TYPE 2 DIABETES MELLITUS Richard Sachson MD Diabetes

TYPE 2 DIABETES MELLITUS Richard Sachson MD

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

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

Global Projections for Diabetes 1995– 2010 26. 5 32. 9 24% 14. 2 17. 5 23% 84. 5 132. 3 57% 15. 6 22. 5 44% Reprinted with permission from Zimmet P et al. Nature. 2001; 414: 782– 787. 9. 4 14. 1 50% World 2000 = 151 million 2010 = 221 million Increase: 46% 1. 0 1. 3 33%

Diabetes and Obesity: The Continuing Epidemic 7. 5 78 Diabetes Mean Body Weight 77 6. 5 76 6. 0 kg Prevalence (%) 7. 0 75 5. 5 74 5. 0 73 4. 5 72 4. 0 1992 1994 Year 1996 1998 2000 • Prevalence of obesity increased by 61% since 1991 • More than 50% of US adults are overweight • Only 43% of obese persons advised to lose weight during checkups • BMI and weight gain major risk factors for diabetes 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.

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

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

Diabetes: 16 Million and Climbing • Estimated 10. 3 million diagnosed + 5. 4 million undiagnosed cases • Type 2 diabetes accounts for 90 -95% of cases Diagnosed Cases (Millions) 12 +60% +17% 8 4 0 1980 1990 From Centers for Disease Control and Prevention, 2000 (Estimated)

Insulin Resistance á FFA production á Glucose production Hyperinsulinemia Dyslipidemia á SNS activity T 2 D Abnormal Na+ handling HTN Atherosclerosis

ACANTHOSIS NIGRICANS

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/d. L HDL < 40 mg/d. L (men); < 50 mg/d. L (women) Blood pressure 130/85 mm Hg FPG 110 mg/d. L • 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.

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

Prevalence of Complications at 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 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. 2 -3† 16

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

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

7 -year incidence rate of MI Type 2 diabetes and CHD: 7 -year incidence of fatal/nonfatal MI (East West Study) 50 45 P < 0. 001 40 35 30 25 20 15 10 4% 5 0 Nondiabetic n = 1373 Diabetic n = 1059 P < 0. 001 19% 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. 45% 20% No prior MI* MI

Target Lipid Levels for Adult Patients with Diabetes LDL Cholesterol: HDL Cholesterol: Triglycerides: < 100 mg/d. L (high risk < 70 mg/dl) Men: > 45 mg/d. L Women: > 55 mg/d. L < 150 mg/d. L Note: The recent NCEP/ATP III guidelines suggest that in patients with triglycerides 200 mg/d. L, the “non-HDL cholesterol” be calculated with a goal being < 130. American Diabetes Association. Diabetes Care. 2002; 25: S 33.

Recommended Treatment Goals for Hypertension for Adults With Diabetes Target BP Patients aged 18 years <130/80 mm Hg Isolated systolic hypertension 180 mm Hg <160 mm Hg 160– 179 mm Hg of 20 mm Hg American Diabetes Association. Diabetes Care. 2001; 24(suppl 1): S 33 -S 43.

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.

Type 2 Diabetes Prevention

Finnish Diabetes Prevention Program • • • 522 patients with IGT Age: 40 -65 years Mean BMI: 31 kg/m 2 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.

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

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

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.

United States Diabetes Prevention Program: Results Placebo (n = 1082) Intensive Lifestyle Intervention (n = 1079) Metformin (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.

United States Diabetes Prevention Program: Results Placebo (n = 1082) Intensive Lifestyle Intervention (n = 1079) Metformin (n = 1073) Wt loss: 0. 1 kg* Wt loss: 5. 6 kg* Wt loss: 2. 1 kg* Diabetes: 29%† Diabetes: 14%† Risk reduction: 58% Diabetes: 22%† Risk reduction: 31% *Average; †Cumulative incidence at 3 years. Diabetes Prevention Program Research Group. N Engl J Med. 2002; 346: 393 -403.

TREATMENT OF TYPE 2 DIABETES

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

Sulfonylureas

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

Sulfonylureas • Mechanism of action: increases pancreatic insulin secretion • Reported A 1 C 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.

Second-Generation Sulfonylureas Drug Glyburide Glipizide Glimepiride Daily Dosage Trade Names (mg) Duration of Action Micronase®, Dia. Beta®, Glynase® Glucotrol® 2. 5 -20 16 -24 hours 5 -40* 12 -24 hours Glucotrol XL® 5 -20 24 hours Amaryl® 1 -8 16 -24 hours *The maximally effective dosage is 20 mg/d, although it is approved for dosages 40 mg/d. De. Fronzo RA. Ann Intern Med. 1999; 131: 281 -303.

