Key result
Enlicitide lowers LDL-C by ~56% from baseline across clinical trials.
Why the study?
Does enlicitide reduce low-density lipoprotein cholesterol in adults with hypercholesterolemia or heterozygous familial hypercholesterolemia?
Meta-Analysis (n=3,894)
Does enlicitide reduce low-density lipoprotein cholesterol in adults with hypercholesterolemia or heterozygous familial hypercholesterolemia?
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Many patients need more than statins and ezetimibe to get to LDL-C goals. Although prices have come down and insurance approval rates are now high, most primary care physicians and even a large proportion of cardiologists are still not routinely prescribing the injectable PCSK9 therapies. I hope that as an easy-to-prescribe oral therapy, enlicitide can ultimately help more patients get to guideline-recommended goals.”
“Although enlicitide is very potent at lowering LDL cholesterol, it has not yet been proven to lower heart attacks and strokes. Those studies are ongoing.”
“In addition to these dramatic improvements when compared with placebo, daily enlicitide resulted in almost identical changes in LDL, non-HDL and ApoB to those achieved with the injectable antibodies alirocumab and evolocumab. And, results with enlicitide were numerically better than what has been shown for the siRNA medication inclisiran, which blocks the production of the PCSK9 protein.”
Enlicitide provides a highly efficacious oral alternative for robust LDL-C reduction comparable to injectable PCSK9 inhibitors, with a durable effect up to 52 weeks.
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.
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Yağmur et al. (2026) conducted a meta-analysis in Hypercholesterolemia or heterozygous familial hypercholesterolemia (HeFH) (n=3,894). Enlicitide vs. None (within-arm pooled analysis) was evaluated on Baseline-to-endpoint percentage change in low-density lipoprotein cholesterol (LDL-C) (MD -55.78 percentage points, 95% CI -61.15 to -50.42, p=<0.0001). Enlicitide achieved a substantial reduction in LDL-C with a mean difference of -55.78 percentage points from baseline.
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