Diabetes Drugs and Cardiac Disease Robert J. Rushakoff, MD - PDF document

4/12/2018 Diabetes Drugs and Cardiac Disease Robert J. Rushakoff, MD Professor of Medicine University of California, San Francisco robert.rushakoff@ucsf.edu Disclosures None 1

4/12/2018 Written Comments • As I have said every time you give a talk – no reason to give anything except metformin and a sulfonylurea • That new ACP review really messed up • Thanks a lot - -DM meds decrease CVD, increase CVD -- what am I supposed to do now • Too many slides DM and Cardiovascular DX Historically • 75% of adults with DM have HTN • DM – 2-4 x increased risk of stroke – 2 x increase risk for CVD death Recently • With all population, decreasing hospitalization for CVD • Still 2-4 times nondiabetes (largest difference in CHF) 2

4/12/2018 The NEW ENGLAND JOURNAL of MEDICINE ESTABLISHED IN 1812 JUNE 14, 2007 VOL. 356 NO. 24 Effect of Rosiglitazone on the Risk of Myocardial Infarction And Death from Cardiovascular Causes Steven E. Nissen, M.D., and Kathy Wolski, M.P.H. CONCLUSIONS Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death…that had borderline significance. Meta-analysis of MI and Death risk with rosiglitazone n = 15,560 on rosiglitazone; n = 12,283 on comparator drug or placebo Rosiglitazone Control group group Odds ratio Study No. of events/Total no. (%) (95% CI) P Myocardial infarction 1.45 (0.88 – 2.39) Small trials combined 44/10,280 (0.43) 22/6105 (0.36) 0.15 1.65 (0.74 – 3.68) DREAM 15/2635 (0.57) 9/2634 (0.34) 0.22 1.33 (0.80 – 2.21) ADOPT 27/1456 (1.85) 41/2895 (1.44) 0.27 1.43 (1.03 – 1.98) Overall 0.03 86 72 86/14371 (.60%) 72/11634 (0.62%) Relative Risk = 86/72 = 1.19 Absolute Risk = -.02% Nissen SE, Wolski K. N Engl J Med. 2007;356. 3

4/12/2018 Center for Drug Evaluation and Research Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee July 30, 2007 David Graham, MD MPH Center for Drug Evaluation and Research Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee July 30, 2007 David Graham, MD MPH 4

4/12/2018 PANIC 5

4/12/2018 ADVANCE: Action in Diabetes and Vascular Disease Goal: To examine effects of reducing HgA1c to < 6.5% and routine use of fixed dose ACE-thiazide combination in >55 y/o Type 2 DM • 11,140 Enrollees • 50% macrovascular dx • 60% male 40% female • 10% microvascular • Mean age 66 Baseline HgA1c: 7.51% “standard” : 7.30% Intensive: 6.53% ADVANCE: Relative Effects of Glucose-Control Strategy on All Prespecified Primary and Secondary Outcomes The ADVANCE Collaborative Group. N Engl J Med 2008;358:2560-2572 6

4/12/2018 ACCORD: Action to Control Cardiovascular Risk in Diabetes  30% macrovascular  10,251 Enrollees dx  60% male 40%  Duration DM: 10 female years  Mean age 62.2  Majority of intensive  Baseline HgA1c group on 3-5 oral 8.1% agents plus insulin  BMI - 32  Hypoglycemia 3 times greater in intensive group Primary and Secondary Outcomes The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559 7

4/12/2018 ACCORD: Hazard Ratios for the Primary Outcome and Death from Any Cause in Prespecified Subgroups The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-2559 Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial Diabetes Care May 2010 vol. 33 no. 5 983-990 8

4/12/2018 VADT - Veterans Administration Diabetes Trial • BMI 31.3 • 72% HTN • 1742 Enrollees • Majority had • 40% macrovascular • 97% male multiple CV risk dx • Mean age 60.4 • 62% retinopathy factors • 43% neuropathy VADT - Veterans Administration Diabetes Trial  Primary Endpoint: NO DIFFERENCE IN CARDIOVASCULAR DISEASE OUTCOMES  Standard: 29.3% (predicted – 40%)  Intensive: 27.4% (predicted – 31.6%) 9

4/12/2018 VADT - Veterans Administration Diabetes Trial  When duration of DM factored in:  Intensive glycemic control showed benefit  Benefit declines until about 12-15 years of disease 10

