Daily oral medication matches injectable therapies in reducing bad cholesterol

Among people with a previous heart attack or stroke, or who are at high risk for one, a daily oral medication may offer an effective alternative to injections of PCSK9 inhibitors to lower low-density lipoprotein (LDL or "bad" cholesterol), according to a preliminary late-breaking science presentation today at the American Heart Association's Scientific Sessions 2025. The meeting, Nov. 7-10, in New Orleans, is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science.

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. Many patients struggle to reach guideline-recommended cholesterol targets despite currently available therapies, leaving them at unnecessary risk of stroke and/or heart attack."

Ann Marie Navar, M.D., Ph.D., FAHA, lead study author, associate professor of cardiology at the University of Texas Southwestern Medical Center, Dallas

In the last decade, a new FDA-approved type of medication became available to reduce bad cholesterol in people who don't achieve recommended levels despite lifestyle changes and maximum treatment with statin medications. Known as PCSK9 inhibitors, these medications include antibodies that block the PCSK9 protein from binding to the LDL receptor, and small interfering RNA, which reduce the production of the PCSK9 protein. Inhibiting PCSK9 helps increase the number of LDL receptors available to help clear "bad" cholesterol out of the bloodstream. Both classes of PCSK9 inhibitors are only administered by injection under the skin.

In 2021, studies found that an investigational, oral small molecule macrocyclic peptide, enlicitide, can also block PCSK9 from binding to LDL receptors, thereby reducing blood levels of LDL when taken daily. This study, Efficacy and Safety of Enlicitide, an Oral PCSK9 Inhibitor, for Lowering LDL Cholesterol in Adults with or At-Risk for ASCVD: The Phase 3 CORALreef Lipids Trial (CORALreef Lipids), is a phase 3 trial in adults evaluating the safety and LDL-lowering ability of enlicitide.

After 24 weeks of daily treatment, the analysis found that compared with those taking a placebo, participants taking enlicitide had:

• up to a 60% reduction in LDL cholesterol, with sustained reductions at 52 weeks;
• a 53% reduction in non-HDL, a combination of all types of cholesterol except for HDL ("good cholesterol");
• a 50% reduction in ApoB, a protein that helps carry fat and various "bad" types of cholesterol throughout the body;
• a 28% reduction in Lp(a), a different type of lipoprotein that is structurally similar to LDL, determined by genetics and a risk factor for heart disease; and
• a similar rate of serious side effects (10% in enlicitide vs. 12% in placebo), a small proportion of participants left the study early because of side effects (3% vs.4%, respectively).

In this study, 7 out of 10 participants taking enlicitide had at least a 50% reduction in LDL-C and also achieved an LDL below 70 mg/dL, and more than two-thirds reduced their LDL-C by at least 50% or more and also achieved levels below 55 mg/dL.

"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."

Study details, background or design:

• The study enrolled 2,912 adults (average age of 63 years; 39% were women) with a previous heart attack or stroke or assessed to be at intermediate or high risk of a heart attack or stroke within the next 10 years.
• All participants had LDL levels above recommended levels despite being on a stable course of lipid-lowering therapy for 30 days or more, including treatment with least moderate or high-intensity statin therapy (or with a history of intolerance to statins).
• At the start of the study, 97% of participants were taking statins, and 26% were also taking a medication that reduces the absorption of cholesterol in the small intestines such as ezetimibe.
• Participants were randomized in a 2-to-1 ratio to receive either 20 mg enlicitide once daily (n=1,935) or placebo (n=969). Five participants never received the study medication, and three were excluded for being enrolled in multiple trials across multiple sites.
• The study data was collected between August 2023 and July 2025 at 168 health care centers in 14 countries.

"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.