This document discusses the management of diabetes mellitus. It covers non-pharmacological and pharmacological treatment methods, goals of treatment for type 1 and type 2 diabetes, steps in glycemic control, drug classifications including sulfonylureas, metformin, alpha-glucosidase inhibitors, thiazolidinediones, and incretins. It also discusses indications for insulin use, characteristics of insulin preparations, hypoglycemia, and combination therapy approaches.

1. Management of Diabetes

5. Basic Steps in Glycemic Control for Type 2 Diabetes + + Lifestyle: diet & exercise oral monotherapy oral combination oral plus insulin insulin +

6. Stepped Care: Type 2 Diabetes Step 1: Nutrition Therapy, exercise, lifestyle changes; training in self-management and self monitoring of blood glucose Step 2: Add oral agents - monotherapy - combination therapy Step 3: Add or change to insulin Step 4: Intensify insulin therapy Consensus Statement. Diabetes Care. 1995;18:1510-1518

8. Classification of Drug Treatment for Diabetes

11. MECHANISM OF ACTION Basic Structure Classification R 1 SO 2 – NH – CO – NH- R 2 1 ST GENERATION (Chlorpropamide) Tolbutamide 2 nd GENERATION Gliclazide Glibenclamide Glipizide Glimepiride

13. Main Site of Action of Sulfonylureas and Meglitinides Adipose tissue Carbohydrate Blood Glucose Digestive enzymes Gut Pancreas Muscle Liver Insulin Sulfonylureas and meglitinides stimulate pancreas to release more insulin

17. Sulfonylureas Action Insulin secretagogue Insulin sensitivity No effect ? Hepatic glucose output No effect Serum insulin Increased Hypoglycaemia Yes Lipids No effect Onset of action Fast Weight Increased Effectiveness over time Reduced Safety Hypoglycemia Drug interactions Weight gain

19. Main Site of Action of Metformin Metformin suppresses hepatic glucose production Carbohydrate Adipose tissue Blood Glucose Digestive enzymes Gut Pancreas Muscle Liver Insulin

22. Metformin Action Reduce liver glucose production Insulin sensitivity Yes (liver predominantly) Hepatic glucose output Reduced Serum insulin No effect Hypoglycaemia No Lipids Reduced Onset of action Moderate Weight Neutral or reduced Effectiveness over time Reduced Safety GI effects Drug interactions Renal insufficiency (Lactic acidosis)

25.  -Glucosidase Inhibitors  -Glucosidase inhibitors delay digestion and absorption of carbohydrates in GI tract Carbohydrate Adipose tissue Blood Glucose Digestive enzymes Gut Pancreas Muscle Liver Insulin

26. Acarbose Action Reduced glucose absorption Insulin sensitivity No effect Hepatic glucose output No effect Serum insulin No effect Hypoglycaemia No effect Lipids No effect Onset of action Moderate Weight Neutral or reduced Effectiveness over time Uncertain (at 3 years) Safety GI effects Hepatic (LFT elevation) Drug interactions (few

28. Main Site of Action of Thiazolidinediones Thiazolidinediones Reduce Insulin Resistance Decreases hepatic glucose production Increases glucose entry into adipose and muscle tissue Glucose (G) Carbohydrate Glucose DIGESTIVE ENZYMES Insulin (I) I I I I I I I I G G G G G G G G I G G G

30. Thiazolidinediones Hepatic (Inc LFT in Troglitazone) Drug interactions (few) Weight gain ? Edema ? Safety Durable Effectiveness over time Increased Weight Moderate to late Onset of action Generally positive Lipids No effect Hypoglycaemia Decreased Serum insulin Slight decrease Hepatic glucose output Increased Insulin sensitivity Insulin sensitizer Action

31. Activation of PPAR  alters expression of specific genes PPRE (DR-1) coding sequences AGGTCA X AGGTCA retinoic RSG RXR lipoprotein lipase, PEPCK, aP 2 PPAR 

