Once-daily pill called enlicitide lowers bad cholesterol levels by 60%

A new experimental pill may soon change how you lower cholesterol. Researchers at UT Southwestern Medical Center report that an oral drug called enlicitide cut levels of low-density lipoprotein, or LDL, cholesterol by nearly 60% in a large clinical trial. The findings were published in The New England Journal of Medicine and could lead to a simpler way to prevent heart attacks and strokes.

The clinical trial was led by Dr. Ann Marie Navar, an Associate Professor in the Department of Internal Medicine and the Department of Public Health. The clinical trial was funded by Merck and involved nearly 3,000 adults at high risk for heart disease.

According to Navar, “Currently less than half of patients with established atherosclerotic cardiovascular disease are able to reach their LDL cholesterol goals. With an oral agent that has proven this to be so effective, we now have a vehicle that can significantly help us prevent both heart attacks and strokes in the general population.”

Heart disease is the number one cause of death in the United States, and the presence of high levels of LDL cholesterol has been identified as one of the biggest contributors to the formation of plaque in the arteries. This buildup decreases blood flow through the arteries. Lowering LDL cholesterol has been a cornerstone of prevention for many years.

The history of enlicitide at UT Southwestern extends back several decades. The original premise for developing enlicitide was researched and hypothesized by Dr. Michael Brown and Dr. In the 1980s, Joseph Goldstein and his colleagues found that liver cells have a type of protein, called an LDL receptor, which helps remove LDL from the bloodstream. This research was the basis for the development of statins, which earned Goldstein and his colleagues the Nobel Prize in Physiology or Medicine in 1985.

Researchers in the Dallas Heart Study later discovered another important insight concerning low LDL levels. Drs. Helen Hobbs and Jonathan Cohen found that some people have genetic variants that reduce or eliminate a protein called PCSK9, which regulates the number of LDL receptors that the liver uses. These discoveries led to injectable drugs that inhibit PCSK9, including monoclonal antibody therapies that lower LDL by approximately 60 percent. Unfortunately, the high cost of these therapies and patient reluctance to use injectable medications have resulted in a low utilization rate for this class of agents.

“Studies by my group and others have shown that these agents were rarely prescribed,” Navar said. She pointed to the earlier barrier of cost and continued hesitancy to inject medications.

Enlicitide is an oral medication targeting the same PCSK9 protein as the injectable therapies. However, it is taken as a pill once each day on an empty stomach. For many patients, this difference may be significant.

Phase III study participants were either patients with known coronary artery disease or patients identified to be at increased risk for developing it. Most patients were taking statins. Participants’ average LDL level at baseline was 96 mg/dL, which is considerably higher than treatment goals.

Two-thirds of the participants received enlicitide, while the remaining participants received a placebo. Following 24 weeks of treatment, those taking enlicitide experienced a mean reduction in LDL of 60 percent. Conversely, the placebo group showed no significant difference in LDL levels at 24 weeks.

“Enlicitide is representative of what we typically encounter in clinical practice,” Navar stated. “Even at the highest intensity, statins alone will not bring people to their therapeutic LDL levels.”

In addition to lowering LDL, enlicitide also reduced the levels of several other markers associated with cardiovascular disease risk. These included non-HDL cholesterol and apolipoprotein B. The effects were sustained for a full year.

“These reductions in LDL cholesterol are significantly greater than the reductions we have ever achieved with oral medications since statins were first developed,” Navar noted.

The safety data for enlicitide were encouraging. There were no significant differences in adverse events reported between the enlicitide group and the placebo group. However, there is one important unanswered question regarding the long-term cardiovascular benefits of lowering cholesterol.

Heart disease is a primary cause of death worldwide, and lowering cholesterol may reduce the risk of heart attacks and strokes. A separate phase IV outcomes trial is currently underway to examine whether treatment with enlicitide will reduce the risk of major cardiovascular events. This study will include more than 14,000 patients.

Dr. William Boden of Boston University and the VA New England Healthcare System, who did not participate in this study, stated that the results were compelling. However, he added that we must wait to determine the long-term overall cardiovascular effects.

Merck has initiated the process of seeking FDA approval for enlicitide. The drug has been placed in the FDA’s fast track program to allow expedited review of promising therapies.

Research findings are available online in the New England Journal of Medicine.

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