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TYPE 2 DIABETES MELLITUS

TYPE 2 DIABETES MELLITUS. Richard Sachson MD. Diabetes: 16 Million and Climbing. Estimated 10.3 million diagnosed + 5.4 million undiagnosed cases Type 2 diabetes accounts for 90-95% of cases. +60%. 12. +17%. 8. Diagnosed Cases (Millions). 4. 0. 1980. 1990. 2000 (Estimated).

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TYPE 2 DIABETES MELLITUS

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  1. TYPE 2 DIABETES MELLITUS Richard Sachson MD

  2. Diabetes: 16 Million and Climbing • Estimated 10.3 million diagnosed + 5.4 million undiagnosed cases • Type 2 diabetes accounts for 90-95% of cases +60% 12 +17% 8 Diagnosed Cases (Millions) 4 0 1980 1990 2000 (Estimated) From Centers for Disease Control and Prevention, 2000.

  3. Diabetes in the U.S. Diabetes and Gestational Diabetes Trends Among Adults in the U.S., BRFSS 1990, 1995 and 2000 1990 1995 2000 > 6% N/A 4-6% % incidence of diabetes among adults < 4% Source: Mokdad et al., Diabetes Care 2000;23:1278-83; J Am Med Assoc 2001;286(10).

  4. DIABETES AND GESTATIONAL DIABETES AMONG ADULTS IN THE U.S. -2001

  5. Type 2 diabetes and CHD: 7-year incidence of fatal/nonfatal MI (East West Study) Nondiabetic Diabetic n = 1373 n = 1059 50 45% 45 P < 0.001 P < 0.001 40 35 30 7-year incidence rate of MI 25 20% 19% 20 15 10 4% 5 0 No prior MI* MI No prior MI* MI MI = myocardial infarction. * These patients had no prior MI at baseline. Haffner SM, et al. N Engl J Med. 1998;339:229–234.

  6. Diabetes and Obesity: The Continuing Epidemic 7.5 78 • Prevalence of obesityincreased by 61%since 1991 • More than 50% of US adults are overweight • Only 43% of obesepersons advised to loseweight during checkups • BMI and weight gain majorrisk factors for diabetes Diabetes 7.0 77 Mean Body Weight 6.5 76 6.0 Prevalence (%) kg 75 5.5 74 5.0 73 4.5 72 4.0 1990 1992 1994 1996 1998 2000 Year BMI = body mass index.Mokdad AH et al. Diabetes Care. 2000;23:1278-1283; Mokdad AH et al. JAMA. 1999;282:1519-1522; Mokdad AH et al. JAMA. 2001;286:1195-1200.

  7. Pathophysiology of Type 2 Diabetes 100 75 Defective -Cell Secretion: Pancreas b-Cell Function (%) 50 N = 376 25 0 –10 –6 –2 2 6 Years After Diagnosis FFAs Liver Muscle Insulin Resistance: Excess Glucose Production ReducedGlucose Uptake Fat Fasting Hyperglycemia Postprandial Hyperglycemia FFAs = free fatty acids.Adapted from UK Prospective Diabetes Study Group. Diabetes. 1995;44:1249-1258. DeFronzo RA. Diabetes. 1988;37:667-687.

  8. Post Meal Glucose 350 250 Glucose Fasting Glucose 150 50 Insulin Resistance 300 Relative Function 200 Insulin Level 100 At risk for Diabetes Beta cell failure 0 -10 -5 0 5 10 15 20 25 30 Years of Diabetes Adapted from D Kendall, R Bergenstal, © International Diabetes Center Progression of Type 2 Diabetes

  9. Insulin Resistance • FFA production • Glucose production Hyperinsulinemia Dyslipidemia • SNS activity Abnormal Na+ handling T2D HTN Atherosclerosis

  10. Metabolic Syndrome • Also known as dysmetabolic syndrome, insulin resistance syndrome, syndrome X, the deadly quartet • Prevalence in the United States: approximately 47 million • Defined by having  3 of the following: • Abdominal obesity: waist > 40" (men); > 35" (women) • TG  150 mg/dL • HDL < 40 mg/dL (men); < 50 mg/dL (women) • Blood pressure  130/85 mm Hg • FPG  110 mg/dL • New ICD-9-CM code for dysmetabolic syndrome X is 277.7 TG = triglycerides; FPG = fasting plasma glucose. Ford ES et al. JAMA. 2002;287:356-359. JAMA. 2001;285:2486-2497. American Association of Clinical Endocrinologists. New ICD-9-CM code for dysmetabolic syndrome X. Available at: http://www.aace.com/members/socio/syndromex.php. Accessed January 10, 2002.

