Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta-Analysis of 35 Randomized Controlled Trials

Background: We sought to examine the efficacy and safety of 2 PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: alirocumab and evolocumab.

Methods and results: We performed a systematic review and meta-analysis of randomized controlled trials comparing treatment with and without PCSK9 inhibitors; 35 randomized controlled trials comprising 45 539 patients (mean follow-up: 85.5 weeks) were included. Mean age was 61.0±2.8 years, and mean baseline low-density lipoprotein cholesterol was 106±22 mg/dL. Compared with no PCSK9 inhibitor therapy, treatment with a PCSK9 inhibitor was associated with a lower rate of myocardial infarction (2.3% versus 3.6%; odds ratio [OR]: 0.72 [95% confidence interval (CI), 0.64-0.81]; P<0.001), stroke (1.0% versus 1.4%; OR: 0.80 [95% CI, 0.67-0.96]; P=0.02), and coronary revascularization (4.2% versus 5.8%; OR: 0.78 [95% CI, 0.71-0.86]; P<0.001). Overall, no significant change was observed in all-cause mortality (OR: 0.71 [95% CI, 0.47-1.09]; P=0.12) or cardiovascular mortality (OR: 1.01 [95% CI, 0.85-1.19]; P=0.95). A significant association was observed between higher baseline low-density lipoprotein cholesterol and benefit in all-cause mortality (P=0.038). No significant change was observed in neurocognitive adverse events (OR: 1.12 [95% CI, 0.88-1.42]; P=0.37), myalgia (OR: 0.95 [95% CI, 0.75-1.20]; P=0.65), new onset or worsening of preexisting diabetes mellitus (OR: 1.05 [95% CI, 0.95-1.17]; P=0.32), and increase in levels of creatine kinase (OR: 0.84 [95% CI, 0.70-1.01]; P=0.06) or alanine or aspartate aminotransferase (OR: 0.96 [95% CI, 0.82-1.12]; P=0.61).

Conclusions: Treatment with a PCSK9 inhibitor is well tolerated and improves cardiovascular outcomes. Although no overall benefit was noted in all-cause or cardiovascular mortality, such benefit may be achievable in patients with higher baseline low-density lipoprotein cholesterol.