1. New Perspectives in the Management of Type 2 Diabetes Herold Merisier, MD, FAAFP Voluntary Assistant Professor of Family Medicine Miller School of Medicine, University of Miami Plantation, FL

2. Disclosure Speaker: Novartis Pharmaceuticals Speaker: Novo-Nordisk

3. Diabetes 2010 Epidemiology Diagnosis Screening Management of Type 2 Diabetes Patient Education Therapeutic Lifestyle Changes (TLC) Pharmacotherapy Treatment of co-morbid conditions

4. Diabetes in the US 23.6 million children and adults affected (7.8% of the population) Diagnosed: 17.9 million people Undiagnosed: 5.7 million people 1.6 million new cases in adults > 20y/o in 2007 4300 new cases every day Pre-Diabetes: 57 million people 2-4 fold increase in cardiovascular mortality and stroke Center for Disease Control and Prevention Available at: http://www.cdc.gov/diabetes/pubs/estimates07.htm#1

5. Diabetes in Canada 1.8 million adults with Diabetes Prevalence: 4.8% (1998): 1 054 000 adult Canadians Prevalence: 5.5% (2005) Available at: http://www.diabetes.ca/files/cpg2008/cpg-2008.pdf

6. 23.0 M 36.2 M ↑ 57.0% 14.2 M 26.2 M ↑ 85% 48.4 M 58.6 M ↑ 21% 43.0 M 75.8 M ↑ 79% 7.1M 15.0 M ↑ 111% 39.3 M 81.6 M ↑ 108% M = million, AFR = Africa, NA = North America, EUR = Europe, SACA = South and Central America, EMME = Eastern Mediterranean and Middle East, SEA = South-East Asia, WP = Western Pacific Diabetes Atlas Committee. Diabetes Atlas 2 nd Edition: IDF 2003. Global Projections for the Diabetes Epidemic: 2003-2025 World 2003 = 194 M 2025 = 333 M ↑ 72% AFR NA SACA EUR SEA WP 19.2 M 39.4 M ↑ 105% EMME 2003 2025

7. Diagnosis Normoglycemia Impaired Glucose Metabolism Diabetes FPG < 100 mg/dl FPG ≥ 100 mg/dl < 126 mg/dl IFG FPG ≥ 126 mg/dl (x 2) 2hPPG < 140 mg/dl 2hPPG ≥ 140 mg/dl < 200 mg/dl IGT 2hPPG ≥ 200 mg/dl or RPG ≥ 200 mg/dl w/ sx of Diabetes HbA1c ≥ 6.5 (x 2) Adapted from Clinical Practice Recommendations. Diabetes Care, 2010 IFG: Impaired Fasting Glucose FPG: Fasting Plasma Glucose RPG: Random Plasma Glucose IGT: Impaired Glucose Tolerance PPG: Post-Prandial Glucose

8. Screening All individuals ≥ 45y/o, particularly if BMI ≥ 25 if normal, repeat every 3 years Start screening at younger age if BMI ≥ 25 and: physically inactive first-degree relative with Diabetes high risk ethnic group h/o IFG, IGT, Gestational Diabetes, PCOS Dyslipidemia or h/o cardio-vascular disease Fasting glucose or 2-hour OGTT Diabetes Risk Calculator

9. Gender Age Prior history of elevated blood glucose Height and weight Diet Smoking history Physical activity Family history Diabetes Care. 2008 May;31(5):1040-5

10. Diabetes Risk Calculator Available at: http://www.diabetes.org/diabetes-basics/prevention/diabetes-risk-test/

11. Diabetes Risk Calculator Available at: http://www.diabetes.org/diabetes-basics/prevention/diabetes-risk-test/

12. QD Score (http://www.qdscore.org) BMJ 2009;338:b880. Available at: http://bmj.com/cgi/content/full/338/mar17_2/b880

13. Management of Type 2 Diabetes Patient Education Therapeutic Lifestyle Changes (TLC) Pharmacotherapy Treatment of co-morbid conditions

