New Pill Cuts 'Bad' Cholesterol by 60% in Landmark Trial

A Pill That Rivals Injections

An experimental daily pill has achieved what cardiologists have long hoped for: matching the cholesterol-lowering power of injectable drugs in a simple oral tablet. Results from the phase 3 CORALreef Lipids trial, published in the New England Journal of Medicine in February 2026, show that enlicitide — developed by Merck — reduced LDL cholesterol by up to 60% in patients at high risk of cardiovascular disease.

"These reductions in LDL cholesterol are the most we have ever achieved with an oral drug by far since statins," said Dr. Ann Marie Navar, cardiologist and associate professor at UT Southwestern Medical Center, who led the trial.

How Enlicitide Works

Enlicitide decanoate is a novel small-molecule macrocyclic peptide that targets PCSK9, a protein that prevents the liver from clearing LDL cholesterol from the bloodstream. Existing PCSK9 inhibitors like evolocumab and alirocumab achieve similar reductions but require regular injections — a significant barrier to widespread adoption. Many physicians, including a substantial share of cardiologists, still hesitate to prescribe them for this reason.

As Merck Research Laboratories president Dr. Dean Y. Li put it: "Enlicitide was designed to deliver PCSK9 antibody-like efficacy and specificity in an easy-to-use pill."

Trial Results at a Glance

The multinational, double-blind trial enrolled 2,909 patients across 168 sites in 14 countries. Two-thirds received enlicitide; one-third received a placebo. Nearly all participants (97%) were already on statin therapy.

• LDL cholesterol: 55.8% reduction vs. placebo at 24 weeks (59.7% in post-hoc reanalysis)
• Non-HDL cholesterol: 53.4% reduction
• Apolipoprotein B: 50.3% reduction
• Lipoprotein(a): 28.2% reduction

At one year, the effect held steady with a 52.4% LDL reduction in reanalysis. More than two-thirds of patients achieved aggressive treatment targets of LDL below 70 mg/dL with at least a 50% reduction — compared to just 1.5% on placebo.

Safety on Par With Placebo

Critically, enlicitide's safety profile was comparable to placebo. Adverse events occurred in 64% of the drug group versus 62% on placebo. Serious adverse events, discontinuation rates, new-onset diabetes, and mortality were virtually identical between groups. Only 3.1% of enlicitide patients discontinued due to side effects, compared with 4.1% on placebo.

Why It Matters

Cardiovascular disease remains the world's leading cause of death, claiming nearly 18 million lives annually. Approximately 40% of adults with atherosclerotic cardiovascular disease need additional LDL-lowering beyond statins and ezetimibe to reach target levels, according to the trial authors.

Dr. William E. Boden, a leading cardiologist, called the results "impressive" and "compelling," emphasizing that "a simpler formulation would represent an important step forward to facilitate greater medication adherence."

What Comes Next

Merck plans to submit data from three CORALreef trials to regulatory authorities. The pivotal question — whether these LDL reductions actually prevent heart attacks and strokes — is being answered by the CORALreef Outcomes trial, which has enrolled over 14,500 participants with results expected by December 2029. If enlicitide gains FDA approval, it could become the first oral PCSK9 inhibitor on the market, potentially transforming how millions of high-risk patients manage their cholesterol.