Alternatives to Popular Cholesterol-Lowering Drug Cut Heart-Attack Risk

The failure to fully protect these millions of people is one reason heart disease remains the nation’s leading killer after decades of lifesaving medical advances, a problem that deepened during the Covid-19 pandemic. “We are backsliding,” said Edward Fry, president of the American College of Cardiology and a cardiologist at Ascension Indiana St. Vincent Heart Center in Indianapolis. 

Research presented at a conference held by the ACC and the World Heart Federation in New Orleans over the weekend and on Monday provided new evidence for nonstatin treatments to reduce cardiovascular risk: two daily cholesterol-lowering pills and an anti-inflammatory drug. 

Cardiologists said they welcome new options to help patients who can’t benefit enough from statins, many of whom are older, at high risk for heart disease and have other conditions such as diabetes. “We need to do whatever we can to lower LDL cholesterol,” said Eugene Yang, a cardiologist at the University of Washington and medical director of the UW Medicine Eastside Specialty Center. 

Drug development for heart treatments is undergoing a renaissance after years when generic brands took over sales of once-blockbuster cholesterol medications. The list of alternatives to statins is short. It includes drugs called PCSK9 inhibitors that are given as injections and sharply lower cholesterol but aren’t widely used because they are costly. Statins, which are generic, cost just a few dollars for each prescription. 

Statins lower low-density lipoprotein (LDL) cholesterol, or “bad” cholesterol, by slowing production of cholesterol in the liver and helping remove it from blood. Those actions reduce the risk of heart attacks and strokes.

A study with 13,970 patients in 32 countries showed that a daily pill, bempedoic acid, significantly lowered the risk of heart attacks, strokes and other cardiovascular complications in people intolerant of statins, according to results published in the New England Journal of Medicine and presented at the conference. Nearly half of the participants were women, who make up a large proportion of statin-intolerant patients. 

The drug, marketed as Nexletol by

Esperion Therapeutics Inc.,

was designed to lower cholesterol without muscle pains by becoming active only once it enters the liver. Patients who can’t tolerate statins “know they’re at risk for cardiovascular disease, but they’re miserable,” said Steven Nissen, lead author of the study and chief academic officer of the Cleveland Clinic’s Heart and Vascular Institute. 

He said the drug isn’t meant to replace statins, whose efficacy has been widely studied. Bempedoic acid reduced cardiovascular risk similarly to other nonstatins in the study, but was less effective at lowering cholesterol than PCSK9 inhibitors. It also significantly reduced inflammation. There were some side effects: a small percentage of participants experienced gout or gallstones. 

Nexletol and another version called Nexlizet that combines bempedoic acid with another nonstatin cholesterol-lowering drug, ezetimibe, have been on the market since 2020, approved by the Food and Drug Administration and European Medicines Agency to lower cholesterol. Esperion said it plans to file by June with both agencies to add cardiovascular risk reduction to the labels.

Cardiologists said they hope the new data make it easier for them to prescribe bempedoic acid to patients who can’t take statins and want an oral drug rather than the PCSK9 inhibitor injections. 

 “We need more options in this huge group of statin-intolerant patients,” said Timothy Hegeman, a cardiologist with UCHealth in Colorado Springs, Colo.

How much it gets used will depend in part on the drug’s cost to patients, Dr. Hegeman and others said. Many insurers haven’t covered it without data proving that it has benefits against heart attacks and strokes, they said, adding that they hope that now changes.

“Many of my patients can’t get bempedoic acid,” said Robert Rosenson, director of metabolism and lipids for the Mount Sinai Health System in New York City. He said he would prescribe bempedoic acid after trying PCSK9 inhibitors and ezetimibe first.

Merck

& Co. said Monday that it is making progress on a potential new PCSK9 inhibitor. Unlike those on the market now, it would come in an oral form. A midstage trial showed that the daily drug significantly lowered LDL cholesterol and was well tolerated. 

While new drug options can make a difference, the most important step first is to improve screening for LDL cholesterol, to identify people who need statins and get them on the medications, said Jamal Rana, chief of cardiology at Kaiser Permanente Medical Center in Oakland, Calif. Less than a third of U.S. adults eligible for statins are taking them, according to an analysis published in January in the Journal of the American Heart Association, and doctors aren’t encouraged to screen for cholesterol. 

“We can break through this clinical inertia by screening LDL cholesterol regularly and incentivizing prevention therapies,” Dr. Rana said. 

Another study published Monday in the Lancet and presented at the conference made the case for giving an anti-inflammatory drug to patients who are on statins yet remain at high cardiovascular risk. The analysis of 31,245 participants who took part in three previous clinical trials found that a marker of inflammation in the body, C-reactive protein, was better at predicting the risk of a major cardiovascular complication or death than measuring LDL cholesterol. 

Two clinical trials have shown that an anti-inflammatory drug called colchicine lowered cardiovascular risk in patients on statins with heart disease, said Paul Ridker, director of the center for cardiovascular disease prevention at Brigham and Women’s Hospital in Boston and lead author of the study. Yet physicians aren’t regularly evaluating patients for inflammation, he said. 

“We’re trying here to say, inflammation is really a major determinant of the risk of your patient and maybe you want to at least think about targeting therapy towards this inflammatory response,” he said. 

Given the results, physicians could consider adding colchicine, bempedoic acid or certain drugs used for diabetes and weight loss which have anti-inflammatory effects, Dr. Ridker said. He said he believes that combining anti-inflammatory drugs and cholesterol-lowering medications will become a standard of care for patients with atherosclerosis.

Agepha Pharma, a family-owned company based in Dubai, said it has a once-daily colchicine pill under priority review by the FDA to prevent cardiac events.

