Safety profile of proprotein convertase subtilisin/kexin type 9 inhibitors alirocumab and evolocumab: an updated meta-analysis and meta-regression.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of comparative trials
PubMed 38836510 · doi:10.1080/03007995.2024.2363971
What was done
A systematic review, meta-analysis, and meta-regression assessed the safety profile of the PCSK9 inhibitors alirocumab and evolocumab compared to control therapies (placebo or statin with or without ezetimibe). The primary outcome was adverse events leading to death. Secondary outcomes included serious adverse events, new-onset diabetes mellitus (DM), worsening of DM, neurocognitive dysfunction, creatine kinase (CK) elevation, elevation of liver enzymes, and local injection site reactions. Factors associated with treatment effects were assessed via meta-regression, and subgroup analyses examined differences by drug type and treatment duration. The analysis included 56 studies with 85,123 adults (29.14% females).
What was found
PCSK9 inhibitors overall were not associated with adverse events leading to death (OR 0.94, 95% CI 0.84 to 1.04, p = 0.22), though alirocumab specifically decreased adverse events leading to death (OR 0.79, 95% CI 0.67 to 0.94, p = 0.008). PCSK9 inhibitors reduced serious adverse events (OR 0.93, 95% CI 0.89 to 0.98, p < 0.001), driven mainly by alirocumab (OR 0.89, 95% CI 0.85 to 0.93, p < 0.001). Evolocumab was associated with worsening DM (OR 2.30, 95% CI 1.26 to 4.20, p = 0.041). Subgroup analysis showed increased odds of worsening DM in the first 12 weeks (<12 weeks: OR 3.82, 95% CI 1.13 to 12.99, p = 0.03) and between 12-24 weeks (OR 2.12, 95% CI 1.20 to 3.73, p = 0.01), whereas therapy >24 weeks reduced the odds of worsening DM (OR 0.89, 95% CI 0.79 to 0.99, p = 0.04). PCSK9 inhibitors did not increase new-onset DM, cognitive dysfunction (OR 1.02, 95% CI 0.88 to 1.18, p = 0.76), liver enzyme elevation (OR 0.91, 95% CI 0.81 to 1.03, p = 0.14), or CK elevation (OR 0.82, 95% CI 0.65 to 1.04, p = 0.10), but did increase local injection site reactions (OR 1.54, 95% CI 1.37 to 1.73, p < 0.01).
Why it matters
This study provides comprehensive safety confirmation across 56 trials, reassuring clinicians that PCSK9 inhibitors do not cause neurocognitive, hepatic, or muscle toxicities, while identifying drug-specific nuances such as alirocumab's mortality benefit and transient early glycemic worsening with evolocumab.
Limits
The abstract pools heterogeneous comparator regimens (placebo vs. active statin and/or ezetimibe controls) without reporting heterogeneity metrics (I²) or risk of bias assessments. Women were substantially underrepresented (29.14% of participants). The precise clinical definition and diagnostic criteria for worsening DM are not specified in the abstract.
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