Is HDL Therapy the Next Target to Reduce Cardiovascular Events in the Statin-Treated Patient? Christie M. Ballantyne, MD Center for Cardiovascular Disease Prevention Methodist DeBakey Heart & Vascular Center Baylor College of Medicine Houston, Texas

Christie M. Ballantyne, MD Financial Disclosure Grant/Research Support (All paid to institution, not individual): Abbott, AstraZeneca, Bristol-Myers Squibb, diaDexus, GlaxoSmithKline, Kowa, Merck, Novartis, Roche, Sanofi-Synthelabo, Takeda, NIH, ADA, AHA Consultant: Abbott, Adnexus, Amylin, AstraZeneca, Bristol-Myers Squibb, Esperion, Genentech, GlaxoSmithKline, Idera Pharma, Kowa, Merck, Novartis, Omthera, Resverlogix, Roche, Sanofi-Synthelabo, Takeda Speakers Bureau: Abbott, AstraZeneca, GlaxoSmithKline, Merck Honorarium: Abbott, AstraZeneca, GlaxoSmithKline, Merck, Sanofi-Synthelabo, Takeda

HDL-C and Statin Trials Do patients with low HDL-C benefit from statin therapy? Are the effects of statins on HDL related to benefits on atherosclerosis progression and event reduction? Are low HDL-C/high TG still associated with increased CVD risk after high-efficacy statin therapy? Does adding a second agent to statin therapy that targets HDL metabolism have additive effects on atherosclerosis/CVD events?

Case 62-year-old male with history of hypertension and hyperlipidemia admitted with unstable angina, had urgent PCI with stent for 95% proximal LAD lesion; multiple <50% lesions in RCA, Circ, and LAD On exam: BMI 28.6, waist 40" Current meds: lisinopril 20 mg/HCTZ 12.5 mg ASA 325 mg

Lab Results on Arrival in ER TC 203 mg/dL TG 330 mg/dL HDL-C 38 mg/dL LDL-C 100 mg/dL non-HDL-C 165 mg/dL Glucose 115 mg/dL Cr 1.2 BUN 20 mg/dL

HDL-C and Statin Trials Do patients with low HDL-C benefit from statin therapy?

Event Reduction with Statin Therapy in Patients with Low vs. High HDL-C Coronary Events (%) 52 38 39 <39 >44 <33 43 <43 40 34 4S LIPID CARE WOSCOPS AFCAPS Adapted from Ballantyne CM et al. Circulation 1999;99:736-743.

HDL-C and Statin Trials Do patients with low HDL-C benefit from statin therapy? Are the effects of statins on HDL related to benefits on atherosclerosis progression and event reduction?

Change in Percent Diameter Stenosis vs On-treatment HDL-C in QCA Trials -1 -0.8 -0.6 -0.4 -0.2 0.2 0.4 0.6 0.8 1 1.2 1.4 MARS MAAS PLAC I LCAS CCAIT ASTEROID 40 45 50 Change in % stenosis per year On-treatment HDL-C (mg/dL) Placebo Statin* * ASTEROID rosuvastatin MAAS simvastatin CCAIT lovastatin MARS lovastatin LCAS fluvastatin PLAC I pravastatin Ballantyne CM et al. Circulation 2008;117:2458–2466.

Beneficial Impact of Lowering LDL-C:HDL-C Ratio on Atherosclerosis Change in PAV (%) 2 1 -1 -2 LDL-C:HDL-C during treatment 3 Nicholls S et al. JAMA 2007;297:499–508

1300 patients with symptomatic CAD (angiographic stenosis >20%) SATURN 1300 patients with symptomatic CAD (angiographic stenosis >20%) LDL-C with (>80 mg/dL) or without (>100 mg/dL) statin use last 4 weeks Rosuvastatin 40 mg (n =650) Atorvastatin 80 mg (n=650) Safety Lipids Safety IVUS Lipids Visit: Week: 1 –4 3 4 13 5 26 6 39 7 52 8 65 9 78 10 91 11 104 Screening Period 2 –2 Atorva 40 mg Rosuva 20 mg Randomization Period

Percent change from baseline, AFCAPS/TexCAPS: Percent Change in HDL-C, Apo A-I, and Apo B/Apo A-I at 1 Year Percent change from baseline, lovastatin – placebo Gotto AM et al. Circulation 2000;101:477–484.

HDL-C and Statin Trials Do patients with low HDL-C benefit from statin therapy? Are the effects of statins on HDL related to benefits on atherosclerosis progression and event reduction? Are low HDL-C/high TG still associated with increased CVD risk after high-efficacy statin therapy?

Low HDL-C and Risk for CVD in Statin Trials: CTT Meta-Analysis Control (n = 45 002) Treatmentb (n = 45 054) 5-Year Risk of Major Vascular Eventsa, % ≤35 35-42.5 >42.5 HDL-C, mg/dL aCombined outcome of nonfatal MI, CHD death, nonfatal or fatal stroke, or coronary revascularization bEvent rate per 1 mmol/L (39 mg/dL) reduction in LDL-C Baigent C, et al. Lancet. 2005;366;1267-1278.

Low HDL-C and CV Events: TNT HDL-C Quintiles,a mg/dL 5-Year Risk of Major CVD Events, % Patients with LDL-C ≤70 mg/dL on statina,b Q1 <37 Q2 37 to <42 Q3 42 to <47 Q5 ≥55 Q4 47 to <55 Hazard Ratio Versus Q1* 0.85 0.57 0.55 0.61 39% Lower Risk aOn-treatment level (3 months statin therapy); n = 2661 bMean LDL-C, 58 mg/dL; mean TG, 126 mg/dL *P=.03 for differences among quintiles of HDL-C Barter P, et al. New Engl J Med. 2007;357:1301-1310.

JUPITER: CVD Event Rates by Quartiles of HDL-C and apo A-I Median LDL-C with rosuvastatin: 55 mg/dL Ridker PM et al. Lancet 2010;376:333-339.

Effects on major vascular events per 1-mmol/L reduction in LDL-C by baseline HDL-C in 5 more-vs-less trials PROVE IT A to Z TNT IDEAL SEARCH Events per annum, % ≤1.0 1.0–1.3 ≥1.3 HDL-C, mmol/L Cholesterol Treatment Trialists' (CTT) Collaboration. Lancet 2010;376:1670-1681.

HDL-C and Statin Trials Do patients with low HDL-C benefit from statin therapy? Are the effects of statins on HDL related to benefits on atherosclerosis progression and event reduction? Are low HDL-C/high TG still associated with increased CVD risk after high-efficacy statin therapy? Does adding a second agent to statin therapy that targets HDL metabolism have additive effects on atherosclerosis/CVD events?

Event Trials ACCORD AIM-HIGH HPS2-THRIVE dal-Outcomes HPS-3 TIMI-55 REVEAL