PCSK9 Inhibitors and Statins: Meta-Analysis Highlights Benefit of Combination Therapy

PCSK9 inhibitors are potent LDL-C–lowering agents that have been incorporated into major cardiovascular prevention guidelines for patients at very high risk. What has remained less certain, however, is how they stack up against statins and whether their benefits extend beyond lipid reduction to the outcomes that matter most to patients and clinicians, such as heart attack, stroke, and cardiovascular death.

A new network meta-analysis published in Frontiers in Pharmacology provides one of the most comprehensive comparisons to date, pooling nearly 69,000 patients to evaluate the effects of statins, PCSK9 inhibitors, and their combinations on major adverse cardiovascular events (MACE), all-cause mortality, and safety.

The investigators reviewed 29 randomized trials evaluating alirocumab, evolocumab, or inclisiran, alone or with statins, against statins, ezetimibe, or placebo. The primary endpoint was MACE, with additional analyses on all-cause mortality and safety outcomes including new-onset diabetes and neurocognitive events.

Combination Therapy Proves Most Effective

Adding a PCSK9 inhibitor to background statins significantly reduced MACE compared with oral agents alone. Evolocumab plus statins lowered risk by 18 percent (risk ratio 0.82), alirocumab plus statins by 15 percent (risk ratio 0.85), and inclisiran plus statins by 24 percent (risk ratio 0.76). In contrast, PCSK9 monotherapy failed to consistently match statin efficacy, and alirocumab monotherapy actually performed worse than statins.

Despite these MACE benefits, subgroup analyses revealed no significant reduction in all-cause mortality when PCSK9 inhibitors were added to statins compared with statin monotherapy. Moreover, no differences were seen among individual PCSK9 agents in mortality outcomes, suggesting a consistent profile across the class.

These findings mirror large randomized trials such as FOURIER and ODYSSEY OUTCOMES, which demonstrated event reduction without clear survival benefit. Taken together, the data suggest that while PCSK9 combinations strengthen prevention against nonfatal cardiovascular events, they have not yet translated into measurable gains in longevity.

Across 19 studies reporting safety, there was no excess risk of diabetes or neurocognitive impairment with PCSK9 inhibitors. Rates were similar to statins, providing reassurance about long-term tolerability.

It’s important to note that this analysis was limited by heterogeneous definitions of MACE, varying follow-up durations, and relatively sparse data for PCSK9 monotherapy. Mortality effects remain underpowered, raising questions about whether longer-term follow-up or broader populations could reveal differences.

Key Clinical Takeaways

Overall, for patients at high cardiovascular risk who require intensive lipid lowering, the strongest evidence supports PCSK9 inhibitors in combination with statins. While PCSK9 monotherapy may be reserved for patients unable to tolerate statins, current evidence suggests it delivers less protection. However, in line with prior studies, evidence for mortality reduction remains elusive.

Reference
Niu Q, Wang Q, Chen F, Li B. Which is the optimal choice in lipid-lowering therapy for reducing major cardiovascular events? A network meta-analysis. Front Pharmacol. 2025;16:1626681. doi:10.3389/fphar.2025.1626681.