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The Role of Cardiovascular Assessment in the Approval Process of Diabetic Medications

The Role of Cardiovascular Assessment in the Approval Process of Diabetic Medications. David M. Nathan, M.D. FDA Advisory Meeting July 1, 2008. Diabetes, Hyperglycemia and Cardiovascular Disease: One and the Same?. David M. Nathan, M.D. FDA Advisory Meeting July 1, 2008. Nosology.

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The Role of Cardiovascular Assessment in the Approval Process of Diabetic Medications

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  1. The Role of Cardiovascular Assessment in the Approval Process of Diabetic Medications David M. Nathan, M.D. FDA Advisory Meeting July 1, 2008

  2. Diabetes, Hyperglycemia and Cardiovascular Disease:One and the Same? David M. Nathan, M.D. FDA Advisory Meeting July 1, 2008

  3. Nosology • Diabetes mellitus is a chronic disease characterized by abnormal metabolism of glucose (blood sugar) as well as other nutrients such as protein and fat, and accompanied by the risk of long-term complications specific to diabetes that affect the eye, kidney and nervous system. • World Book Encyclopedia, 2000

  4. Retinopathy and Glucose Control Type 2 diabetes (n-185) Retinopathy Prevalence % Hemoglobin A1c (%) Nathan et al. Diabetes 1986;35:797 P=.002 for trend

  5. Association of Glycemia with Complications Pima Retinopathy PimaEgyptNHANES FPG 116 108 110 2h 180 155 154 A1c 6.0 6.0 6.0 Egyptian NHANES 1997 ADA Expert Committee

  6. Risk of Retinopathy [Glycemia] Diagnostic Criteria for Diabetes Mellitus • Predicated on glucose levels associated with risk for complications • Although risk increases with rising glycemia, there is a threshold below which complications do not occur

  7. Retinopathy in Recent Onset Diabetes and Non-diabetic Persons at High Risk of Diabetes in the Diabetes Prevention Program Diabetes Prevention Program Outcomes Study Research Group Writing Group: D. Nathan (Chair), E. Chew, C. Christophi, M. Davis, S. Fowler, B. Goldstein, R. Hamman, L. Hubbard, W. Knowler, M. Molitch

  8. Diabetic Medicine 2007:24:137

  9. Tight Control and Type 1 Diabetes 2% Primary Prevention Secondary Intervention 54% 76% DCCT Research Group NEJM 1993;342:381

  10. Intensive Therapy of Type 1 Diabetes Hypoglycemia Weight gain Effort Expense DCCT SDIS Reduced development and progression of all complications

  11. UKPDS Results DCCT 2% 1% Obese and non-obese treated with conventional vs insulin/sulphonylureas UKPDS Lancet 1998;352; 837.

  12. Intensive Therapy of Type 2 Diabetes Minimal hypoglycemia Weight gain No excess CVD Effort Expense UKPDS Kumamoto Reduced development and progression of complications

  13. Relationship between Glycemia and Complications DCCT and UKPDS 43% reduction in risk for every 10% decrease in HbA1c Event Rate per 1000 Pt-Y DCCT 37% reduction in risk for every 1% decrease in HbA1c UKPDS Current Mean HbA1c (%) ©2005 David M. Nathan

  14. D I A G N O S I S Retinopathy Categories and Continua: Hyperglycemia and its Consequences R I S K IGT IFG Diabetes [Glycemia] © 2005 David M. Nathan

  15. Glycemia and Complications • Apparent glycemic thresholds for the development of complications define the diagnostic cut-points for diabetes • Glycemia in the “diabetic” range is associated with risk for developing complications • Treatment that lowers glycemia reduces the risk for development and progression of microvascular diabetic complications

  16. Glycemia and Diabetes • On the basis of the intimate association between glycemia, and in particular measures of chronic glycemia, and diabetes complications (epidemiology, clinical trials), the effectiveness of medications to lower HbA1c has been used as a metric in considering new diabetes medications • However, recent experience has suggested that some anti-diabetic medications may worsen CVD risk

  17. Glycemia and Diabetes • Some have questioned whether the FDA posture of approving diabetes medications on the basis of their effects on glycemia (a “surrogate”) is adequate • Should the effect(s) of diabetes medications on CVD be required during approval process • Toxicity • Benefits

  18. Circulation 1999; 100:1132-46

  19. Thus, diabetes must take its place alongside the other major risk factors as important causes of CVD. In fact, from the point of view of cardiovascular medicine, it may be appropriate to say, “diabetes is a cardiovascular disease.” Circulation 1999; 100:1134

  20. Effect of Type 2 DM on CVD Outcome Population-based Finnish Study 1373 Non-diabetic 1059 diabetic Aged 45-64 7 year incidence (%) MI CVA Mort MI CVA Mort No Prior MI Prior MI Haffner et al. NEJM 1998;339:229 © 2005 David M. Nathan

