1. Diabetes Update Glycemic Control Raymond O. Estacio, MD Denver Health Associate Professor of Medicine University of Colorado, Denver School of Medicine Director of Medical Affairs, Colorado Prevention Center

2. Why are We Concerned about Diabetes? Every 24 hours... 3,600 new cases of diabetes are diagnosed 3,600 new cases of diabetes are diagnosed 580 people die of diabetes-related complications 580 people die of diabetes-related complications 225 people have a diabetes-related amputation 225 people have a diabetes-related amputation 120 people with diabetes progress to end-stage renal disease 120 people with diabetes progress to end-stage renal disease 55 people with diabetes become blind 55 people with diabetes become blind www.diabetes.orb

3. Increasing Prevalence of Diagnosed Diabetes in US Adults 19942005

4. The Burden of Diabetes in the United States 21 million Americans have diabetes 21 million Americans have diabetes 6 th leading cause of death in the US (225,000) 6 th leading cause of death in the US (225,000) Direct and indirect cost = $174 billion Direct and indirect cost = $174 billion Diabetes accounts for 19% of health care expenditures in the US Diabetes accounts for 19% of health care expenditures in the US Source: American Diabetes Association

5. ADA, Diabetes Care. 2003;26:917-932 Projected Increase in the US Population with Diagnosed Diabetes by 2020 by Ethnicity

6. Diabetic Complications Complications of diabetes include: Complications of diabetes include: Cardiovascular Disease Cardiovascular Disease Heart Attacks Heart Attacks Stroke Stroke Heart Failure Heart Failure Renal Disease Renal Disease Retinopathy Retinopathy Neuropathy Neuropathy

7. Reduction in Life Expectancy According to Age at Time of Diagnosis Years Roper et al, BMJ 2001

8. Ischemic heart disease % of Deaths Geiss LS et al. In: Diabetes in America. 2 nd ed. 1995; chap 11. Mortality in People with Diabetes Causes of Death Other heart disease Diabetes CancerStroke Infection Other

9. Trends in Mortality Rates for CVD in NHANES Subjects with and without Diabetes Gregg et al., Ann Inttern Med 2007 Progress in reducing mortality rates among persons with diabetes has been limited to men. Diabetes continues to greatly increase the risk for mortality, particularly among women. Mortality rates are calculated as annual deaths per 1000 persons

10. Glycemic Control in Type 2 Diabetes

11. Glycemic Control on Diabetic Microvascular Complications Type 2 UKPDS 8  7% 17-21% 24-33% - HbA1c Retinopathy Nephropathy Neuropathy Type 1 DCCT 9  7% 76% 54% 60% Type 2 Kumamoto 9  7% 69% 70% - DCCT Research Group, NEJM 1993, Ohkubo et al., Diab Res Clin Pract 1995, UKPDS Group, Lancet 1998

12. Glycemic Control and Diabetic Macrovascular Complications Epidemiologic data demonstrating a 2 – 4x increased in CVD outcomes Epidemiologic data demonstrating a 2 – 4x increased in CVD outcomes Blood Sugar Related to Lipoproteins, Syndrome X, Clotting, AGE, Renal Disease Therefore, improved glycemic control over a long period of time should lead to a decrease in CVD outcomes?

13. Veterans Affairs Diabetes Feasibility Study 150 patients over 2 years Randomized to Standard versus Intensive therapy 2.07% separation of glycosylated hemoglobin (HbA1c) 61 new cardiovascular events 32% intensive treatment 20% standard treatment (P =.10). Intensive Standard Abraira et al., Arch Int Med 1997

14. UKPDS 3800 newly diagnosed type 2 DM patients Randomized to Intensive versus Standard therapy Over 10 years of follow up A1C 7% vs 8%

15. UKPDS Aggregate endpoints by treatments EndpointIntensiveConventionalRR for Intensive Treatment (N=2729) (N=1138) Any diabetes endpoint 963 438 0.88 (0.79-0.99) Diabetes-related death 285 129 0.90 (0.73-1.11) All-cause mortality 489 213 0.94 (0.8-1.10) MI 387 186 0.84 (0.71-1.00) Stroke 148 55 1.11 (0.81-1.51) Amputation/ PVD death 29 18 0.65 (0.36-1.18) Microvascular 225 121 0.75 (0.60-0.93) UKPDS Group, Lancet 1998

16. DCCT/EDIC Metabolic Results DCCT Intervention DCCT Intervention S t u d y Y e a r DCCT 1 2 3 4 5 6 7 8 9 EDIC Observation EDIC ObservationTraining EDIC Conventional EDIC mean 8.2% Intensive EDIC mean 8.0% DCCT/EDIC Study Research Group, NEJM 2005

