Efficacy and Safety of Oral PCSK9 Inhibitor Enlicitide in Adults With Heterozygous Familial Hypercholesterolemia

Importance Persons with heterozygous familial hypercholesterolemia (HeFH) are at increased risk of atherosclerotic cardiovascular disease due to lifelong elevated levels of low-density lipoprotein cholesterol (LDL-C). Many patients with HeFH do not achieve guideline-recommended LDL-C goals with the currently available lipid-lowering therapies. Objective To evaluate the efficacy of enlicitide decanoate (an oral proprotein convertase subtilisin/kexin type 9 inhibitor) vs placebo in adults with HeFH requiring further lowering of LDL-C levels despite use of statin therapy. Design, Setting, and Participants This phase 3, randomized clinical trial included persons aged 18 years or older with HeFH currently using lipid-lowering therapy (taking at least a moderate- or high-intensity statin) and either an LDL-C level of 55 mg/dL or greater and a history of major atherosclerotic cardiovascular disease or an LDL-C level of 70 mg/dL or greater without a history of major atherosclerotic cardiovascular disease. The trial was conducted at 59 sites across 17 countries; the first participant was screened on August 8, 2023, and the last follow-up visit occurred on April 7, 2025. Interventions Participants were randomized (2:1) to 20 mg of enlicitide (n = 202) or placebo (n = 101) once daily for 52 weeks. Main Outcomes and Measures The primary outcome was the mean percentage change in LDL-C level at week 24. The secondary outcomes included the mean percentage change in LDL-C level at week 52, the mean percentage change at week 24 in levels of non–high-density lipoprotein cholesterol (non–HDL-C) and apolipoprotein B, and the median percentage change at week 24 in lipoprotein(a). Results Of the 303 participants (mean age, 52.4 [SD, 13.5] years; 51% were female) randomized, 293 (96.7%) completed the trial. The mean LDL-C level was 119.0 mg/dL (SD, 41.0 mg/dL) at baseline, all had statin current use (81.5% were taking a high-intensity statin), and 64.4% were taking ezetimibe. The mean percentage change in LDL-C level at week 24 was −58.2% in the enlicitide group vs 2.6% in the placebo group (between-group difference, −59.4% [95% CI, −65.6% to −53.2%]; P < .001). The mean percentage change in LDL-C level at week 52 was −55.3% in the enlicitide group vs 8.7% in the placebo group (between-group difference, −61.5% [95% CI, −69.4% to −53.7%]; P < .001). At week 24, the mean percentage change in non–HDL-C level was −52.3% in the enlicitide group vs 2.1% in the placebo group (between-group difference, −53.0% [95% CI, −58.5% to −47.4%]; P < .001), the mean percentage change in apolipoprotein B level was −48.2% vs 1.8%, respectively (between-group difference, −49.1% [95% CI, −54.0% to −44.3%]; P < .001), and the median percentage change in lipoprotein(a) level was −24.7% vs −1.6% (between-group difference, −27.5% [95% CI, −34.3% to −20.6%]; P < .001). The incidence of adverse events, serious adverse events, and study discontinuation due to adverse events was similar between groups. Conclusions Among adults with HeFH, treatment with enlicitide was well tolerated and significantly reduced levels of LDL-C, apolipoprotein B, non–HDL-C, and lipoprotein(a). Trial Registration ClinicalTrials.gov Identifier: NCT05952869