Clinical Pearls & Morning Reports
Published April 12, 2023
Nissen et al. conducted a double-blind, randomized, placebo-controlled trial to determine the effects of bempedoic acid on adverse cardiovascular events in patients for whom primary or secondary prevention was clinically indicated but who were unable or unwilling to take guideline-recommended doses of statins. Read the NEJM Original Article here.
Q: What percentage of patients report adverse musculoskeletal effects with statin treatment?
A: Administration of statins to lower elevated levels of low-density lipoprotein (LDL) cholesterol is the cornerstone of contemporary therapy to reduce the risk of major adverse cardiovascular events in patients for whom primary or secondary prevention is clinically indicated. However, 7 to 29% of patients report adverse musculoskeletal effects that prevent them from using statins or limit their ability to receive guideline-recommended doses. Withdrawal from statin therapy is associated with an increased risk of adverse cardiovascular events.
Q: How are statins and bempedoic acid similar and how do they differ?
A: Bempedoic acid is an ATP citrate lyase inhibitor that targets cholesterol synthesis upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the enzyme inhibited by statins. Bempedoic acid is similar to statins in that it reduces hepatic cholesterol synthesis and raises LDL receptor expression, thereby increasing clearance of LDL cholesterol from the circulation. However, bempedoic acid is a prodrug that is activated in the liver and not in most peripheral tissues, including skeletal muscle, a factor that may reduce the potential for adverse effects on muscles.
A: A primary end-point event (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) occurred in 819 patients (11.7%) in the bempedoic acid group and in 927 patients (13.3%) in the placebo group (hazard ratio, 0.87; 95% CI, 0.79 to 0.96; P = 0.004). Death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (the first key secondary end point) occurred in 575 patients (8.2%) in the bempedoic acid group and in 663 patients (9.5%) in the placebo group (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006). Fatal or nonfatal myocardial infarction (the second key secondary end point) occurred in 261 patients (3.7%) in the bempedoic acid group and in 334 patients (4.8%) in the placebo group (hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002). Coronary revascularization (the third key secondary end point) occurred in 435 patients (6.2%) in the bempedoic acid group and in 529 patients (7.6%) in the placebo group (hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). The results for the other key secondary end points (fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause) did not differ significantly between the bempedoic acid group and the placebo group.
A: Treatment with bempedoic acid appeared to lead to few adverse events, and the incidences of discontinuation for any reason, including adverse musculoskeletal effects, were similar to those with placebo. As previously reported, a reduction in the renal tubular excretion of uric acid and creatinine was observed in the bempedoic acid group, and the incidences of elevated hepatic-enzyme levels and gout were higher with bempedoic acid than with placebo. The incidence of cholelithiasis was higher with bempedoic acid than with placebo, a finding that had not been observed in previous trials.