Cardiovascular Disease in Diabetes

Cardiovascular Disease in Diabetes Where Do We Stand in 2012? David M. Kendall, MD Distinguished Medical Fellow Lilly Diabetes Associate Professor of Medicine University of MInnesota

Disclosure - Duality of Interest Research committees and grant support HealthPartners (MN) NIH trial data safety and monitoring University of California San Diego Cancer Center NIH grant oversight committee Consultant, Advisory Board, or other Committee Activity Sanford Burnham Medical Research Institute and the Florida Hospitals Translational Research Institute scientific advisory board Decade of Discovery in Diabetes (Minnesota): Program Oversight and Research committee Medicaid Health Plans of America (MHPA) Best Practices Oversight committee Employment Full time employee and shareholder - Eli Lilly and Company Spouse is full time employee of OREXIGEN The views and opinions presented herein are my own, and do not necessarily reflect official position of Eli Lilly and Company.

Treatment Targets for Adults with Diabetes Minimizing Micro and Macrovascular Disease Risk Measures A1C Pre-meal glucose Peak post-meal glucose Targets < 7% 90 130 mg/dl < 180 mg/dl Blood Pressure < 130/80 mm Hg LDL-c Triglycerides HDL-c < 100 mg/dl < 150 mg/dl > 40 mg/dl American Diabetes Association. Diabetes Care 35 (Suppl 1), 2012

Glycemic Control in Diabetes A Brief History of Intervention Trials UGDP Oxford Steno Kroc Dallas Oslo Kumamoto VACS SDIS UKPDS DCCT PROactive RECORD BARI -2D VADT ADVANCE ACCORD UKPDS EDIC 1960 1970 1980 1990 2000 2010

Glycemic Control in Diabetes A Brief History of Intervention Trials UGDP Oxford Steno Kroc Dallas Oslo Kumamoto VACS SDIS UKPDS DCCT PROactive RECORD BARI -2D VADT ADVANCE ACCORD UKPDS EDIC 1960 1970 1980 1990 2000 2010

Glucose Control and Cardiovascular Risk There is strong support for the association between hyperglycemia and CVD risk Framingham, EPIC-Norfolk, NHANES, UKPDS There is strong support for the hypothesis that glucose lowering may reduce CVD UKPDS, Kumamoto, EDIC What have recent randomized, controlled, clinical trial data taught us about glucose control and CV risk? ACCORD ADVANCE - VADT

UKPDS Post-hoc Analysis Association of A1C with CVD and Stroke Risk 5 6 7 8 9 5 6 7 8 9 UKPDS 35. Stratton IM. BMJ. 2000;321:405-412.

UKPDS: Myocardial Infarction in Glucose Control Study Cumulative: 537 of 3867 Patients (15%) Patients with events 30% 20% 10% 0% Conventional (n=1138) Intensive (n=2729) P=0.052 Risk reduction 16% (95% CI: 0 % to 29%) 0 3 6 9 12 15 Years from randomization Fatal or nonfatal myocardial infarction, sudden death. UKPDS Group. Lancet. 1998;352:837-853.

The UKPDS and Glycemic Control What Did It Teach Us? Fatal or non-fatal myocardial infarction or sudden death Intensive (SU/Ins) vs. Conventional glucose control UKPDS. Lancet.. 1998;352:837-853. 853. UKPDS. N Engl J Med.. 2008;359 epub ahead of print

DCCT/EDIC: Early Intensive Glycemic Control Reduces Risk of CAD in Type 1 Diabetes No evidence of reduction in CVD risk observed in DCCT Early intensive therapy reduced CVD risk more than 10 years after the intervention 42% EDIC Research Group. N Engl J Med 2005;353:2643-53

A Broader View of Complications and Diabetes Implications of ACCORD, ADVANCE and VADT Study UKPDS A1C 9 7.9 7 DCCT/EDIC 9 7.1 ACCORD 7.5 6.4 ADVANCE 7.3 6.5 VADT 8.4 6.9 Adapted from Bergenstal RM, Bailey C and Kendall DM. Am J Med 123:374e9-e18, 2010 UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865. Holman RR. N Engl J Med. 2008 Oct 9;359(15):1577-89. DCCT Research Group. N Engl J Med 329;977-986, 1993 Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. Gerstein HC, et al. N Engl J Med. 2008;358:2545-2559. Patel A, et al. N Engl J Med. 2008;358:2560-2572. Duckworth W et al N Engl J Med 2009;360:129-39 EY Chew for ACCORD. N Engl J Med (10.1056/NEJMoa1001288) was published on June 29, 2010, at NEJM.org. Initial Trial Long Term Follow-up

