1. Implementing Diabetes Guidelines in the “Real World” Martin J. Abrahamson, MD FACP Associate Professor of Medicine, Harvard Medical School Senior Vice President for Medical Affairs, Joslin Diabetes Center

2. What I will cover Pathophysiology of type 2 diabetes The guidelines – do they help us? How should we choose drugs to add on metformin Is there an alternative “approach” to treating diabetes?

3. Pathophysiology of Type 2 DM: From the Triumvirate… From DeFronzo Diabetes 2009; 58:773-795

4. To the Ominous Octet From DeFronzo Diabetes 2009; 58:773-795

5. Non Insulin Medications to Treat Type 2 DM TZD Metformin TZD Metformin α glucosidase inhibitors Incretins Pramlintide Colesevelam Dopamine receptor agonists Serotonin receptor agonists Incretins SGLT2 Inhibitors β cells Sulfonylureas Meglitinides Incretins α cells Incretins Pramlintide © M.J. Abrahamson, MD FACP

6. Type 2 Diabetes Management 2014 Lowering A1c to around 7% especially early after diagnosis can reduce the risk for the development or progression of the long term complications of diabetes There are many medications available today to treat type 2 diabetes – if used appropriately this could translate to improved control and less risk for complications The challenge for the practicing physician is to know which medications to use and when best to use them

7. Type 2 Diabetes Management 2014 There IS consenus that metformin should be first line therapy There is NO clear consensus what to add to metformin when A1c goals are not met – Few head to head comparator trials – Even fewer long term studies evaluating durability of medications on glycemic control, especially when added to metformin

8. T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

9. T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

10. Fig. 2. T2DM Antihyperglycemic Therapy: General Recommendations Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

11. Diabetes Care 2012;35:1364–1379 Diabetologia 2012;55:1577–1596

14. Choice of drug depends on Safety Efficacy Tolerability/acceptability Durability Cost Phenotypic and genotypic approaches to determine most effective therapy are lacking

15. Safety Hypoglycemia Cardiac safety

16. Hypoglycemia Insulin Sulfonylureas (SUs) NOT (when used alone/without insulin or SUs) – Metformin – DPP-IV Inhibitors – GLP-1 agonists – TZD – SGLT-2 inhbitors

17. Hypoglycemia Glyburide is associated with more hypoglycemia than other sulfonylureas 1 Hypoglycemia in ADOPT 2 – Minor: about 28% had symptoms – Major: about 0.6% during the 5 years of the study UKPDS - rates of major hypoglycemia 3 ConventionalChlorpropamideGlibenclamideInsulin Hypoglycemia rate (per year) 0.71.01.41.8 Gangji AS et al. Diabetes Care 2007; 30:389-394 Kahn S et al. New Engl J Med 2006;355:2427-2443 UKPDS 33. Lancet 1998; 352:837-853

18. UKPDS Long Term Follow Up: Outcomes (Relative Risk Reduction) SU – InsulinMetformin Any diabetes related end point9% (p = 0.04)21% (p = 0. 01) Death from any cause13% (p = 0.007)27% (p = 0.002) Microvascular disease24% (p = 0.001) Myocardial infarction15% (p = 0.01)33% (p = 0.005) Holman RR et al. New Engl J Med 2008; 359:1577-1589 Improved outcomes despite no difference in A1c between treatment groups which occurred within a year of study end “Legacy effect”

19. ADOPT: HbA1c Over Time 01 234 5 Time (years) HbA1c % 0 6.0 8.0 7.0 6.5 7.5 Rosiglitazone Glyburide Metformin Rosiglitazone vs Metformin  0.13 (  0.22 to  0.05), P=0.002 Rosiglitazone vs Glyburide  0.42 (  0.50 to  0.33), P<0.001 Kahn SE et al: N Engl J Med 2006; 355:2427-2443

20. ADOPT – Blood Glucose Control GlibenclamideMetforminRosiglitazone Mean A1c (%) Year 16.56.76.8 Year 26.86.76.8 Year 37.06.96.8 % with A1c < 7% at 4 years 263640 Time to A1c > 7% (yr) 2.753.754.75 Al-Ozairi E et al Diabetes Care 2007; 30:1677-1680 Kahn S et al New Engl J Med 2006; 355:2427-2443

21. What Are Some of the “Take Home” Points from ADOPT? ADOPT was not a “combination” therapy study Average glucose control better with SU during first year of study Glucose control really began to diverge at 3 years – average control very similar for 3 groups during first 3 years None of the 3 therapies were satisfactory (A1c < 6.5%) as monotherapy – Combination therapy is going to be needed earlier on in the natural history of the disease if more people are going to get to goal No adverse cardiovascular events with glibenclamide

22. Cost of Diabetes and Medications to Treat Hyperglycemia Estimated annual cost of diabetes in US is $ 245 billion Estimated annual cost of glucose-lowering medications is > $ 18 billion (up from $ 13 b American Diabetes Association American Diabetes Association. Diabetes Care 2013; 36: 1033-1046

