Oral PCSK9 inhibitors could overcome barriers to the wider use of injectable agents.

Network meta-analyses of four RCTs showed significant changes in lipid levels.

The extent of LDL-C reduction was as robust as injectable PCSK9 inhibitors.

Favorable changes in other lipids highlight their broader lipid-lowering effects.

Gastrointestinal adverse events, especially diarrhea, were a concern.

Clinical Relevance

The network meta-analysis indicates that oral PCSK9 inhibitors are a viable alternative to injectable treatments for hypercholesterolemia, providing LDL-C reductions similar to injectables and generally maintaining a good safety profile, with the exception of a higher risk of diarrhea. These agents improve various lipid measures, helping more patients reach LDL-C targets as per guidelines and potentially enhancing access and adherence through oral use. They provide options for those intolerant to statins or injectable PCSK9 inhibitors, possibly reducing ASCVD risk with longer-term data pending. Limitations include short trial durations, small sample sizes, potential publication bias, and unconfirmed long-term safety and cardiovascular benefits.

Oral PCSK9 inhibitors show promise for the management of hypercholesterolemia, but a systematic review and network meta-analysis (NMA) is needed to inform clinical practice; we aimed to fill this gap.

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 (AEs) 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 NMA in R, employing a frequentist approach and random-effects models.

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) (MD -62.6%, P score = 0.88) and NNC0385-0434 HiD (MD -61.8%, P score = 0.88) being the most effective, followed by enlicitide medium dose (MeD) (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 MeD reduced TG.

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.