FDA Approves First Oral PCSK9 Inhibitor LIPFENDRA (Enlicitide) for Adults With Hypercholesterolemia

The Food and Drug Administration (FDA) has approved Lipfendra (enlicitide; Merck, Rahway, NJ) as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH). Lipfendra is the first FDA-approved oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor and is indicated for patients requiring additional LDL-C lowering despite standard therapy.

Approval was supported by the phase 3 CORALreef Lipids and CORALreef HeFH trials. CORALreef Lipids enrolled 2,904 adults with hypercholesterolemia and established or elevated risk for atherosclerotic cardiovascular disease who required additional LDL-C reduction despite stable lipid-lowering therapy. CORALreef HeFH included 303 adults with heterozygous familial hypercholesterolemia receiving background lipid-lowering treatment. In both studies, participants were randomized 2:1 to receive once-daily oral enlicitide 20 mg or placebo for 52 weeks, with percent change in LDL-C at week 24 serving as the primary endpoint.

What the Data Showed

• Lipfendra treatment reduced LDL-C by 56% vs placebo at week 24 in CORALreef Lipids (95% CI, –61 to –51; P<.001).
• In CORALreef HeFH, LDL-C was reduced by 59% vs placebo at week 24 (95% CI, –66 to –53; P<.001).
• Treatment also significantly reduced non-HDL cholesterol and apolipoprotein B in both trials.
• In CORALreef Lipids, adverse event rates were similar between treatment groups. In CORALreef HeFH, diarrhea (7% vs 2%) and dizziness (9% vs 4%) occurred more frequently with LIPFENDRA than placebo, although treatment discontinuations due to adverse events were comparable between groups.

An ongoing cardiovascular outcomes trial is evaluating whether LDL-C lowering with Lipfendra translates into reductions in cardiovascular morbidity and mortality. According to Merck, this benefit has not yet been established.

Source

Merck & Co., Inc. 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. News release. Published July 16, 2026. Accessed July 28, 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/