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.