1. Treatment of Type II DM: The Current Model is Flawed Richard Amerling, MD Associate Professor of Clinical Medicine Albert Einstein College of Medicine

5. What’s Wrong with our Current Treatment Paradigm?  Based largely on experience with Type I DM  Overly focused on glycemic control  In Type I DM, hyperglycemia is the disease  In Type II DM, hyperglycemia is a symptom  Most patients with Type II DM in the US have metabolic syndrome and obesity  Most drug treatment of hyperglycemia worsens obesity

6. Case Study: James G  1997: 57 yr. old Bl man  BP 170/100; Wt: 239 lbs.  Naldolol 40, amlodipine 2.5, modiuretic  Glucose 113; normal BUN/creat  2003: Now 63 years old  BP 226/110; Wt: 236 lbs  Amlodipine 10, naldolol 120, HCTZ/triamterene  Glucose 415; HbA1C 13.8; Chol 315, LDL 210; Uprot/creat 1.0; 25 OH D <7; aldo 24; renin <2  How would you proceed?

7. Type I DM: Pathophysiology

8. Genetic susceptibility to Type I DM

9. Autoantibodies: ICAs Target autoantigens in type 1 diabetes mellitus  Glutamic acid decarboxylase  Insulin and proinsulin  Glycolipids, ganglioside GT3  Carboxypeptidase H, PM-1 polar antigen  Islet cell proteins of varying size and unknown function - 37 or 40 kD, 38 kD, 52 kD, 69 kD  Peripherin  Heat shock protein 65  Insulin receptor  Endocrine cell antigens  Cytoskeletal proteins - tubulin, actin, reticulin  Nuclear antigens - single-stranded DNA and RNA

10. Type II DM: Pathophysiology

12. Type II DM Trials  UGDP (1970)  Showed increased mortality in group taking sulfonylureas  UKPDS (1988)  ACCORD (2008)  ENHANCE (2008)  VADT (2009)

13. UKPDS: Overview  20 year study  23 Centers  Over 5000 patients recruited  Aim: to determine the effect of intensive blood glucose control with sulphonylureas, insulin, or metformin on 21 predetermined clinical end points. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-853 Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) Lancet 1998; 352: 854-865

14. UKPDS: Effect of 10 years' treatment with chlorpropamide, glibenclamide, or insulin on patients with newly diagnosed type 2 diabetes (McCormack: BMJ 2000;320:1720-1723) Any DM endpoint (%)* Microvascular disease (%) Individual macro endpoints** Median HbA1C Diet + Ch, Gl, or insulin 35.38.2No signif diff between Ch 6.7, Gl 7.2, insulin 7.1 Diet only38.510.6groups for any7.9 Rel risk reduct8.222.6individual Abs risk reduct3.22.4endpoint*** NNT 10/13142 * Sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, cataract extraction. **Deaths related to diabetes, all cause mortality, myocardial infarction, stroke, blindness, renal failure, or neurological events. ***P value for myocardial infarctions was 0.052 (dietary advice plus drug treatment 14.2% v dietary advice 16.3%). However, because the study was continued after the initial results showed no differences, a breakpoint for significance of 0.05 is debatable. § 2.7% of this 3.2% was due to a significant reduction in retinal photocoagulation.

15. UKPDS: Obese patients Any DM endpoint (%) Diabetes deaths (%) All cause mortality (%) MI (%)Stroke (%) Microvasc disease (%) Median Hb A1c (%) Diet+metf or 28.78.214.611.43.57.07.4 Diet +ch, gl, insulin 36.810.820.014.66.37.8All sim met Diet only38.913.421.717.85.69.28.0 Rel risk red (met v diet) 26.238.832.736.044.4NSSig low Abs risk red (met v diet) 10.25.27.16.42.8NS NNT 10/1 (met v diet) 1019141636NS McCormack: BMJ 2000;320:1720-1723