Nonsulfonylurea Secretagogues

Nonsulfonylurea Secretagogues (Repaglinide or Nateglinide) • Mechanism of action: increases pancreatic insulin secretion • Reported A 1 C 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.

Nonsulfonylurea Secretagogues Drug Daily Dosage Trade Names (mg) Repaglinide Prandin® 1. 5 -16 Nateglinide Starlix® 180 -360 De. Fronzo RA. Ann Intern Med. 1999; 131: 281 -303. Starlix® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2000.

Biguanides

Biguanides (Metformin) • Mechanism of action: decreased hepatic glucose production • Reported A 1 C 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.

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 B 12 levels, change in clinical status, hypoglycemia, loss of control of blood glucose • Pregnancy category B *Serum creatine levels ≥ 1. 5 mg/d. L in males, ≥ 1. 4 mg/d. L in females. Glucophage® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2000.

Thiazolidinediones

Thiazolidinediones • Mechanism of action: increased peripheral glucose disposal • Reported A 1 C 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 , sulfonylurea, metformin Inzucchi SE. JAMA. 2002; 287: 360 -372.

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

-Glucosidase Inhibitors

-Glucosidase Inhibitors • Mechanism of action: decreased gut carbohydrate absorption • Reported A 1 C 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.

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

Combination Therapy

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

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.

Avandamet Avandia + Metformin

Basic Steps in the Management of Type 2 Diabetes co die ex t & er cis e mo O no ral th er a O mb ral ina tio n py Or al Ins plu uli s n ins uli n + + +

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

Insulins for Type 2 Diabetes 72

Pre-Mixed Insulin Analogs Humalog Mix 75/25 Novolog mix 70/30 73

Why NPL Was Developed R L L + L R R NPH L L + NPL 74

Premix Insulin Profiles Insulin aspart 30% 70% 30% Insulin aspart protamine suspension Novo. Log® Mix 70/30 70% Human regular Neutral Protamine Hagedorn (NPH) Human Premixed 70/30

Glucose Infusion Rate mg/min/kg NPL Component Compared to Human NPH 8 7 6 5 4 3 2 1 0 Human NPH (0. 4 U/kg) NPL Component (0. 4 U/kg) n=8 Non-diabetic Subjects 0 2 4 6 8 10 12 Hours After Injection 14 16 76

Lispro Mix 75/25: Pharmacodynamics Glucose Infusion Rate mg/kg/min 12 Lispro Mix 75/25 10 8 NPL 6 4 2 0 0 4 8 Heise T, et al. Diabetes Care. 1998; 21: 800 -803. 12 Hours 16 20 24

Recommended Dosing 2/3 or 1/2 AM Weight (kg*) x units/kg = total daily dose Dosing Guidelines 0. 2— 0. 5 for nonobese individuals 0. 4 – 0. 8 for obese individuals 1 kg = 2. 2 lbs Obese= BMI over 30 Kgm 1/3 or 1/2 PM

GLP-1

GLP-1 Modes of Action in Humans Upon ingestion of food… • Stimulates glucose-dependent insulin secretion • Suppresses glucagon secretion • Slows gastric emptying GLP-1 is secreted from the L-cells in the intestine • Reduces food intake • Improves insulin sensitivity Long term effects demonstrated in animals… This in turn… Drucker DJ. Curr Pharm Des 2001; 7: 1399 -1412 Drucker DJ. Mol Endocrinol 2003; 17: 161 -171 • Increases beta-cell mass and maintains beta-cell efficiency

• Exendin-4 was originally isolated from the salivary secretions of the Gila monster Plasma Exendin-4 Concentration (pg/m. L) Exendin-4 in the Gila Monster • Exendin-4 was subsequently found to circulate as a meal-related peptide in this animal • Exendin-4 has possible endocrine function in the lizard Heloderma suspectum (Gila monster) 4 mice 1 rat 400000 300000 200000 100000 0 0 3 Data from: Young AA. Glucagon-like peptide-1, exendin and insulin sensitivity. In Hansen B, Shafrir E, Editors. Insulin Resistance and Insulin Resistance Syndrome. 1 st ed. Harwood Academic Press; 2002, 6 9 Time After Meal (h) 12

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ACANTHOSIS NIGRICANS