Simvastatin Increases HDL-C and Apolipoprotein A-1 Levels Significantly More Than Atorvastatin John P. Kastelein, Evan A. Stein, Michael A. Davidson, John R. Crouse, Leiv Ose, Minzhi Liu, Michael R. Melino, Laura O’Grady, Michel Mercuri, Yale B. Mitchel For the Simvastatin Atorvastatin HDL Study Group; Academic Medical Center, Amsterdam, The Netherlands Merck Research Laboratories, Rahway, New Jersey, USA JACC February 2000 Volume 35 Number 2 (supplement A): 315A ACC 2000, Anaheim, CA

Simvastatin/Atorvastatin HDL Study Background HDL-C and apolipoprotein (apo) A-1 levels are inversely related to the risk of coronary heart disease.HDL-C and apolipoprotein (apo) A-1 levels are inversely related to the risk of coronary heart disease. Recently the VA-HIT study suggested that modest increases in HDL-C could have significant benefits on cardiovascular events.Recently the VA-HIT study suggested that modest increases in HDL-C could have significant benefits on cardiovascular events. Statins, in addition to lowering LDL-C and TG, increase HDL-C levels.Statins, in addition to lowering LDL-C and TG, increase HDL-C levels. However, recent data suggest that a differential effect of simvastatin and atorvastatin on HDL-C exists, in that at higher doses of both drugs simvastatin raises HDL-C more than atorvastatin.However, recent data suggest that a differential effect of simvastatin and atorvastatin on HDL-C exists, in that at higher doses of both drugs simvastatin raises HDL-C more than atorvastatin. JACC February 2000 Volume 35 Number 2 (supplement A): 315A ACC 2000, Anaheim, CA

Simvastatin/Atorvastatin HDL Study Methods This multicenter, double-blind, 36-week dose titration study was designed to evaluate the effects of simvastatin and atorvastatin on HDL-C and apo A-1 levels.This multicenter, double-blind, 36-week dose titration study was designed to evaluate the effects of simvastatin and atorvastatin on HDL-C and apo A-1 levels. Following a 4-week diet run-in period, 826 patients (47% female) with LDL-C > 160 mg/dL and TG 160 mg/dL and TG < 350 mg/dL were randomized to simvastatin or atorvastatin for 36 weeks. JACC February 2000 Volume 35 Number 2 (supplement A): 315A ACC 2000, Anaheim, CA

Simvastatin/Atorvastatin HDL Study Design TreatmentTreatment –Simvastatin 40 mg/day period 1 (6 weeks), and 80 mg/day periods 2 (6 weeks) and 3 (24 weeks) –Atorvastatin 20 mg/day period 1 (6 weeks), 40 mg/day period 2 (6 weeks) and 80 mg/day period 3 (24 weeks) Primary lipid endpoint for week 6, 12 and 18/36 efficacy analysisPrimary lipid endpoint for week 6, 12 and 18/36 efficacy analysis –HDL cholesterol Key secondary lipid endpoint for week 6, 12 and 18/36 efficacy analysisKey secondary lipid endpoint for week 6, 12 and 18/36 efficacy analysis –Apolipoprotein A-1 JACC February 2000 Volume 35 Number 2 (supplement A): 315A ACC 2000, Anaheim, CA

Study Design Diet run-in Kastelein et al, JACC Vol 35: 2: Suppl. A, pg 315 Abstract Double Blind, randomized, 36-week dose titration study Double Blind, randomized, 36-week dose titration study Patient eligibility: LDL-C > 160mg/dL and TG 160mg/dL and TG < 350mg/dL 826 patients (47% female) 826 patients (47% female) Treatment Treatment Treatment Simvastatin 40 Simvastatin 80 Atorvastatin 20 Atorvastatin 40 Atorvastatin 80 VisitWeek Screening Period 1 6 weeks Period 2 6 weeks Period 3 24 weeks randomization Primary lipid endpoint for week 6, 12 and 18/36 * - HDL cholesterol Primary lipid endpoint for week 6, 12 and 18/36 * - HDL cholesterol Key secondary lipid endpoint for week 6, 12, and 18/36* - Apolipoprotein A-1 Key secondary lipid endpoint for week 6, 12, and 18/36* - Apolipoprotein A-1 * Avg. of weeks 18, 24, 30 and 36

Simvastatin/Atorvastatin HDL Study Demographic Characteristics Simvastatin Atorvastatin Total (n=414) (n=412) (n=826) Gender [No. (%)] Females 177 (42.8%) 213 (51.7%) 390 (47.2) Males 237 (57.2%) 199 (48.3%)436 (52.8%) Mean Age, yrs 55 ACC 2000, Anaheim, CA

Simvastatin/Atorvastatin HDL Study Baseline Lipid Levels SimvastatinAtorvastatin Baseline Lipid, mg/dLN=414N=412 HDL-C Apolipoprotein A LDL-C Total cholesterol Triglycerides (median) ACC 2000, Anaheim, CA

Simvastatin/Atorvastatin HDL Study Changes in HDL-C and Apo A-1 at Week 6/12 S 40/80 A 20/40 HDL-C HDL-C S 40/80 A 20/40 Apo A-1 Apo A-1 * * *p<0.001 between treatment groups JACC February 2000 Volume 35 Number 2 (supplement A): 315A ACC 2000, Anaheim, CA

Simvastatin/Atorvastatin HDL Study Change in HDL-C for Each Treatment Period 1.3%3.2%*4.4%* Bars represent difference between treatment groups Week Simvastatin40 mg 80 mg 80 mg Atorvastatin20 mg 40 mg 80 mg ACC 2000, Anaheim, CA Mean % Change *p<0.001

