Oral Cholesterol Medication Shows Promise as Alternative to Injectable Therapies

Among people with previous heart attacks or strokes, or those at high risk for cardiovascular events, a daily oral medication may provide an effective alternative to injectable PCSK9 inhibitors for lowering low-density lipoprotein cholesterol. The preliminary findings from the CORALreef Lipids trial were presented at the American Heart Association's Scientific Sessions 2025, showing that the investigational drug enlicitide reduced LDL cholesterol by up to 60% over 24 weeks of treatment.

This development represents a significant advancement in cardiovascular care because many patients struggle to reach guideline-recommended cholesterol targets despite available therapies. According to lead study author Ann Marie Navar, M.D., Ph.D., FAHA, 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 study enrolled 2,912 adults with an average age of 63 years, 39% of whom were women, all of whom had LDL levels above recommended levels despite stable lipid-lowering therapy.

The research builds upon findings from 2021 that identified enlicitide as an oral small molecule macrocyclic peptide that blocks PCSK9 from binding to LDL receptors. In the current phase 3 trial, participants taking 20 mg of enlicitide daily demonstrated not only substantial LDL reduction but also showed 53% reduction in non-HDL cholesterol, 50% reduction in ApoB, and 28% reduction in Lp(a). Importantly, the safety profile appeared comparable to placebo, with 10% of enlicitide participants experiencing serious side effects versus 12% in the placebo group.

The implications for patient care are substantial because current PCSK9 inhibitors, while effective, require injection administration. 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." The convenience of oral administration could improve treatment adherence and accessibility for patients who require additional cholesterol management beyond statins and lifestyle modifications. Additional information about cardiovascular health can be found at https://www.heart.org.

Beyond the cholesterol-lowering benefits, the study showed that 70% of participants taking enlicitide achieved both at least 50% reduction in LDL-C and LDL levels below 70 mg/dL, while more than two-thirds reached levels below 55 mg/dL. These targets are clinically significant because current guidelines recommend LDL levels below 70 mg/dL for very high-risk patients and below 55 mg/dL for those at extreme risk. The ongoing CORALreef outcomes trial will determine whether these cholesterol reductions translate to reduced cardiovascular events, which represents the next critical step in establishing enlicitide's clinical utility.

The potential impact extends beyond patient convenience to broader public health considerations. Cardiovascular disease remains a leading cause of mortality worldwide, and improved cholesterol management options could significantly reduce the burden of heart attacks and strokes. As noted in the American Heart Association's positioning, these findings remain preliminary until published in a peer-reviewed journal, but they suggest a promising direction for cardiovascular pharmacotherapy that could eventually provide clinicians with more tools to address residual cardiovascular risk in appropriately selected patients.