Blood Pressure and Lipid Trials: Rationale, Importance and Design Presented at the American Diabetes Association 68th Scientific Sessions on June 10, 2008.

DSMB Recommendation and NHLBI Decision Discontinue intensive glycemia treatment Transition all participants to the standard glycemia treatment Continue the BP and Lipid trials “These trials continue to address important questions” NHLBI Press Release, February 6, 2008

ACCORD Background: Diabetes and CVD Hypertension and dyslipidemia Are more common in persons with diabetes Disproportionately higher CVD risk with each risk factor (combination multiplicative) Optimal treatments for these CVD risk factors in diabetes are unknown Goff et al., Am J Cardiol 2007;99[suppl]:4i-20i

ACCORD Blood Pressure Trial 4

Ischemic CHD Mortality VS. Usual BP Stratified by Age 120 140 160 180 1 2 4 8 16 32 64 128 256 Usual systolic BP (mm Hg) Usual diastolic BP (mm Hg) Ischemic Heart Disease mortality (floating absolute risk and 95% CI) 70 80 90 100 110 Age at risk: 80-89 years 70-79 years 60-69 years 50-59 years 40-49 years Systolic Blood Pressure Diastolic Blood Pressure Systolic BP increases linearly with age whereas diastolic increases until about age 50, then declines Prospective Studies Collaboration. Lancet. 2002;360:1903.

ACCORD BP Question “In middle-aged or older men and women with type 2 diabetes who are at high risk for having a CVD event, in the context of good glycemic control, does a therapeutic strategy that targets a systolic blood pressure <120mmHg reduce the rate of CVD events more than a strategy that targets a systolic blood pressure of <140 mmHg?”

Rationale for BP Trial SHEP DM Participants same RRR as others, but still at 2X AR. HOT DM Sub-Group 51% RRR, others not. UKPDS-Intensive Group (<150/85 vs <180/105) Reduced DMRE 24% Reduced Deaths DMR 32% Reduced Strokes 44% Reduced MVEP 37% SystEUR-Similar to SHEP ABCD-Microvascular Events Reduced Evidence very modest for BPs <144/<82 Regimens: Used agents shown beneficial in DM ACE-I or ARB: Strongly suggest use in those with previous events

Clinical Trials of BP Lowering in Diabetic Patients: Mean Achieved Systolic (SBP) Mean SBP < intense > intense CVD Risk Reduction SHEP 583 155 146 22-56% Syst-EUR 492 162 153 62-69% HOT 1,501 148 144 30-67% UKPDS 1,148 154 32-44% ABCD 470 138 132 No CVD ↓ ADVANCE 11,140 140 135 14% mortality ↓

Treatment Algorithm for Intensive BP (SBP Goal <120 mmHb)

Treatment Algorithm for Standard BP (SBP Goal >140 mmHg)

BP Agents Used: A Test of Strategy Number single antihypertensive medications – 13 Number of combination medications – 7 Number of classes – 10 Diuretics – 2 ACE-inhibitors – 3 β-blockers – 1 Dihydropyridine CCB – 1 Non-dihydropyridine CCB – 1 ARBs – 2 α-blockers – 1 Sympatholytics – 1 α-β blockers – 1 Vasodialators – 1

ACCORD Lipid Trial 12

Mortal Events/mmol/L Reduction in LDL-C in those With or Without DM CTT Collaborators, Lancet 2008 - 371:117-125.

Major CVD Events/mmol/L Reduction in LDL-C in those With or Without DM CTT Collaborators,The Lancet 2008 - 371:117-125.

Serum cholesterol quintile Cholesterol Predicts CHD Mortality Rate in Diabetic and Nondiabetic Men: MRFIT Study Rate/1000 Serum cholesterol quintile 80 60 40 20 1 2 3 4 5 Diabetic Nondiabetic Bierman EL. Arterioscler Thromb. 1992;12:647-656

ACCORD Lipid Question “In the context good glycemic control, does a therapeutic strategy that uses a fibrate to increase HDL-C and lower triglyceride levels together with statin to lower LDL-C reduce the rate of CVD events compared with a strategy that uses a statin plus a placebo?”

Rational for Lipid Trial Increasing importance of DM: ATP I to III CHD event rates high in trials even with effective statin treatment Dyslipidemia in DM: HDL-C Decreased TGs Increased TC similar in men, slightly higher in women Treatment beyond statins needed to address LDL-C and other aspects of dyslipidemia Concern about niacin and ultimately gemfibrozil Fenofibrate selected

BP Lipid Intensive (SBP<120) Standard (SBP<140) Statin + Masked Study Drug Statin + Masked Study Drug Intensive Glycemia (A1C<6%) 1178 1193 1383 1374 5128* Standard Glycemia (A1C 7-7.9%) 1184 1178 1370 1391 5123* 2362* 2371* 2753* 2765* 10,251 *Primary analyses compare the marginals for main effects

Statistical Power for BP and Lipid BP: 94% power to detect 20% effect Lipid: 87% power to detect 20% effect Composite CVD outcome Nonfatal MI, nonfatal stroke, CVD death ACCORD Study Group, Am J Cardiol 2007;99[suppl]:21i-33i

Decision to discontinue intensive glycemia treatment 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 RFP & Funding Main Trial Starts Recruitment ends Tx continues FU ends Results Published Vanguard Phase (1,174 pts) starts