Residual Risk Reduction and design of the ACCORD trial Michel P. HERMANS

1. Residual Risk Reduction and design of the ACCORD trial Michel P. HERMANS MD PhD DipNatSci DipEarthSci DipGeogEnv PGCert (SocSc) Endocrinologie & Nutrition Cliniques universitaires St-Luc Université Catholique de Louvain

2. ASCVD : atherosclerotic cardiovascular disease; RFs: risk factors; LDL : low-density lipoprotein; ApoB: apolipoprotein B-100; HDL: high-density lipoprotein; BMI: body mass index

3. Residual Risk • Risk of macrovascular events and microvascular complications persisting in patients receiving current standards of care, including lipid-, BP-, and glucose-lowering therapies in addition to lifestyle intervention

4. Absolute ASCVD Risk Reduction & Residual Risk Absolute risk (prior to intervention) Risk Reduction (following intervention) Residual Risk Absolute ASCVD Risk (%) Time (months / years)

5. Other Thrombosis / platelet Inflammatory Cardiometabolic Lipid-related Major modifiable Non-modifiable RFs Modifiable Component of Absolute Residual Risk

6. Modifiable RFs coronary artery calcification, LVH, aspecific ST segment ECG changes, Nt-proBNP, collagen vascular disease, CPC and EPC, cystatin C, CKD, OSAHS endothelial dysfunction, microalbuminuria, endothelin-1, hyperuricemia, SNS overactivity, rest tachycardia Other Major modifiable Thrombosis / platelet fibrinogen, PAI-1, vWF Ag, TPA, factor V, VII, VIII, D-dimer, fibrinopeptide A, prothrombin fragments 1+2, platelet agregation, activity, size and volume fasting/postprandial hyperglycemia, insulin resistance, hyperinsulinemia, metabolic syndrome, lipoprotein(a), LDL particle number, non-HDL-C, high fasting TG, homocysteinemia Lipid-related hsCRP, IL-6, SAA, VCAM, ICAM, soluble CD40 ligand, leucocyte count, Lp-PLA2, periodontitis Cardiometabolic oxidised LDL, remnants lipoproteins, HDL subtypes, low apoA-I, apoC-III-containing apoB, high posprandial TG, Lp-PLA2 Inflammatory current smoking, elevated blood pressure, hypercholesterolemia (total, LDL-C &/or apoB), hypo-HDL-emia, overweight/obesity, enlarged waist, sedentarity age, gender, ethnicity, former smoking, CVD family history, diabetes mellitus history, genetic polymorphisms Non-modifiable RFs Columns heights are arbitrary and for didactic purpose; they do not aim at representing real life risk proportion

7. ASCVD : atherosclerotic cardiovascular disease; RFs: risk factors; LDL: low-density lipoprotein; ApoA1: apolipoprotein A1; ApoB: apolipoprotein B-100; Lp-PLA2: lipoprotein-associated phospholipase A(2)

8. ASCVD : atherosclerotic cardiovascular disease; RFs: risk factors

9. ASCVD : atherosclerotic cardiovascular disease; RFs: risk factors; Lp-PLA2: lipoprotein-associated phospholipase A(2)

19. Estimating Residual Risk • Secondary prevention • high to very high • short-term & long-term • Secondary prevention equivalent • T2DM • Primary prevention • Absolute long-term CVD risk estimation • Framingham • SCORE • PROCAM • UKPDS

20. T2DM males in PP (n= 130) LDL-C <100 mg/dlUKPDS Risk

21. T2DM males in PP (n= 130) LDL-C <100 mg/dlUKPDS Risk

24. T2DM males in PP (n= 130) LDL-C <100 mg/dlUKPDS Risk

26. Clinically important lipoproteins parameters • LDL-C (underestimated with raising TG) • HDL-C • non-HDL-C • apolipoprotein B100(apoB) • total burden of VLDL, IDL, LDL & Lp(a) • apolipoprotein A-I (apoA-I) : surrogate for HDL • TG-rich lipoproteins • fasting TG : surrogate for VLDL • postprandialTG: combined VLDL, IDL, chylo • LDL number / size • Lp (a)