Write to Betsy McKay at [email protected]

The failure to fully protect these millions of people is one reason heart disease remains the nation’s leading killer after decades of lifesaving medical advances, a problem that deepened during the Covid-19 pandemic. “We are backsliding,” said Edward Fry, president of the American College of Cardiology and a cardiologist at Ascension Indiana St. Vincent Heart Center in Indianapolis. 

Research presented at a conference held by the ACC and the World Heart Federation in New Orleans over the weekend and on Monday provided new evidence for nonstatin treatments to reduce cardiovascular risk: two daily cholesterol-lowering pills and an anti-inflammatory drug. 

Cardiologists said they welcome new options to help patients who can’t benefit enough from statins, many of whom are older, at high risk for heart disease and have other conditions such as diabetes. “We need to do whatever we can to lower LDL cholesterol,” said Eugene Yang, a cardiologist at the University of Washington and medical director of the UW Medicine Eastside Specialty Center. 

Drug development for heart treatments is undergoing a renaissance after years when generic brands took over sales of once-blockbuster cholesterol medications. The list of alternatives to statins is short. It includes drugs called PCSK9 inhibitors that are given as injections and sharply lower cholesterol but aren’t widely used because they are costly. Statins, which are generic, cost just a few dollars for each prescription. 

Statins lower low-density lipoprotein (LDL) cholesterol, or “bad” cholesterol, by slowing production of cholesterol in the liver and helping remove it from blood. Those actions reduce the risk of heart attacks and strokes.

A study with 13,970 patients in 32 countries showed that a daily pill, bempedoic acid, significantly lowered the risk of heart attacks, strokes and other cardiovascular complications in people intolerant of statins, according to results published in the New England Journal of Medicine and presented at the conference. Nearly half of the participants were women, who make up a large proportion of statin-intolerant patients. 

The drug, marketed as Nexletol by

Esperion Therapeutics Inc.,

was designed to lower cholesterol without muscle pains by becoming active only once it enters the liver. Patients who can’t tolerate statins “know they’re at risk for cardiovascular disease, but they’re miserable,” said Steven Nissen, lead author of the study and chief academic officer of the Cleveland Clinic’s Heart and Vascular Institute. 

He said the drug isn’t meant to replace statins, whose efficacy has been widely studied. Bempedoic acid reduced cardiovascular risk similarly to other nonstatins in the study, but was less effective at lowering cholesterol than PCSK9 inhibitors. It also significantly reduced inflammation. There were some side effects: a small percentage of participants experienced gout or gallstones. 

Nexletol and another version called Nexlizet that combines bempedoic acid with another nonstatin cholesterol-lowering drug, ezetimibe, have been on the market since 2020, approved by the Food and Drug Administration and European Medicines Agency to lower cholesterol. Esperion said it plans to file by June with both agencies to add cardiovascular risk reduction to the labels.

Cardiologists said they hope the new data make it easier for them to prescribe bempedoic acid to patients who can’t take statins and want an oral drug rather than the PCSK9 inhibitor injections. 

 “We need more options in this huge group of statin-intolerant patients,” said Timothy Hegeman, a cardiologist with UCHealth in Colorado Springs, Colo.

How much it gets used will depend in part on the drug’s cost to patients, Dr. Hegeman and others said. Many insurers haven’t covered it without data proving that it has benefits against heart attacks and strokes, they said, adding that they hope that now changes.

“Many of my patients can’t get bempedoic acid,” said Robert Rosenson, director of metabolism and lipids for the Mount Sinai Health System in New York City. He said he would prescribe bempedoic acid after trying PCSK9 inhibitors and ezetimibe first.

Merck

& Co. said Monday that it is making progress on a potential new PCSK9 inhibitor. Unlike those on the market now, it would come in an oral form. A midstage trial showed that the daily drug significantly lowered LDL cholesterol and was well tolerated. 

While new drug options can make a difference, the most important step first is to improve screening for LDL cholesterol, to identify people who need statins and get them on the medications, said Jamal Rana, chief of cardiology at Kaiser Permanente Medical Center in Oakland, Calif. Less than a third of U.S. adults eligible for statins are taking them, according to an analysis published in January in the Journal of the American Heart Association, and doctors aren’t encouraged to screen for cholesterol. 

“We can break through this clinical inertia by screening LDL cholesterol regularly and incentivizing prevention therapies,” Dr. Rana said. 

Another study published Monday in the Lancet and presented at the conference made the case for giving an anti-inflammatory drug to patients who are on statins yet remain at high cardiovascular risk. The analysis of 31,245 participants who took part in three previous clinical trials found that a marker of inflammation in the body, C-reactive protein, was better at predicting the risk of a major cardiovascular complication or death than measuring LDL cholesterol. 

Two clinical trials have shown that an anti-inflammatory drug called colchicine lowered cardiovascular risk in patients on statins with heart disease, said Paul Ridker, director of the center for cardiovascular disease prevention at Brigham and Women’s Hospital in Boston and lead author of the study. Yet physicians aren’t regularly evaluating patients for inflammation, he said. 

“We’re trying here to say, inflammation is really a major determinant of the risk of your patient and maybe you want to at least think about targeting therapy towards this inflammatory response,” he said. 

Given the results, physicians could consider adding colchicine, bempedoic acid or certain drugs used for diabetes and weight loss which have anti-inflammatory effects, Dr. Ridker said. He said he believes that combining anti-inflammatory drugs and cholesterol-lowering medications will become a standard of care for patients with atherosclerosis.

Agepha Pharma, a family-owned company based in Dubai, said it has a once-daily colchicine pill under priority review by the FDA to prevent cardiac events.

Write to Betsy McKay at [email protected]