose but also: </li></ul><ul><ul><li>improves fasting and postprandial hypertriglyceridemia, </li></ul></ul><ul><ul><li>reduces the number of abnormally small low-density lipoprotein (LDL) particles, and </li></ul></ul><ul><ul><li>tends to return decreased high-density lipoprotein (HDL) levels to normal. </li></ul></ul><ul><li>Why and How does this occur? </li></ul>
  45. 45. Glimepiride – Extra Pancreatic Effects <ul><li>Glimepiride remarkably improved insulin resistance, suggested by a reduction in HbA 1c without changing extrapancreatic ß-cell function. </li></ul><ul><li>Apart from the improvement of insulin resistance with glimepiride, there is also increased plasma adiponectin and i ncrease in insulin sensitivity is associated with increased adiponectinemia. </li></ul>Diabetes Care, 26:285-289, 2003.
  46. 46. Glimepiride – Adiponectin Effects <ul><li>Adiponectin is secreted by adipose tissue and it has 2 effects </li></ul><ul><ul><li>anti-inflammatory activity, </li></ul></ul><ul><ul><li>opposes atherogenesis. </li></ul></ul><ul><li>insulin suppresses expression and secretion of adiponectin in both in vitro and in vivo studies </li></ul><ul><li>This means more Insulin [  Insulinaemia]= Less Adiponectin = Increased chances of atherogenesis </li></ul><ul><li>Glimepiride = decrease in insulinemia = increase circulating adiponectin concentration = decreased risk of atherosclerosis . </li></ul>Effect of glimepiride on serum adiponectin level in subjects with type 2 diabetes - Observations Diabetes Care,  July, 2003  by Shoichiro Nagasaka
  47. 47. Glimepiride - Summary <ul><li>In clinical studies, glimepiride was generally associated with a lower risk of hypoglycemia and less weight gain than other SUs. </li></ul><ul><li>Other studies suggest that glimepiride may be having useful extra pancreatic effects that may help to overcome insulin resistance. </li></ul><ul><li>There is evidence that glimepiride preserves myocardial preconditioning. </li></ul><ul><li>Glimepiride can be used in combination with other oral antidiabetic agents or insulin to optimize glycemic control. </li></ul>Clin Ther. 2003 Mar;25(3):799-816, Glimepiride in type 2 diabetes mellitus: a review of the worldwide therapeutic experience by Massi-Benedetti M, Dipartimento di Medicina Interna, Universita di Perugia, Perugia, Italy.
  48. 48. What Needs to Be Done After Knowing? What Are the Lessons?
  49. 49. The Future of Sulfonylureas: What Are the Lessons? Lesser Chances of weight gain / hypoglycaemia Decreased Insulinaemia Improvement In FBS, PPBG & Glycosylated Hb Lesser risks of atherosclerosis Increased Adiponectinaemia Extrapancreatic Effects Beta-Cell specific Preserves Myocardial preconditioning Action on both Phases of Insulin Secretion Rapid and Longer Duration Of Action
  50. 50. References <ul><li>Sulfonylureas and Heart Disease in Diabetes Management, Diabetes Spectrum, Volume 12 Number 2, 1999, Pages 95–97. </li></ul><ul><li>Ashcroft FM: Recent advances in our understanding of sulfonylurea receptors and ATP-sensitive K-channels in pancreatic B-cells. Diabetes Annual 11:1-17, 1998. </li></ul><ul><li>Smits P: Cardiovascular effects of sulfonylurea derivatives. Diabetologia 40:S160-61, 1997. </li></ul><ul><li>Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium. Circulation. 1997;96:29–32. </li></ul><ul><li>Sulfonylureas Differ in Effects on Ischemic Preconditioning—Is it Time to Retire Glyburide? By Matthew C. Riddle, The Journal of Clinical Endocrinology & Metabolism, 2003, Vol. 88, No. 2 528-530 </li></ul><ul><li>Impairment of myocardial protection in type 2 diabetic patients by Lee T-M, Chou T-F. J Clin Endocrinol Metab, 2003 88:531–537 </li></ul>
  51. 51. References <ul><li>Glimepiride, a Novel Sulfonylurea, Does Not Abolish Myocardial Protection Afforded by Either Ischemic Preconditioning or Diazoxide by Mihaela M. Mocanu,Circulation. 2001;103:3111. </li></ul><ul><li>Glimepiride Pharmacokinetics in Obese Versus Non-Obese Diabetic Patients by Umesh A Shukla, The Annals of Pharmacotherapy: 2004, Vol. 38, No. 1, pp. 30-35. </li></ul>

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