The results of a phase three clinical trial for a cholesterol-lowering drug have shown that this drug, called enlicitide, can reduce the levels of low-density lipoprotein (LDL) cholesterol by 60% compared to a placebo. The findings have been reported in the New England Journal of Medicine. If the Food and Drug Administration approves the drug, it may help people significantly reduce their risk of heart attacks or strokes. The study was sponsored by Merck & Co. Inc.
"Fewer than half of patients with established atherosclerotic cardiovascular disease currently reach LDL cholesterol goals. An oral therapy this effective has the potential to dramatically improve our ability to prevent heart attacks and strokes on a population level," said Ann Marie Navar, MD, Ph.D., a cardiologist and Associate Professor at UT Southwestern Medical Center.
It’s long been known that high levels of LDL cholesterol can lead to cardiovascular disease. LDL can build up in blood vessels to cause atherosclerosis, and subsequently, heart attacks and strokes. As such, clinicians recommend keeping LDL cholesterol levels low to reduce the risk of heart attacks and strokes.
Scientists determined that some people naturally have lower levels of LDL cholesterol, because they carry certain genetic variants that lead them to generate unusually low levels of a protein called PCSK9. This protein can cause liver cells to have fewer LDL cholesterol receptors, so the liver takes up less LDL from the bloodstream. This knowledge led to the development of drugs that can disrupt PCSK9, and reduce LDL uptake. These drugs are very expensive, however and since they are also injectables, not many patients can access or use them.
Enlicitide also works by attaching to PCSK9 in the bloodstream, but it is a monoclonal antibody that can be taken daily in pill form.
This trial showed tested the effects of enlicitide in 2,909 individuals who had previously been diagnosed with atherosclerosis or who were at risk of developing it. Two-thirds of these volunteers got the drug, and the remainder got a placebo.
The people who took enlicitide for 24 weeks were found to have LDL cholesterol levels that were about 60% lower compared tp those who took the placebo. Other biomarkers that are associated with cardiovascular disease were reduced as well, such as apolipoprotein B, non-HDL lipoprotein cholesterol, and lipoprotein(a).
"These reductions in LDL cholesterol are the most we have ever achieved with an oral drug by far since the development of statins,” said Navar.
There is another clinical trial underway that aims to determine whether these LDL reductions translate into a reduced risk of heart attacks and strokes.
Sources: UT Southwestern Medical Center, Navar et al NEJM 2026, Boden et al NEJM 2026