Enlicitide, the first oral PCSK9 inhibitor, consistently lowers LDL-C levels across all cardiovascular risk strata, according to data presented at the American Heart Association Scientific Sessions 2026.
The findings, from an analysis of the CORALreef Lipids study, suggest the once-daily pill provides a viable alternative for patients who prefer to avoid injectable cholesterol medications.
Researchers examined 843 patients from the larger CORALreef Lipids trial, which originally randomized 2,909 participants to receive either 20 mg of enlicitide or a placebo. The patient cohort for this analysis was categorized by 10-year cardiovascular risk, ranging from low to high.
At week 24, the placebo-corrected reductions in LDL-C were significant across all groups: 62.6% for low-risk patients, 57.6% for borderline risk, 57.1% for intermediate risk, and 58.0% for high-risk individuals, HCPLive reported. The study also recorded reductions in apolipoprotein B (ApoB), non-HDL-C, and lipoprotein(a) levels across these same strata.
“If someone doesn’t want to take an injectable, we have another option which gives the same efficacy as that injectable: an easy once-a-day pill,” Christie Ballantyne, MD, told HCPLive.
While the primary analysis focused on the 24-week mark, additional data points to sustained performance over longer durations. An interim analysis of the CORALreef Extension study showed that LDL-C reductions were maintained through week 104, according to coverage by AJMC.
This extension study enrolled over 2,700 participants who had completed parent trials, including CORALreef Lipids.
By the January 19, 2026, data cutoff, 1,014 participants had at least 1.74 years of exposure to the drug.
The data suggests a narrowing of efficacy over time, however. While mean LDL-C reductions were approximately 65% early in treatment, they shifted to about 50% by week 104, AJMC reported. Despite this change, the drug’s safety profile remained steady, with a 1.6% discontinuation rate due to adverse events and no reported drug-related serious adverse events.
Despite the success in lowering cholesterol markers, the ultimate impact of enlicitide on major cardiovascular events remains an open question. Researchers are currently waiting for results from a large, fully enrolled outcomes trial to confirm if these lipid-lowering effects translate into reduced heart attacks or strokes.
“There’s a very large outcomes trial that’s fully enrolled—we haven’t heard anything from that, but I think we can have enough confidence in what we have now,” Ballantyne told HCPLive.
Data presented at the AHA Scientific Sessions 2026 showed a 62.6% placebo-corrected reduction in LDL-C for the low-risk group at week 24, though AJMC noted this estimate carried a wider confidence interval due to the smaller sample size of 66 participants in that specific category.
In the CORALreef Extension study, the discontinuation rate due to adverse events was 1.6%, and no individual adverse event occurred in 5% or more of the participants, according to AJMC.
The FDA approved enlicitide as the first oral PCSK9 inhibitor for the treatment of high cholesterol on July 16, 2026, as reported by AJMC.
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