Efficacy and Safety of Oral PCSK9 Inhibitors in Adults With Hypercholesterolemia: An Updated and GRADE Assessed Systematic Review and Meta-Analysis of Randomised Controlled Trials
In brief
Oral PCSK9 inhibitors lower LDL cholesterol by roughly 50 mg/dL in hypercholesterolemic adults
A meta-analysis of five randomized trials (4,268 participants) found that oral PCSK9 inhibitors reduced LDL-C by about 50 mg/dL and triglycerides by 12 mg/dL, with additional drops in non-HDL-C, apoB and lipoprotein(a). Mortality and overall adverse events were unchanged, and fewer patients stopped treatment because of side effects. Longer trials are needed to confirm cardiovascular benefit.
- Journal
- Diabetes, obesity & metabolism (Q1)
- Published
- 10 August 2026
- Study design
- Systematic review / meta-analysis of RCTs
- Evidence level
- Level 1, High (CEBM 1a)
- Authors
- Muhammad Huzaifa Khattak, Sohana Memon, Humaira Bibi, Irshad Munir Hassan, Javaria Gul, Kosar Ajmal, et al.
- PMID
- 42575851
- DOI
- 10.1111/dom.71208
Why clinicians should know about it
- Picked for Internal Medicine (top studies of the week, 16 August 2026): Ranked by evidence level and journal quartile
Abstract
PURPOSE: To evaluate the efficacy and safety of oral PCSK9 inhibitors in adults with hypercholesterolemia by synthesizing evidence from randomised controlled trials. METHODS: This systematic review and meta-analysis followed PRISMA guidelines and was registered on PROSPERO (CRD420261303350). PubMed, Embase and Scopus were searched from inception to March 2026 for randomised controlled trials comparing oral PCSK9 inhibitors with placebo in adults with hypercholesterolemia. Primary outcomes were changes in low-density lipoprotein cholesterol (LDL-C) and triglycerides. Secondary outcomes included other lipid parameters, adverse events and mortality. Random-effects models were used to calculate mean differences (MD) and risk ratios (RR) with 95% confidence intervals (CI). Quality of the included studies was assessed using the RoB2 tool and certainty of evidence was assessed using the GRADE approach. RESULTS: Five randomised controlled trials (n = 4268) were included. Oral PCSK9 inhibitors significantly reduced LDL-C (MD -49.49 mg/dL; 95% CI -54.81 to -44.18; p < 0.00001) and triglycerides (MD -11.65 mg/dL; 95% CI -15.53 to -7.78; p < 0.00001). Significant reductions were also observed in non-HDL cholesterol, apolipoprotein B, lipoprotein(a) and total cholesterol. Dose-dependent effects were noted, with greater reductions at higher doses. No significant differences were observed in mortality or overall adverse events. Treatment discontinuation due to adverse events was lower with intervention. CONCLUSIONS: Oral PCSK9 inhibitors were associated with clinically meaningful improvements in multiple lipid parameters while maintaining a favourable short-term safety profile. However, the available evidence is derived primarily from short-term randomised trials evaluating surrogate lipid outcomes. Larger randomised trials with longer follow-up and cardiovascular outcome data are needed to better define the long-term clinical role of oral PCSK9 inhibitors.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.