CLEAR Outcomes Trial: Bempedoic Acid for LDL Management
Drug and Dosage
Bempedoic acid 180 mg once daily was used in the CLEAR Outcomes trial, administered orally with or without food. 1, 2, 3 This is the only approved dose for bempedoic acid, and no dose adjustments are made based on LDL-C response. 2
Study Population Characteristics
The CLEAR Outcomes trial enrolled 13,970 statin-intolerant patients with specific high-risk features: 3, 4
- Mean age: 66 years (range 21-92 years), with 59% ≥65 years old 3
- Gender distribution: 48% female 3
- Cardiovascular disease status:
- High-risk criteria for primary prevention patients included: 3
- Diabetes mellitus in females >65 years or males >60 years
- Reynolds Risk score >30% or SCORE Risk score >7.5% over 10 years
- Coronary artery calcium score >400 Agatston units
Critical baseline characteristics: 3
- Mean baseline LDL-C: 139 mg/dL
- Hypertension: 85%
- Diabetes mellitus: 46%
- Current tobacco use: 22%
- eGFR <60 mL/min/1.73 m²: 21%
Background lipid therapy at baseline: Only 38% were taking any lipid-modifying therapy, including less than low-intensity statin dosages (23%), ezetimibe (12%), or fibrates (5%). 3 Importantly, 19% were on very-low-dose statin therapy at baseline, emphasizing the statin-intolerant nature of this population. 1
LDL-Cholesterol Reduction Results
Bempedoic acid achieved a 29.2 mg/dL absolute reduction in LDL-C compared to placebo at 6 months, representing a 21.1 percentage point greater reduction than placebo. 3, 4 The American Diabetes Association reports this translates to approximately 21-23% LDL-C reduction. 1, 5
Major Adverse Cardiovascular Event Reduction
Bempedoic acid reduced the primary four-component MACE endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization) by 13% compared to placebo (HR 0.87; 95% CI 0.79-0.96; p=0.004). 1, 3, 4
Specific cardiovascular outcomes: 3, 4
- MACE-3 composite (CV death, nonfatal MI, nonfatal stroke): 15% reduction (HR 0.85; 95% CI 0.76-0.96; p=0.006)
- Nonfatal myocardial infarction: 23% reduction (HR 0.77; 95% CI 0.66-0.91; p=0.002)
- Coronary revascularization: 19% reduction (HR 0.81; 95% CI 0.72-0.92; p=0.001)
- Nonfatal stroke: No significant reduction (HR 0.82; 95% CI 0.64-1.05)
- Cardiovascular death: No significant effect (HR 1.04; 95% CI 0.88-1.24)
- All-cause mortality: No significant effect 1
Differential Effects by Prevention Status
The benefit was substantially greater in primary prevention patients compared to secondary prevention: 1
- Primary prevention group (n=4,206): 32% reduction in primary endpoint (HR 0.68; 95% CI 0.53-0.87; p=0.002) with NNT=43 1
- Secondary prevention group (established CVD): 9% reduction (HR 0.91; 95% CI 0.81-1.01) 1
This striking difference suggests bempedoic acid may be particularly valuable in high-risk primary prevention patients who cannot tolerate statins. 1
Safety Profile
Bempedoic acid demonstrated a favorable muscle safety profile with lower myalgia rates than placebo (4.7% vs 7.2%). 5 However, specific adverse effects were more common with bempedoic acid: 1, 3, 4
- Gout: 3.1% vs 2.1% with placebo (1.5% vs 0.4% in another analysis)
- Cholelithiasis: 2.2% vs 1.2% with placebo
- Mean serum uric acid increase: 0.8 mg/dL 2, 5
- Elevated liver enzymes: Increased rates observed 6
Clinical Significance
The median follow-up duration was 40.6 months (3.4 years), with 95.3% of patients followed until trial end or death. 3, 4 The trial definitively established that bempedoic acid reduces cardiovascular events in statin-intolerant patients, filling a critical treatment gap for this challenging population. 1 The American College of Cardiology now recommends bempedoic acid as an adjunct therapy for adults with atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia requiring additional LDL-C lowering when statins are not tolerated or inadequately effective. 1, 5