  21. Framingham Heart Study Relative Risk MenWomen CHF 2.8 7.7 CAD 1.9 3.6 CAD Death 2.6 7.2 Stroke 3.3 5.6 Claudication 4.7 8.9 Kannel, McGee JAMA 1979;241:2035 © 2005 David M. Nathan

  22. LDL HDL Hypertension Smoking Hyperglycemia Renal disease Auto. Neuropathy Glycated lipoproteins Hemorheologic PAI-1 Platelet activ. Endothel. Dysf. Obesity Insulin resistance Hyperinsulinemia Type 2 Pathophysiology of CVD in Diabetes Mellitus Attained Age Dyslipidemia Triglycerides/VLDL Small, dense LDL Oxidized lipoproteins FFA Inflammation CVD © 2008 David M. Nathan

  23. Diabetes and CVD: How Sweet it is (or is it?) © 2008 David M. Nathan

  24. Association of Glycemia with CVD • 1045 survivors of original Framingham cohort • (44% of survivors) • HbA1c measured in 1986-89 • Prevalence of CVD (CAD,CHF, PVD, stroke/TIA) • correlated with A1c (more strongly in women than men) • A1c remained significant factor in models where other • known risk factors included • 39% increase in risk for CVD for each 1% increase in A1c • D. Singer, D. Nathan • Diabetes 1992;41:202 • Early studies could not establish relationship, owing in part to poor measures of chronic glycemia • In 1992, we established a significant relationship between glycemia, measured with A1c, and prevalent CVD in the predominantly non-diabetic Framingham population • Subsequently, numerous studies confirmed association © 2008 David M. Nathan

  25. Association of HbA1c with CVD Framingham Heart Study P=.001 Relative Risk P=.04 Results unchanged if diagnosed diabetics removed HbA1c: < 5.1 5.1-5.46 5.47-5.92 > 5.92 N- women 145 164 165 155 men 112 104 93 107 Diagnosed diabetes (%) 3.4 4.3 4.2 25 © 2005 David M. Nathan

  26. Hemoglobin A1c as a CVD Risk Factor EPIC Study Men, n=4662 Followup ~ 6 years RR* Diagnosed diabetes Hemoglobin A1c *Age adjusted. No significant change when adjusted for other CVD risk factors. Khaw Ann Int Med 2004;141:413 © 2005 David M. Nathan

  27. Framingham Offspring Study Population-based Cohort- children of original Framingham Heart Study population: OGTT at 4th four year cycle exam FPGHbA1cNumber (mg/dL) (%) NGT 1 60-85 5.1 418 NGT 2 86-90 5.2 541 NGT 3 91-95 5.2 635 NGT 4 96-100 5.3 502 NGT 5 101-139 5.4 559 IGT 76-140 5.5 329 DM 89-298 6.8 125 Meigs, Nathan et al. Ann Int Med 1998; 128:524 Framingham Offspring Study

  28. P< .001, for trend CVD Risk Associated with Glycemia Prevalence of Hypertension: Diastolic > 95, Systolic > 160, or Treatment 60 50 % 40 Men 30 Women 20 10 0 NGT 1 NGT 2 NGT 3 NGT 4 NGT 5 IGT Type 2 Meigs, Nathan et al. Ann Int Med 1998; 128:524 Framingham Offspring Study

  29. CVD Risk Associated with Glycemia Prevalence of Dyslipidemia: HDL < 35 men, women < 45 mg/dL P< .001, for trend % Meigs, Nathan et al. Ann Int Med 1998; 128:524 Framingham Offspring Study

  30. Distribution of Hemostatic Factors Q1 Q2 Q3 Q4 Q5 IGT NIDDM P Fibrinogen 285 289 292 298 302 302 315 * Factor VII 95 95 97 97 98 101 101 * PAI-1 17 18 20 22 24 30 35 * t-PA 7.6 7.7 8.5 8.7 9.7 10.9 11.8 * vW factor 125 124 126 127 128 133 140 + * <.0001 for trend; + < .05 Framingham Offspring Study

  31. D I A G N O S I S CVD Retinopathy Categories and Continua: Hyperglycemia and its Consequences R I S K IGT IFG Diabetes [Glycemia] © 2005 David M. Nathan

  32. The Effect of Intensive Diabetes Management on Cardiovascular Events in Type 1 Diabetes DCCT/EDIC Research Group June 12, 2005

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

  34. Type 1 LDL LDL HDL HDL Hypertension Hypertension Smoking Hyperglycemia Renal disease Auto. Neuropathy Glycated lipoproteins Hemorheologic PAI-1 Platelet activ. Endothel. Dysf. Hemorheologic PAI-1 Platelet activ. Endothel. Dysf. Obesity Obesity Insulin resistance Hyperinsulinemia Insulin resistance Hyperinsulinemia Type 2 Pathophysiology of CVD in Diabetes Mellitus A t t a I n e d A g e Dyslipidemia Triglycerides/VLDL Small, dense LDL Oxidized lipoproteins FFA Inflammation CVD

