FDA Approves Enlicitide, the First Oral PCSK9 Inhibitor for High Cholesterol

Merck announced that the FDA has approved enlicitide (Lipfendra; Merck), marking a major breakthrough as the first-ever oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor for adults with hypercholesterolemia. The 20-mg once-daily tablet is indicated as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C), commonly known as "bad" cholesterol, including in patients with heterozygous familial hypercholesterolemia (HeFH).¹

Until now, PCSK9 inhibitors were primarily available through injections. Dean Y. Li, MD, PhD, president of Merck Research Laboratories, described the approval as a "pivotal moment," noting that the drug utilizes novel macrocyclic peptide technology to provide a convenient oral alternative.¹

“Enlicitide is now the most potent oral therapy available after high-intensity statins,” Ann Marie Navar, MD, PhD, associate professor in the Department of Internal Medicine at UT Southwestern Medical Center and a lead author of the studies, said in an interview with Pharmacy Times. “An obvious patient group for enlicitide will be patients who are unable or unwilling to take an injection.”

Clinical Data Supporting the Approval

The FDA's decision was supported by 2 phase 3 trials in the CORALreef clinical program. In the CORALreef Lipids trial (NCT05952856), enlicitide demonstrated a 56% placebo-adjusted reduction in LDL-C at week 24. Results were even higher in the CORALreef HeFH trial (NCT05952869), showing a 59% reduction. Navar highlighted that these "impressive reductions" offer a new pathway for managing a major risk factor for cardiovascular disease.^1-4

CORALreef Lipids randomly assigned 2904 patients with hypercholesterolemia—with and without HeFH—who had a history of a major atherosclerotic cardiovascular disease (ASCVD) event or elevated risk of a first event 2:1 to enlicitide 20 mg once daily (n = 1935) or placebo (n = 969) for 52 weeks (5 individuals did not receive enlicitide or placebo). All required additional LDL-C reduction despite stable therapy with moderate- or high-intensity statins, and patients already taking PCSK9 inhibitors were excluded. CORALreef HeFH applied the same design in 303 patients with HeFH diagnosed by clinical criteria or genotyping.¹

Beyond LDL-C, both trials showed reductions in other atherogenic lipoproteins tied to ASCVD risk. In CORALreef Lipids, enlicitide produced a 54% mean reduction in non–high-density lipoprotein cholesterol (non–HDL-C) and a 50% reduction in apolipoprotein B from baseline at week 24; corresponding reductions in CORALreef HeFH was 52% and 48%. Full CORALreef Lipids results were published in the New England Journal of Medicine in February 2026.^1,4

What Pharmacists Should Know

Enlicitide's safety profile was generally similar to placebo. In CORALreef HeFH, the most common adverse reactions, occurring more often than with placebo, were dizziness (9% vs 4%) and diarrhea (7% vs 2%). In both trials, similar proportions of patients in the enlicitide and placebo arms discontinued treatment because of an adverse reaction.^1,4

The oral route is the central practice-level change. Injectable PCSK9 inhibitors have long faced adherence and access friction tied to administration and specialty distribution, and a daily tablet shifts counseling toward routine-building and refill persistence rather than injection technique. Speaking with Pharmacy Times earlier this year about the CORALreef Lipids results, Navar noted that clear dosing instructions may support routine formation and that enabling patient choice of formulation could itself improve adherence.⁵

“Pharmacists will be key in reminding patients about how to take enlicitide—first thing in the morning on an empty stomach and wait 30 minutes before eating,” Navar explained. “Patients can take other medications with it, like their other lipid-lowering therapies.”

Pharmacists should also be prepared for the limits of the current label. Although enlicitide's ability to lower cholesterol is established, an ongoing phase 3 trial—CORALreef Outcomes (NCT06008756), which has completed enrollment with more than 14,500 participants—is investigating whether the drug also reduces cardiovascular morbidity and mortality. It is not known whether enlicitide lowers that risk, and counseling should frame the drug as an LDL-C–lowering therapy pending those data.^1,6

Enlicitide received the FDA Commissioner's National Priority Voucher in December 2025, a designation intended to shorten review timelines for products deemed critical to public health. The broader CORALreef program continues to evaluate more than 19,000 participants, with additional trials underway in extension, pediatric, and combination settings.^1,7

REFERENCES

1. 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. News release. Merck. July 16, 2026. Accessed July 16, 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. A Study of enlicitide decanoate (MK-0616 oral PCSK9 inhibitor) in adults with hypercholesterolemia (MK-0616-013) CORALreef Lipids. ClinicalTrials.gov. Updated September 10, 2025. Accessed July 16, 2026. https://clinicaltrials.gov/study/NCT05952856

3. A study of enlicitide decanoate (MK-0616 oral PCSK9 inhibitor) in adults with heterozygous familial hypercholesterolemia (MK-0616-017/​CORALreef HeFH). ClinicalTrials.gov. Updated February 24, 2026. Accessed July 16, 2026. https://clinicaltrials.gov/study/NCT05952869

4. Navar AM, Mikhailova E, Catapano AL, et al. A placebo-controlled trial of the oral PCSK9 inhibitor enlicitide. N Engl J Med. 2026;394(6):529-539. doi:10.1056/NEJMoa2511002

5. Navar AM, Halpern L. CORALreef Lipids trial: what pharmacists should know about enlicitide. Pharmacy Times. February 26, 2026. Accessed July 16, 2026. https://www.pharmacytimes.com/view/coralreef-lipids-trial-what-pharmacists-should-know-about-enlicitide

6. Enlicitide decanoate (MK-0616 oral PCSK9 inhibitor) cardiovascular outcomes study (MK-0616-015) CORALreef Outcomes. ClinicalTrials.gov. Updated April 23, 2026. Accessed July 16, 2026. https://clinicaltrials.gov/study/NCT06008756

7. Antrim A. New oral contender outshines standard add-on therapies for LDL-C. Pharmacy Times. March 30, 2026. Accessed July 16, 2026. https://www.pharmacytimes.com/view/new-oral-contender-outshines-standard-add-on-therapies-for-ldl-c