Enlicitide Receives FDA Approval for Hypercholesterolemia Following CORALreef Trials

The US Food and Drug Administration (FDA) has officially approved the first-ever oral PCSK9 inhibitor, enlicitide, for the reduction of LDL-C in adult patients with hypercholesterolemia alongside high-intensity statins.¹

Parent company Merck announced the approval on July 16, 2026, which followed positive data from the CORALreef Lipids and CORALreef HeFH trials. Enlicitide, approved under the name Lipfendra, substantially reduced LDL-C in both trials compared to placebo. The drug is administered in the form of 20 mg tablets as an adjunct to diet and exercise and has been approved for patients with heterozygous familial hypercholesterolemia (HeFH) in addition to hypercholesterolemia.¹

“This is really big,” Ann Marie Navar, MD, PhD, associate professor of medicine in the Division of Cardiology at UT Southwestern Medical Center, told HCPLive in an exclusive interview. “We now have an oral option that lowers LDL cholesterol by up to 60% on top of high-intensity statins and other background therapies. That’s huge in terms of getting more patients to goal.”

CORALreef Lipids was a multinational, double-blind, randomized, placebo-controlled trial including patients with a history of major atherosclerotic cardiovascular disease (ASCVD) events with an LDL-C level of ≥55 mg/dL or those who were at risk of a first ASCVD event with an LDL-C ≥70 mg/dL. These patients were assigned in a 2:1 ratio to receive either 20 mg enlicitide or placebo daily for 52 weeks.²

The primary endpoint for CORALreef Lipids was mean percent change in LDL-C level from baseline to week 24. Secondary endpoints included mean percent LDL-C level changes at week 52 and mean percent change in non-HDL-C, apolipoprotein B (apoB), and lipoprotein(a) levels at week 24.²

A total of 2909 patients were enrolled in CORALreef Lipids, of whom 1935 received enlicitide and 969 received placebo. Mean LDL-C level at baseline was 96.1 +/- 38.9 mg/dL, while mean percent change by week 24 was -57.1% (95% CI, -61.8 to -52.5) with enlicitide and 3% (95% CI, 0.9 to 5.1) with placebo. This represented an adjusted between-group difference of -55.8% (95% CI, -60.9 to -50.7; P <.001). The percent change in LDL-C at week 52, as well as the changes in Lp(a), non-HDL-C, and apoB at week 24, were all greater with enlicitide than placebo.²

The CORALreef HeFH trial included patients ≥18 years old with HeFH who were actively using lipid-lowering therapy – either a moderate- or high-intensity statin – and who had an LDL-C level ≥55 mg/dL with a history of major ASCVD or an LDL-C level ≥70 mg/dL without a history of major ASCVD.³

Participants were randomly assigned in a 2:1 ratio to receive either 20 mg of enlicitide or placebo once daily for 52 weeks. The primary outcome for CORALreef HeFH was the same as in CORALreef Lipids, while secondary endpoints included the same measurements of apoB and non-HDL-C, as well as percent change in LDL-C at week 52.³

A total of 303 patients were enrolled and randomized, with 202 receiving enlicitide and 101 receiving placebo. Mean LDL-C at baseline was 119 mg/dL (standard deviation [SD], 41 mg/dL). Mean percentage change at week 24 in LDL-C was -58.2% in the enlicitide group versus 2.6% in the placebo group, with a between-group difference of -59.4% (95% CI, -65.6% to -53.2%; P <.001). The mean percentage change in LDL-C at week 52 was -55.3% in the enlicitide group versus 8.7% in the placebo group, with a between-group difference of -61.5% (95% CI, -69.4% to -53.7%; P <.001).³

While the approval itself was based on the positive results from these 2 trials, Merck has also launched the ongoing CORALreef Outcomes study, which is examining the effects of enlicitide on cardiovascular morbidity and mortality over the long term.¹

“This approval is just the first step,” Navar said. “Now we actually have to get it into the hands of our clinician prescribers, and then ultimately into our patients. It’s going to come down to: are people going to use it, and are we going to be able to get payers and insurers to cover it for the patients that need it?”

Editors’ Note: Navar reports disclosures with Esperion Therapeutics, Bristol Myers Squibb, Amgen, Janssen Pharmaceuticals, Eli Lilly, Novo Nordisk, and others.

References

1. Merck. Merck’s LIPFENDRA (enlicitide) is the First and Only Once-Daily Oral PCSK9 Inhibitor Approved by the US FDA to Reduce LDL-C in Adults with Hypercholesterolemia. July 16, 2026. July 17, 2026. https://www.merck.com/news/mercks-lipfendra-enlicitide-is-the-first-and-only-once-daily-oral-pcsk9-inhibitor-approved-by-the-u-s-fda-to-reduce-ldl-c-in-adults-with-hypercholesterolemia/

2. Navar AM, Mikhailova E, Catapano AL, et al. A placebo-controlled trial of the oral PCSK9 inhibitor enlicitide. NEJM. 2026;394(6):529-539. doi:10.1056/nejmoa2511002

3. Ballantyne CM, Gellis L, Tardif J-C, et al. Efficacy and safety of oral PCSK9 inhibitor enlicitide in adults with heterozygous familial hypercholesterolemia. JAMA. 2026;335(2):129. doi:10.1001/jama.2025.20620