  11. Visceral Fat Distribution:Normal vs Type 2 Diabetes Normal Type 2 Diabetes 2-11

  12. Prevalence of Complicationsat Time of Diagnosis: UKPDS Complication Prevalence (%)* Any complication 50 Retinopathy 21 Abnormal ECG 18 Absent foot pulses ( 2) and/or ischemic feet 14 Impaired reflexes and/or decreased vibration sense 7 Myocardial infarction/angina/claudication 2-3† Stroke/transient ischemic attack 1 *Some patients had more than 1 complication at diagnosis. †Prevalence of each individual condition. UKPDS = United Kingdom Prospective Diabetes Study. UKPDS Group. Diabetologia. 1991;34:877-890.

  13. Adult Treatment Panel III (ATP III) Guidelines National Cholesterol Education Program

  14. Diabetes In ATP III, diabetes is regarded as a CHD risk equivalent.

  15. Target Lipid Levels forAdult Patients with Diabetes LDL Cholesterol: < 100 mg/dL Men: > 45 mg/dL Women: > 55 mg/dL HDL Cholesterol: Triglycerides: < 150 mg/dL Note: The recent NCEP/ATP III guidelines suggest that in patients with triglycerides  200 mg/dL, the “non-HDL cholesterol” be calculated with a goal being < 130. American Diabetes Association. Diabetes Care. 2002;25:S33.

  16. Target BP Patients aged 18 years <130/80 mm Hg Isolated systolic hypertension 180 mm Hg <160 mm Hg160–179 mm Hg  of 20 mm Hg Recommended Treatment Goals for Hypertension for Adults With Diabetes • American Diabetes Association. Diabetes Care. 2001;24(suppl 1):S33-S43.

  17. Aspirin • Use aspirin therapy ( 75-325 mg/day ) in all adult patients with diabetes and macrovascular disease. • Consider aspirin therapy for primary prevention in patients over age 40 with diabetes and one or more other CV risk factors ( including obesity ). • Also consider patients between age 30-40.

  18. Type 2 Diabetes Prevention

  19. Finnish Diabetes Prevention Program • 522 patients with IGT • Age: 40-65 years • Mean BMI: 31 kg/m2 • Intervention: diet and exercise • Mean duration of follow up: 3.2 years IGT = impaired glucose tolerance; BMI = body mass index. Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

  20. The Finnish Diabetes Prevention Study: Lifestyle Modifications 2-Hour PPG FPG Incidence of Diabetes (Cases/1000 Person-Years) Change from Baseline (mg/dL) • 58% P < .001 P < .001 P < .003 Control Intervention (Diet and Exercise) FPG = fasting plasma glucose; PPG = postprandial glucose. Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

  21. Finnish DPP: Results Quintile Weight Change (%) Risk Reduction (%) 1 11 83 2 5 61 3 2 13 4 No change No change 5 3 218 Each 3-kg weight loss doubles the benefit.DPP = diabetes prevention program.Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

  22. United States Diabetes Prevention Program • 3234 patients with IGT • 32.3% male; 67.7% female • Mean age: 50.6 years ± 10.7 years • 55% Caucasian, 20% African American, 16% Hispanic, 9% Asian and American Indian • Interventions: diet (reduced calorie, 25% fat) and exercise (≥ 150 minutes/week physical activity) or metformin (850 mg b.i.d.) • Average follow-up: 2.8 years (range: 1.8-4.6 years) IGT = impaired glucose tolerance. Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

