For individuals at high risk of cardiovascular events who struggle to reach recommended cholesterol levels with existing treatments, new research suggests an oral medication may provide significant additional cholesterol reduction. According to preliminary findings from the phase 3 CORALreef Lipids trial presented at the American Heart Association's Scientific Sessions 2025, the investigational drug enlicitide reduced LDL cholesterol by up to 60% in patients who had not achieved recommended levels despite standard therapies.
The study evaluated 2,912 adults with an average age of 63 years, all of whom had either experienced a previous heart attack or stroke or were assessed to be at intermediate or high risk of cardiovascular events within the next decade. Despite 97% of participants taking statins and 26% also using cholesterol absorption inhibitors like ezetimibe at the study's outset, their LDL levels remained above recommended targets. After 24 weeks of daily treatment with 20 mg of enlicitide, participants showed substantial improvements across multiple cholesterol markers, with the 60% reduction in LDL cholesterol sustained at 52 weeks.
Researchers observed a 53% reduction in non-HDL cholesterol, a 50% reduction in ApoB protein, and a 28% reduction in Lp(a) lipoprotein. The medication demonstrated a similar safety profile to placebo, with 10% of enlicitide participants experiencing serious side effects compared to 12% in the placebo group. Lead study author Ann Marie Navar, M.D., Ph.D., FAHA, emphasized the clinical significance, stating that many patients struggle to reach guideline-recommended cholesterol targets despite currently available therapies, leaving them at unnecessary risk. The research abstract is available through the American Heart Association Scientific Sessions 2025 Online Program Planner.
Enlicitide represents a new approach to PCSK9 inhibition, the same mechanism used by injectable medications like alirocumab and evolocumab. Unlike these antibody-based treatments and the small interfering RNA medication inclisiran, enlicitide is an oral small molecule macrocyclic peptide that blocks PCSK9 from binding to LDL receptors. Navar noted that enlicitide's effects on LDL, non-HDL, and ApoB were almost identical to those achieved with injectable antibodies and numerically better than what has been shown for inclisiran.
The practical implications are substantial, as seven out of ten participants taking enlicitide achieved both at least a 50% reduction in LDL cholesterol and levels below 70 mg/dL. More than two-thirds reached the more aggressive target of below 55 mg/dL while maintaining the 50% reduction. These results suggest that enlicitide could eventually provide a more convenient option for patients who require additional cholesterol management beyond statins and other oral medications. While these findings are promising, researchers caution that the results are preliminary until published in a peer-reviewed journal. The ongoing CORALreef outcomes trial will determine whether the cholesterol reductions achieved with enlicitide translate into reduced risk of major cardiovascular events, which will be crucial for establishing the medication's potential role in preventing heart attacks and strokes among high-risk populations.
