FDA Approves First Oral PCSK9 Inhibitor to Lower LDL Cholesterol

The FDA approved Lipfendra (enlicitide), an oral PCSK9 inhibitor, as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia, including those with heterozygous familial hypercholesterolemia (HeFH). The approval, granted to Merck Sharp & Dohme LLC with priority review, makes Lipfendra the first FDA-approved oral therapy in a drug class previously limited to injectable formulations.^1,2

Lipfendra is a novel macrocyclic peptide, taken as a once-daily tablet, that binds to circulating PCSK9 and blocks its interaction with the LDL receptor. By preventing PCSK9 from promoting degradation of the receptor, the drug increases the number of LDL receptors available on the surface of liver cells to clear LDL-C from the blood.²

Patients are instructed to take the tablet in the morning on an empty stomach and to avoid food or beverages other than water for 30 minutes after dosing.^3,4

The efficacy and safety of Lipfendra were established in 2 randomized, double-blind, placebo-controlled phase 3 trials involving a total of 3207 adults with severe hypercholesterolemia, with and without HeFH, who were already taking maximally tolerated statin therapy.¹

In the CORALreef Lipids (NCT05952856) trial, which enrolled adults with a history of, or at high risk for, atherosclerotic cardiovascular disease (ASCVD) and a mean baseline LDL-C of 96 mg/dL, enlicitide produced a mean percent change in LDL-C from baseline to week 24 of −57.1%, compared with an increase of 3.0% with placebo, for an adjusted between-group difference of −55.8 percentage points (95% CI, −60.9 to −50.7; P < .001).³

Results in Patients With Familial Hypercholesterolemia

In the CORALreef HeFH (NCT05952869) trial, which enrolled 303 adults with a genetic or clinical diagnosis of HeFH and a mean baseline LDL-C of 120.7 mg/dL, enlicitide reduced LDL-C by a mean of 58.2% from baseline at week 24, compared with 2.6% with placebo, for an adjusted between-group difference of 59.4 percentage points (95% CI, −65.6 to −53.2; P < .001). Reductions in LDL-C were evident by week 4 and sustained through week 52 in both trials.^3,4

Both trials also showed significant reductions in other atherogenic lipid markers. In CORALreef Lipids, enlicitide lowered nonhigh-density lipoprotein (nonHDL) cholesterol by an adjusted 53.4 percentage points and apolipoprotein B by 50.3 percentage points versus placebo, along with a median 28.2-percentage-point reduction in lipoprotein(a), all with P < .001.3 In CORALreef Lipids, 70.3% of enlicitide-treated participants achieved an LDL-C level below 70 mg/dL with at least a 50% reduction from baseline, compared with 1.5% of those on placebo; 67.5% reached an LDL-C level below 55 mg/dL with the same degree of reduction, compared with 1.2% of the placebo group.³

“High LDL-C is a major risk factor for atherosclerotic cardiovascular disease, which is the leading cause of death globally,” Ann Marie Navar, MD, PhD, lead author of the CORALreef Lipids study and associate professor of medicine in the Division of Cardiology at UT Southwestern Medical Center, said in a statement.² “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.”

Safety Profile Comparable With Placebo

Adverse event rates were similar between treatment groups in both trials. In CORALreef Lipids, the frequency and severity of adverse events, along with rates of treatment discontinuation due to adverse events, were comparable between enlicitide and placebo.^1,3

In CORALreef HeFH, the most common adverse events occurring more frequently with enlicitide than placebo were diarrhea (7% vs 2%) and dizziness (9% vs 4%), according to Merck. The JAMA report of the same trial specified diarrhea (7.4% vs 2.0%) and dizziness (6.9% vs 4.0%), with similar proportions of patients in each group discontinuing therapy because of an adverse event. Neither trial identified a signal for drug-induced liver injury, and rates of new-onset or worsening diabetes were similar between groups.^2-4

“By harnessing the innovative science of PCSK9 inhibitors and novel macrocyclic peptide technology, LIPFENDRA was designed to significantly lower LDL-C in the form of a convenient once-daily pill,” Dean Y. Li, MD, PhD, president of Merck Research Laboratories, said in the same statement.²

An ongoing cardiovascular outcomes trial, CORALreef Outcomes, has completed enrollment of more than 14,500 participants. It is not yet known whether enlicitide reduces the risk of cardiovascular morbidity and mortality.²

A New Option for an Undertreated Population

For pharmacists, the approval addresses a long-standing access barrier: injectable PCSK9 inhibitors remain infrequently used relative to the number of patients whose LDL-C levels exceed guideline-recommended targets.³

“One of the greatest opportunities to help manage the risk of ASCVD lies in the timely identification and appropriate treatment of risk factors, such as LDL-C,” Katherine Wilemon, CEO of the Family Heart Foundation, said in a statement.² “We are encouraged by the approval of a new oral PCSK9 inhibitor option for adults who need additional LDL-C lowering.”

Because Lipfendra is formulated with sodium caprate, a permeation enhancer that facilitates oral absorption of the peptide, and requires fasting before and after the morning dose, pharmacists counseling patients on this therapy will want to reinforce proper administration technique to support the adherence levels—above 97% in both pivotal trials—seen in the clinical trial program.^3,4

REFERENCES

1. FDA. FDA approves first oral therapy that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) to lower bad cholesterol in adults with high cholesterol. FDA.gov. July 16, 2026. Accessed July 16, 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-oral-therapy-inhibits-proprotein-convertase-subtilisinkexin-type-9-pcsk9-lower

2. 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. Merck & Co, Inc. 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/

3. 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

4. Ballantyne CM, Gellis L, Tardif JC, et al. Efficacy and safety of oral PCSK9 inhibitor enlicitide in adults with heterozygous familial hypercholesterolemia: a randomized clinical trial. JAMA. 2026;335(2):129-139. doi:10.1001/jama.2025.20620