Simvastatin/Atorvastatin HDL Study Change in Apo A-1 for Each Treatment Period 1.6%4.5%*6.0%* Bars represent difference between treatment groups Week Simvastatin40 mg 80 mg 80 mg Atorvastatin20 mg 40 mg 80 mg ACC 2000, Anaheim, CA Mean % Change *p<0.001

Larger Increases in HDL-C with Simvastatin Were Seen in Patients with Both Low and High HDL-C Levels Simvastatin 40 mg 80 mg80 mg Atorvastatin 20 mg 40 mg 80 mg Mean % Difference Between Treatment Groups Low HDL-C Stratum (M: < 40 mg/dL; F: < 50 mg/dL) 40 mg 80 mg80 mg 40 mg 80 mg80 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg High HDL-C Stratum (M: > 40 mg/dL; F: > 50 mg/dL) ACC 2000, Anaheim, CA

Simvastatin/Atorvastatin HDL Study Change in LDL-C for Each Treatment Period 3.7%* 2.6%* 5.6%* Bars represent difference between treatment groups Week Simvastatin40 mg 80 mg 80 mg Atorvastatin20 mg 40 mg 80 mg ACC 2000, Anaheim, CA Mean % Change *p<0.001

Simvastatin/Atorvastatin HDL Study Change in TG for Each Treatment Period 1.3%* 5.7%* 7.8%* Bars represent difference between treatment groups Week Simvastatin40 mg 80 mg 80 mg Atorvastatin20 mg 40 mg 80 mg ACC 2000, Anaheim, CA Mean % Change *p<0.001

Number of Patients with Clinically Relevant Elevations in ALT and CK During the Third Treatment Period S 80 mgA 80 mg n/m*(%) n/m*(%) n/m*(%) n/m*(%)Consecutive ALT > 3X ULN 2/384(0.5) 15/392**(3.8) Female 1/162(0.6) 12/202(5.9) Female 1/162(0.6) 12/202(5.9) Male 1/222(0.5) 3/190(1.6) Male 1/222(0.5) 3/190(1.6) CK > 10X ULN 3/384(0.8) 2/392(0.5) Female 0/162(0.0) 0/202(0.0) Female 0/162(0.0) 0/202(0.0) Male 3/222(1.4) 2/190(1.1) Male 3/222(1.4) 2/190(1.1) ACC 2000, Anaheim, CA Note: There were no clinically significant events during the first two treatment periods *Number of patients with elevated tests/patients tested **2 patients with aesthenia, fatigue Simvastatin 80 mg vs atorvastatin 80 mg, p<0.004

Simvastatin/Atorvastatin HDL Study ~ Summary At clinically equipotent doses for lowering LDL-C, simvastatin increased HDL-C and apo A-1 more than atorvastatin:At clinically equipotent doses for lowering LDL-C, simvastatin increased HDL-C and apo A-1 more than atorvastatin: –Differences between the drugs in increasing HDL-C were larger at higher doses. –80 mg simvastatin increased HDL-C by 7.6% (compared to 3.1% with atorvastatin 80 mg) and raised apo A-1 2.5% (compared to a 3.5% decrease with atorvastatin). These data on HDL and apo A-1 confirm previously reported results of another large comparative multicenter trial.These data on HDL and apo A-1 confirm previously reported results of another large comparative multicenter trial. Both drugs produced comparable and substantial reductions in LDL-C.Both drugs produced comparable and substantial reductions in LDL-C. –Differences between atorvastatin and simvastatin were statistically significant but small in comparison to the magnitude of LDL-C reduction. Both drugs produced substantial reductions in TGs, with atorvastatin showing slightly larger reductions than simvastatin.Both drugs produced substantial reductions in TGs, with atorvastatin showing slightly larger reductions than simvastatin. At the 80 mg dose more patients treated with atorvastatin were discontinued due to clinically significant increases in ALT (3.8% of total participants or 5.9% of women) compared to simvastatin (0.5% and 0.6%, respectively).At the 80 mg dose more patients treated with atorvastatin were discontinued due to clinically significant increases in ALT (3.8% of total participants or 5.9% of women) compared to simvastatin (0.5% and 0.6%, respectively). ACC 2000, Anaheim, CA

Simvastatin/Atorvastatin HDL Study ~ Conclusions Simvastatin increased HDL-C and apo A-1 consistently more than atorvastatinSimvastatin increased HDL-C and apo A-1 consistently more than atorvastatin Both agents were well tolerated at doses that led to approximately 50% reductions in LDL-C (atorvastatin 40 mg and simvastatin 80 mg).Both agents were well tolerated at doses that led to approximately 50% reductions in LDL-C (atorvastatin 40 mg and simvastatin 80 mg). LDL-C reduction achieved with 80 mg atorvastatin during the final 24 week period was 2.3% greater than that achieved with 40 mg atorvastatin.LDL-C reduction achieved with 80 mg atorvastatin during the final 24 week period was 2.3% greater than that achieved with 40 mg atorvastatin. However, at the highest dose of atorvastatin (80 mg), the benefit of the small additional percent LDL-C reduction may be offset by:However, at the highest dose of atorvastatin (80 mg), the benefit of the small additional percent LDL-C reduction may be offset by: –higher risk of clinically significant and consecutive increases in ALT necessitating withdrawal from study –reduction in apo A-1 –modest effect on HDL-C Benefits need to be weighed against the risk for the increased incidence of liver adverse effects with 80 mg atorvastatinBenefits need to be weighed against the risk for the increased incidence of liver adverse effects with 80 mg atorvastatin ACC 2000, Anaheim, CA