23. Comparison of Medications that Could be Added to Metformin SUTZDDPP-IVGLP-1 Efficacy High ModerateHigh Tolerability HighModerateHighModerate Side effects Hypoglycemia Weight gain Edema/CHF/Fra ctures /Weight gain Rare pancreatitis GI Rare pancreatitis Risk of hypoglycemia ModerateLow CV Safety Neutral Unknown Durability ???? Cost LowLow - ModHigh Adapted from Goldfine, Phua and Abrahamson, 2014 in press

24. Comparison of Medications that Could be Added to Metformin SGLT 2 Inhibitor BromocriptineColesevalamInsulin Efficacy HighModerate Highest Tolerability HighModerateHigh Side effects UTI Vag yeast infn Orthostasis Nausea/Vomitin g NilHypoglycemia Weight gain Risk of hypoglycemia Low High CV Safety ?Neutral Durability ???Yes Cost HighMod Variable Adapted from Goldfine, Phua and Abrahamson, 2014 in press

25. So what would you add on to metformin if glycemic goals are not being met?

26. Choose One Only! 1.Sulfonylurea 2.DPP-IV inhibitor 3.GLP-1 receptor agonist 4.TZD 5.SGLT 2 inhibitor 6.Basal Insulin

27. We need more data!

28. Glycemia Reduction Approaches in Diabetes (GRADE) Study: Comparative Effectiveness Nathan DM et al. Diabetes Care epub May 20, 2013

29. What about the “new kid on the block”? SGLT-2 Inhibitors

30. Canagliflozin (Invokana) Dapagliflozin (Farxiga) –Once daily dosing before 1 st meal of the day Mechanism of action –Inhibition of SGLT2 reduces reabsorption of glucose in the kidney, resulting in increased urinary glucose excretion, with a consequent lowering of plasma glucose levels as well as weight loss. –Blocks approximately 50-80 grams of glucose per day from being reabsorbed –New finding – increased glucose production SGLT-2 Inhibitors

31. Positive effects –Reduction in body weight and systolic blood pressure Side effects –Vaginal yeast infection, urinary tract infection and increased urination –Hypoglycemia (<5%), dehydration, dizziness or fainting, hyperkalemia Contraindications –Type 1 diabetes, patients with type 2 diabetes and ketonuria or ketosis –Severe renal impairment, end-stage renal disease or patients receiving dialysis SGLT-2 Inhibitors

32. Canagliflozin vs Sitagliptin as Add on to Metformin and Sulfonylurea G Scherthaner et al. Diabetes Care 2013; epub April 5

33. Canagliflozin vs Sitagliptin add on to MTF and SU: Change in A1c G Scherthaner et al. Diabetes Care 2013; epub April 5

34. Canagliflozin vs. Sitagliptin: Change in Weight G Scherthaner et al. Diabetes Care 2013; epub April 5

35. But which sulfonylurea you choose, and what dose you use DOES matter! And avoid them in people at increased risk of hypoglycemia

36. Can we simplify the guidelines/treatment approach? Is there evidence to support this approach?

39. A1c Change with Liraglutide followed by Detemir 60% of subjects achieved A1c < 7% with liraglutide alone 43% of the remainder achieved A1c < 7% with additional detemir Almost 75% of subjects achieved A1c < 7% with GLP-1 RA and detemir

40. Weight Change with Liraglutide Followed by Detemir

41. Exenatide Added on to Glargine Treated Subjects Improves A1c Buse JB et al Ann Internal Med 2011: 154:103-112 60% achieved A1c < 7% with vs 35% with placebo

42. Weight Loss Associated with Addition of Exenatide to Glargine Buse JB et al Ann Internal Med 2011: 154:103-112

43. Cost notwithstanding, is there an alternate approach to treating type 2 diabetes? Lifestyle + Metformin + GLP-1 analogue/ DPP-IV inhibitor/ SGLT 2 Inh + Insulin Lifestyle + Metformin Lifestyle + Metformin + GLP-1 analogue or DPP-IV inhibitor Or ? SGLT 2 Inh Bariatric surgery?

44. List A Diabetes Medications and Body Weight Weight Gain Weight Neutral Weight Loss SignificantModest Pioglitazone Sulfonylureas Glyburide Glipizide Insulin NPH Glargine Regular Aspart Lispro Glulisine Sulfonylureas Glimepiride Glipizide XL Glinides Repaglinide Nateglinide Insulin Detemir Glulisine (PP) Metformin DPP-4 Inhibitors Sitagliptin Saxaglipitin Linagliptin Alogliptin α-glucosidase Inhibitors Acarbose Miglitol Colesevelam Bromocriptine GLP-1 Analogs Exenatide Exenatide ER Liraglutide Pramlintide SGLT-2 inhibitors Stop, reduce, or switch Continue Add Mitri J, Hamdy O. Expert Opin Drug Saf. 2009;8(5):573-84. List B

45. Summary Type 2 diabetes is a progressive disease While more people are reaching therapeutic goals, many more need to get there We have many tools available to help patients achieve optimal metabolic control The challenge is which ones to use, and when to use them We need to treat all cardiovascular risk factors aggressively Lifestyle modification remains the cornerstone of therapy

46. Summary Don’t be afraid to add medications or even start combination therapy simultaneously Start insulin earlier if control not possible with oral medications and incretins