Bempedoic acid reduces adverse CV outcomes in statin-intolerant patients: CLEAR Outcomes trial

The findings from the randomized, double-blind, placebo-controlled trial were presented at the American College of Cardiology/World Congress of Cardiology (ACC/WCC) 2023 meeting and subsequently featured in the New England Journal of Medicine.

Bempedoic acid is an ATP citrate lyase inhibitor that reduces LDL (low-density lipoprotein) cholesterol levels and is linked with a low incidence of muscle-related adverse events; however, its effects on cardiovascular outcomes remain unclear. The EMA (European Medicines Agency) and US FDA (Food and Drug Administration) approve the drug as an adjunct to lifestyle and diet changes for lowering LDL cholesterol.

Steven E. Nissen, Cleveland Clinic, Cleveland, OH, and colleagues conducted the trial to show if the already-approved drug, bempedoic acid (Nexletol; Esperion), reduced the risk of MACE. The trial included patients who were unwilling or unable to take statins due to unacceptable adverse effects and who had or were at high risk of CVD (cardiovascular disease).

The patients were allocated to receive oral bempedoic acid, 180 mg daily, or a placebo. A four-component composite of major adverse cardiovascular events was determined (primary endpoint).

Thirteen thousand nine hundred seventy patients underwent randomization; 6992 were allocated to the bempedoic acid group and 6978 to the placebo group. They were followed for a median duration of 40.6 months.

The study revealed the following findings:

• At baseline, in both groups, the mean LDL cholesterol level was 139.0 mg per deciliter, and after six months, the reduction in the level was more significant with bempedoic acid compared with placebo by 29.2 mg per deciliter; the observed difference in the percent reductions was 21.1 percentage points in favour of bempedoic acid.
• With bempedoic acid, the incidence of a primary endpoint event was significantly lower than with placebo (11.7% versus 13.3%; hazard ratio, 0.87), as were the incidences of a composite of nonfatal stroke, death from cardiovascular causes, or nonfatal myocardial infarction (8.2% versus 663 9.5% hazard ratio, 0.85); fatal or nonfatal myocardial infarction (3.7% versus 4.8%; hazard ratio, 0.77); and coronary revascularization (6.2% versus 7.6%; hazard ratio, 0.81).
• Bempedoic acid did not significantly impact death from any cause, fatal or nonfatal stroke, and death from cardiovascular causes.
• The incidences of cholelithiasis and gout were higher with bempedoic acid than with placebo (3.1% versus 2.1% and 2.2% versus 1.2%, respectively), as were the incidences of small increases in uric acid, serum creatinine, and hepatic-enzyme levels.

"Treating high-risk patients who are unable to tolerate statin therapy with bempedoic acid reduced the risk of major adverse cardiovascular events," the researchers conclude.

Reference:

The study, "Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients," was published in the New England Journal of Medicine on March 4, 2023. DOI: 10.1056/NEJMoa2215024