Efficacy and Safety of Enlicitide in Hypercholesterolemia: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials

Background Atherosclerotic cardiovascular disease remains a leading cause of global mortality, with low‐density lipoprotein cholesterol (LDL‐C) reduction being the cornerstone of prevention. Despite effective therapies, many high‐risk patients do not achieve recommended LDL‐C targets. Enlicitide (MK‐0616), an oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, offers a potential alternative to injectable PCSK9‐directed therapies. Objective To evaluate the efficacy and safety of enlicitide in adults with hypercholesterolemia and assess its dose‐dependent effects on lipid parameters. Methods We conducted a systematic review and meta‐analysis of randomized controlled trials (RCTs) according to PRISMA 2020 guidelines. PubMed, Embase, Scopus, ClinicalTrials.gov, and Google Scholar were searched from inception through March 2026. Random‐effects meta‐analysis using restricted maximum likelihood estimation was performed. The primary outcome was the percentage change in LDL‐C from baseline. Secondary outcomes included non‐high‐density lipoprotein cholesterol (non‐HDL‐C), apolipoprotein B (ApoB), lipoprotein(a), triglycerides, and safety outcomes. Risk of bias and certainty of evidence were assessed using RoB 2.0 and GRADE. Results Three placebo‐controlled RCTs involving 3593 participants were included. Enlicitide significantly reduced LDL‐C compared with placebo (mean difference [MD], −56.19%; 95% CI, −64.14 to −48.25; p < 0.0001), with moderate heterogeneity ( I 2 = 56.9%). Significant reductions were also observed in non‐HDL‐C (MD, −51.36%), ApoB (MD, −47.09%), lipoprotein(a) (MD, −20.10%), and triglycerides (MD, −13.12%). A numerical dose–response gradient was observed, although subgroup differences were not statistically significant. Sensitivity analyses supported the robustness of the findings. Rates of adverse events, serious adverse events, and treatment discontinuation were comparable between groups. Conclusion Enlicitide produced substantial reductions in LDL‐C and other atherogenic lipid parameters without an apparent increase in adverse events. However, findings should be interpreted cautiously given the limited number of trials, moderate heterogeneity, and reliance on surrogate endpoints. Dose–response, duration‐related lipoprotein(a), and triglyceride findings were exploratory and substantially driven by single trials. Long‐term cardiovascular outcomes trials are needed to establish clinical benefit.