New pill helps lower LDL levels by over 58%

• A new study investigates the cholesterol-lowering effects of an experimental drug called enlicitide.
• The scientists found that it reduces levels of low-density lipoprotein (LDL), or “bad” cholesterol by up to 60%.
• If these findings are replicated, this drug could be useful for people whose cholesterol levels are resistant to statins and lifestyle changes.

A recent study, published in JAMA on November 9, investigates a drug called enlicitide.

For these individuals, lifestyle changes and statins are often inadequate to bring their levels of LDL cholesterol down.

In the latest study, enlicitide produced profound reductions in LDL cholesterol.

Elevated levels of LDL cholesterol are associated with an increased risk of heart disease.

Although lifestyle interventions, such as dietary changes, and drugs, like statins, effectively reduce levels for many, they do not work for all people.

PCSK9 inhibitors work via a different mechanism than statins, so using them in combination can be particularly effective.

PCSK9 effectively blocks receptors on cells that help clear LDL cholesterol from the blood. So, by inhibiting PCSK9, these drugs increase the number of available receptors, improving the clearance of LDL cholesterol.

Unlike existing PCSK9 inhibitors, which are only available in an injectable form, the new drug, enlicitide, can be taken as a pill, making it more convenient.

Medical News Today contacted Maria Knöbel, MD, MBBS, a board certified lifestyle medicine doctor and medical director at Medical Cert UK, who was not involved in the research. She explained how important the pill format can be for some people:

“Individuals reluctant to have injections tend to be more consistent in taking a daily dose of pills. I tend to see an increase of adherence by approximately 20% amongst individuals who switch.”

In the study, the scientists recruited 303 people with heterozygous familial hypercholesterolemia. All participants were already taking statins, but their LDL cholesterol levels remained elevated.

This was a multisite study, involving people from 59 sites in 17 countries. In total, 202 participants received enlicitide once per day for 52 weeks, and the remaining 101 received a placebo each day.

After 24 weeks, 58.2% of those in the enlicitide group experienced an average drop in LDL cholesterol of 58.2%. In comparison, the average LDL cholesterol level increased by 2.6% in the placebo group.

At the 52-week mark, the enlicitide group reduced their levels by an average of 55.3%, compared to an 8.7% rise in the placebo group.

The scientists also found that other lipid markers were improved to a similar degree:

• Non–high-density lipid (HDL) cholesterol (52.3% in the enlicitide group versus 2.1% in placebo): Non-HDL cholesterol is the total cholesterol level, minus HDL, or “good” cholesterol.
• Apolipoprotein B (apo B) (−48.2% versus 1.8%): Apo B helps carry LDL cholesterol around the body and is a marker for increased heart disease risk.
• Lipoprotein(a) (−24.7% versus −1.6%): A genetically determined risk factor for heart disease.

MNT asked Knöbel about the significance of lowered lipoprotein(a). She explained that lipoprotein(a) is similar to LDL cholesterol, but it is even more difficult for the body to clear.

As an example, she told us of patients who are regular exercisers with a healthy diet who still have stubbornly high levels.

“In addition to these dramatic improvements when compared with placebo, daily enlicitide resulted in almost identical changes in LDL, non-HDL, and ApoB to those achieved with the injectable antibodies alirocumab and evolocumab,” explains lead author, Ann Marie Navar, MD, PhD, an associate professor of cardiology at the University of Texas Southwestern Medical Center in Dallas.

Although these results are impressive, longer and larger trials are needed to verify effectiveness in a broader group of participants. However, such a robust effect across all participants is heartening.

Also, because the study focused on individuals with heterozygous familial hypercholesterolemia, it will be important to test the drug on people without the condition.

MNT reached out to Yu-Ming Ni, MD, a board certified cardiologist and lipidologist, to ask whether enlicitide might work in other populations.

“This medication is in the same drug class as other established injectable PCSK9 inhibitors and appears to have a similar overall effect on cholesterol levels,” he explained. “Therefore, I do expect that it has similar efficacy on cholesterol in patients without genetically driven high cholesterol.”

However, he also explained the importance of longer trials to see whether the reductions in LDL cholesterol are associated with a reduced risk of cardiovascular events in the long term.

Ni is based at MemorialCare Heart and Vascular Institute at Orange Coast Medical Center in Fountain Valley, CA and was not involved in the study.

MNT also contacted Trevor Coke II, a registered dietitian nutritionist at Dietician Live, who was not involved in the study. He was also upbeat about the results:

“From a dietitian’s perspective, the possibility of an oral option that’s as effective as an injectable is exciting. It could make advanced cholesterol-lowering therapies more accessible, especially for people who are needle-averse or face barriers to injectable medications.”