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

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.