Role of Rosuvastatin in the Treatment of Dyslipidemia Core Unmet Need (CM) 4/20/2017 11:56 PM Role of Rosuvastatin in the Treatment of Dyslipidemia Daniel J. Rader, MD Associate Professor of Medicine Director, Preventive Cardiology and Lipid Clinic University of Pennsylvania School of Medicine

Core Unmet Need (CM) 4/20/2017 11:56 PM Evolution of Lipid Management Guidelines: The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) ATP I (1988) ATP II (1993) ATP III (2001) Diet; low-dose, nonstatin monotherapy Low- to moderate-dose statin monotherapy High-dose statin, combination therapy Increasing aggressiveness of cholesterol-lowering therapy

Core Unmet Need (CM) 4/20/2017 11:56 PM Most Patients Failed to Achieve ATP II LDL-C Goals With Lipid-Lowering Therapy < 160 mg/dL < 130 mg/dL ≤ 100 mg/dL Pearson TA, et al. Arch Intern Med. 2000;160:459-467; Jacobson TA, et al. Arch Intern Med. 2000;160:1361-1369; Sloan KL, et al. Am J Cardiol. 2001;88:1143-1146; Sueta CA, et al. Am J Cardiol. 1999;83:1303-1307.

Core Unmet Need (CM) 4/20/2017 11:56 PM Many Patients With CHD Do Not Come Close to Achieving ATP II LDL-C Goal: L-TAP n = 1,460 Pearson TA, et al. Arch Intern Med. 2000;160:459-467.

Core Unmet Need (CM) 4/20/2017 11:56 PM Many High Risk Patients Are Not Titrated or Do Not Reach LDL-C Goal Even After Titration 2,989 high-risk patients† (with known NCEP LDL-C goal) 53% not at goal on starting dose (n = 1575) 47% at goal on starting dose (n = 1414) 53% Not titrated (n = 838) 47% Titrated (n = 737) 31% Not at goal (n = 478) 16% at goal (n = 259) †CHD and/or diabetes mellitus with high-density lipoprotein cholesterol (HDL-C) ≤ 45 mg/dL. Simpson RJ Jr. Circulation 2001.

Cholesterol Treatment in NHANES (1999-2000) Core Unmet Need (CM) 4/20/2017 11:56 PM Cholesterol Treatment in NHANES (1999-2000) Only 47% of hypercholesterolemic patients treated with drug therapy are adequately controlled. Ford et al. Circulation. 2003;107:5185.

Core Unmet Need (CM) 4/20/2017 11:56 PM Many Patients With CHD Fail to Achieve LDL-C and Non-HDL-C Goals Even With Dose Titration ACCESS At Wk 54 n = 2,543† †Patients in CHD risk category. Ballantyne CM, et al. Am J Cardiol. 2001;88:265-269.

On-Treatment LDL-C Is Closely Related to CHD Events in Statin Trials Core Unmet Need (CM) 4/20/2017 11:56 PM On-Treatment LDL-C Is Closely Related to CHD Events in Statin Trials HPS-Rx HPS-plac CARE-Rx 4S-plac 4S-Rx LIPID-plac CARE-plac LIPID-Rx WOSCOPS-plac WOSCOPS-Rx AFCAPS-plac ASCOT-plac AFCAPS-Rx ASCOT-Rx 2° prevention 1° prevention 5 10 15 20 25 30 80 100 120 140 160 180 200 Mean on-treatment LDL-C level at follow-up (mg/dL) % with CHD event CHD + revasc + stroke CHD pIac = Placebo; Rx = Treatment. Adapted from Ballantyne CM. Am J Cardiol. 1998;82:3Q-12Q.

Core Unmet Need (CM) 8 4/20/2017 11:56 PM HPS: Major Vascular Events in Highest and Lowest LDL-C Tertiles and Effect of Therapy Placebo Simvastatin Highest LDL-C tertile Lowest LDL-C tertile www.hpsinfo.org

Medical Need in the Treatment of Dyslipidemia Core Unmet Need (CM) 4/20/2017 11:56 PM Medical Need in the Treatment of Dyslipidemia A need exists for more efficacious therapy to achieve Greater LDL-C and non-HDL-C lowering at start dose

% of Patients Achieving Both LDL-C and Non-HDL-C ATP III Goals Core Unmet Need (CM) 4/20/2017 11:56 PM % of Patients Achieving Both LDL-C and Non-HDL-C ATP III Goals Trials 24 - 26 Trials 27 - 28 * *P < .05 vs comparators. Baseline TG ≥ 200 mg/dL.

Medical Need in the Treatment of Dyslipidemia Core Unmet Need (CM) 4/20/2017 11:56 PM Medical Need in the Treatment of Dyslipidemia A need exists for more efficacious therapy to achieve Greater LDL-C and non-HDL-C lowering at start dose Greater LDL-C and non-HDL-C lowering at maximal dose

Familial Hypercholesterolemia (FH) Core Unmet Need (CM) 4/20/2017 11:56 PM Familial Hypercholesterolemia (FH) FH is common There are 500,000 patients in the US (frequency, 1 person in 500) FH causes early CHD Average age of CHD onset is 45 to 50 yr in men, 55 to 60 yr in women FH is difficult to treat Most FH patients cannot be adequately treated to NCEP LDL-C goal

Stein et al. J Am Col Cardiol 2003. Core Unmet Need (CM) 4/20/2017 11:56 PM % of High-Risk FH Patients Achieving NCEP ATP III LDL-C Goal in 2 Different Studies Rosuvastatin 40 mg Atorvastatin 40 mg + Ezetimibe 10 mg Atorvastatin 80 mg Atorvastatin 80 mg Note: no statistical analyses were performed. LDL-C: < 100 mg/dL (2.59 mmol/L). Stein et al. J Am Col Cardiol 2003.

Low HDL-C Is Common and Represents an Important Medical Need Core Unmet Need (CM) 4/20/2017 11:56 PM Low HDL-C Is Common and Represents an Important Medical Need Low HDL-C is one of the most common risk factors in patients with premature CHD ATP III placed new emphasis on low HDL-C as a risk factor and potential target for intervention Modest increases in HDL-C may translate into substantial cardiovascular risk reduction Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497.

Medical Need in the Treatment of Dyslipidemia Core Unmet Need (CM) 4/20/2017 11:56 PM Medical Need in the Treatment of Dyslipidemia A need exists for more efficacious therapy to achieve Greater LDL-C and non-HDL-C lowering at start dose Greater LDL-C and non-HDL-C lowering at maximal dose Improved HDL-C raising

Core Unmet Need (CM) 4/20/2017 11:56 PM HDL-C: % Change From Baseline Rosuvastatin: Baseline HDL-C < 40 mg/dL or ≥ 40 mg/dL Trial 65 – STELLAR (Wk 6) HDL-C < 40 mg/dL HDL-C ≥ 40 mg/dL Data presented as LS mean.

Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk Core Unmet Need (CM) 4/20/2017 11:56 PM Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk 1% decrease in LDL-C reduces CHD risk by 1% 1% increase in HDL-C reduces CHD risk by 3% Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670. 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

Role of Rosuvastatin in the Treatment of Dyslipidemia Core Unmet Need (CM) 4/20/2017 11:56 PM Role of Rosuvastatin in the Treatment of Dyslipidemia Greater LDL-C and non-HDL-C lowering at start dose Greater LDL-C and non-HDL-C lowering at maximal dose Improved HDL-C raising