What were the findings of the CLEAR Outcomes trial of bempedoic acid (180 mg once daily) on low‑density lipoprotein cholesterol (LDL‑C) reduction and major adverse cardiovascular events (MACE) in statin‑intolerant patients at high cardiovascular risk (primary and secondary prevention)?

CLEAR Outcomes Trial Summary: Bempedoic Acid for LDL-C Management

Bempedoic acid 180 mg once daily reduced major adverse cardiovascular events by 13% in statin-intolerant patients at high cardiovascular risk, with particularly striking benefit in primary prevention (32% risk reduction), while lowering LDL-C by approximately 21-23% compared to placebo. 1

Trial Design and Study Population

The CLEAR Outcomes trial enrolled approximately 14,000 adults aged 18-85 years who were unable to tolerate statins and had LDL-C ≥100 mg/dL. 1 The population consisted of:

• 70% with established atherosclerotic cardiovascular disease (ASCVD) - secondary prevention cohort 1
• 30% at high risk for ASCVD without prior disease - primary prevention cohort 1
• Mean age in mid-60s with approximately 50% female participants 2
• 85% had hypertension and 46% had diabetes mellitus 2
• Only 38% were on any lipid-modifying therapy at baseline, with 19% on very-low-dose statin therapy 1, 2

Dosing Regimen

The trial used bempedoic acid 180 mg taken orally once daily, which is the FDA-approved fixed dose requiring no adjustment based on LDL-C response. 2, 3

LDL-C Reduction Efficacy

Bempedoic acid achieved robust lipid lowering across all glycemic strata:

• Absolute LDL-C reduction of approximately 29 mg/dL at 6 months 2
• Relative reduction of 21-23% compared to placebo 1, 2
• This represents a 21.1 percentage-point greater reduction than placebo 2
• LDL-C lowering was consistent in patients with diabetes, prediabetes, and normoglycemia 4

Cardiovascular Outcomes: The Critical Distinction

Overall Population Results

The composite primary endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization) was reduced by 13% overall (HR 0.87; 95% CI 0.79-0.96; p=0.004). 1, 2

Individual components showed:

• Nonfatal myocardial infarction: 23% reduction (HR 0.77; 95% CI 0.66-0.91; p=0.002) 2
• Coronary revascularization: 19% reduction (HR 0.81; 95% CI 0.72-0.92; p=0.001) 2
• No statistically significant effect on nonfatal stroke (HR 0.82) or cardiovascular death (HR 1.04) 2

Dramatic Divergence by Prevention Status

This is where the trial reveals its most clinically important finding:

Primary prevention subgroup (≈4,200 participants without established ASCVD):

• 32% relative risk reduction in primary endpoint (HR 0.68; 95% CI 0.53-0.87; p=0.002) 1, 2
• Number-needed-to-treat of only 43 over the trial duration 2
• A preplanned subanalysis showed 30% reduction in primary composite outcome 1

Secondary prevention subgroup (participants with established ASCVD):

• Only 9% risk reduction (HR 0.91; 95% CI 0.81-1.01) 1, 2
• This did not reach statistical significance 2

This striking difference (HR 0.68 vs 0.91) suggests bempedoic acid may be particularly valuable in high-risk primary prevention patients who cannot tolerate statins, while the benefit in secondary prevention is more modest. 1

Safety Profile: Key Advantages and Monitoring Points

Muscle-Related Adverse Events

Unlike statins, bempedoic acid showed LOWER rates of muscle symptoms:

• Myalgia occurred in 4.7% with bempedoic acid vs 7.2% with placebo 2, 5
• This favorable profile stems from bempedoic acid being a prodrug activated only in liver cells (not muscle cells) by very-long-chain acyl-CoA synthetase-1 1

Adverse Events Requiring Monitoring

Bempedoic acid was associated with increased rates of:

• Gout: 3.1% vs 2.1% with placebo (also reported as 1.5% vs 0.4% in earlier trials) 1, 2
• Mean serum uric acid increase of 0.8 mg/dL 2, 5
• Cholelithiasis: 2.2% vs 1.2% with placebo 2
• Tendon rupture: 0.5% vs 0% 1
• Elevated liver enzymes at higher rates than placebo 2
• Benign prostatic hyperplasia: 1.3% vs 0.1% 1
• Atrial fibrillation: 1.7% vs 1.1% 1

Metabolic Safety

No increase in new-onset diabetes: 11.1% with bempedoic acid vs 11.5% with placebo (HR 0.95; 95% CI 0.83-1.09) among patients without diabetes at baseline. 4 HbA1c levels remained similar between groups. 4

Clinical Significance and Guideline Integration

The 2024 American Diabetes Association guidelines and 2022 American College of Cardiology consensus recommend bempedoic acid as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering. 1

The cardiovascular benefit per unit of LDL-C lowering with bempedoic acid (HR 0.75 per 1 mmol/L reduction) is comparable to that achieved with statins (rate ratio 0.78 in the Cholesterol Treatment Trialists' Collaboration meta-analysis). 6 This validates that bempedoic acid's mechanism—inhibiting ATP-citrate lyase upstream of HMG-CoA reductase—produces clinically meaningful cardiovascular risk reduction equivalent to statins when normalized for LDL-C lowering. 6

Common Pitfalls to Avoid

• Do not adjust the 180 mg daily dose based on LDL-C response—this is a fixed dose with no titration required 2, 3
• Avoid combining with simvastatin >20 mg or pravastatin >40 mg daily due to increased drug exposure risk 3
• Monitor serum uric acid before initiation and if symptoms of hyperuricemia develop 3
• Discontinue immediately if tendon rupture occurs 3
• When combining with bile acid sequestrants, administer bempedoic acid either 2 hours before or 4 hours after the sequestrant 3