SynthesisEndocrine2026
Comparative efficacy and safety of orally administered PCSK9 inhibitors in patients with Hypercholesterolaemia: a dose-stratified systematic review and network meta-analysis.
Synthesis in Endocrine, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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9 authors.
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Abstract
backgroundInjectable PCSK9 inhibitors are effective but remain under-used because of cost, the subcutaneous route, cold-chain storage and patient preference. Orally administered PCSK9 inhibitors, comprising two peptide-based agents and one small molecule, have recently completed phase 3 evaluation.
methodsWe searched four databases from inception to 1 May 2026 for randomised trials of orally administered PCSK9 inhibitors versus placebo. A frequentist random-effects network meta-analysis treated each drug-dose combination as a separate node. The primary outcome was the mean percentage change from baseline in LDL-C, as a mean difference in percentage points (pp). Certainty was rated with CINeMA. Treatments were ranked by SUCRA with simulation-based 95% intervals; rankings are exploratory.
resultsFive trials (4,227 participants) were included. All twelve drug-dose combinations reduced LDL-C versus placebo, most with NNC0385-0434 100 mg (- 61.8 pp, 95% CI - 78.1 to - 45.5), MK-0616 30 mg (- 60.9 pp, - 75.0 to - 46.8) and MK-0616 20 mg (- 58.5 pp, - 67.8 to - 49.2). Of 66 active-versus-active comparisons, the 51 between agents were wholly indirect; the 20 excluding the null all contrasted a low dose with a much higher one; none of the six among the four highest-ranked doses was significant, and their SUCRA intervals overlapped (0.42-1.00). Dose-response was significant for all three agents (P ≤ 0.005). Other lipid parameters also improved. Goal attainment was analysed separately by definition: against an absolute threshold, risk ratios were 4.36-9.73; against a composite of ≥ 50% reduction plus LDL-C < 70 mg/dL, MK-0616 20 mg gave a risk difference of + 68.9 pp. No short-term safety signal was detected. Heterogeneity (I² = 80.6%) reflected the comparison timepoint and fell to 0% at week 24.
conclusionOral PCSK9 inhibitors produce large, dose-dependent LDL-C reductions versus placebo with no short-term safety signal. Comparative rankings between agents and doses remain uncertain, and certainty of evidence is low.
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