Investigational Oral PCSK9 Inhibitor Matches Injectable Efficacy in Patients with HeFH: Daily Dose

Patient Care brings primary care clinicians a lot of medical news every day—it’s easy to miss an important study. The Daily Dose provides a concise summary of one of the website's leading stories you may not have seen.

On November 10, 2025, we reported on a study published in the Journal of the American Medical Association that examined the efficacy of the investigational oral PCSK9 inhibitor enlicitide decanoate compared to placebo in adults with heterozygous familial hypercholesterolemia (HeFH) requiring further lowering of LDL-C levels despite use of statin therapy.

The study

The phase 3, randomized clinical trial included 303 individuals 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 (ASCVD) or an LDL-C level of 70 mg/dL or greater without a history of major ASCVD. Participants were randomized to 20 mg of enlicitide (n=202) or placebo (n=101) once daily for 52 weeks.

The findings

Results showed that the mean percentage change in LDL-C level at week 24 was −58.2% in the enlicitide group compared to 2.6% in the placebo group (between-group difference, −59.4% [95% CI, −65.6% to −53.2%]; P < .001).

Enlicitide also demonstrated significant reductions in secondary endpoints vs placebo at 24 weeks, including:

• Non-HDL-C of 53.0% (95% CI, -58.5 to -47.4, P <.001)

• Apolipoprotein B of 49.1% (95% CI, -54.0 to -44.3, P <.001)

• Lipoprotein(a) of 27.5% (95% CI, -34.3 to -20.6, P <.001)

Authors’ comments

“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).”

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