17. Conventional Intensive Non-Fatal MI, Stroke or CVD Death Cardiovascular Events 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Number at Risk Intensive: 705 686 640 118 Conventional: 721 694 637 96 Years from Study Entry 0.00 0.02 0.04 0.06 0.08 0.10 0.12 Cumulative Incidence Risk reduction 57% 95% CI: 12, 79 Log-rank P = 0.018 DCCT/EDIC Study Research Group, NEJM 2005

18. Recent Studies Evaluating Glycemic Control on CVD ACCORD ACCORD ADVANCE ADVANCE VADT VADT

19. ACCORD: Study design ACCORD Study Group. Am J Cardiol. 2007;99(suppl):21i-33i. www.accordtrial.org *Statin + fibrate vs statin, treatment group assignment blinded until end of trial Primary outcome: CV death, MI, stroke Glycemia trial N = 10,251 with T2DM and existing CVD or additional CV risk factors 1178 1184 1193 1178 1383 1370 1374 1391 5128 5123 2362237127532765 SBP <120 mg Hg SBP <140 mg Hg Group AGroup B 47335518 BP trial (n)Lipid trial* (n) A1C <6% A1C 7.0%-7.9%

20. ACCORD: Treatment effects on glucose control ACCORD Study Group. N Engl J Med. 2008;358:2545-59. A1C (%) Time (years) Standard therapy Intensive therapy 6 9.0 8.5 8.0 7.5 7.0 6.5 6.0 0 012345

21. ACCORD Action To Control Cardiovascular Risk In Diabetes Intensive Glycemia Arm Stopped 2/6/08, About 18 Months Early Intensive Glycemia Arm Stopped 2/6/08, About 18 Months Early Excess Mortality In Intensive Group Excess Mortality In Intensive Group

22. ACCORD: Treatment effect on all-cause mortality ACCORD Study Group. N Engl J Med. 2008;358:2545-59. Patients with events (%) Time (years) 25 0 20 15 10 5 0 123456 Standard therapy Intensive therapy HR 1.22 (1.01-1.46) P = 0.04 CVD Death: HR 1.35 (1.04–1.76) P=0.02

23. ACCORD Action To Control Cardiovascular Risk In Diabetes 257 Deaths In Intensive Arm 257 Deaths In Intensive Arm 203 Deaths In Conventional Arm 203 Deaths In Conventional Arm Not Due To Hypoglycemia Not Due To Hypoglycemia Not Due To Medication Or Medication Combinations Not Due To Medication Or Medication Combinations ACCORD Study Group. N Engl J Med. 2008;358:2545-59.

24. ACCORD: Treatment effect on primary outcome ACCORD Study Group. N Engl J Med. 2008;358:2545-59. 25 0 20 15 10 5 0 123456 Standard therapy Intensive therapy Patients with events (%) Time (years) HR 0.90 (0.78-1.04) P = 0.16 Primary Outcome: NFMI, NF Stroke or CVD Death

25. HR for Death from Any Cause in Prespecified Subgroups ACCORD Study Group. N Engl J Med. 2008;358:2545-59.

26. Intensive glucose control + Perindopril/Indapamide Intensive glucose control Perindopril + Indapamide Placebo Intensive glucose control + Placebo Standard glucose control + Perindopril/Indapamide Standard glucose control + Placebo ADVANCE: Study design n = 5569n = 5571 N = 11,140 with T2DM and high risk for CV events ADVANCE Collaborative Group. J Hypertens. 2001;19(suppl 4):S21-S28. www.advance-trial.com Primary outcome: Macro (CV death, MI, stroke), micro (new/worsening nephropathy, retinopathy)

27. ADVANCE Treatment effect on glucose control ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72. Mean A1C (%) Follow-up (months) Standard control Intensive control 10.0 9.0 8.0 7.0 6.0 5.0 0.0 0612182430364248546066 P < 0.001

28. ADVANCE Treatment effect on primary macrovascular outcome ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72. CV death, MI stroke Cumulative incidence (%) Follow-up (months) 25 20 15 10 5 0 0612182430364248546066 HR 0.94 (0.84-1.06) P = 0.32 Standard control Intensive control

29. ADVANCE Treatment effect on primary microvascular outcome ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72. New/worsening nephropathy, retinopathy 66 Cumulative incidence (%) Follow-up (months) HR 0.86 (0.77-0.97) P = 0.01 Standard control Intensive control 25 20 15 10 5 0 06121824303642485460