27. Journal of the American College of Cardiology,2008, vol 51;1512-1524

28. Journal of the American College of Cardiology,2008, vol 51;1512-1524

29. Residual Risk • Risk of macrovascular events and microvascular complications persisting in patients receiving current standards of care, including lipid-, BP-, and glucose-lowering therapies in addition to lifestyle intervention

31. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial

32. ACCORD Original Goals • To determine whether CVD event rates can be reduced in people with diabetes by intensively targeting 3 major CVD RFs • Hyperglycemia • Dyslipidemia • HBP

33. ACCORD: Three Trials in One Research Program • Randomized, multicenter, double 2 x 2 factorial trial in 10,251 middle-aged or older people with T2DM at high risk for having a CVD event • Glycemic control arm • Intensive glycemic control: target = HbA1c < 6.0% • Standard glycemic control: target = HbA1c 7.0% to 7.9% • Lipid intervention arm • Fenofibrate-simvastatin combination therapy • Simvastatin therapy alone • Blood pressure control arm • Intensive BP control: target = SBP < 120 mmHg • Standard BP control: target = SBP < 140 mm Hg 33

34. ACCORD Primary Outcome • Primary outcome common to the 3 study arms

35. ACCORD Secondary Outcomes Each component of the primary outcome Expanded macrovascular outcome: Primary endpoint + any revascularization + hospitalization for chronic heart failure (CHF) Major CHD event: Cardiovascular deaths (- fatal stroke) + nonfatal-MI + unstable angina Main microvascular endpoint (ACCORD Eye Substudy): Progression of diabetic retinopathy of at least 3 stages on ETDRS scale + photocoagulation + vitrectomy Second microvascular endpoint (used in UKPDS): Fatal or non-fatal renal failure + photocoagulation + vitrectomy (entire population)

36. Assessing the macro- and microvascular benefits of statin + fibrate combination therapy THE ACCORD LIPID TRIAL

37. ACCORD Lipid trial To test whether, in the context of good glycemic and LDL-C control, a lipid-lowering strategy that targets TG and HDL-C levels provides any additional macrovascular and microvascular benefits Simvastatin 20-40 mg + Fenofibrate *According to patients’ LDL-C levels and CVD history 5,518patients Simvastatin 20-40 mg+ Placebo Mean 5.6-year follow-up 1ACCORD Protocol – May 11, 2005 Version. Available at: http://www.accordtrial.org/public/protocol_2005-05-11.pdf. 2 Buse JB et al. Am J Cardiol. 2007;99(12A):21i-33i.

38. In the context of good glycemic control, does a therapeutic strategy that uses a fibrate to increase HDL-C and lower TG together with a statin to lower LDL-C reduce the rate of CVD events compared with a statin-only strategy ? The lipid arm* of ACCORD (using statin/fibrate combination therapy) evaluates the benefits of fenofibrate in a broader patient population than currently recommended by guidelines for fenofibrate treatment (i.e. TG >200 mg/dL or 2.3 mmol/L) ACCORD Lipid Question 1ACCORD Protocol – May 11, 2005 Version. Available at: http://www.accordtrial.org/public/protocol_2005-05-11.pdf. 2 Buse JB et al. Am J Cardiol. 2007;99(12A):21i-33i.

39. ACCORD Lipid trial: macrovascular endpoints Prespecified macrovascular endpoints1,2 1 ACCORD Protocol – May 11, 2005 Version. Available at: http://www.accordtrial.org/public/protocol_2005-05-11.pdf. 2 Buse JB et al. Am J Cardiol. 2007;99(12A):21i-33i.

40. ACCORD Lipid trial: microvascular endpoints • Pre-specified microvascular endpoints1,2 *ETDRS: Early Treatment Diabetic Retinopathy Study • ACCORD-EYE (n=3,537) is investigating the effect of fenofibrate-simvastatin therapy on diabetic retinopathy 1ACCORD Protocol – May 11, 2005 Version. Available at: http://www.accordtrial.org/public/protocol_2005-05-11.pdf. 2 Buse JB et al. Am J Cardiol. 2007;99(12A):21i-33i.