The Benefits and Limits of Enlicitide, With Ninel Hovnanians, MD

Enlicitide, first approved by the US Food and Drug Administration (FDA) on July 16, 2026, to lower LDL-C in adults with hypercholesterolemia, became available for prescription in August; however, the drug’s lack of a cardiovascular indication limits its use beyond an addition to statins.^1,2

Enlicitide is the first oral PCSK9 inhibitor to receive FDA approval – historically, they have only been available as injectables administered once or twice a month. A leading draw for enlicitide is the avoidance of treatment adherence issues raised by regular injections. Currently, however, it is only cleared as an add-on to statin therapy following evidence that statins alone are not sufficiently reducing LDL-C to the clinical target level.^1,2

“A lot of my patients were calling and asking whether they could just switch to enlicitide now that it’s been approved, but none of the studies have actually been done on their own, and all of them have been in addition to moderate or high intensity or the highest tolerable dose of statins,” Ninel Hovnanians, MD, general cardiologist and medical director of the Cardiac Fitness Center at UWMC Northwest, told HCPLive in an exclusive interview. “We don’t have any comparison to say whether these medications really have the same benefits on their own.

The FDA’s approval was based on the CORALreef Lipids trial, a multinational, double-blind, randomized, placebo-controlled trial evaluating patients with a history of a major atherosclerotic cardiovascular disease (ASCVD) event who had an LDL-C of ≥55 mg/dL, as well as patients at risk for a first ASCVD event with an LDL-C of ≥70 mg/dL. Patients were assigned in a 2:1 ratio to either enlicitide 20 mg or placebo daily for 52 weeks.³

The primary endpoint of CORALreef Lipids was mean percent change in LDL-C from baseline to week 24. Secondary endpoints included the mean percent change in LDL-C at week 52 and in non-HDL cholesterol, apolipoprotein B, and lipoprotein(a) at week 24.³

Of the 2909 patients enrolled in the trial, 1935 received enlicitide and 969 received placebo, while 5 did not receive either. Mean age was 63 years, and 39.3% of enrolled patients were women. Mean LDL-C (+/- standard deviation [SD]) at baseline was 96.1 +/- 38.9 mg/dL. By week 24, mean percent change was -57.1% (95% CI, -61.8 to -52.5%) with enlicitide and 3% (95% CI, 0.9 to 5.1) with placebo, with a between-group difference of -55.8% (95% CI, -60.9 to -50.7%; P <.001). Additionally, mean percent changes in all secondary endpoints were significantly greater with enlicitide than with placebo.³

Despite these positive data, neither the CORALreef Lipids trial nor the accompanying CORALreef HeFH trial was powered to determine its effects on cardiovascular outcomes directly. The current FDA approval only clears it for use alongside statins to reduce lipid levels; further investigation is needed before it can be evaluated as a cardioprotective medication in isolation.¹

However, an ongoing trial from Merck, the phase 3 CORALreef Outcomes study, is currently evaluating enlicitide’s capacity to increase time to first occurrence of major adverse cardiovascular events compared to placebo. With an expected completion date of November 2029, this program aims to bridge the aforementioned gap in indication and allow clinicians to prescribe enlicitide for cardiovascular benefit as well.⁴

“The most important thing to remember is that this is an add-on therapy to statins and not a standalone medication,” Hovnanians said. “I think that this is the question that’s brought up to me by my patients the most.”

Editors’ Note: Hovnanians reports no relevant disclosures.

References

1. Donohue B. Statins not enough? New pill expected to lower cholesterol. UW Medicine Newsroom. August 26, 2026. Accessed October 5, 2026. https://newsroom.uw.edu/blog/statins-not-enough-new-pill-expected-to-lower-cholesterol/

2. Merck. Merck’s 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. July 16, 2026. Accessed October 5, 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/

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

4. Merck Sharp & Dohme. Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) Cardiovascular Outcomes Study (MK-0616-015) CORALreef Outcomes. ClinicalTrials.gov Identifier: NCT06008756. Updated April 23, 2026. Accessed October 5, 2026. https://clinicaltrials.gov/study/NCT06008756