A new experimental pill, called enlicitide, has shown the ability to cut “bad” cholesterol, known as low-density lipoprotein (LDL), by up to 60%, according to a recent phase three clinical trial published in The New England Journal of Medicine. If the U.S. Food and Drug Administration (FDA) approves it, this drug could help millions of Americans lower their risk of heart attacks and strokes.
Currently, many people with heart disease struggle to reach recommended cholesterol levels. “Fewer than half of patients with established heart and blood vessel disease hit their LDL cholesterol goals,” said Dr. Ann Marie Navar, a cardiologist and associate professor at UT Southwestern Medical Center. She led the study, which was sponsored by Merck & Co. Inc. “A daily pill that is this effective could change how we prevent heart attacks and strokes on a large scale.”
For decades, scientists have known that high LDL cholesterol causes cardiovascular problems. LDL particles deposit in blood vessel walls in a process called atherosclerosis, which can eventually lead to heart attacks and strokes. Reducing LDL cholesterol has long been a key part of preventing heart disease and protecting those already affected.
The creation of enlicitide builds on years of research at UT Southwestern. In the 1970s and 1980s, Drs. Michael Brown and Joseph Goldstein made an important discovery. They found the LDL receptor on liver cells. This receptor helps remove LDL cholesterol from the blood. Their work won them the Nobel Prize in 1985. It also led to the creation of statins, drugs that lower cholesterol.
Later studies, including the Dallas Heart Study led by Drs. Helen Hobbs and Jonathan Cohen, found that people with genetic mutations lowering levels of a protein called PCSK9 also had naturally low LDL cholesterol levels. PCSK9 normally reduces the number of LDL receptors on liver cells, slowing cholesterol clearance from the blood. This discovery led to the development of injectable PCSK9 inhibitors, including monoclonal antibodies like evolocumab and alirocumab, which can reduce LDL cholesterol by about 60%.
Despite their effectiveness, these drugs are not widely prescribed. Dr. Navar and her colleagues found that high cost, insurance hurdles, and the fact that they require injections have limited their use. Even with better pricing and coverage today, most primary care doctors and some cardiologists still rarely prescribe these drugs. Enlicitide works similarly to these monoclonal antibodies by targeting PCSK9 in the blood. The major difference is that enlicitide is a daily oral pill, making it much easier for patients to take.
The phase three trial tested enlicitide in 2,909 patients, including people with established atherosclerosis and those at risk due to related health conditions. About two-thirds of participants received enlicitide, while the remaining third received a placebo. Many participants were already taking statins, but their average LDL cholesterol was 96 mg/dL—well above the recommended 70 mg/dL for people with atherosclerosis and 55 mg/dL for those at high risk.
“This study population reflects real-world patients,” Dr. Navar explained. “Even the strongest statins often aren’t enough to get people to their target cholesterol levels.”
After 24 weeks, patients taking enlicitide reduced their LDL cholesterol by roughly 60% compared with those taking a placebo. The pill also lowered other blood markers linked to heart disease, such as non-HDL cholesterol, apolipoprotein B, and lipoprotein(a). These benefits were maintained over a year of follow-up.
Dr. Navar emphasized, “The LDL reductions seen with enlicitide are the largest ever achieved by an oral drug since statins were introduced.” A separate ongoing study is now examining whether the LDL-lowering effect of enlicitide actually reduces heart attacks and strokes. While those results are still pending, the new pill represents a promising step forward in preventing cardiovascular disease, particularly for patients who cannot reach cholesterol targets with statins alone.
If approved, enlicitide could make it far easier for people to manage their cholesterol and protect themselves against life-threatening heart problems. By offering a once-daily pill instead of injections, it may overcome barriers that have limited the use of previous PCSK9-targeting therapies, such as patient discomfort and adherence issues associated with more frequent injections. For millions of Americans at risk, the drug could be a game-changer.
