Separate industry-funded studies find benefit to bempedoic acid as preventive medication, CRP as biomarker

Bempedoic acid was associated with a lower risk of major adverse cardiovascular events among statin-intolerant patients, according to an industry-funded study.

Researchers conducted a double-blind, randomized, placebo-controlled trial in patients who were unable or unwilling to take statins due to adverse effects yet had or were at high risk for cardiovascular disease. Patients were randomized to 180 mg of oral bempedoic acid (n=6,992) or placebo (n=6,978) daily. The median duration of follow-up was 40.6 months. The primary end point was major adverse cardiovascular events (MACE), defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. The study was funded by Esperion Therapeutics. Results were published March 4 by the New England Journal of Medicine.

At baseline, mean low-density lipoprotein (LDL) cholesterol level was 139.0 mg/dL in both groups, and after six months, it was significantly lower in the bempedoic acid group by a difference of 29.2 mg/dL (21.1 percentage points). The rate of MACE was also significantly lower with bempedoic acid (11.7% vs. 13.3%; hazard ratio [HR], 0.87 [95% CI, 0.79 to 0.96]; P=0.004), as were rates of a composite outcome of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (8.2% vs. 9.5%; HR, 0.85 [95% CI, 0.76 to 0.96]; P=0.006); fatal or nonfatal myocardial infarction (3.7% vs. 4.8%; HR, 0.77 [95% CI, 0.66 to 0.91]; P=0.002); and coronary revascularization (6.2% vs. 7.6%; HR, 0.81 [95% CI, 0.72 to 0.92]; P=0.001).

Individual outcomes of fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause were not significantly different. Rates of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs. 2.1% and 2.2% vs. 1.2%, respectively), as were incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels.

The study authors noted that all included patients were at high cardiovascular risk but unwilling or unable to take statins and hence had high mean LDL cholesterol level at baseline. “The concept of statin intolerance remains controversial, with some recent studies suggesting that reported adverse effects represent an anticipation of harm, often described as the nocebo effect,” they wrote. “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. Accordingly, alternative nonstatin therapies are needed to manage the LDL cholesterol level in these patients.”

One editorial agreed about the drug's use in patients who can't or don't want to take statins but added a caveat that it is premature to consider bempedoic acid an alternative. “Given the overwhelming evidence of the vascular benefits of statins, clinicians should continue their efforts to prescribe them at the maximum tolerated doses for appropriate patients, including those who may have discontinued statins because of presumed side effects,” the editorialist wrote. Another editorial discussed the future potential of bempedoic acid as an adjunct to statin and nonstatin therapies.

Another study, conducted entirely among patients on statins, aimed to evaluate the relative importance of high-sensitivity C-reactive protein (CRP) and LDL cholesterol as determinants of risk for MACE and death in the PROMINENT, REDUCE-IT, or STRENGTH trials. Funding came from Kowa Research Institute, Amarin, and AstraZeneca. Results were published March 6 by The Lancet.

With data from 31,245 patients, researchers compared those in the highest and lowest CRP quartiles and found that higher CRP was significantly associated with MACE (adjusted HR, 1.31 [95% CI, 1.20 to 1.43]; P<0.0001), cardiovascular mortality (HR, 2.68 [95% CI, 2.22 to 3.23]; P<0.0001), and all-cause mortality (HR, 2.42 [95% CI, 2.12 to 2.77]; P<0.0001). In contrast, comparisons of highest to lowest LDL cholesterol quartiles had no or little significance for MACE (adjusted HR, 1.07; [95% CI, 0.98 to 1.17]; P=0.11), cardiovascular death (HR, 1.27 [95% CI, 1.07 to 1.50]; P=0.0086), and all-cause death (HR,1.16 [95% CI, 1.03 to 1.32]; P=0.025). An accompanying editorial observed that “the findings remain potentially clinically relevant for practising physicians when deciding if further lipid-lowering therapy or inflammation-reduction therapy should be added for patients on statin therapy.”