A Broader View of Complications and Diabetes Implications of ACCORD, ADVANCE and VADT Study A1C Microvascular UKPDS 9 7.9 7 DCCT/EDIC 9 7.1 ACCORD 7.5 6.4 ADVANCE 7.3 6.5 VADT 8.4 6.9 Adapted from Bergenstal RM, Bailey C and Kendall DM. Am J Med 123:374e9-e18, 2010 UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865. Holman RR. N Engl J Med. 2008 Oct 9;359(15):1577-89. DCCT Research Group. N Engl J Med 329;977-986, 1993 Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. Gerstein HC, et al. N Engl J Med. 2008;358:2545-2559. Patel A, et al. N Engl J Med. 2008;358:2560-2572. Duckworth W et al N Engl J Med 2009;360:129-39 EY Chew for ACCORD. N Engl J Med (10.1056/NEJMoa1001288) was published on June 29, 2010, at NEJM.org. Initial Trial Long Term Follow-up

A Broader View of Complications and Diabetes Implications of ACCORD, ADVANCE and VADT Study A1C Microvascular CVD Mortality UKPDS 9 7.9 7 DCCT/EDIC 9 7.1 ACCORD 7.5 6.4 ADVANCE 7.3 6.5 VADT 8.4 6.9? Adapted from Bergenstal RM, Bailey C and Kendall DM. Am J Med 123:374e9-e18, 2010 UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854-865. Holman RR. N Engl J Med. 2008 Oct 9;359(15):1577-89. DCCT Research Group. N Engl J Med 329;977-986, 1993 Nathan DM, et al. N Engl J Med. 2005;353:2643-2653. Gerstein HC, et al. N Engl J Med. 2008;358:2545-2559. Patel A, et al. N Engl J Med. 2008;358:2560-2572. Duckworth W et al N Engl J Med 2009;360:129-39 EY Chew for ACCORD. N Engl J Med (10.1056/NEJMoa1001288) was published on June 29, 2010, at NEJM.org. Initial Trial Long Term Follow-up

Potential Risks of Intensive Control Who Are the Highest Risk Individuals? Conventional Wisdom: Older individuals with established CVD Those who achieved lower A1C values Use of insulin therapy Individuals with longer duration diabetes Who May Be at Risk with more intensive Rx Longstanding poor control History of severe hypoglycemia Those less responsive to intensive Rx NO NO NO MAYBE YES YES MAYBE

Epidemiologic Relationships Between A1c and All-cause Mortality in the ACCORD Trial Adjusted log (HR) by Treatment Strategy Excess Progressive risk with increase intensive of risk strategy from 6 vs to standard 9% A1c with occurred intensive above strategy A1c A 7% Relative to standard at A1c of 6% Linear Prediction 1 0 1 Intensive strategy Standard strategy 6 7 8 9 Average A1c % Riddle M et al. Diabetes Care 2010

The ORIGIN Trial Impact of Early Insulin Therapy on CVD Risk In high risk people with IFG, IGT or early diabetes, Does insulin glargine replacement therapy targeting fasting glucose 5.3 mm or 95 mg/dl), reduce CV outcomes more than standard approaches to dysglycemia? ORIGIN Trial Investigators. Published on June 11, 2012, at NEJM.org. N Engl J Med 2012

Blood Pressure Control and Lipid Management in Diabetes Treatment Targets Treatment Approaches Implications of ACCORD and ADVANCE

Treatment Targets for Adults with Diabetes Minimizing Micro and Macrovascular Disease Risk Measures A1C Pre-meal glucose Peak post-meal glucose Targets < 7% 90 130 mg/dl (5-7.2 mm) < 180 mg/dl (10 mm) Blood Pressure < 130/80 mm Hg LDL-c Triglycerides HDL-c < 100 mg/dl (2.59 mm) < 150 mg/dl (1.69 mm) > 40 mg/dl (1.03 mm) American Diabetes Association. Diabetes Care 35 (Suppl 1), 2012

