OBJECTIVES: Elevated low-density lipoprotein-cholesterol (LDL-C) is a major risk factor for development of atherosclerosis and cardiovascular disease. A systematic review and NMA was performed to compare the efficacy of the proprotein convertase subtilisin-kexin 9 serine protease (PCSK9) inhibitor evolocumab with other LLTs, for the management of patients with hyperlipidemia inadequately controlled by statins alone. METHODS: MEDLINE, EMBASE and other sources were searched up to August 2015 for randomized controlled trials assessing treatments for patients with hyperlipidemia insufficiently controlled by statins alone. As no trials have directly compared evolocumab with other PCSK9 inhibitors, Bayesian random effects NMA and indirect comparisons were used to analyze percentage LDL-C reduction at 12 weeks. RESULTS: The review identified 74 trials with 16 included in the NMA. Evolocumab was generally associated with greater LDL-C reductions than other LLT. Evolocumab 140 mg every two weeks (Q2W) showed greater percentage reductions in LDL-C than alirocumab 75 mg Q2W (-22.46, 95% credible interval [CrI]: -29.57, -15.54); alirocumab 150 mg Q2W (-11.99, 95% CrI: -20.37, -5.07); anacetrapib (-33.29, 95% CrI: -42.82, -24.29); bococizumab 150 mg (-20.17, 95% CrI: -33.46, -7.14); ezetimibe (-47.46, 95% CrI: -54.02, -40.99); and fenofibrate (-73.03, 95% CrI: -81.84, -64.87) at 12 weeks. Based on indirect comparisons from US package insert data in patients with clinical atherosclerotic cardiovascular disease also on statins, evolocumab 140 mg Q2W showed a greater reduction in LDL-C than alirocumab 75 mg Q2W (-25.0, 95% CI: -37.2, -12.8) at 12 weeks. CONCLUSIONS: Based on indirect comparisons, evolocumab 140 mg Q2W was generally associated with greater percentage LDL-C reductions than other LLTs in patients not adequately controlled by statins alone. LDL-C reduction is a strong predictor of reduced cardiovascular risk; these results imply that evolocumab is a viable treatment option for patients with high cardiovascular risk and persistently elevated LDL-C levels.