14. Pharmacotherapy: Oral Agents ClassDrugsMechanism of action α-Glucosidase Inhibitor Acarbose Miglitol Decrease carbohydrate absorption in GI tract Biguanides Metformin Decrease hepatic neoglucogenesis Secretagogues Sulfonylureas Meglitinides Glyburide, Glipizide, Glimepiride Repaglinide, Nateglinide Stimulate β-cell to increase insulin output Thiazolidinediones Pioglitazone (Actos®) Rosiglitazone (Avandia®) Improve insulin sensitivity, decrease insulin resistance DDP-4 Inhibitors Sitagliptin (Januvia®) Saxagliptin (Onglyza®) Slow incretin metabolism, Increase insulin synthesis/release, Decrease glucagon levels

15. DPP-4 Inhibitors

16. Rosiglitazone Evaluated for Cardiovascular Outcomes Variable Group Rosiglitazone (n = 2220) Control (n = 2227) HR (95% CI) P value Primary end point217202 1.08 (0.89–1.31) 0.43 Death from cardiovascular causes 2935 0.83 (0.51–1.36) 0.46 Death from any cause 7480 0.93 (0.67–1.27) 0.63 Acute myocardial infarction 4337 1.16 (0.75–1.81) 0.5 Congestive heart failure 3817 2.24 (1.27–3.97) 0.006 Home PD, et al. N Engl J Med. 2007;357:28-38.

17. Rosiglitazone (Avandia®) Contraindicated in patients with CHF Meta-analysis of 42 clinical studies: Mean duration 6 months; 14,237 total patients Rosiglitazone vs. placebo Increased risk of risk of myocardial ischemic events Three other studies Mean duration 41 months; 14,067 total patients Rosiglitazone vs. other oral diabetes medications or placebo Increased of MI neither confirmed nor excluded this risk

18. 18 Progressive  -cell Failure in Type 2 Diabetes -12 -606 12 0 20 40 60 80 100  -cell Function (%  ) Based on data of UKPDS 16: conventional (diet) treatment group. Diabetes. 1995. Years Diagnosis

19. Pharmacotherapy: Non-Insulin Injectables ClassDrugMechanism of action GLP-1 Analog (Incretin Mimetic) Exenatide (Byetta®) Liraglutide (Victoza®) increases beta-cell response decreases glucagon secretion delays gastric emptying AmlynomimeticPramlintide (Symlin®) slows gastric emptying decreases glucagon secretion early satiety → weight loss

20. Insulin PreparationOnsetPeakDuration Short acting Regular30-60 min.3-4h6-8h Intermediate NPH Lente Ultralente 2-4h 3-4h 4-6h 6-10h 6-12h 10-16h 14-18h 16-20h 20-24h Combinations 70% NPH / 30% reg 75% NPH / 25% reg 30-60 min. 15-60 min. Dual 14-18h Pharmacotherapy: Insulin (Older Agents)

21. Pharmacotherapy: Insulin (Newer Agents: Insulin Analogs) Insulin PreparationOnsetPeakDuration Rapid acting Lispro (Novolog®) Aspart (Humalog®) Glulisine (Apidra®) 15-30 min. 30-90 min. 4-6h Long acting Glargine (Lantus®) Detemir (Levemir®) 1-2h flat 24h Combinations 70% / 30% lispro 75% / 25% aspart 50% / 50% aspart 30-60 min. 15-60 min. Dual 14-18h

22. Therapy for Type 2 Diabetes: Sites of Action Liver Pancreas Glucose Hyperglycemia ↑HGO * ↑Sulfonylureas ↑Repaglinide TZD ↑Metformin  Thiazolidinediones Gut Muscle ↑Metformin ↑Thiazolidinediones ↓  -Glucosidase inhibitors Adipose tissue ↓ Glucose uptake Acarbose Miglitol Rosiglitazone Pioglitazone * HGO=hepatic glucose output. Adapted from DeFronzo RA. Ann Intern Med. 1999;131:281-303. Package Inserts for AVANDIA ® (rosiglitazone maleate, GlaxoSmithKline), Actos ® (pioglitazone HCl, Takeda), Prandin ® (repaglinide, Novo Nordisk), Precose ® (acarbose tablets, Bayer), Glyset ® (miglitol, mfd. by Bayer for Pharmacia & Upjohn).