50. Combination Therapy in Type 2 Diabetes Acarbose Reduces absorption Sulphonylurea Repaglinide Stimulates pancreas Metformin Reduces hepatic glucose output (??muscle/fat effects) Glucose (G) Carbohydrate Glucose DIGESTIVE ENZYMES Insulin (I) I I I I I I I I G G G G G G G G I G G G Thiazolidinediones Reduce Insulin Resistance - + -

52. Drawbacks of therapies limit patient compliance Scheen and Lefebevre Drug Safety 1995; 12:32-45; Repaglinide Package Insert. 1998. Scheen and Lefebevre Drugs 1998; 55:225-236. Kobayashi Diabetes, Obesity and Metabolism 1999; 1 (Supplement 1): S32. Lydick, Gaskin and Bakst Diabetes 1998; 47 (Supplement 1):A387 (Abstract 1490). SU Metfor min  GIs Megli tinide Increased risk of hypoglycemia Drug interactions GI side effects  Risk of  cell exhaustion Lactic acidosis Caution with elderly Poor patient compliance

56. Insulin release in non-diabetic Glucose Glucose Glucose Glucose ATP Insulin release Metabolism Glucokinase Glut 2 Opening of Ca 2+ channel Arrest of K + release Ca 2+ ATP Ca 2+ K + K + K +

57. Insulin release in diabetic Less Glucose ATP Glucose K + K + K + K + Partial Arrest of K + release ATP Ca 2+ channel Ca 2+ Glucokinase Metabolism Glucose Glucose Glut 2 Insulin release

58. Insulin release with existing SUs 140 kDa 65 kDa Glucose ATP Augmentation of K + blockage Glucokinase Metabolism Ca 2+ channel Ca 2+ Ca 2+ ATP K + K + K + Glucose Glucose Glucose Glut 2 Insulin release

60. Glimepiride interacts with a subunit of the K + channel at the  - cell, which seems to be absent at the K + channels in the cardiovascular system Lesser Cardiovascular Complications glibenclamide glimepiride K + 140 kDa 65 kDa  - cell membrane Sulfonylurea receptor K + K ATP channel Different binding site at  - cell

62. Ischemic Preconditioning Glyburide and tolbutamide inhibit ischemic preconditioning resulting in a large infarct size

64. Mean ST Segment Depression Klepzig et al. Eur Heart J 1999;20:439. Glimepiride reduced the mean ST segment depression during balloon occlusion by 34% (placebo 35%) suggesting no detrimental effect on ischemic preconditioning,whereas the effect of glyburide was negligible % Change Mean ST Shift 0 50 100 150 Placebo Glimepiride Glyburide/ Glibenclamide Dilation 2 (Baseline) Dilation 3 (After treatment) P = .01 P = NS P = .049

66. HYPERGLYCEMIA GLUCOSE AUTO-OXIDATION LDL Oxidation Protein Glycation Endoneural blood flow NCV Heparan sulphate Polyol pathway NO dependent Vasodilatation VSMC proliferation Microangiopathy UKPDS 1998 Haemorrheological disturbance Coagulation activation RETINOPATHY NEUROPATHY NEPHROPATHY HYPERGLYCAEMIC “PEAKS” AND “COMPLICATIONS”

67. Glimepiride inhibited the oxidative modification of LDL in a dose-dependent manner (IC50 = 8.8 x 10-7 M) without cytotoxicity; glibenclamide and gliclazide did not. Effect of glimepiride on HCAEC-modified LDL oxidation *Inhibition % of vehiccle control Data are mean + SD of 3 experiments performed in triplicate Control level (1% EtOH-0.1% DMSO) Glimepiride Glibenclamide Gliclazide 50 mM Indomethacin 20 mM BHT Blank level Test compunds (- log M) 10 8 6 4 2 0 8 7 6 5 4 TBARS (nmol/mL)

