In an episode of Managed Healthcare Executive’s “Between the Lines” video series, Leslie Cho, M.D., and Seth Shay Martin, M.D., M.H.S., discussed bempedoic acid, the CLEAR Outcomes trial and the implications for cardiovascular disease prevention.
Lowering low-density lipoprotein (LDL) with statin therapy reduces the risk of major adverse cardiovascular events such as myocardial infarction and stroke and is a mainstay of cardiovascular disease prevention. However, between 10% to 20% of patients can’t tolerate the side effects of statins or are unwilling to take them. Bempedoic acid, sold under the brand name Nexletol, has been proposed as an alternative to statins. Positive results from the CLEAR Outcomes clinical trial reported in March 2023 have fueled interest in bempedoic acid.
In this episode of Managed Healthcare Executive’s “Between the Lines” video series, Leslie Cho, M.D., and Seth Shay Martin, M.D., M.H.S., discussed bempedoic acid, the CLEAR Outcomes trial and the implications for cardiovascular disease prevention. Cho is section head of preventive cardiology and rehabilitation at the Cleveland Clinic in Ohio and one of the CLEAR Outcomes trial investigators. Martin is a professor of medicine in the Division of Cardiology at Johns Hopkins Hospital.
Mechanism of action
Cho explained that bempedoic acid is an ATP citrate lyase inhibitor that prevents cholesterol formation two steps upstream of HMG-CoA reductase, the enzyme that the statins target. It is a prodrug that is activated in the liver, not in peripheral tissues, and Cho noted that may explain why it doesn’t cause the muscle-related side effects associated with the statins. Martin noted that bempedoic acid works in similar ways to other “lipid drugs that we’re comfortable with.”
Study population and consent
Cho noted the CLEAR Outcomes trial was large — 13,970 patients were randomly assigned to take bempedoic acid or a placebo — and was designed to be pragmatic, which meant including patients who had a previous cardiovascular event (secondary prevention) and those who hadn’t but were at high risk of having one (primary prevention). The secondary and primary prevention percentage was 70% and 30%, respectively. “Many (cardiovascular prevention) trials have been exclusive to the secondary prevention space, so allowing high-risk primary prevention patients really did broaden the population,” Martin commented.
Cho and Martin agreed that it was noteworthy that the study population was 48.2% female. “We’re very, very proud of that (because) as you know, the 30% women enrollment rate in most of the cardiovascular trials — that has been the bane of our existence,” Cho said.
Cho also discussed the consent form for the trial, which physicians also had to sign, that spelled out the benefits of statins and that the patient couldn’t take them: “It was an incredibly rigorous way to help patients understand that ‘Hey, statins are really great, and we would love for you to take statins, and only if you can’t take statins can you be in this trial.’ ”
The main outcome
Patients in the bempedoic acid group were 13% less likely than those in the placebo group to experience the primary end point, a four-component composite of death from cardiovascular disease, nonfatal myocardial infarction, nonfatal stroke or coronary revascularization. Martin and Cho noted that the decrease in major cardiovascular events was consistent with expectations for the amount by which bempedoic acid lowered LDL cholesterol, which was 30 mg/dL. “I think the drug works. The drug works by lowering LDL, and the LDL hypothesis is a good hypothesis,” Cho said.
Martin said the proportion of study participants in the bempedoic acid and placebo groups who had a serious adverse event was the same, at 25%. He noted differences in gout (3.1% in the bempedoic acid group versus 2.1% in the placebo group), hyperuricemia (10.9% versus 5.6%), and cholelithiasis (2.2% versus 1.2%) and that clinicians would need to consider those results in patients with a relevant history.
Implications for clinical practice
Cho stressed that statins are a cornerstone of therapy to prevent cardiovascular events but added that “there are people who can’t or won’t take statins, and I think this (bempedoic acid) is a legitimate option” for them. She and Martin also discussed bempedoic acid as an alternative to the PCSK9 inhibitors of cholesterol-lowering medications, noting that some patients may prefer bempedoic acid because it is an oral agent whereas the PCSK9 inhibitors are injected. Martin mentioned the fixed-dose combination of bempedoic acid and ezetimibe achieving LDL cholesterol reductions of 40%.
Cho said it may seem benign when people with high LDL levels don’t address the problem, but the risk of a serious cardiovascular event is far from harmless: “There’s a huge cost when patients don’t take cholesterol-lowering (medication) and they go on to have events.”
Cho and Martin agreed that the CLEAR Outcomes trial informed consent process might serve as a model for shared decision-making in clinical practice and help people achieve a lower LDL level.