Among people with a previous heart attack or stroke or who are at high risk for one, a daily oral medication may provide an effective alternative to injections of PCSK9 inhibitors in lowering low-density lipoprotein (LDL, or “bad” cholesterol), according to a preliminary scientific presentation completed today at the American Heart Association’s Scientific sessions20. 7-10, in New Orleans, is a leading global exchange of the latest scientific advances, research and evidence-based clinical practice updates in cardiovascular science.
This oral drug is going to be another powerful addition to the treatments we currently have to lower LDL cholesterol and hopefully prevent cardiovascular events. “Many patients struggle to achieve guideline-recommended cholesterol goals despite currently available treatments, putting them at unnecessary risk of stroke and/or heart attack.”
Ann Marie Navar, MD, Ph.D., FAHA, lead study author, associate professor of cardiology at the University of Texas Southwestern Medical Center, Dallas
In the past decade, a new FDA-approved type of drug has become available to lower bad cholesterol in people who do not achieve recommended levels despite lifestyle changes and maximal statin drug therapy. Known as PCSK9 inhibitors, these drugs include antibodies that block the binding of the PCSK9 protein 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 remove “bad” cholesterol from the bloodstream. Both classes of PCSK9 inhibitors are only given 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 LDL blood levels 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 CORALreef Lipids Phase 3 Trial (CORALreef Lipids), is a phase 3 trial in adults evaluating safety and LDL.
After 24 weeks of daily treatment, the analysis found that compared to those who received placebo, participants who received enlicitide had:
- up to 60% reduction in LDL cholesterol, with continued reductions at 52 weeks.
- 53% reduction in non-HDL, a combination of all types of cholesterol except HDL (“good cholesterol”).
- 50% reduction in ApoB, a protein that helps transport fat and various “bad” types of cholesterol throughout the body.
- 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
- similar rate of serious adverse events (10% in enlicitide vs. 12% in placebo), a small percentage of participants left the study early due to side effects (3% vs. 4%, respectively).
In this study, 7 out of 10 participants who received enlicitide had at least a 50% reduction in LDL-C and also achieved 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 compared to placebo, daily enlicitide resulted in nearly identical changes in LDL, non-HDL, and ApoB to those achieved with the injectable antibodies alirocumab and evolocumab,” Navar said. “And, the results with enlicitide were numerically better than those shown for the siRNA drug inclisiran, which blocks the production of the PCSK9 protein.”
Study details, background or design:
- The study involved 2,912 adults (mean age 63, 39% were women) with a previous heart attack or stroke or who were estimated 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 stable lipid-lowering therapy for 30 days or more, including treatment with at least moderate- or high-intensity statin therapy (or with a history of statin intolerance).
- At the start of the study, 97% of participants were taking statins, and 26% were also taking a drug that reduces cholesterol absorption in the small intestine, such as ezetimibe.
- Participants were randomized 2 to 1 to receive either 20 mg enlicitide once daily (n=1,935) or placebo (n=969). Five participants never received study drug and three were excluded because they were enrolled in multiple trials at multiple sites.
- Study data were collected between August 2023 and July 2025 at 168 healthcare centers in 14 countries.
“The CORALreef results trial is still ongoing and will determine whether and to what extent the lower LDLs achieved with enlicitide will prevent major cardiovascular events,” said Navar.
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