68. The addition of glimepiride to the 1% CHOL diet resulted in a significant reduction in the observed percentage of oil red-positive atherosclerotic lesions in studies one and two (p <0.01). Examples of typical oil red-positive atherogenic lesions observed in thoracic aorta in rabbits treated with a diet containing 1% CHOL with or without glimepiride, glibenclamide or gliclazide Effect of glimepiride on atherosclerotic lesions in thoracic aorta in rabbits treated with 1% CHOL-diet with or without glimepiride, glibenclamide or gliclazide for 10 weeks. 100 80 60 40 20 0 Control Glimepiride 0.1 mg/kg Glibenclamide 0.25 mg/kg Gliclazide 0.4 mg/kg Control (n=14) Glimepiride 0.1 mg/kg (n=15) 100 80 60 40 20 0 Atherosclerotic lesions (%) Mean + SE (n=8) *p < 0.05 ** p < 0.01) ** * Mean + SE (n=8) ***p < 0.001 Study one Study two *** NORMAL CONTROL GLIMEP GLIBEN GLICLA

69. Glimepiride treatment upregulates adiponectin and downregulates TNF  levels in the plasma and ameliorates insulin resistance Baseline 8 weeks Data are means ± SD * P < 0.05 ( Diabetes Care 2003; 26:285–289) 5 10 0 25 50 0 * TNF-  PAI-1 * 0 10 20 Adiponectin  g/ml 5 10 0 * Glucose disposal rate mg  kg -1  min -1 pg/ml ng/ml

70. MAPK Raf RAS Grb 2 IRS PI-3K Glut 4 Translocation p Caveolae Growth and Gene Expression Target cell Insulin G G G G PDK-1 PKC

71. MAPK Raf RAS Grb 2 IRS PI-3K Glut 4 Translocation p Caveolae Growth and Gene Expression Target cell Insulin G G G G PDK-1 PKC

72. MAPK Raf RAS Grb 2 IRS PI-3K Akt Glycogen Synthesis Glut 4 Translocation Lipid Synthesis p Caveolin Caveolae p Growth and Gene Expression Target cell Protein Synthesis Insulin Action Insulin glimepiride PDK-2 PDK-1 PKC

73. Weight Profile Weight Change (kg) Large - scale (>22,000 patients) Postmarketing Surveillance Study (Germa ny):  Change in body weight (kg) after 2 months of glimepiride treatment Body Mass Index Herrmann et al. Diabetes Res Clin Pract 2000;15(suppl 1). 0.2 -0.4 -1.4 -2.2 -1.4 -3 -2 -1 0 1 < 20 20 < 25 25 - 30 > 30 All patients

74. Large - scale Surveillance Study (Germany): Change of body weight - individual data no change body weight gain (kg) body weight loss (kg) Number of Patients Weight Profile Data on file, submitted for publication. 0 1000 2000 3000 4000 5000 6000 -15 -12 -9 -6 -3 0 3 6 9 12 15 18 21 24

76. Shorter - Lasting Interaction with the  - cell Glimepiride associates to the receptor 2.5 - 3 times faster glibenclamide. Glimepiride dissociates from its binding protein 8 - 9 times more rapidly than glibenclamide. Glimepiride Glibenclamide min min SU association SU dissociation W. Kramer Half-life & Hypos

77. Sulfonylurea Prescriptions + Prevalence of Severe* Hypoglycemia (Germany ) * Defined as impaired consciousness, requiring IV glucose or glucagon injection and confirmed by blood glucose measurement 1997 1998 1999 Periods - Quarters Number of Prescriptions (Patients) 0 500 1000 1500 2000 2500 3000 I II III IV I II III IV I II III IV 0 2 4 6 8 10 Glibenclamide hypoglycemia Glimepiride hypoglycemia Glibenclamide Glimepiride Cases of Severe* Hypoglycemia Favorable Hypoglycemia Profile Holstein et al. Diabetologia 2000;43:A40.

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