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 [40 mg], or rosuvastatin [5 mg]) or 
high-intensity (atorvastatin [80 mg], rosuvastatin [40 mg]) statin. After a 
4-week lipid-stabilization period, patients (n = 1899) were randomized to 
compare evolocumab (140 mg every 2 weeks or 420 mg 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 2 weeks) 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 2 weeks 
reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean 
of 39 to 49 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 123 
to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity 
statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89 
to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL; monthly evolocumab 
reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 
33 to 35 mg/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.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01763866.