FDA approves Lipfendra, first oral PCSK9 inhibitor to lower LDL cholesterol

FDA has approved Lipfendra (enlicitide), the first oral PCSK9 inhibitor, for adults with primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH), as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C). The once-daily tablet is indicated for patients who need additional LDL-C lowering despite lipid-lowering therapy.

PCSK9 inhibitors have become an important option for patients who remain above LDL-C goals despite maximally tolerated statin therapy, but until now all approved therapies in this class have required injection. The availability of an oral PCSK9 inhibitor may make this highly effective treatment approach more acceptable for some patients and broaden options for intensifying lipid-lowering therapy.

Approval was based on two phase 3, randomized, double-blind, placebo-controlled trials involving 3,207 adults receiving maximally tolerated statins with or without other lipid-lowering therapy. One trial enrolled patients with established atherosclerotic cardiovascular disease (ASCVD) or at high risk for ASCVD, while the second enrolled patients with HeFH. An ongoing cardiovascular outcomes trial is evaluating whether enlicitide also reduces cardiovascular morbidity and mortality.

At 24 weeks, enlicitide reduced LDL-C by 56% versus placebo in patients with ASCVD or high cardiovascular risk and by 59% versus placebo in patients with HeFH. Treatment also significantly reduced non-HDL cholesterol and apolipoprotein B, two additional markers associated with ASCVD risk.

The safety profile was generally similar to placebo. In the HeFH trial, diarrhea (7% vs 2%) and dizziness (9% vs 4%) occurred more frequently with enlicitide than placebo. Rates of treatment discontinuation because of adverse events were similar between groups.

"High LDL-C is a major risk factor for atherosclerotic cardiovascular disease, which is the leading cause of death globally," said Ann Marie Navar, MD, associate professor of medicine in the Division of Cardiology at UT Southwestern Medical Center and a lead author of the CORALreef Lipids study. "In two 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."

Sources: U.S. Food and Drug Administration. (2026 Jul 16). FDA approves first oral therapy that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) to lower bad cholesterol in adults with high cholesterol; Merck. (2026 Jul 16). 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