Type 2 Diabetes and Blood Pressure: BP Control and Risk in the ACCORD and ADVANCE Era Microvascular 40 Complication Rate per 1000 person-years 30 20 10??? -10% -30% ~ 15% reduction in risk for each 10 mm Hg decrease in SBP ACCORD ADVANCE UKPDS 0 110 120 130 140 150 160 170 Modified from Adler A. BMJ 321;412-419, 419, 2000 Mean SBP (mm Hg)

Multi-Risk Factor Intervention in Diabetes The ACCORD Trial - Blood Pressure Intensive (SBP<120) BP Trial Standard (SBP<140) Group A Statin only Lipid Trial Group B Statin+Fibrate Intensive Glycemic Control (HbA1c<6%) Target SBP 1178 1193 < 120 vs < 140 1383 1374 5128* Standard Glycemic Control (HbA1c 7-7.9%) Multi-drug therapy Systematic titration 1184 1178 Target driven approach 1370 1391 5123* 2362* 2371* 2753* 2765* 10,251 *Primary analysis compares marginals for main effects ACCORD Study Group. Am J Cardiol 99(12A):21i-33i, 2007.

Effects of Intensive Blood Pressure Control The ACCORD Trial ACCORD Study Group. N Engl J Med 2010. Published on March 14, 2010, at NEJM.org.

Effects of Intensive Blood Pressure Control The ACCORD Trial More intensive control of SBP did not further reduce CVD risk in type 2 diabetes ACCORD Study Group. N Engl J Med 2010. Reduced rates of total and non-fatal stroke ACCORD Study Group. N Engl J Med 2010. Published on March 14, 2010, at NEJM.org.

Multi-Risk Factor Intervention in Diabetes The ACCORD Trial - Lipids Intensive (SBP<120) BP Trial Standard (SBP<140) Group A Statin only Lipid Trial Group B Statin+Fibrate Intensive Glycemic Control (HbA1c<6%) Standard Glycemic Control (HbA1c 7-7.9%) No significant added benefit Fenofibrate (in 1178 reducing MI, 1193 stroke or CVD 1383death) 1374 or with ~85% Placebo of addition of fibrate to subjects statin Background therapy receiving statin statin LDL therapy 60-180 1184 1178 HDL 1370 < 50 and TG 1391 <750 The ACCORD Study Group. N Engl J Med 2010. Published at www.nejm.org March 14, 2010 (10.1056/NEJMoa1001286) 5128* 5123* 2362* 2371* 2753* 2765* 10,251 *Primary analysis compares marginals for main effects ACCORD Study Group. Am J Cardiol 99(12A):21i-33i, 2007.

CVD Outcomes in Diabetes A Rational Approach in 2012

Treatment Targets for Adults with Diabetes Minimizing Micro and Macrovascular Disease Risk Measures A1C Pre-meal glucose Peak post-meal glucose Targets < 7% 90 130 mg/dl < 180 mg/dl Blood Pressure < 130/80 mm Hg LDL-c Triglycerides HDL-c < 100 mg/dl or statin < 150 mg/dl > 40 mg/dl American Diabetes Association. Diabetes Care 35 (Suppl 1), 2012

Multi-factorial Intervention and CVD in Patients with Type 2 Diabetes: Long Term Follow-up STENO -2 Study design Mortality CVD Risk 46% 59% reduction CVD risk interventions (160 subjects renal disease and CV risk) Multi-factor risk factor approach Randomized, Reduced open-label risk therapy of morbidity of conventional and vs intensive multi-factorial interventions (BP, glucose, lipids, ASA) mortality in high risk group with Composite primary endpoint diabetes CVD death, NFMI, stroke, revascularization, amputation, vascular surgery Gaede P. N Engl J Med. 2008;358:580-91

Reducing CVD and Complications Risk Summary and Conclusions Treatment targets for comprehensive diabetes management: 1. Early, individualized and intensive glycemic control to limit the risk of microvascular disease 2. Glycemic control and control of SBP (<130) to limit the risk and progression of renal and retinal disease 3. Targeting LDL-c and SPB to limit the risk of CVD. Addition of fibrate if very low HDL-c/high TG Lower SBP targets for those at highest risk of stroke American Diabetes Association. Diabetes Care 35 (Suppl 1), 2012

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