The Cholesterol Pill That Could Replace the Needle

For 40 years, the cholesterol story has been a statin story. The drugs work, they're cheap, and doctors prescribe them reflexively. But there's a dirty secret in cardiology: a large body of real-world evidence shows that even on maximum-dose statins, most high-risk patients still don't hit their LDL cholesterol targets. A retrospective cohort study published in Cardiology — drawing on electronic medical records for more than 14,000 patients with atherosclerotic cardiovascular disease in Germany — found that approximately 80% of patients on moderate- or high-intensity statins had LDL-C at or above 70 mg/dL. A companion finding: 79–81% of patients made no change to their statin regimens despite being below goal.

The drugs that could close the gap — injectable PCSK9 inhibitors like Repatha and Praluent — have been available for nearly a decade. They're remarkably effective. And they're remarkably underused.

The reason is almost comically simple: people don't like needles.

A phase 3 trial published in the New England Journal of Medicine now suggests that barrier may be about to disappear. Enlicitide, an oral PCSK9 inhibitor developed by Merck, reduced LDL cholesterol by 57% at 24 weeks in patients already on statins — roughly matching what the injectables achieve, but in a once-daily pill.

The Trial

The CORALreef Lipids study enrolled 2,909 participants across 168 sites in 14 countries, randomizing them 2:1 to 20 mg of daily enlicitide or placebo. Most were already taking statins, yet their average LDL sat at 96 mg/dL — well above the recommended targets of 70 mg/dL for patients with existing cardiovascular disease and 55 mg/dL for those at highest risk.

The results were unambiguous. At 24 weeks, enlicitide cut LDL by 57.1% compared to placebo, according to the NEJM paper. A post-hoc reanalysis correcting for five biologically impossible baseline values pushed the number to 59.7%. At one year, the effect held: a sustained 52.4% reduction in the reanalysis.

Beyond LDL, enlicitide lowered non-HDL cholesterol by 53.4%, apolipoprotein B by 50.3%, and lipoprotein(a) — an emerging and notoriously stubborn cardiovascular risk marker — by 28.2%. Two-thirds of treated patients hit the stringent combined target of LDL below 55 mg/dL with at least a 50% reduction from baseline. In the placebo group, 1.2% got there.

Safety looked clean. Adverse event rates were essentially identical between the drug and placebo groups. Adherence was 97% — a number that will matter enormously if this reaches the market, though it reflects controlled trial conditions rather than real-world prescribing patterns where persistence with daily medication typically drops significantly over time.

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

The Lineage

There's a pleasing scientific symmetry here. Enlicitide traces its intellectual ancestry directly to UT Southwestern, where Michael Brown and Joseph Goldstein identified the LDL receptor in work that won the 1985 Nobel Prize. Later, the Dallas Heart Study — led by UTSW's Helen Hobbs and Jonathan Cohen — revealed that some people carry natural genetic variants that reduce PCSK9, giving them lower cholesterol and fewer heart attacks. That finding launched the entire PCSK9 inhibitor class.

The injectables that followed — evolocumab (Repatha) and alirocumab (Praluent) — proved the biology emphatically. They cut LDL by up to 60–70% and reduced cardiovascular events. But uptake has been persistently disappointing. Early pricing debacles, insurance battles, and the simple friction of self-injection kept them from becoming the population-level tools they could be. Fewer than half of patients with established atherosclerotic cardiovascular disease currently reach their LDL goals.

Enlicitide targets the same protein via a different molecular approach — it's a macrocyclic peptide, not a monoclonal antibody. The practical difference is that it survives the gut and can be swallowed.

What's Missing

The CORALreef Lipids trial proved enlicitide lowers cholesterol. What it didn't prove — and can't, by design — is whether that translates into fewer heart attacks and strokes. That question is being tested in the CORALreef Outcomes trial, a larger study with a projected completion date of December 2029.

This isn't a formality. The relationship between LDL reduction and cardiovascular outcomes is well established across drug classes, and PCSK9 inhibitors have already demonstrated the link. But regulators and clinicians will want to see the data for this specific molecule, particularly given its novel formulation.

In an accompanying NEJM editorial, cardiologist William Boden called the results "impressive" and "compelling evidence that enlicitide provides incremental benefit," noting that an oral formulation "would represent an important step forward to facilitate greater medication adherence."

The Regulatory Signal

Merck is expected to file for FDA approval in April 2026, with a potential launch in 2027. And the FDA appears to be leaning in: the agency awarded enlicitide a National Priority Voucher under the Commissioner's pilot program, designed to accelerate review of products addressing large unmet medical needs.

That voucher is a meaningful signal. Cardiovascular disease remains the leading cause of death globally. The tools to prevent it have been sitting in medicine cabinets and — too often — not in patients' arms. If enlicitide can deliver injectable-grade cholesterol reduction in a pill people actually take, the impact won't be measured in percentage points. It'll be measured in heart attacks that don't happen.

The trial was sponsored by Merck. Navar disclosed consulting fees from Merck and other pharmaceutical companies that make lipid-lowering drugs.