New Pill Cuts “Bad” Cholesterol by 60%—A Potential Game Changer in Cardiovascular Disease Prevention

A new experimental pill, enlicitide, has demonstrated a significant reduction in low-density lipoprotein (LDL) cholesterol—often referred to as “bad” cholesterol—by up to 60% in a phase three clinical trial published in The New England Journal of Medicine. This breakthrough offers a potentially simpler and more accessible alternative to existing treatments, particularly for individuals who struggle to manage their cholesterol levels with current therapies.

Understanding the Impact of High LDL Cholesterol

For decades, scientists have understood that elevated LDL cholesterol plays a central role in the development of cardiovascular diseases. Cholesterol-containing particles can deposit in artery walls, a process called atherosclerosis, increasing the risk of heart attacks and strokes. Fewer than half of patients with established atherosclerotic cardiovascular disease currently reach recommended LDL cholesterol goals, highlighting the need for more effective treatment options.

How Enlicitide Works

Enlicitide is an oral PCSK9 inhibitor, meaning it works by blocking the PCSK9 protein. This action increases the number of LDL receptors available to clear LDL cholesterol from the bloodstream. Currently available PCSK9 inhibitors require subcutaneous injections. Enlicitide, taken as a once-daily pill, offers a more convenient administration route.

Clinical Trial Results: The CORALreef Lipids Trial

The phase three CORALreef Lipids Trial involved 2,912 adults across 14 countries with elevated LDL-C despite stable lipid-lowering therapy, with nearly all participants already taking statins and one-quarter also taking ezetimibe. Participants were randomized to receive either 20 mg of enlicitide daily or a placebo. The study demonstrated that enlicitide led to reductions in LDL and other cholesterol measures similar to those achieved with injectable PCSK9 inhibitors.

The Foundation of PCSK9 Inhibitor Development

The development of PCSK9 inhibitors, including enlicitide, builds upon decades of research. The discovery of the LDL receptor by Michael Brown and Joseph Goldstein at UT Southwestern Medical Center earned them the Nobel Prize in Medicine in 1985 and paved the way for the development of statins. Later, research by Helen Hobbs and Jonathan Cohen at UT Southwestern further elucidated the importance of the PCSK9 protein, leading to the design of PCSK9 inhibitors.

Challenges with Current PCSK9 Inhibitors and the Promise of an Oral Alternative

While injectable PCSK9 inhibitors are highly effective, their high cost, the need for regular injections, and administrative hurdles have limited their widespread use. Enlicitide’s oral formulation could improve treatment adherence, simplify medical follow-up, and reduce logistical costs, potentially increasing access to this important therapy.

What’s Next?

A cardiovascular outcome clinical trial is currently underway to determine whether the LDL cholesterol reduction achieved with enlicitide translates into a lower incidence of heart attacks and strokes. The study is sponsored by Merck & Co. Inc., and Dr. Ann Marie Navar, the lead researcher, has received consulting fees from Merck and other companies involved in cardiovascular therapy development.