New Orleans, LA — A daily oral medication called enlicitide may provide an effective alternative to injectable PCSK9 inhibitors for lowering low-density lipoprotein (LDL) cholesterol in people at high risk for heart attack or stroke, according to preliminary research presented at the American Heart Association’s Scientific Sessions 2025.
The phase 3 CORALreef Lipids trial found that after 24 weeks of treatment, enlicitide reduced LDL cholesterol by up to 60% compared with placebo, with sustained reductions at 52 weeks. The study enrolled 2,912 adults (average age 63 years; 39% women) who had a previous heart attack or stroke or were at intermediate or high risk for one. All participants had LDL levels above recommended targets despite stable lipid-lowering therapy, with 97% taking statins and 26% also taking ezetimibe.
“This oral medication is set to be another powerful addition to the treatments we currently have to lower LDL cholesterol and hopefully prevent cardiovascular events,” said 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.”
Participants were randomized 2:1 to receive either 20 mg enlicitide once daily or placebo. At 24 weeks, enlicitide also produced a 53% reduction in non-HDL cholesterol, a 50% reduction in apolipoprotein B (ApoB), and a 28% reduction in lipoprotein(a) [Lp(a)], a genetic risk factor for heart disease. The rate of serious side effects was similar between groups (10% enlicitide vs. 12% placebo), and few participants discontinued due to side effects (3% vs. 4%).
“In addition to these dramatic improvements when compared with placebo, daily enlicitide resulted in almost identical changes in LDL, non-HDL and ApoB to those achieved with the injectable antibodies alirocumab and evolocumab,” Navar said. “And, results with enlicitide were numerically better than what has been shown for the siRNA medication inclisiran, which blocks the production of the PCSK9 protein.”
Enlicitide is an oral small molecule macrocyclic peptide that blocks PCSK9 from binding to LDL receptors, thereby increasing the number of receptors available to clear LDL from the bloodstream. Currently available PCSK9 inhibitors are injectable antibodies or small interfering RNA therapies.
“A longer, ongoing cardiovascular outcomes study will examine whether enlicitide can reduce the risk of heart attack or stroke,” Navar added. The CORALreef outcomes trial is still ongoing.
The study, funded by the manufacturer, was conducted at 168 health care centers across 14 countries between August 2023 and July 2025. As a research abstract presented at a scientific meeting, the findings are considered preliminary until published in a peer-reviewed journal. Additional details are available in the abstract on the AHA Scientific Sessions 2025 online program planner.
