Key Points
- In pooled on-treatment analyses, enlicitide reduced LDL-C by 63.6% at 24 Weeks and 59.6% at 52 Weeks versus placebo.
- At Week 24, 86.8% of enlicitide-treated participants reached LDL-C <70 mg/dL and 79.9% reached LDL-C <55 mg/dL.
- Adherence remained high in the on-treatment population, with 98% reporting they followed dosing instructions all or most of the time.
LDL lowering is only as good as its power to keep LDL low. At ACC.26, investigators presented an on-treatment look at enlicitide that focused less on whether the oral PCSK9 inhibitor works at its peak and more on whether that effect holds over time in patients who remain on therapy.
Ann Marie Navar, MD, PhD, presented “Durability Of Enlicitide For Lipid Lowering: On-treatment Analysis Of Data From CORALreef Lipids And CORALreef HeFH Trials.” The analysis drew on two phase 3, randomized, placebo-controlled trials. The first trial was CORALreef Lipids (NCT05952856) with the results published in The New England Journal of Medicine while the second trial was CORALreef HeFH (NCT05952869) with its results published in The Journal of the American Medical Association. Both trials evaluated enlicitide 20 mg once daily on top of background lipid-lowering therapy. The primary endpoint was the mean percentage change in LDL-C from baseline to day 52. Secondary endpoints included mean percentage changes in apolipoprotein B (ApoB) and non–HDL-C.
This post hoc analysis asked a practical question: what happens when patients stay on therapy. The primary endpoint was the mean percentage change in LDL-C, Non-HDL-C, ApoB, Lp(a) from baseline to week 24 and 52. Of the 3207 participants in the pooled modified intention-to-treat population, 2137 received enlicitide and 1070 received placebo. Treatment persistence remained high through follow-up, with 2010 enlicitide-treated participants and 1004 placebo-treated participants still on treatment at Week 24, and 1916 and 966, respectively, at Week 52. The on-treatment cohort was clinically relevant, not unusually selected: mean age was 61.6 years, 55.3% had a history of major ASCVD event, 17.8% had heterozygous familial hypercholesterolemia, and baseline LDL-C was 98.3 mg/dL.
The lipid effect was not just deep. It held. Placebo-adjusted LDL-C reduction reached 63.6% (95% CI: -66.0%, -61.2%) at 24 Weeks and remained 59.6% (95% CI: -62.4%, -56.9%) at 52 Week, suggesting only modest loss of effect over a full year. Absolute LDL-C in the enlicitide group fell from 97.8 mg/dL to 38.9 mg/dL at 24 Weeks and was still 44.0 mg/dL at 52 Weeks, while placebo was largely unchanged. The effect also extended beyond LDL-C, with sustained reductions in non-HDL-C, ApoB, and Lp(a).
Goal attainment made the clinical signal easier to grasp. By Week 24, 86.8% of enlicitide-treated participants reached LDL-C <70 mg/dL, compared with 21.8% on placebo. For LDL-C <55 mg/dL, the figures were 79.9% versus 7.9%. Those are large separations, not marginal gains. Investigators also reported high self-reported adherence, with 98% following dosing instructions all or most of the time and 87% enrolling in the optional open-label extension study.
The caveat is straightforward: this was an on-treatment analysis, so it describes efficacy among participants who remained on therapy rather than the full randomized population. Still, it answers an important question cleanly. For enlicitide, the LDL-C reduction was not fleeting, it remained substantial through 52 weeks.