16. UKPDS: Complications  “The UK prospective diabetes study 33 suggests that the drugs used were well tolerated, although only hypoglycaemic events and weight gain were reported. Nevertheless, participants in the sulphonylurea and insulin groups gained a mean of 3.1 kg more weight than the diet alone group. Major hypoglycaemic episodes (those requiring third party help) occurred in 0.1%, 0.6%, 0.6%, and 2.3% of participants per year in the diet, chlorpropamide, glibenclamide, and insulin groups respectively (note that benefit was expressed over 10 years). The incidence of minor hypoglycaemic events was 1%, 11%, 18%, and 37% per year, respectively.” McCormack: BMJ 2000;320:1720-1723

17. UKPDS: Conclusions (1)  “Contrary to expectations, treatment with sulphonylureas and insulin had no significant benefit on the occurrence of microvascular or macrovascular end points over 10 years in this obese population. Metformin also produced significant reductions in the aggregated diabetes related end points, all cause mortality, and stroke compared with the sulphonylureas and insulin.”  “With regard to the results of these two trials, one message seems to have been lost from many of the commentaries on the UK prospective diabetes study. That is, patients with type 2 diabetes seem to benefit not so much from the overall control of glucose but rather from taking metformin.” McCormack: BMJ 2000;320:1720-1723

18. UKPDS: Conclusions (2)  “…it is not known whether reducing the Hb A1c … leads to an improved outcome. To establish a causal relation between a surrogate marker and a clinical outcome, it must be shown that a dose-response relation exists--- that is, that a consistent, progressive clinical benefit is seen with progressive reductions in the surrogate marker. In the UKPDS, changes in Hb A1c produced by drug treatment did not seem to correlate with treatment outcomes.”  “In study 33 an absolute reduction of 1% in Hb A1c was observed with chlorpropamide, glibenclamide, or insulin over 10 years compared with diet alone; yet there was virtually no significant reduction in macrovascular outcomes.”  “In study 34, all the drugs produced similar mean absolute differences in HbA1c over the 10 years compared with diet alone, but only metformin produced significant reductions in clinically important macrovascular events.” McCormack: BMJ 2000;320:1720-1723

19. UKPDS: Conclusions (3)  “Not only did metformin reduce clinically important events compared with diet alone, it also produced reductions in some outcomes compared with other glucose lowering drugs. This shows that the studies in question were large enough, and of sufficient duration, to show macrovascular benefits.”  “ Clinicians and patients need to be aware of this and consider that either metformin may be conferring benefit independent of, or in addition to, blood glucose reduction, or that sulphonylureas and insulin may have an adverse effect on overall risk.” McCormack: BMJ 2000;320:1720-1723

20. The case against aggressive treatment of type 2 diabetes: critique of the UKPDS RM Ewart; BMJ VOLUME 323 13 OCTOBER 2001  Endpoints kept changing  Study unblinded  Subgroup analysis changed  Length of follow up continued to expand  Results not clinically significant

21. ACCORD Trial  Randomized trial, >10,000 patients, to target glycated Hb of 8.1% vs. 6.0%  No difference in primary outcome (composite non-fatal MI or stroke, CV death)  Higher mortality in intensive group led to study termination  Hypoglycemia and weight gain>10 kg more frequent in intensive Rx group

22. ACCORD Data (1)

23. ACCORD Data (2)

24. ACCORD Data (3)

25. ACCORD Data (4)

26. ACCORD Data (5)

27. ACCORD: Conclusions  Intensive Rx group had relative increase in mortality of 22%  Study not designed to test components  “…if there is any benefit associated with intensive glucose lowering, it may take several years to emerge, during which time there is an increased risk of death.”

28. ADVANCE Trial  Randomized prospective study, >11,000 pts.  Intensive Rx group: glycated Hb <6.5%, use of gliclazide plus other drugs  Primary endpoints included macro and microvascular events  Overall “positive” outcome resulted from 20% relative reduction in incidence of nephropathy (4.1% vs. 5.2%)

29. ADVANCE Endpoints  Macro: CV Deaths, nonfatal MI or stroke  Micro: New or worsened nephropathy (microalbuminuria, doubling creatinine, RRT, death from renal disease, retinopathy

