Bempedoic acid receives FDA approvaal for expanded indication in CVD Prevention

23 Apr 2024

Bempedoic acid inhibits ATP citrate lyase, an enzyme upstream of 3-hydroxy-3-methalglutaryl-coenzyme (HMG-CoA) reductase which is the rate-limiting step of cholesterol biosynthesis.1,2 This reduces hepatic cholesterol synthesis and raises LDL receptor expression, increasing the clearance of LDL-C from the circulation.1 Bempedoic acid is a prodrug mostly activated in the liver but not in most peripheral tissues, which limits the risk of adverse effects in the muscles.1,2 Bempedoic acid was previously approved in 2020 as an adjunct to diet and maximally tolerated statin therapy for adults who require additional LDL-C reduction due to heterozygous familial hypercholesterolemia or atherosclerotic CVD.3 Recently, its indication has been expanded to include CVD prevention regardless of statin use based on data from the CLEAR outcomes study, which demonstrated a reduction in risk of MACE among statin-intolerant patients treated with bempedoic acid.1,4

The CLEAR (Cholesterol Lowering via Bempedoic Acid [ECT1002], an ACL-Inhibiting Regimen) Outcomes trial was a double-blind, randomized, placebo-controlled trial involving patients from 1,250 sites across 32 countries.1 Patients aged 18-85 years were eligible for the study if they had clinical features that placed them at high risk of a cardiovascular event (primary-prevention patients) or had a previous cardiovascular event (secondary-prevention patients).1 All patients also reported being unable or unwilling to receive statins due to adverse effects.1 In total, 13,970 patients were randomized 1:1 to receive a daily oral dose of 180mg bempedoic acid (n=6,992) or a placebo (n=6,978).1 Patients were followed for a median duration of 40.6 months.1 The primary endpoint was a four-component composite of MACEs defined as death from cardiovascular causes, nonfatal myocardial infarction (MI), nonfatal stroke or coronary revascularization.1

At baseline, the mean LDL-C level was 139.0mg/dL in both groups.1 After 6 months, LDL-C levels were reduced to 107.0mg/dL in patients treated with bempedoic acid while there was minimal change at 136.0mg/dL with placebo, resulting in a 29.2mg/dL, or a 21.1% (95% CI: 20.3-21.9) difference in favor of bempedoic acid.1

The rate of primary endpoint event was also significantly lower with bempedoic acid than with placebo (11.7% vs. 13.3%; HR=0.87; 95% CI: 0.79-0.96; p=0.004).1 Several key secondary endpoints were also reduced in the bempedoic acid group, including death from cardiovascular causes, nonfatal stroke, or nonfatal MI (8.2% vs. 9.5%; HR=0.85; 95% CI: 0.76-0.96; p=0.006), fatal or nonfatal MI (3.7% vs. 4.8%; HR=0.77; 95% CI: 0.66-0.91; p=0.002), and coronary revascularization (6.2% vs. 7.6%; HR=0.81; 95% CI: 0.72-0.92; p=0.001).1 However, other key secondary endpoints (fatal or nonfatal stroke, death from cardiovascular causes, and death from any cause) did not differ significantly between the two groups.1

The incidences of prespecified adverse events of special interest were largely similar in both groups, including myalgias (5.6% vs. 6.8%).1 However, elevations in hepatic enzyme levels (4.5% vs. 3.0%) and incidences of hyperuricemia (10.9% vs. 5.6%), gout (3.1% vs. 2.1%) and cholelithiasis (2.2% vs. 1.2%) were higher in the bempedoic acid group than the placebo group.1 With the exception of cholelithiasis, these safety signals have already been reported in previous trials.1

In summary, the results of this trial demonstrate that treatment with bempedoic acid could significantly lower the risk of MACEs among patients for whom primary or secondary prevention of cardiovascular disease is clinically indicated but who are unable or unwilling to take the recommended doses of statins.1

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