Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists · 2026
Safety and Efficacy of Oral PCSK9 Inhibitors in Hypercholesterolemia: A Systematic Review and Network Meta-Analysis.
СтатьяСистематический обзорNetwork Meta-AnalysisНазвание и аннотация: Перевод в очереди
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Kamrul-Hasan A B M, Mahajan Kunal, Khalil Ibrahim, Shahriar Md Nafis, Nagendra Lakshmi, Dutta Deep, Pappachan Joseph M
Аннотация
OBJECTIVE: Oral proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) show promise for the management of hypercholesterolemia, but a systematic review and network meta-analysis are needed to inform clinical practice; we aimed to fill this gap.
METHODS: Multiple databases were searched through November 14, 2025, to identify randomized controlled trials (RCTs) comparing oral PCSK9i with placebo in adults with hypercholesterolemia. Primary outcomes were adverse events and percent change in low-density lipoprotein cholesterol (LDL-C); secondary outcomes included LDL-C goal attainment and changes in other lipids. Meta-analyses were conducted using RevMan and network meta-analysis in R, employing a frequentist approach and random-effects models.
RESULTS: Four multicenter, low-bias RCTs (N = 1387, follow-up 8-52 weeks) were included. Oral PCSK9i showed a safety profile similar to placebo, except for a higher risk of diarrhea (risk ratio: 3.25). All oral PCSK9i outperformed placebo in the percent reduction of LDL-C, with enlicitide high dose (HiD) (mean difference [MD] -62.6%, P score = 0.88) and NNC0385-0434 HiD (MD -61.8%, P score = 0.88) was the most effective, followed by enlicitide medium dose (MD -59.1%, P score = 0.77). A higher proportion of patients receiving enlicitide (any dose) achieved LDL-C targets. All oral PCSK9i also improved total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apolipoprotein B, and lipoprotein(a). NNC0385-0434 HiD increased HDL-C; NNC0385-0434 HiD, enlicitide HiD and medium dose reduced triglycerides.
CONCLUSION: Limited short-term data suggest that oral PCSK9i are reasonably safe and effective, reducing LDL-C and improving other lipids. Longer, larger RCTs are required to confirm safety, efficacy, and cardiovascular benefits before broader use.
METHODS: Multiple databases were searched through November 14, 2025, to identify randomized controlled trials (RCTs) comparing oral PCSK9i with placebo in adults with hypercholesterolemia. Primary outcomes were adverse events and percent change in low-density lipoprotein cholesterol (LDL-C); secondary outcomes included LDL-C goal attainment and changes in other lipids. Meta-analyses were conducted using RevMan and network meta-analysis in R, employing a frequentist approach and random-effects models.
RESULTS: Four multicenter, low-bias RCTs (N = 1387, follow-up 8-52 weeks) were included. Oral PCSK9i showed a safety profile similar to placebo, except for a higher risk of diarrhea (risk ratio: 3.25). All oral PCSK9i outperformed placebo in the percent reduction of LDL-C, with enlicitide high dose (HiD) (mean difference [MD] -62.6%, P score = 0.88) and NNC0385-0434 HiD (MD -61.8%, P score = 0.88) was the most effective, followed by enlicitide medium dose (MD -59.1%, P score = 0.77). A higher proportion of patients receiving enlicitide (any dose) achieved LDL-C targets. All oral PCSK9i also improved total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apolipoprotein B, and lipoprotein(a). NNC0385-0434 HiD increased HDL-C; NNC0385-0434 HiD, enlicitide HiD and medium dose reduced triglycerides.
CONCLUSION: Limited short-term data suggest that oral PCSK9i are reasonably safe and effective, reducing LDL-C and improving other lipids. Longer, larger RCTs are required to confirm safety, efficacy, and cardiovascular benefits before broader use.