Comparative efficacy and safety of orally administered PCSK9 inhibitors in patients with Hypercholesterolaemia: a dose-stratified systematic review and network meta-analysis.

Authors

Ahmed Talkhan, Mohamed Hamouda Elkasaby, Amr M Abou Elezz, Nermin Ezzat Borham, Ahmed Noureldeen Abbas, Ahmed W Abbas, Noha Hammad, Kareem Khalefa, Mazen Momtaz Shehata

Published in

Endocrine. Volume 91. Issue 1. Oct 06, 2026. Epub Oct 06, 2026.

Abstract

Injectable 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.
We 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.
Five 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.
Oral 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.

PMID:
42837061
Bibliographic data and abstract were imported from PubMed on 07 Oct 2026.

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