Effect of Evolocumab or Ezetimibe Added to Moderate- or High-Intensity Statin Therapy on LDL-C Lowering in Patients With Hypercholesterolemia The LAPLACE-2 Randomized Clinical Trial

IMPORTANCE In phase 2 studies, evolocumab, a fully human monoclonal antibody to PCSK9, reduced LDL-C levels in patients receiving statin therapy. OBJECTIVE To evaluate the efficacy and tolerability of evolocumab when used in combination with a moderate-vs high-intensity statin. DESIGN, SETTING, AND PATIENTS Phase 3, 12-week, randomized, double-blind, placebo-and ezetimibe-controlled study conducted between January and December of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries. INTERVENTIONS Patients (n = 2067) were randomized to 1 of 24 treatment groups in 2 steps. Patients were initially randomized to a daily, moderate-intensity (atorvastatin [10 mg], simvastatin [40mg], or rosuvastatin [5 mg]) or high-intensity (atorvastatin [80 mg], rosuvastatin [40mg]) statin. After a 4-week lipid-stabilization period, patients (n = 1899) were randomized to compare evolocumab (140 mg every 2 weeks or 420mg monthly) with placebo (every 2 weeks or monthly) or ezetimibe (10 mg or placebo daily; atorvastatin patients only) when added to statin therapies. MAIN OUTCOMES AND MEASURES Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) level at the mean of weeks 10 and 12 and at week 12. RESULTS Evolocumab reduced LDL-C levels by 66%(95% CI, 58% to 73%) to 75%(95% CI, 65% to 84%) (every 2weeks) and by 63%(95% CI, 54% to 71%) to 75%(95% CI, 67% to 83%) (monthly) vs placebo at the mean of weeks 10 and 12 in the moderate-and high-intensity statin-treated groups; the LDL-C reductions at week 12 were comparable. For moderate-intensity statin groups, evolocumab every 2weeks reduced LDL-C from a baseline mean of 115 to 124mg/ dL to an on-treatment mean of 39 to 49mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126mg/dL to an on-treatment mean of 43 to 48mg/dL. For highintensity statin groups, evolocumab every 2weeks reduced LDL-C from a baseline mean of 89 to 94mg/dL to an on-treatment mean of 35 to 38mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 89 to 94mg/dL to an on-treatment mean of 33 to 35mg/dL. Adverse events were reported in 36%, 40%, and 39% of evolocumab-, ezetimibe-, and placebo-treated patients, respectively. The most common adverse events in evolocumab-treated patients were back pain, arthralgia, headache, muscle spasms, and pain in extremity (all < 2%). CONCLUSIONS AND RELEVANCE In this 12-week trial conducted among patients with primary hypercholesterolemia and mixed dyslipidemia, evolocumab added to moderate-or high-intensity statin therapy resulted in additional LDL-C lowering. Further studies are needed to evaluate the longer-term clinical outcomes and safety of this approach for LDL-C lowering.