FDA Approves Enlicitide for LDL-C Lowering in Adults With Hypercholesterolemia

On July 16, 2026, the US Food and Drug Administration (FDA) approved enlicitide (Lipfendra) 20 mg tablets to reduce LDL-C in adults with hypercholesterolemia.1

Announced by parent company Merck, the decision positions enlicitide as an adjunct to diet and exercise for the reduction of LDL-C in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH). Enlicitide is a once-daily oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.1

The decision was supported by 2 phase 3, placebo-controlled trials in which enlicitide produced placebo-adjusted LDL-C reductions of 56% and 59% at week 24. The approved indication addresses LDL-C lowering; an ongoing outcomes trial is assessing cardiovascular morbidity and mortality, and cardiovascular risk reduction has not been established for enlicitide.1

“High LDL-C is a major risk factor for atherosclerotic cardiovascular disease, which is the leading cause of death globally,” Ann Marie Navar, MD, associate professor of medicine in the Division of Cardiology at UT Southwestern Medical Center, said in a statement. “In 2 phase 3 trials, LIPFENDRA led to impressive reductions in LDL-C. Now, for the first time, patients have an oral PCSK9 inhibitor for LDL lowering.”1

What the Phase 3 CORALreef Lipids Trial Showed

CORALreef Lipids enrolled 2904 adults with hypercholesterolemia, including patients with and without HeFH, who had experienced a major atherosclerotic cardiovascular disease (ASCVD) event or were at increased risk for a first event. Participants required additional LDL-C lowering despite stable moderate- or high-intensity statin therapy, unless statin intolerance was documented, with or without other lipid-modifying treatment. Patients receiving another PCSK9 inhibitor were excluded. Participants were randomized 2:1 to enlicitide 20 mg once daily or placebo for 52 weeks.1

At week 24, the primary endpoint LDL-C declined 57% from baseline with enlicitide and increased 3% with placebo, yielding a 56% placebo-adjusted reduction (95% CI, −61 to −51; P <.001). Enlicitide also resulted in a mean non–high-density lipoprotein cholesterol reduction of 54% and a mean apolipoprotein B reduction of 50%, compared with a 3% increase in both measures with placebo.1

A post hoc analysis excluding biologically impossible LDL-C values of 0 or less produced a 60% reduction from baseline with enlicitide. Because this analysis used revised data-handling rules after the fact, the prespecified primary analysis remains the central efficacy result.

What the Phase 3 CORALreef HeFH Trial Showed

CORALreef HeFH enrolled 303 adults with HeFH diagnosed through clinical criteria or genotyping. Participants required further LDL-C reduction despite stable moderate- or high-intensity statin treatment, with or without other lipid-modifying therapy. In a 2:1 randomization, 202 received enlicitide and 101 received placebo for 52 weeks.1

At week 24, LDL-C decreased 58% from baseline with enlicitide and increased 3% with placebo, corresponding to a 59% placebo-adjusted reduction (95% CI, −66% to −53%; P <.001). Mean non–high-density lipoprotein cholesterol and apolipoprotein B declined 52% and 48%, respectively, with enlicitide; both increased 2% with placebo.1

Adverse reaction frequencies in CORALreef Lipids were similar between groups. In CORALreef HeFH, diarrhea occurred in 7% of enlicitide recipients and 2% of placebo recipients, while dizziness occurred in 9% and 4%, respectively. The proportions discontinuing treatment because of an adverse reaction were similar between treatment groups in both trials.1,2

Enlicitide Mechanism and Remaining Evidence Gaps

Enlicitide is a macrocyclic peptide designed to bind PCSK9 and inhibit its interaction with LDL receptors. This mechanism is intended to preserve LDL receptor availability and increase clearance of circulating LDL-C. Unlike previously available PCSK9-directed treatments administered by injection, enlicitide is formulated as an oral tablet.1,2

The approval was based on lipid end points rather than cardiovascular events. CORALreef Outcomes, an ongoing trial with more than 14,500 enrolled participants, is evaluating effects on cardiovascular morbidity and mortality. Longer-term efficacy and safety data also remain relevant because the pivotal trials’ primary efficacy assessments occurred at 24 weeks, although randomized treatment continued for 52 weeks.1

References

1. 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. Business Wire. Published July 16, 2026. https://www.businesswire.com/news/home/20260715942620/en/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. Lipfendra (enlicitide) prescribing information. Merck & Co, Inc. https://www.merck.com/product/usa/pi_circulars/l/lipfendra/lipfendra_pi.pdf