  23. United States Diabetes Prevention Program: Results Intensive LifestylePlacebo Intervention Metformin (n = 1082) (n = 1079) (n = 1073) Wt loss: 0.1 kg* Wt loss: 5.6 kg* Wt loss: 2.1 kg* Diabetes: 29%† Diabetes: 14%† Diabetes: 22%† *Average; †Cumulative incidence at 3 years. Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

  24. United States Diabetes Prevention Program: Results Intensive LifestylePlacebo Intervention Metformin (n = 1082) (n = 1079) (n = 1073) Wt loss: 0.1 kg* Wt loss: 5.6 kg* Wt loss: 2.1 kg* Diabetes: 29%† Diabetes: 14%† Diabetes: 22%†Risk reduction: Risk reduction: 58% 31% *Average; †Cumulative incidence at 3 years. Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

  25. TREATMENT OF TYPE 2 DIABETES

  26. Liver Muscle Insulin Deficiency Impaired Insulin Secretion = Hyperglycemia Hyperglycemia Hyperglycemia Acarbose Miglitol Gut Pancreas Carbohydrate Metabolism Hepatic GlucoseProduction Glucose Uptake Insulin Resistance = Hyperglycemia Sulfonylurea Rosiglitazone Repaglinide Metformin Nateglinide Pioglitazone Exogenous Insulin Rx Therapy for Type 2 Diabetes: Sites of Action

  27. Sulfonylureas

  28. [ATP] [ADP] Sulfonylurea Effects on the -cell Ca++ VDCC (+) Depolarization -Cell K+ATP Channel Free Ca++ K+ SUR Metabolism Sulfonylurea Insulin Release Glucose Hu S et al. J Pharmacol Exp Ther 2000;293:444–52

  29. Sulfonylureas • Mechanism of action: increases pancreatic insulin secretion • Reported A1C reduction: 0.9%-2.5% • Advantages: well-established, decreases microvascular risk, convenient daily dosing • Disadvantages: hypoglycemia, weight gain, hyperinsulinemia (role uncertain) • FDA approval status: monotherapy; combination with insulin, metformin, thiazolidinedione, -glucosidase inhibitors Inzucchi SE. JAMA. 2002;287:360-372.

  30. Second-Generation Sulfonylureas Drug Trade Names Daily Dosage (mg) Duration of Action Glyburide Micronase®, DiaBeta®, Glynase® 2.5-20 16-24 hours Glipizide Glucotrol® 5-40* 12-24 hours Glucotrol XL® 5-20 24 hours Glimepiride Amaryl® 1-8 16-24 hours *The maximally effective dosage is 20 mg/d, although it is approved for dosages  40 mg/d.DeFronzo RA. Ann Intern Med. 1999;131:281-303.

  31. Nonsulfonylurea Secretagogues

  32. Nonsulfonylurea Secretagogues (Repaglinide or Nateglinide) • Mechanism of action: increases pancreaticinsulin secretion • Reported A1C reduction: 0.6%-1.9% • Advantages: targets postprandial glycemia, possibly less hypoglycemia and weight gain than with sulfonylureas • Disadvantages: 3-times daily dosing, hypoglycemia, weight gain, no long-term data, hyperinsulinemia (role uncertain) • FDA approval status: monotherapy; combination with metformin Inzucchi SE. JAMA. 2002;287:360-372.

  33. Nonsulfonylurea Secretagogues Drug Trade Names Daily Dosage (mg) Repaglinide Prandin® 1.5-16 Nateglinide Starlix® 180-360 DeFronzo RA. Ann Intern Med. 1999;131:281-303. Starlix® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2000.

  34. Biguanides

  35. Biguanides (Metformin) • Mechanism of action: decreased hepatic glucose production • Reported A1C reduction: 0.8%-3.0% • Advantages: well established, weight loss, no hypoglycemia, decreases microvascular risk, decreases macrovascular risk, nonglycemic benefits (decreased lipid levels, increased fibrinolysis, decreased hyperinsulinemia), convenient daily dosing • Disadvantages: adverse gastrointestinal effects, many contraindications, lactic acidosis (rare) • FDA approval status: monotherapy; combination with insulin, sulfonylurea, nonsulfonylurea secretagogue, thiazolidinedione Inzucchi SE. JAMA. 2002;287:360-372.

