Evidence Base Medicine Family Practice Michelle Cho

Diabetes Annually 1 million new cases of diabetes 17 million Americans (~8% of the population) is believed to have diabetes at least 90% have diabetes type 2 Prevention of other comorbidities and complications Micro- and macrovascular complications. Microvascular complications include retinopathy, neuropathy, and nephropathy. Macrovascular complications include heart disease, hypertension, hyperlipidemia, stroke, and peripheral vascular disease.

Purpose Current therapy for type 2 DM Lifestyle modification Monitoring blood glucose levels Hemoglobin A1C First-line of therapy is metformin. Combination therapy is initiated such as metformin with alpha- glucosidase inhibitor, sulfonylurea, thiazolidinedione, or insulin. Sulfonylureas are not widely used today because of the many side effects Side effects of weight gain and hypoglycemia. Sulfonylureas - decrease blood glucose by stimulating insulin release Beta cell “exhaustion” theory Glimepiride is the newest sulfonylurea that has a similar mechanism without the side effects and additional cardiovascular benefits.

PICO question In the type 2 diabetic patients, is Glimepiride (Amaryl) a better Sulfonylurea than glyburide and/or glipizide in effectiveness of glucose control and side effects?

Sulfonylureas Side effects: Hypoglycemia and weight gain Weight gain leads to obesity, which strongly correlates with insulin resistance. Glyburide - long-acting insulin secretor Glimepiride stimulates insulin release and has extra-pancreatic affects by improving insulin resistance in the peripheral tissue. increases metabolic clearance rates for glucose and lipids. Less weight gain Elderly patients older than 65 there was no significant weight gain noted Decreases the incidence of hyperglycemia by having a smaller increase in fasting insulin and C-peptide levels than glyburide. In a study of 37 diabetic patients, there was no significant difference between glipizide or glyburide with glimepiride in fasting plasma glucose and HbA1c. (Hamaguchi 2004, Inoue 2003, Muller 2005, Rendell 2004)

Figure 1 Changes in glycemic control during the 6-month treatment with glimepiride. Fasting plasma glucose (FPG) and HbA1c before ( □ ) and after ( ■ ) glimepiride therapy. □  glipizide or glyburide therapy ■  glimepiride therapy Figure 2 Changes in body weight after the 6- month treatment with glimepiride. None (0%: 0/9) of the elderly patients had an increase in weight, whereas 9 of the 28 nonelderly patients (32%) showed weight gain (P< 0.05).

Postprandial hyperglycemia Glimepiride, most potent 2nd generation sulfonylurea lower dose is indicated. improves first- and late-phase glucose response important to reduce the rise of glucose after a meal (postprandial hyperglycemia) Glipizide and glyburide does not increase both the first- and late-phase insulin responsiveness resulting in postprandial hyperglycemia. (Korythowski 2004)

Comparison of efficacy 577 patients comparing glyburide and glimepiride’s efficacy Incidence of hypoglycemia in glyburide was significantly increased. Data showed a 1.7% cumulative symptomatic hypoglycemia in the first month with glimepiride as oppose to 5% with glyburide. Over 12 months, 12 % with glimepiride and 17% with glyburide. (Korytkowski 2004)

Study of effects of glimepiride 66 outpatient diabetics were switched from glyburide to glimepiride No significant change in… fasting plasma glucose (FG) HbA1c serum total cholesterol Triglycerides high-density lipoprotein cholesterol Glimepiride showed a insignificant reduction of fasting immuno- reactive insulin levels (IRI) Homeostasis model assessment insulin resistance (HOMA-R) is an index of insulin resistance, which showed an insignificant reduction HOMA-β, an index of pancreatic beta cell function, showed a slight increase in beta cell function. May prevent the beta cell “exhaustion” phenomena. (Hamaguchi 2004)

