Enlicitide, a Novel Oral Macrocyclic Peptide PCSK9 Inhibitor for Lipid Lowering: A Systematic Review and Meta-Analysis

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• Picked for Pharmacology (medical) (top studies of the week, 30 August 2026).

Abstract

Enlicitide (MK-0616) is an oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor for the treatment of hypercholesterolemia. We conducted the first systematic review and meta-analysis evaluating the efficacy and safety of enlicitide across randomized controlled trials enrolling adults with hypercholesterolemia or heterozygous familial hypercholesterolemia (HeFH). The primary outcome was the baseline-to-endpoint percentage change in low-density lipoprotein cholesterol (LDL-C); secondary outcomes included apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a) [Lp(a)], and safety. Four randomized controlled trials involving 3894 participants were included. Enlicitide achieved a substantial reduction in LDL-C (mean difference [MD]: -55.78 percentage points; 95% confidence interval [CI]: -61.15 to -50.42; p < 0.0001; I2 = 99.58%), with sustained efficacy demonstrated in the newly available 52-week Phase 3 CORALreef data. Significant reductions were also observed in ApoB (MD: -47.95 pp; 95% CI: -51.22 to -44.67), non-HDL-C (MD: -49.42 pp; 95% CI: -54.23 to -44.60), and Lp(a) (MD: -22.70 pp; 95% CI: -28.62 to -16.78). The pooled incidence of any adverse event was not statistically significant (event rate: 0.21; p = 0.087), and treatment discontinuation due to adverse events was uncommon (event rate: 0.007). Enlicitide demonstrated substantial lipid-lowering efficacy with an acceptable safety profile. The ongoing CORALreef Outcomes trial will determine whether these lipid improvements translate into reductions in major adverse cardiovascular events.

Abstract as published, via PubMed.