30. ADVANCE Treatment effect on all-cause mortality ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-72. Cumulative incidence (%) Follow-up (months) Standard control Intensive control 25 20 15 10 5 0 06121824303642 48 546066 HR 0.93 (0.83-1.06) P = 0.28

31. ADVANCE 11,140 Patients, Age ~66, With Type 2 DM, And High CV Risk 11,140 Patients, Age ~66, With Type 2 DM, And High CV Risk Intensive (A1c 6.4%) vs Conventional (A1c 7.3%) Intensive (A1c 6.4%) vs Conventional (A1c 7.3%) Benefit with regard to microvascular complications Benefit with regard to microvascular complications No Excess Mortality In Intensive Group No Excess Mortality In Intensive Group

32. Why do we have different results for the same intervention?

33. ACCORD & ADVANCE Differences Int vs StdInt vs Std Dluhy et al, NEJM 2008

34. ACCORD & ADVANCE Total Mortality Follow-up (months) 25 20 15 10 5 0 0612182430364248546066 Standard control Intensive control Intensive therapy Standard therapy Time (years) 25 0 20 15 10 5 0 123456 3 years ACCORD ADVANCE

35. ACCORD & ADVANCE: Differences ACCORD ADVANCE ACCORD ADVANCE Baseline A1C 8.1 7.2 Months to final A1c 12 36 A1C Reduction 1.4% /4 mos.0.5%/6 mos. Treatment Insulin 77 & 55%41 & 24% TZD 92 & 58% 17 & 11%

36. ACCORD & ADVANCE Glycemic Control A1C (%) Intensive ADVANCE, blue & purple ACCORD, red & yellow More rapid rate of glucose lowering in the intensive group of ACCORD, 1.4% over 4 months. Follow-up (months) Standard 10.0 9.0 8.0 7.0 6.0 5.0 0.0 0612182430364248546066 Hypoglycemia (%/year) ACC – Std – 1 ADV – Std – 0.4 ADV-Int – 0.7 ACC-Int – 3.1

37. ACCORD & ADVANCE: Other Differences ACCORD ADVANCE ACCORD ADVANCE Weight Gain (kg) Intensive 3.5 0.0 Standard 0.4 -1.0 Other Medications Statin 88% 47% ASA76% 56% 73% of CVD events occured in patients not taking statins

38. ACCORD & ADVANCE Observations Mortality difference after only 3.5 years not anticipated in ACCORD Mortality difference after only 3.5 years not anticipated in ACCORD Hypoglycemia triggered events? Hypoglycemia triggered events? Dluhy et al -possible misclassification of some events, “unexpected or presumed CVD” actually “precipitated by hypoglycemia?” Dluhy et al -possible misclassification of some events, “unexpected or presumed CVD” actually “precipitated by hypoglycemia?” TZD’s role TZD’s role Poorer CV risk factor control may account for the higher event rates in ADVANCE Poorer CV risk factor control may account for the higher event rates in ADVANCE

39. VADT Veterans Affairs Diabetes Trial 1800 participants in 20 VAMC’s 1800 participants in 20 VAMC’s Mean Age 60 years Mean Age 60 years 97% Male 97% Male 16% AfAm, 16% Hispanic White 16% AfAm, 16% Hispanic White Good between glycemic separation (6.9% vs 8.4%) Good between glycemic separation (6.9% vs 8.4%) Optimal cv risk factor control Optimal cv risk factor control Completed May and presented at the ADA June, 2008 Completed May and presented at the ADA June, 2008 Duckworth WC. ADA 68 th Scientific Sessions; June 8, 2008; San Francisco, CA.

40. Hazard Ratio & CL 0.868 (0.728, 1.036) P=0.12 01234567 0.0 0.2 0.4 0.6 0.8 1.0 Follow-Up (years) Proportion Free of Primary Outcome Duckworth WC. ADA 68 th Scientific Sessions; June 8, 2008; San Francisco, CA. VA Diabetes Trial Primary Outcome Standard Intensive MI, Stroke, CVD death, HF, Revascularization

41. 7 Follow-Up (years) VA Diabetes Trial Total Mortality Duckworth WC. ADA 68 th Scientific Sessions; June 8, 2008; San Francisco, CA. Hazard Ratio & CL 1.065 (0.801, 1.416) P=0.67 0123456 0.0 0.2 0.4 0.6 0.8 1.0 Proportion Free of All Deaths StandardIntensive