Fig. 1. Changes in HOMA-R, fasting IRI and HOMA-b during the trial. (a) HOMA-R, (b) fasting IRI, (c) HOMA-b. Values are mean _ S.D. Closed circle represents the responder group (n = 10), and open circle represents the non-responder group (n = 56). GB: glibenclamide, GM: glimepiride. *P < 0.05, ***P < (Hamaguchi 2004)

Cardioprotection Both cardiac and smooth muscles contain sulfonylurea receptors (SUR), which is a part of the potassium channel. K+ channels in 2 areas: Sarcolemnal membranes and mitochrnodrial membranes Closed potassium channel will limit the ischemia. Binding to these potassium receptors interrupt ischemic preconditioning (IP). IP is a protective response to a myocardial infraction by limiting the infract size. Glimepiride bind/close potassium channels Preventing activation of cardiac potassium channels during periods of ischemia. Glyburide has shown to impair ischemic preconditioning, whereas glimepiride does not. Glyburide binds to the mitochondrial potassium channels, which is associated with IP. Mitochrondrial K+ channels mediated IP Glimepiride selectively binds to the SUR1 receptors, which do not interfere with IP. Glimepiride has a distinct advantage over glyburide in limiting myocardial ischemia. (Korythowski 2004, Lee 2003)

Evidence of Cardioprotection 11 glimepiride- treated pts vs. 12 glyburide- treated pts These patients were catheterized at the great cardiac vein and aortic root to measure lactate content. After their angioplasty procedure, the balloon was placed on the lesion. The balloon was to inflate twice for 120-sec and separated by 120-sec intervals of reperfusion. (Lee 2003)

With the first inflation, no significant difference in cardiac pain of ST-segment shift. With the second inflation, glyburide resulted in 5.5± 1.5 in cardiac pain scale verse glimepiride with 3.4±0.9. On the EKG with the second inflation, glyburide resulted in 0.98± 0.12 in ST segment shift verse glimepiride with 0.68±0.13. Glimepiride showed significantly less cardiac pain and ST- segment shifts on the EKG

Conclusion Glimepiride (Amaryl) is a better sulfonylurea than glyburide and/or glipizide Reducing the incidence of the side effects: hypoglycemia and weight gain. Glimepiride-cardioprotection during a myocardial infraction Glimepiride reduce postprandial hyperglycemia, improving insulin resistance, and decreasing hyperinsulinemia. No distinct advantage over controlling fasting plasma glucose, HbA1c, serum total cholesterol, triglycerides and high-density lipoprotein cholesterol.

(Korythowski 2004)

Application Ideally, every patient In a young obese type 2 diabetic with cardiovascular risk factors, glimepiride is the superior choice in preventing ischemic preconditioning and reducing the incidence of weight gain. Glyburide has been theoretical linked to beta cell exhaustion thus my goal is to preserve the pancreas function. Glimepiride should be prescribed over glyburide or glipizide because of the improved insulin resistance and decrease in hyperinsulinemia.

Bibliography Hamaguchi, T. Hirose, T., Asakawa, H., Itoh, Y., Kamado, K. (2004) Efficacy of glimepiride in type 2 diabetic patients treated with gibenclamide. Diabetes research and Clinical Practice, 66S, S129-S132. Inoue, K., Ikegami, H., Fujisawa, T., Shintani, M., Yumiko, K. (2003). Less frequent body weight gain in elderly type 2 diabetic patients treated with glimepiride. Geriatrics and Gerontology International, 3, Korythowski, M. (2004) Sulfonylurea Treatment of Type 2 Diabetes Mellitus Focus on Glimepiride. Pharmacotherapy, 24(5), Lee, T., Chou, T. (2003) Impairment of Myocardial Protection in Type 2 Diabetic Patients. The Journal of Clinical Endocrinology & Metabolism, 88(2), Muller, G. (2005) The Mode of Action of the Antidiabetic Drug Glimepiride- Beyond Insulin Secretion. Curr. Med. Chem. – Endoc. & Metab. Agents, 5, Rendell, M. (2004) The Role of Sulphonylureas in the Management of Type 2 Diabetes Mellitus. Drugs, 64(12),