  36. Metformin (Glucophage®) • Usual starting dose is 500 mg b.i.d. or 850 mg q.d. given with meals • Dosage increases should be made in increments of 500 mg weekly or 850 mg every 2 weeks up to 2000 mg q.d. • Maximum daily dose of 2550 mg per day • doses > 2000 mg may be better tolerated given t.i.d. with meals • Contraindications: renal disease or renal dysfunction*, congestive heart failure requiring pharmacologic treatment, known hypersensitivity to the drug, acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma, temporarily discontinue in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials • Warning: if lactic acidosis is suspected, the drug should be discontinued immediately and general supportive measures promptly instituted • Precautions: monitoring of renal function, hypoxic states, surgical procedures, alcohol intake, impaired hepatic function, vitamin B12 levels, change in clinical status, hypoglycemia, loss of control of blood glucose • Pregnancy category B *Serum creatine levels ≥ 1.5 mg/dL in males, ≥ 1.4 mg/dL in females.Glucophage® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2000.

  37. Thiazolidinediones

  38. Thiazolidinediones • Mechanism of action: increased peripheral glucose disposal • Reported A1C reduction: 1.5%-1.6% • Advantages: reverses one of the primary defects of type 2 diabetes, no hypoglycemia, nonglycemic benefits (decreased lipid levels, increased fibrinolysis, decreased hyperinsulinemia, improved endothelial function), possible beta-cell preservation, convenient daily dosing • Disadvantages: liver function test monitoring, weight gain, edema, slow onset of action, no long-term data • FDA approval status: monotherapy; combination with insulin (pioglitazone only), sulfonylurea, metformin Inzucchi SE. JAMA. 2002;287:360-372.

  39. Drug Trade Names Daily Dosage (mg) Rosiglitazone Avandia® 2-8 Pioglitazone Actos® 15-45 Thiazolidinediones DeFronzo RA. Ann Intern Med. 1999;131:281-303.

  40. a-Glucosidase Inhibitors

  41. a-Glucosidase Inhibitors • Mechanism of action: decreased gut carbohydrate absorption • Reported A1C reduction: 0.4%-1.3% • Advantages: targets postprandial glycemia, no hypoglycemia, nonsystemic • Disadvantages: t.i.d. dosing, adverse gastrointestinal effects, no long-term data • Miglitol FDA approval status: monotherapy; combination with sulfonylurea • Acarbose FDA approval status: monotherapy; combination with sulfonylurea, insulin, and metformin Inzucchi SE. JAMA. 2002;287:360-372.

  42. a-Glucosidase Inhibitors Drug Trade Names Daily Dosage (mg) Acarbose Precose® 25 q.d. to 50-75 t.i.d. Miglitol Glyset® 25 t.i.d. to 100 t.i.d. DeFronzo RA. Ann Intern Med. 1999;131:281-303.

  43. Combination Therapy

  44. Synergistic Mechanisms of Action of Glyburide and Metformin Enhances Insulin Secretion Glyburide/ Metformin • Decreases Insulin Resistance • Increases peripheral glucose uptake • Decreases hepatic glucose production • Decreases intestinal absorption of glucose Improves Glycemic Control

  45. Complementary Mechanisms of Action Metaglip™ (glipizide and metformin HCl) tablets • Glipizide • Enhances insulin secretion • Metformin • Improves insulin sensitivity by increasing peripheral glucose uptake • Decreases hepatic glucose production • Decreases intestinal absorption of glucose Improves Glycemic Control Please see full prescribing information, including boxed WARNING regarding Lactic Acidosis.

  46. AvandametAvandia + Metformin

  47. + + + Basic Steps in the Management of Type 2 Diabetes insulin Oral plus Insulin Oral combination Oral monotherapy diet & exercise

  48. Advantages Can control all patients Used to overcome glucose toxicity Flexibility in dosing Multiple insulin preparations available Use during pregnancy Disadvantages Hypoglycemia Weight gain Parenteral administration Insulin DeFronzo. Ann Intern Med. 1999;131:281–303.

  49. Insulins for Type 2 Diabetes 68

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