4/12/2018 Safety Studies for Diabetes Medications • FDA change in 2008 regarding expectation of drug studies for new diabetic medications to ensure there is no unacceptable cardiovascular risk • Prompted by – Recommendations of the 2008 Endocrinologic and Metabolic Drugs Advisory Committee – High cardiovascular risk in patients with diabetes – Safety issues with • Rosiglitazone • Muraglitizar • Intense glucose lowering in the ACCORD trial Safety Studies for Diabetes Medications • FDA expectations – Independent cardiovascular endpoints committee – Evaluation of • Cardiovascular mortality • Stroke • Myocardial infarction – Design studies so can be easily and clearly analyzed via a meta-analysis at study completion – Should include patients with high cardiovascular risk • Elderly • Renal impairment • Advanced cardiovascular disease – Pre and post-marketing trials may be required for new drugs depending upon estimated risk of pre-marketing studies 11

4/12/2018 Completed and ongoing Cardiovascular Outcome Trials (CVOT) William T. Cefalu et al. Dia Care 2018;41:14-31 CVOT • Most phase 4 trials – Required >600 primary end points – 3 point MACE* (CV death, nonfatal MI, nonfatal stroke) – 4 point MACE (added hospitalization for unstable angina) – 5 point MACE (hosp for angina or CHF) • Glycemic equipoise (hence difference in overall meds and sl higher glucoses in placebo groups) *Major Adverse Cardiac Event 12

4/12/2018 Heart Failure • Kaiser (older 2001 Diabetes Care study) : – Type 2 DM <75: 3 fold higher prevalence – Type 2 DM 75-84: 2 fold higher prevalence • Generally between 10-30% of patients in clinical trials. • Associated with higher HbA1c • In summary – high HbA1c levels in T2DM and HF are consistently associated with higher mortality. – HbA1c levels can be associated with good outcomes (at least in a clinical trial cohort), but can be associated with worse outcomes (in population-based studies and those with very advanced HF). Journal of the American College of Cardiology 2018 71:1379-1390 European Journal of Heart Failure (2018) Heart Failure • close relationship between DM and HF • HF was the second most common initial presentation of CV disease, after peripheral artery disease – (large observational study of patients with DM) • among patients hospitalized for HF, the prevalence of DM may exceed 40% Journal of the American College of Cardiology 2018 71:1379-1390 13

4/12/2018 Metformin 14

4/12/2018 Effect of Metformin-Containing Antidiabetic Regimens on All-cause Mortality in Veterans With Type 2 Diabetes Mellitus • Decreased Hazard Ratio for all cause mortality for patients on metformin – vs no metformin – 0.77 (p<0.01) • Increased Hazard Ratio for all cause mortality for patients on insulin: – 1.62 (p<0.001) • Decreased Hazard Ratio for all cause mortality for patients on metformin and insulin vs insulin – 0.62 (p<0.04) Am J Med Sci 2008; 336:241-247 Metformin and CHF • At 2 years in patients with DM and CHF Metformin No Metformin Dead 15.8% 25.5%* Hospitalized 12% 16%* (CHF) Hospitalized 41% 48%* (any cause) * P<0.001 Circ Heart Fail. 2011 Jan 1;4(1):53-8 15

4/12/2018 Cumulative incidence of heart failure hospitalization or cardiovascular death over time. Christianne L. Roumie et al. J Am Heart Assoc 2017;6:e005379 Adjusted hazard ratio and 95%CIs of subgroups. Christianne L. Roumie et al. J Am Heart Assoc 2017;6:e005379 16

4/12/2018 Metformin CVD • Meta analysis of 40 trials – compared with any other treatment or placebo – metformin was associated with a statistically significant decrease in cardiovascular mortality (OR, 0.74; 95% CI, 0.62-0.89). Arch Int Med. 2008;168:2070 – 2080. Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998, 352 (9131): 854-865. Sgambato S, Varricchio M, Tesauro P, Passariello N, Carbone L: Use of metformin in ischemic cardiopathy. Clin Ther. 1980, 94: 77-85. Hanefeld M, Brunetti P, Schhernthaner GH: One year glycemic control with sulphonylurea plus pioglitazone versus sulphonylurea plus metformin in patients with type 2 diabetes. Diabetes Care. 2004, 27: 141-147. 10.2337/diacare.27.1.141. Kao J, Tobis J, Mc Clelland RL: Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol. 2004, 93: 1347-1350. 10.1016/j.amjcard.2004.02.028. PubMedView ArticleGoogle Jadhav S, Ferrell W, Greer IA, Petrie JR, Cobbe SM, Sattar N: Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries. J Am Coll Cardiol. 2006, 48: 956-963. 10.1016/j.jacc.2006.04.088. Kooy A, de Jager J, Lehert P: Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. 2009, 169: 616-625. 10.1001/archinternmed.2009.20. 17