Pharmacology

People whose high cholesterol is resistant to treatment with statin drugs may soon have a new treatment option. This new class of drugs helps block synthesis of artery-clogging cholesterol; researchers explained. The drugs target an enzyme called ATP citratelyase (ACL), part of the production pathway for “bad” LDL cholesterol in the body.

Increasing the dose

In the new trial, bempedoic acid; a pill that blocks ACL, reduced LDL cholesterol levels significantly when added to standard statin therapy. The addition of bempedoic acid on top of a statin drug showed “a much greater reduction in LDL-C than what would be expected simply by increasing the dose of statin therapy;” said study author Dr. Brian Ference.

He directs transnational therapeutics research at the University of Cambridge in England. His team published its findings in the March 14 issue of The New England Journal of Medicine. But experts aren’t certain how useful bempedoic acid might be, given the wide cholesterol-lowering arsenal now available to heart doctors.

Accompanying the study.

The clinical trial results represent “a rather modest reduction as compared to statins, which lower LDL cholesterol concentrations on average by 20 to 30 %t, and newer drugs such as PCSK9 inhibitors; which can lower LDL cholesterol concentrations by over 50 %;” said Dr. Michael Holmes. He’s an associate professor at the University of Oxford in England, and wrote an editorial accompanying the study.

Bempedoic acid also doesn’t appear to outperform ezetimibe (Zetia), a drug already on the market, said Dr. Robert Eckel; who holds an endowed chair in atherosclerosis at the University of Colorado School of Medicine in Aurora. An earlier clinical trial has shown that combining bempedoic acid and ezetimibe lowered LDL cholesterol by about 28 %t more than placebo, said Eckel; an expert with the American Heart Association who was not involved with the new study.

Background notes.

“It suggests that adding ezetimibe, which is typically an 18 to 20 % reduction, to bempedoic acid only produces a modest additional benefit;” Eckel said. “It’s not like the 40 % you would expect.” The body uses ACL further upstream in the same cholesterol synthesis process that also employs the enzyme targeted by statins; known as HMGCR, researchers said in background notes.
Further; people who carry genetic variants that inhibit ACL have lower LDL cholesterol levels and lower risk of heart health problems, researchers found. Based on this; researchers decided to test how well a drug that blocks ACL would lower cholesterol levels in average people.
That drug, bempedoic acid, is randomly assigned to 1,488 people with high LDL cholesterol despite being on high-intensity statin therapy. Another 742 statin users are give a placebo. After a year, bempedoic acid lowered LDL cholesterol levels by 18 percentage points, researchers found.