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

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.