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…
How strong is the evidence?
Evidence Hub reads this as a meta-analysis, done in people. Its evidence level is 1 of 5 (Highest · pooled evidence). Pooled evidence from several studies sits at the top of the evidence pyramid. Reported size: 949 participants or records.
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