Enlicitide Pill Cuts LDL Cholesterol 60% in Phase 3 Trial
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- Enlicitide reduced LDL ("bad") cholesterol by ~60% versus placebo in a 24-week phase three trial of 2,909 patients, published in The New England Journal of Medicine — the largest LDL reduction ever achieved with an oral drug since statins.
- The Merck-funded study, led by Dr. Ann Marie Navar at UT Southwestern, found that even though most participants were already on statins, their average baseline LDL was 96 mg/dl — above the 70 mg/dl target for atherosclerosis patients and 55 mg/dl for at-risk patients.
- Enlicitide is a once-daily oral pill that hits the same PCSK9 pathway as injectable drugs evolocumab and alirocumab, which also lower LDL by ~60% but remain underused largely because they require shots.
- The trial also showed reductions in non-HDL lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) — a marker statins barely affect — with the LDL benefits sustained over a full year of follow-up.
- Enlicitide builds on the 1985 Nobel Prize–winning work of UT Southwestern's Michael Brown and Joseph Goldstein, who identified the LDL receptor, and the Dallas Heart Study's later PCSK9 discoveries led by Helen Hobbs and Jonathan Cohen.
- A second clinical trial is now underway to determine whether the LDL reductions translate into fewer heart attacks and strokes.
- Fewer than half of patients with established atherosclerotic cardiovascular disease currently reach LDL goals, per Navar — leaving a large unmet need that an effective oral option could fill if the FDA approves it.
Why it matters: For the roughly half of atherosclerotic cardiovascular disease patients who don't hit LDL targets on statins, enlicitide would offer a once-daily pill matching the 60% LDL reduction of injectable PCSK9 inhibitors — potentially shifting prescribing away from evolocumab, alirocumab, and the RNA-based therapies that physicians still hesitate to use because of the injection barrier.
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