For patients with a history of heart attack or stroke, or those at high risk for cardiovascular events, a new daily oral medication may provide an effective alternative to injectable cholesterol-lowering therapies. Research presented at the American Heart Association's Scientific Sessions 2025 indicates that the investigational drug enlicitide reduced LDL cholesterol by up to 60% in clinical trials, matching the effectiveness of currently available injectable PCSK9 inhibitors.
This development is significant because many patients struggle to achieve recommended cholesterol targets despite existing treatments, leaving them at continued risk of cardiovascular events. According to lead study author Dr. Ann Marie Navar, an associate professor of cardiology at the University of Texas Southwestern Medical Center in Dallas, "Many patients struggle to reach guideline-recommended cholesterol targets despite currently available therapies, leaving them at unnecessary risk of stroke and/or heart attack."
The phase 3 CORALreef Lipids trial enrolled 2,912 adults with an average age of 63 years, 39% of whom were women. All participants had 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 being on stable lipid-lowering therapy, including statins for 97% of participants, their LDL levels remained above recommended targets.
After 24 weeks of daily treatment, participants taking enlicitide showed substantial improvements across multiple cholesterol measures compared to those taking placebo. The medication achieved a 53% reduction in non-HDL cholesterol, a 50% reduction in ApoB protein, and a 28% reduction in Lp(a) lipoprotein. Importantly, the safety profile appeared comparable to placebo, with similar rates of serious side effects (10% versus 12%) and only a small proportion of participants discontinuing treatment due to side effects.
The study found that seven out of ten participants taking enlicitide achieved both at least a 50% reduction in LDL-C and levels below 70 mg/dL, while more than two-thirds reached levels below 55 mg/dL with similar percentage reductions. Dr. Navar noted that "daily enlicitide resulted in almost identical changes in LDL, non-HDL and ApoB to those achieved with the injectable antibodies alirocumab and evolocumab," and performed numerically better than the siRNA medication inclisiran.
PCSK9 inhibitors work by blocking the PCSK9 protein from binding to LDL receptors, helping increase the number of receptors available to clear "bad" cholesterol from the bloodstream. While existing PCSK9 inhibitors require injection, enlicitide represents the first oral medication in this class. The American Heart Association provides additional cardiovascular health information at https://www.heart.org.
The ongoing CORALreef outcomes trial will determine whether the cholesterol reductions achieved with enlicitide translate to reduced risk of major cardiovascular events. This research represents an important step toward expanding treatment options for patients who need additional cholesterol management beyond statins and lifestyle changes. As cardiovascular disease remains a leading cause of death worldwide, more convenient and effective treatment options could significantly impact public health outcomes.