  35. Cardiovascular Events in Type 2 Diabetes • No CCTs have demonstrated a benefit of • intensive therapy aimed at lowering glycemia • on CVD events • UGDP ADVANCE RECORD • UKPDS PROACTIVE • ACCORD VADT • Some trials have suggested harm with specific • drugs or regimens • UGDP- tolbutamide ACCORD regimen • UKPDS- SU + metformin • Some trials have suggested benefit • UKPDS-metformin • PROACTIVE- pioglitazone

  36. Are Diabetes and CVD the Same? Common Soil • Are there common antecedent risk factors that underlie CVD and diabetes? • Demographic • Clinical • Biochemical • Genetic • If common soil is present, are there treatments that modify such factors that might ameliorate both diabetes and CVD?

  37. FFA Resistin Leptin TNF Adiponectin Hypertension IGT Inflammation Dyslipidemia Endothelial dysfunction IL-6 CRP VLDL HDL Thrombosis + VCAM ICAM MCP E-selectin NO Fat Mass t-PA PAI-1 vWF Insulin deficiency Diabetes CVD Are Diabetes and CVD the Same? Common Soil: Obesity Insulin resistance

  38. Are Diabetes and CVD the Same? Common Soil Insulin resistance Diabetes CVD

  39. Are Diabetes and CVD the Same? Common Soil Inflammation Diabetes CVD

  40. Reykjavik Heart Study • Population-based study • Mean followup- 18 years • 2459 fatal or non-fatal Mis • 3969 controls • Age 59 • 70% males • Cases were heavier, higher • BP, BMI, T-chol, triglycerides • CRP 1.8 vs 1.3 mg/L, P< .001 * * * CRP CRP ESR ESR vWF vWF Adjusted for Adjusted for other other risk factors risk & inflam. factors OR for MI, top 1/3 vs bottom significant Diabetes and CVD: Common Soil Inflammation: CRP Danesh et al. NEJM 2004;350:1387 *

  41. Diabetes and CVD: Common Soil Inflammation: CRP • MONICA Study • Population-based study • N= 3993 • Mean followup- 7 years • 101 incident cases of diabetes Arch Int Med, 2003 Adjusted for Adjusted for age, Age and BMI BMI,smoking, BP OR for Incident Diabetes by CRP quartile

  42. Diabetes and CVD: Common Soil Inflammation: CRP • Rotterdam Study • Population-based study • N= 6,935 • Mean followup- 9.8 years • 544 incident cases of diabetes Dehgan et al. Diabetes 2007;56:872 Adjusted for Adjusted for age, sex Age and sex BMI, BPsys, BP diast, HDL OR for Incident Diabetes by CRP quartile

  43. No good examples of CVD interventions • that improve glycemia • DREAM study failed to demonstrate the • putative benefit of ACE-inhibitors • Several CVD medications (beta-adrenergic • blockers) worsen glycemia • The TINSAL study is studying the effects of • an anti-inflammatory on diabetes Cultivating the Common Soil Effects of CVD Treatments on Diabetes

  44. Life-style interventions • Glycemic medication therapy • Chronic • Acute • Toxic drugs? • Beneficial interventions? Cultivating the Common Soil Effects of Diabetes Treatments on CVD

  45. Effects of Life-style on CVD Risk Factors Look:AHEAD Study- 1 year results 47 89% 45 7.25 6.61 7.15 165 15 69 127 67 153 13 x101 107 107 121 79% Diabetes Care 2007;30:1374

  46. Life-style interventions • Glycemic medication therapy • Chronic- ACCORD,ADVANCE, etc • Acute • Toxic drugs? • Beneficial interventions? Cultivating the Common Soil Effects of Diabetes Treatments on CVD

  47. Life-style interventions • Glycemic therapy • Chronic • Acute • Toxic drugs? • Beneficial interventions? Cultivating the Common Soil Effects of Diabetes Treatments on CVD

  48. Role of Specific Anti-diabetic Agents in CVD • Are specific therapies cardiotoxic? • Sulfonylureas-UGDP 1%/yr excess CVD mortality • Biguanides- UKPDS (with sulfonylureas) • Rosiglitazone • ACCORD intensive regimen • Are specific therapies cardioprotective? • Insulin- DIGAMI • Metformin- UKPDS monotherapy • Acarbose • Pioglitazone

  49. Life-style interventions • Glycemic therapy • Chronic • Acute • Toxic drugs? • Beneficial interventions? Cultivating the Common Soil Effects of Diabetes Treatments on CVD

  50. Role of Specific Anti-diabetic Agents in CVD • Are specific therapies cardiotoxic? • Sulfonylureas-UGDP 1%/yr excess CVD mortality • Biguanides- UKPDS (with sulfonylureas) • Rosiglitazone • Are specific therapies cardioprotective? • Insulin- DIGAMI, Leuven • Metformin- UKPDS monotherapy • Acarbose- STOPNIDDM • Pioglitazone- PROACTIVE

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