Systematic Review and Network Meta‐Analysis on the Efficacy of Evolocumab and Other Therapies for the Management of Lipid Levels in Hyperlipidemia

Abstract

BackgroundThe proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors evolocumab and alirocumab substantially reduce low‐density lipoprotein cholesterol (LDL‐C) when added to statin therapy in patients who need additional LDL‐C reduction.Methods and ResultsWe conducted a systematic review and network meta‐analysis of randomized trials of lipid‐lowering therapies from database inception through August 2016 (45 058 records retrieved). We found 69 trials of lipid‐lowering therapies that enrolled patients requiring further LDL‐C reduction while on maximally tolerated medium‐ or high‐intensity statin, of which 15 could be relevant for inclusion in LDL‐C reduction networks with evolocumab, alirocumab, ezetimibe, and placebo as treatment arms. PCSK9 inhibitors significantly reduced LDL‐C by 54% to 74% versus placebo and 26% to 46% versus ezetimibe. There were significant treatment differences for evolocumab 140 mg every 2 weeks at the mean of weeks 10 and 12 versus placebo (−74.1%; 95% credible interval −79.81% to −68.58%), alirocumab 75 mg (−20.03%; 95% credible interval −27.32% to −12.96%), and alirocumab 150 mg (−13.63%; 95% credible interval −22.43% to −5.33%) at ≥12 weeks. Treatment differences were similar in direction and magnitude for PCSK9 inhibitor monthly dosing. Adverse events were similar between PCSK9 inhibitors and control. Rates of adverse events were similar between PCSK9 inhibitors versus placebo or ezetimibe.Conclusions PCSK9 inhibitors added to medium‐ to high‐intensity statin therapy significantly reduce LDL‐C in patients requiring further LDL‐C reduction. The network meta‐analysis showed a significant treatment difference in LDL‐C reduction for evolocumab versus alirocumab.

New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons from the Past and Future Challenges

“…Another big program is the ODYSSEY trials testing Alirocumab. As for evolocumab, several data from this program have already been published, showing the power and safety of this approach in reducing LDL-C plasma concentrations by up to 47% in patients at high risk [14,60,66]. The latest results from the ODYSSEY Outcomes trial, presented at the American College of Cardiology in 2018, indicate that treatment with alirocumab reduced cardiovascular outcomes and all-cause deaths by 15% in a group of high-risk patients.…”

Inflammatory Mechanisms in Atherosclerosis

“…In patients with LDL levels that remain above the treatment target, despite statin treatment (residual LDL risk); adding a PCSK9 inhibitor should be considered. Recent network meta-analysis demonstrates that PCSK9 inhibitors significantly reduce LDL cholesterol, on top of medium to high statin therapy [81]. Of direct relevance for inflammation, a very recent study, the CANTOS trial, suggests that those with residual inflammatory risk could benefit from interleukin-1β inhibition by Canakinumab.…”

Lipid Target in Very High-Risk Cardiovascular Patients: Lesson from PCSK9 Monoclonal Antibodies

“…Another big program is the ODYSSEY trials testing Alirocumab. As for evolocumab, several data from this program have already been published, showing the power and safety of this approach in reducing LDL-C plasma concentrations by up to 47% in patients at high risk [ 14 , 60 , 66 ]. The latest results from the ODYSSEY Outcomes trial, presented at the American College of Cardiology in 2018, indicate that treatment with alirocumab reduced cardiovascular outcomes and all-cause deaths by 15% in a group of high-risk patients.…”