A nonstatin therapy approved almost 3 years ago to treat low-density lipoprotein (LDL) cholesterol also cuts the risk of major cardiovascular events, especially heart attacks, according to data presented.
Bempedoic acid, approved in February 2020 as Nexletol (Esperion), reduced by 13% the risk of a 4-part composite end point of major adverse cardiovascular events (MACE), according to results from the CLEAR Outcomes trial presented today at the 72nd American College of Cardiology (ACC) Scientific Sessions Together With the World Congress of Cardiology, being held in New Orleans, Louisiana.
The end point, known as 4-point MACE, included death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. Results were simultaneously reported in the New England Journal of Medicine.1
According to the FDA, bempedoic acid is currently approved for 2 groups of patients: those with an inherited condition called heterozygous familial hypercholesterolemia or those atherosclerotic cardiovascular disease, which can cause heart attacks and strokes due to elevated LDL cholesterol. The drug is given as an oral tablet that patients are instructed to take with the highest statin dose they can tolerate, along with improved diet and exercise.
However, it is known that that up to 9% of patients are unable to tolerate statins due to muscle effects or hyperglycemia. Bempedoic acid works through a different mechanism and has not been associated with the side effects that cause some patients to stop taking the statins (or refuse to try them).
CLEAR Outcomes randomized 13,970 patients who reported being unable or unwilling to take statins due to adverse effects and who had or were at high risk for cardiovascular disease. Patients received 180 mg of bempedoic acid or placebo, taken daily. Both arms began the trial with a mean cholesterol level of 139.0 mg per deciliter. After 6 months, the reduction for those taking the study drug exceeded the placebo arm by 29.2 mg per deciliter, for a difference of 21.1%.
“We’re very pleased with the results,” Steven E. Nissen, MD, chief academic officer of the Heart Vascular & Thoracic Institute at Cleveland Clinic and study chair, said in a statement released by ACC. “People who couldn’t tolerate a statin did tolerate bempedoic acid and had a very good outcome. We are glad that we were able to demonstrate this level of efficacy on the outcomes that really matter to patients.”
How does bempedoic acid work? Statins work by inhibiting HMG-CoA reductase, and while they have an outstanding track record in preventing cardiovascular events, their target can produce unwanted consequences for some patients. As John F. Keaney, MD, of Brigham and Women’s Hospital writes in a commentary appearing in NEJM, “Given the ubiquitous expression of HMG-CoA reductase, it is not surprising that the use of statins could have important implications for cellular functions in many tissues.”2
Bempedoic acid, by contrast, is ATP citrate lyase inhibitor, and blocks hepatic cholesterol synthesis upstream of HMG-Co-A reductase. Called a “prodrug,” it is activated in the liver, but not peripheral tissues, which means the likelihood of muscle-related adverse events is dramatically reduced.
Patient population. A total of 6992 participants were assigned to the bempedoic acid group and 6978 to the placebo group. The trial followed patients fora median of 40.6 months. The mean age of the study population was 65.5 years (SD 9.0 years); 48.2% of the patients were female. In both the study drug arm and the placebo arm, most patients were White (91.5% for study drug; 90.8% placebo); just under a fifth were Hispanic (17% for the study drug arm, 16.4% for the placebo arm).
Among the population, 45.6% had diabetes, 69.9% had already experienced a cardiovascular event, 22.7% were taking a statin, and 11.5% were taking ezetimibe. Nissen explained circumstances in which some patients were taking a background statin at lower than the recommended dose.
Results. Incidence of a events making up the primary end point was significantly lower with bempedoic acid than placebo. Results showed:
- Events were seen in 819 patients in the study drug group (11.7%) compared with 927 patients in the placebo group (13.3%), for a hazard ratio (HR) of 0.87 (95% CI, 0.79-0.96; P = .004).
- For 3-point MACE, another common measure of cardiovascular outcomes trials, the composite of death from cardiovascular causes, nonfatal stroke, and nonfatal myocardial infarction favored bempedoic acid, HR 0.85 (95% CI, 0.76-0.96; P = .006).
- The reduced risk of heart attacks—fatal or nonfatal—was 23%, with 261 events in bempedoic acid group vs 334 in the placebo group, HR 0.77 (95% CI, 0.66-0.91; P = .002).
- Bempedoic acid also significantly cut the risk of coronary revascularization, with 435 events vs. 529 events for the placebo group, HR 0.81 (95% CI, 0.72-0.92, P= .001).
- Those taking bempedoic acid experienced higher rates of several adverse events than those taking a placebo. Events included renal impairment, gout (3.1% study drug vs 2.1% placebo) and gallstones (2.2% vs 1.2%), as well as elevated hepatic enzymes, likely due to the drug’s activity in the liver. These events did not lead to higher rates of discontinuation.
Will payers, PBMs balk anyway? Another nonstatin class, PCSK9 inhibitors, requires administration in a physician’s office, and the CLEAR Outcomes authors note that cost limited uptake despite the cholesterol-lowering qualities of these drugs.
Many cardiologists were jubilant when PCKS9 inhibitors hit the market in 2015, but payers balked at the original $14,000 a year cost and erected strict barriers to uptake. Today, prices for this class have been cut in half.
Asked during the press conference if pharmacy benefit managers (PBMs) will make access to bempedoic acid difficult because of cost, both Yang and Nissen acknowledged that prior authorization is a burden—but Nissen said that’s why the results from CLEAR Outcomes are so important.
Payers aren’t going to be swayed by results involving a biomarker. “We have to show it changes things that patients care about,” Nissen said. “I was very pleased with a 23% reduction in heart rate myocardial infarction. You can talk to payers about coronary revascularization—you know, bypass surgery is very expensive.”
Nissen emphasized that the best opportunity for bempedoic acid will come when it is used in with ezetimibe—the combination therapy is already on the market as Nexlizet—because it will offer patients who are statin intolerant a nonstatin equivalent of a moderate-intensity statin. According to JoAnne Foody, MD, chief medical officer for Esperion, both Nexlitol and Nexlizet will have the same pricing; the current wholesale acquisition cost is $396 for a 30-day supply, compared with $527 for alirocumab and $590 for evolocumab, both PCSK9 inhibitors.
Foody said Esperion has scheduled about 30 meetings with payers to discuss the CLEAR Outcomes data, and she said cost-effectiveness analyses are planned to show the value of preventing heart attacks, surgeries, and hospitalizations. A broader label is planned as well. “We anticipate with these data, that first and foremost, we’ll expand to a broad population of primary and secondary [prevention],” she said, and this will include removing the requirement for a statin.
In announcing topline results for CLEAR Outcomes in December, Esperion officials cited the fact that bempedoic acid was the first oral nonstatin to meet a 4-point MACE end point in a clinical trial.
“Whether real or perceived, statin intolerance remains a vexing clinical problem that can prevent patients who are guideline-eligible for statin treatment from reaching LDL cholesterol levels associated with clinical benefits,” the study authors write. “Accordingly, alternative nonstatin therapies are needed to manage the LDL cholesterol level in these patients.”
- Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. Published online March 4, 2023. doi: 10.1056/NEJMoa2215024
- Keaney JF. Bempedoic acid and the prevention of cardiovascular disease. N Engl J Med. Published online March 4, 2023.doi: 10.1056/NEJMe2300793
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