Lipids & metabolic liver disease
Safety and Efficacy of Oral PCSK9 Inhibitors in Hypercholesterolemia: A Systematic Review and Network Meta-Analysis
Authors' 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.
Study context
- Population
- Adults with hypercholesterolemia in randomized controlled trials (RCTs) comparing oral PCSK9i with placebo (searched through November 14, 2025)
- Participants
- 1,387 adults4 RCTs
- Comparison
- Oral PCSK9 inhibitors vs placebo
- Outcome
- Adverse events and percent change in LDL-C
Methodological detailsfrequentist approach, random-effects models
- Frequentist approach
- Random-effects models
Pooled result
As reported in the abstract
Percent change in LDL-C · follow-up 8-52 weeks
MD
−62.6 %
Enlicitide high dose (HiD) · P score = 0.88
MD
−61.8 %
NNC0385-0434 HiD · P score = 0.88
MD
−59.1 %
Enlicitide medium dose · P score = 0.77
Further pooled results
Low-density lipoprotein cholesterol (LDL-C) goal attainment
- A higher proportion of patients receiving enlicitide (any dose) achieved LDL-C targets
Other lipids
- All oral PCSK9i 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 TG
Safety
| Outcome | RR |
|---|---|
| Adverse eventsOral PCSK9i vs Placebo · diarrhea | 3.25 |
Adverse events
- Safety profile similar to placebo, except higher risk of diarrhea
Original publication
Safety and Efficacy of Oral PCSK9 Inhibitors in Hypercholesterolemia: A Systematic Review and Network Meta-Analysis. Endocr Pract. Published 12 February 2026. doi:10.
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