Dose-stratified lipid-lowering efficacy and safety of oral PCSK9 inhibitors: a systematic review and meta-analysis.

Abstract

Background: Oral PCSK9 inhibitors are investigational agents that may broaden therapeutic choice beyond injectable PCSK9-targeting therapies, but their efficacy and short-term safety across evaluated dose strata remain incompletely characterized.

Objectives: To assess lipid-lowering efficacy and short-term safety across the lowest and highest evaluated dose strata in randomized trials.

Methods: We systematically searched PubMed, Embase, and CENTRAL from inception to November 2025 and included randomized, placebo-controlled trials of oral PCSK9 inhibitors reporting lipid or safety outcomes. Primary efficacy analyses evaluated percentage change in LDL-C separately for the lowest and highest evaluated dose strata. Secondary outcomes included ApoB, non-HDL-C, and Lp(a). Safety outcomes included any adverse event, serious adverse events (SAEs), and selected individual adverse events. Random-effects pairwise meta-analyses were performed separately for the two prespecified dose strata, with exploratory tests for subgroup differences. Sensitivity analyses excluded the HeFH trial. Certainty of evidence was graded using GRADE.

Results: Four trials (949 participants) met inclusion criteria. Both dose strata significantly reduced LDL-C, ApoB, non-HDL-C, and Lp(a), with larger pooled reductions generally observed in the highest evaluated stratum. Available short-term safety analyses did not detect statistically significant increases in overall, serious, or selected individual adverse events in either stratum. Sensitivity analyses yielded consistent estimates. Certainty of evidence for all primary efficacy outcomes was moderate.

Conclusion: Oral PCSK9 inhibitors substantially reduced atherogenic lipoproteins across the evaluated dose strata. These findings demonstrate pharmacodynamic lipid-lowering efficacy but do not establish a class-wide dose-response relationship, cardiovascular outcome benefit, or clinical equivalence to outcome-proven PCSK9 monoclonal antibodies. Longer-term safety and dedicated cardiovascular outcome trials are required.