42. Increasing data suggesting that post- prandial glucose is an important risk factor for all-cause and CVD mortality 20 studies, 95,783 people (94% men) followed 12 yrs. (Studies excluded if purely diabetic). RR (95% CI) FPG  110 mg/dl 1.33 (1.06 – 1.67) 2 hr G  140 mg/dl1.58 (1.19 – 2.10) FPG p=0.056, 2 hr p=0.0006 Coutinho, Diabetes Care 1999

43. Both FPG and PPG Contribute to A1C Monnier et al, Diabetes Care 2003 PPG – Clear FPG - Black

44. Major Targeted Sites of Drug Classes Pancreas ↓Glucose level Gut  -Glucosidase Inhibitors Muscle and fat Liver TZDs Biguanide Biguanides Sulfonylureas Meglitinides  -cell Dysfunction Glucose Absorption Hepatic glucose overproduction Insulin resistance TZDs DPP 4 Inhibitors Exenatide

45. Anti-hyperglycemic Agents Glucose (mg/dL) Basal Glucose 150 120 50 0 789121112123456789 A.M.P.M. Time of Day Prandial Glucose Glucose (mg/dL) Basal Glucose 150 120 50 0 789121112123456789 A.M.P.M. Time of Day Prandial Glucose Metformin Sulfonylureas TZD Basal Insulin Acarbose GLP-1 analogues DPP-4 inhbitor Rapid Insulin Riddle, Diabetes Care 1990

46. GLP-1 Effect : Blocked By DPP-4 GLP-1 Actions Mixed Meal GLP-1(7-36)Active Plasma IntestinalGLP-1Secretion GLP-1(9-36) Inactive DPP-IV Rapid Inactivation RenalClearance Deacon et al. Diabetes 1995 IntestinalGLP-1Secretion

47. Incretins Gut peptide hormones (GLP-1, GIP) Gut peptide hormones (GLP-1, GIP) Response to food ingestion Response to food ingestion Stimulate glucose-dependent insulin secretion Stimulate glucose-dependent insulin secretion Account for 60% of insulin response in healthy subjects Account for 60% of insulin response in healthy subjects Potent inhibition of glucagon secretion Potent inhibition of glucagon secretion Increase satiety Increase satiety Promote beta-cell growth and survival Promote beta-cell growth and survival

48. Incretin-based Therapy GLP-1 Analogues DPP-4 Inhibitor AdministrationInjectionOral Mechanism of Action GLP-1 GLP-1 + GIP Insulin secretion ++++ Glucagon Inhibition ++++ A1C Reduction 0.8 – 2% 0.5 – 1.5% Expansion of beta-cell YesYes Nausea and Vomiting YesNo Weight Loss Yes (3 – 5 kg) No HypoglycemiaNoNo Gastric Emptying Inhibited+/-

49. Potential Use of Incretin-Modifying Therapy Potential for use after metformin failure before TZD’s and Insulin secretagogues Potential for use after metformin failure before TZD’s and Insulin secretagogues No hypoglycemia unlike secretagogues No hypoglycemia unlike secretagogues Advantage of weight loss or absence of weight gain Advantage of weight loss or absence of weight gain Beta-cell preservation Beta-cell preservation

50. Summary of Results for Glycemic Control and CVD The overall effect of glycemic target on macrovascular events, if any, is small The overall effect of glycemic target on macrovascular events, if any, is small Tight glycemic control in high risk patients is potentially associated with increased events secondary to hypoglycemia? Tight glycemic control in high risk patients is potentially associated with increased events secondary to hypoglycemia? Increasing data suggesting that post-prandial glucose is important in predicting CV outcomes including mortality Increasing data suggesting that post-prandial glucose is important in predicting CV outcomes including mortality Lipid and BP control, smoking cessation and anti-platelet therapy remain most important for reducing CVD risk in diabetes Lipid and BP control, smoking cessation and anti-platelet therapy remain most important for reducing CVD risk in diabetes

51. Reaching Glycemic Targets Strong evidence for improving microvascular complications, specifically nephropathy and retinopathy Strong evidence for improving microvascular complications, specifically nephropathy and retinopathy Current Target per ADA is A1C level < 7.0% Current Target per ADA is A1C level < 7.0% Should be individualized Should be individualized Given recent results need to be careful with high risk CVD patients Given recent results need to be careful with high risk CVD patients Incretin-based therapies potentially effective addition to our medication regimen Incretin-based therapies potentially effective addition to our medication regimen

52. Saydah S et.al JAMA 2004;291:335 Percentage of Adults with Diabetes Who Achieved Recommended Goals of Cardiovascular Risk Factors in NHANES %