23. 23 ++ Diet & exercise Oral monotherapy Oral combination Oral plus insulin Insulin + Stepwise Management of Type 2 Diabetes Adapted from Williams G. Lancet 1994; 343: 95-100.

24. Pharmacotherapy Stepwise Management Glycemic targets often not met Monotherapy often not effective long term Therapy fails to address multiple impairments Step-wise approach tends to perpetuate “failure”

25. New Treatment Paradigm Treatment designed to address multiple impairments Simultaneous rather than sequential therapy Combination therapy from the outset Early titrations to meet glycemic targets

26. Combination Oral Diabetic Agents Glucovance® ( Glyburide + Metformin) Metaglip® (Glipizide + Metformin) Avandamet® (Rosiglitazone + Metformin) Avandaryl® (Rosiglitazone + Glimepiride) ActoPlus Met® (Pioglitazone + Metformin) Janumet® (Januvia + Metformin)

27. ADA/EASD Consensus Algorithm 2009 Nathan and Associates: Diabetes Care, Vol. 32, Number 1, January 2009 At Diagnosis Lifestyle+Metformin Tier 1: Well-validated core therapies Step 1 Lifestyle + Metformin +Sulfonylurea + Basal Insulin Step 2 Lifestyle + Metformin +Pioglitazone + GLP1- Agonist Tier 2: Less well validated therapies Lifestyle + Metformin + Intensive Insulin Step 3 Lifestyle + Metformin +Pioglitazone+Sulfonylurea + Basal Insulin

28. ACCE Diabetes Algorithm 2009 Glycemic Control Algorithm, Endocr Pract. 2009;15(No. 6)

29. Type 2 diabetes Postprandial hyperglycemia Basal hyperglycemia Glucose Dynamics: Basal and Prandial Riddle MC. Am J Med. 2004;116(suppl):3S-9. Plasma glucose (mg/dL) Time of day 200 250 150 100 50 0 06001200180006002400 Normal

30. Basal-Bolus Combination Therapy 4:0016:0020:0024:004:00 BreakfastLunchDinner 8:00 12:008:00 Time Bolus insulin Plasma Insulin Levels Basal insulin

31. 31 Basal Bolus Combination: A Simple Approach Total Daily Insulin Requirement 0.5-1 unit/kg/day Basal Insulin 50% Bolus Insulin Breakfast Lunch Dinner 1/3

32. Treatment of co-morbid conditions Dyslipidemia Hypertension

33. Diabetes CV Risk Calculator Available at: http://www.dtu.ox.ac.uk/riskengine/

34. Diabetes CV Risk Calculator (Canada) http://www.diabetes.ca/documents/about-diabetes/FINAL_PATIENT_TOOL_FOR_WEBSITE.pdf

35. The ABCs of Diabetes Care A1C ADA recommends < 7% in general, < 6% for selected individuals AACE/IDF recommend ≤ 6.5% Blood pressure < 130/80 mm Hg Cholesterol LDL-C: < 100 mg/dL (< 70 mg/dL in very high-risk patients) HDL-C: > 40 mg/dL in men and > 50 mg/dL in women Non-HDL-C: < 130 mg/dL (< 100 mg/dL in high-risk patients) Triglycerides: < 150 mg/dL American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4-S41. American Association of Clinical Endocrinologists. Endocr Pract. 2007;13(suppl 1):3-68. International Diabetes Federation. Diabet Med. 2006;23:579-593.

36. Additional Recommendations Individualized Medical Nutrition Therapy Exercise Aspirin (75-325 mg/d) Smoking cessation Screening for microvascular complications (eyes, kidneys, feet) Immunization ( Flu vaccine, Pneumovax) Recommended cancer screening

37. ADA. Diabetes Care. 2005;28(suppl 1):S1-79. Proper nutrition Physical activity program Smoking cessation Weight control HbA 1c <7% Glucose (mg/dL): Preprandial 90–130 Postprandial <180 Dyslipidemia: Statin Hypertension: ≥2 drug classes, include ACEI or ARB Microalbuminuria: ACEI or ARB Use of aspirin CHD: ACEI,  -blocker CVD/high risk: ACEI Lifestyle interventions Intensive glycemic control Aggressive Rx for CV risk reduction Optimal Care of the Diabetic Patient

38. Thank You For Your Attention