30. ADVANCE Baseline

31. ADVANCE: Results

32. ADVANCE Results

33. ADVANCE: Results

34. ADVANCE: Comment  Most of micro benefit due to decreased development of macroalbuminuria (2.9 vs. 4.1%, p<0.001)  No effect on doubling of Screat  No change in retinopathy  BP significantly lower in intensive Rx group  More hospitalizations in intensive Rx group  More hypoglycemia: 150 severe events vs. 81 in standard group. 53% vs 38% over study

35. VADT Trial  Randomized, prospective, study of 1791 veterans poorly controlled with type 2 DM to intensive vs. standard glycemic control  High baseline incidence of CV disease and long duration of DM  Intensive goal was absolute decrease of 1.5% for glycated Hb.  Primary outcome: Time to 1 st occurrence of CV event

36. VADT Methods and Outcomes  Primary outcome: Time to any of a composite of CV events: MI, stroke, CV death, new or worsened CHF, CV or vascular surgery including amputation for gangrene.  Microvascular: Nephropathy, retinopathy and neuropathy all evaluated and tracked

37. VADT Medication protocol  BMI>27: metformin and rosiglitazone  BMI<27: glimepiride and rosiglitazone  Insulin added to intensive group pts who did not achieve glycated Hb<6% and in standard group pts with level <9%

38. VADT Results  No significant difference in any component of primary outcome or in overall death rate  No difference in microvascular complications  Higher adverse event rate in intensive group

39. VADT Results

41. VADT Microvascular

42. A Rational Approach to DM II  Therapy aimed at metabolic syndrome  Primary goal should be weight reduction  Low carbohydrate diet is key  Eliminate HFCS  Regular exercise: Walking is best  Metformin  Permissive hyperglycemia and glycosuria

43. Low Carb Diets: Data  Systematic review of randomized controlled trials of low-carbohydrate vs. low-fat/low- calorie diets in the management of obesity and its comorbidities  “Evidence … demonstrates that low- carbohydrate/high-protein diets are more effective at 6 months and are as effective, if not more, as low-fat diets in reducing weight and cardiovascular disease risk up to 1 year.” Obes Rev. 2009 Jan;10(1):36-50. Hession, et al.

44. Low Carb Diets: Data  Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials.  “Triglyceride and high-density lipoprotein cholesterol values changed more favorably in individuals assigned to low-carbohydrate diets”  “Low-carbohydrate, non-energy-restricted diets appear to be at least as effective as low-fat, energy- restricted diets in inducing weight loss for up to 1 year.” Arch Intern Med. 2006 Feb 13;166(3):285- 93. Nordman, et al

45. Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women: the A TO Z Weight Loss Study: a randomized trial.  Weight loss was greater for women in the Atkins diet group compared with the other diet groups at 12 months, and mean 12- month weight loss was significantly different between the Atkins and Zone diets (P<.05). Mean 12-month weight loss was as follows: Atkins, -4.7 kg (95% confidence interval [CI], -6.3 to -3.1 kg), Zone, - 1.6 kg (95% CI, -2.8 to -0.4 kg), LEARN, -2.6 kg (-3.8 to -1.3 kg), and Ornish, -2.2 kg (-3.6 to -0.8 kg).  At 12 months, secondary outcomes (low-density lipoprotein, high- density lipoprotein, and non-high-density lipoprotein cholesterol, and triglyceride levels), for the Atkins group were comparable with or more favorable than the other diet groups. Gardiner, et al. JAMA. 2007 Mar 7;297(9):969-77

53. Follow up: James G  Treated with low carb diet, exercise  Naldolol to carvedilol, added eplerenone, ergocalciferol, telmisartan, atorvastatin  Metformin 1 g BID started  2007: Wt down to 202; BP 140/70  LDL 61 HDL 69; HbA1C 5.0; Umicroalb 3.1; 25-OH D 42  Off metformin since 2006

54. Treatment of Type II DM  In most patients, weight reduction should be primary goal  Diet (low carb), exercise are mainstay  Short term permissive hyperglycemia  Metformin is drug of choice; serious side effects are very rare  Insulin only for documented insulin deficiency  Newer agents: Use with caution!  SGLT2 inhibitors: A promising alternative