Cholesterol-lowering drugs called statins are credited with dramatically reducing heart attacks and are some of the most-prescribed pills in the United States. But roughly 10 to 30 percent of people who try statins stop taking them because of muscle pain or other side effects.
Now, new research shows that a different cholesterol drug, called bempedoic acid, can significantly lower heart attack risk in the statin-intolerant. The drug, sold under the brand name Nexletol, will not replace statins as a first-line therapy, but the new data shows the pill is an effective alternative for a large number of adults at high risk of heart attack who cannot or will not take a statin.
“Statins are still the cornerstone,” said Steven Nissen, the chair of cardiovascular medicine at the Cleveland Clinic and a lead author of the study. “But if you cannot tolerate statins, and there are millions of people like that out there, then we’ve established an effective alternative for reducing morbidity.”
The research, published Saturday in the New England Journal of Medicine, was paid for by the drug’s manufacturer, Esperion Therapeutics, which is based in Ann Arbor, Mich.
Fewer heart attacks and surgical procedures
The study recruited 13,970 patients, about half of whom were randomized to a group taking bempedoic acid and half who took a placebo. The average LDL or “bad” cholesterol in both groups at the start of the study was 139 mg per deciliter. Nearly half the study subjects were women.
In this study, bempedoic acid reduced cholesterol by 21 percent. People who took the drug had a 23 percent lower risk of myocardial infarction and a 19 percent lower risk of having a revascularization procedure.
“The benefits of bempedoic acid are now clearer,” wrote John H. Alexander, the director of cardiovascular research at the Duke Clinical Research Institute, in an accompanying editorial. “It is now our responsibility to translate this information into better primary and secondary prevention for more at-risk patients, who will, as a result, benefit from fewer cardiovascular events.”
The drug’s ability to lower cholesterol and heart attack risk without creating muscle pain may be due to the fact that it targets an enzyme in the liver, not in the muscles.
Muscle aches were actually more common in the placebo group (6.8 percent) than in the drug group (5.6 percent.) Patients in the bempedoic acid group had a small increased risk for gout, which is caused by a buildup of uric acid in the blood, a condition that causes intense pain in the big toe. The study reported gout in 2.1 percent of patients in the placebo group and 3.1 percent of patients in the study group.
Bempedoic acid isn’t a brand new drug; it was approved by the Food and Drug Administration in 2020 on the basis of studies that showed it reduced LDL cholesterol by 28 percent in patients who could not tolerate statins. When given to patients already taking moderate- or high-dose statins, the drug reduced cholesterol by an additional 18 percent.
Proving that a drug helps the heart
But proving that a drug lowers cholesterol does not mean it will prevent heart attacks or other cardiovascular events. One of the great disappointments in cardiovascular drug development was a drug called evacetrapib, made by Eli Lilly, which dramatically lowered LDL cholesterol, doubled HDL “good” cholesterol and yet did not prevent heart attacks.
Without “outcome data” showing bempedoic acid reduces heart attacks, doctors are less likely to prescribe the drug, and insurers may not pay for it, Nissen said.
“In the current era where we have other cholesterol-lowering drugs, people are not going to use a drug that does not have demonstrated outcome benefits,” Nissen said. “People want evidence. Everybody has been waiting for this trial.”
Another type of drug, called a PCSK9 inhibitor, also lowers cholesterol and heart risk, but it is given as an injection. While drug prices vary widely, the list price for PCSK9 is about $112 a week. Bempedoic acid costs about $70 a week. By comparison, statins, which are available in generic forms, cost about $7 a week.
But the research needed to prove that bempedoic acid could prevent heart attacks was a challenge. A large body of research already shows that statins, which were introduced in the 1980s and are taken by 1 in 4 four adults, have a proven record of reducing heart attacks in at-risk patients and preventing additional heart attacks in those who have already had one. Denying at-risk patients a proven treatment to study a new drug would be unethical.
But there are many patients who have tried statins but stopped taking them because of undesirable side effects — most often because of muscle pain, but some also complained of cognitive effects including fuzzy thinking or memory lapses.
The bempedoic acid study, conducted at 1,250 sites in 32 countries, recruited nearly 14,000 of these patients. They were counseled on the proven benefits of statins and the risks of not taking them.
“To do it ethically, we had to get people to sign a rather scary statement,” Nissen said. “They had to agree they might get a placebo for up to five years. Patients are phenomenal in their willingness to contribute to studies like this.”
Solving the problem of statin intolerance
For years doctors were skeptical of patients’ complaints about statin side effects, speculating that the problem was psychological — the “nocebo” effect — or that pain from another condition was wrongly attributed to the statin. But a 2016 study, which tested patients who complained of side effects with statins and placebo, finally showed that statin intolerance is real.
Nissen said that most patients have no problem taking statins but that for the minority of patients who experience statin intolerance, the problem is disturbing.
“Statin intolerance is controversial, but for the people who suffer from it, it is just exasperating,” Nissen said. “We now have a new tool in the tool chest.”
