Skip to main content

All Access Subscription

Get unlimited access to our full publication and article library.

Get Access Now

Interested in Group Sales? Learn more


Cardiovascular Outcomes with Bempedoic Acid, a New Statin Alternative

By Michael H. Crawford, MD

Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco

SYNOPSIS: A trial of bempedoic acid vs. placebo for statin-intolerant patients showed bempedoic acid significantly lowered LDL cholesterol levels and prevented more major adverse cardiovascular events after a median follow-up of 41 months. Although nonserious side effects were numerically higher for those on bempedoic acid, serious adverse events were not significantly different from placebo.

SOURCE: Nissen SE, Lincoff DB, Ray KK, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med 2023;388:1353-1364.

The FDA approved bempedoic acid (BA) in 2020 because randomized, controlled trials showed it lowered LDL cholesterol levels significantly.1 However, at that time, there were no completed outcomes trials. Therefore, this report of the Cholesterol Lowering via BA, an ACL-inhibiting Regimen (CLEAR) outcomes trial is of interest.

CLEAR was a double-blind, randomized, placebo-controlled trial that included patients at 1,250 sites in 32 countries. Enrolled patients were between age 18 and 85 years, statin-intolerant, and had experienced either a prior cardiovascular (CV) event or exhibited clinical features that placed them at high risk for such an event. Patients on minimal doses of statins or on other lipid-lowering therapies were included. At six months, if LDL levels were 25% or more higher than at baseline, those patients were counseled about a healthy lifestyle, and investigators could adjust any other lipid-lowering medication they were taking.

The primary endpoint was a composite of CV death, myocardial infarction (MI), stroke, or coronary revascularization. Between 2016 and 2019, the authors enrolled 13,970 patients: mean age = 66 years; 48% were women. After a median follow-up of 41 months, 29% on BA and 32% on placebo dropped out of the trial, but the duration of exposure to the two regimens was similar: 83% and 81%, respectively, of the potential follow-up time. Thus, a complete assessment of the primary endpoint was available for 95% of patients, and vital status was available for 99%. The baseline LDL was 139 mg/dL in both groups.

At six months, BA had lowered LDL levels by 21% more than placebo (-21.7% vs. -0.6%). Over the course of the trial, the time-averaged difference was 16%. BA reduced high-sensitivity CRP levels by 25% more at six months (-22.2% vs. +2.4% for placebo). The primary endpoint occurred at a significantly lower rate with BA compared to placebo (11.7% vs. 13.3%; HR, 0.87; 95% CI, 0.79-0.96; P = 0.004), which was driven by significantly lower rates of MI and coronary revascularization.

There was no difference in the rates of stroke, CV death, or all-cause death. Also, there were no significant differences in serious adverse events between the two groups. The incidence of hyperuricemia was higher in the BA group (10.9% vs. 5.6% for the placebo group), as were the rates of gout and cholelithiasis (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively).

Further, elevated hepatic enzymes were more frequent with BA (4.5% vs. 3% in the placebo group), as were adverse renal events (11.5% vs. 8.6%). Myalgias were reported in 5.6% of patients who took BA vs. 6.8% who took placebo.

The authors concluded treatment with BA was associated with 13% fewer major adverse CV events than placebo in statin-intolerant patients after 41 months follow-up, with an absolute difference of 1.6%.


All of us who care for patients with CV disease and those who are at high risk for such appreciate the vexing problem of statin therapy. The mere mention of them often provokes an immediate negative reaction from patients.

Like any drug, statins do produce side effects; blinded, placebo-controlled studies have shown their incidence is far lower than patients believe.2 Some have described this as the “nocebo effect,” or the anticipation of harm based on what they have heard about statins. In my experience, science-based arguments work in a minority of patients, so it is important to discuss alternatives. Taking an injection (i.e., PCSK9 inhibitors), no matter how infrequently, is a non-starter for most patients. This leaves diet, exercise, weight loss, and ezetimibe, all of which are not effective for patients who need major reductions in LDL cholesterol.

An oral alternative is attractive, but BA has not taken off partly because of a lack of outcome data. The experience with HDL-raising drugs taught physicians that just changing the serum level of a lipid does not always translate to fewer adverse CV events. In the Nissen et al study, although the beneficial effect on outcomes of BA was not large (absolute difference compared to placebo = 1.6%), it was statistically significant.

Patients’ most frequent complaint about statins is muscle pain associated with taking statins. In the Nissen et al study, participants who took BA complained of such pain less often than those who took placebo. This should be a strong selling point, but there were other adverse events that could hamper acceptance of BA.

Elevations in creatinine, uric acid, and hepatic enzymes are concerning, as is the more frequent occurrence of gout and cholelithiasis. However, elevated blood glucose levels and episodes of new diabetes, which can be seen with statins, were not more frequent.

Another plus for BA is that it reduces CRP levels like statins, and there was no observed neurocognitive decline, tendon problems, or increases in cancer diagnoses among BA subjects. Real-world experience will tell if this is the drug for which we all have been waiting.


1. Esperion. Esperion announces FDA approval of Nexletol (bempedoic acid) tablet, an oral, once-daily, non-statin LDL-cholesterol lowering medicine. Feb. 21, 2020.

2. Cai T, Abel L, Langford O, et al. Associations between statins and adverse events in primary prevention of cardiovascular disease: Systematic review with pairwise, network, and dose-response meta-analyses. BMJ 2021;374:n1537.