NEW ORLEANS — A new daily oral medication may provide a more convenient yet equally effective alternative to injectable PCSK9 inhibitors for lowering low-density lipoprotein (LDL) cholesterol in people at high risk of heart attack or stroke, according to preliminary research presented at the American Heart Association’s Scientific Sessions 2025.
The investigational drug, enlicitide, is a small molecule macrocyclic peptide that blocks the PCSK9 protein from binding to LDL receptors, thereby increasing the removal of LDL cholesterol from the bloodstream. In the phase 3 CORALreef Lipids trial, participants taking 20 mg of enlicitide daily achieved up to a 60% reduction in LDL cholesterol after 24 weeks, with sustained effects at 52 weeks. This reduction is comparable to that seen with injectable PCSK9 inhibitors such as alirocumab and evolocumab.
“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.”
The study enrolled 2,912 adults with a history of heart attack, stroke, or intermediate to high risk for such events. All participants had LDL levels above recommended targets despite stable lipid-lowering therapy, including statins. Participants were randomized 2:1 to receive either enlicitide 20 mg once daily or placebo. At baseline, 97% were taking statins, and 26% also used ezetimibe.
At 24 weeks, enlicitide also lowered non-HDL cholesterol by 53%, apolipoprotein B by 50%, and lipoprotein(a) by 28%. Serious side effects occurred in 10% of the enlicitide group versus 12% in the placebo group, and early discontinuation due to side effects was low (3% vs. 4%, respectively).
“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.”
Seven out of 10 participants taking enlicitide had at least a 50% reduction in LDL cholesterol and achieved levels below 70 mg/dL, while more than two-thirds reduced LDL by at least 50% and achieved levels below 55 mg/dL.
The findings are preliminary, as the CORALreef outcomes trial is still ongoing to determine whether the LDL reductions translate into fewer major cardiovascular events. “The CORALreef outcomes trial is still ongoing and will determine if and by how much the lower LDLs achieved with enlicitide will prevent major cardiovascular events,” Navar said.
The study was conducted at 168 health care centers in 14 countries. Enlicitide is not yet approved by the U.S. Food and Drug Administration. The research abstract was presented at the American Heart Association’s Scientific Sessions 2025, which is a premier global exchange of the latest scientific advancements in cardiovascular science.
