Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol (CLEAR Harmony)

The CLEAR Harmony trial randomized 2,230 patients with ASCVD or heterozygous familial hypercholesterolemia already on maximally tolerated statin therapy to bempedoic acid 180 mg daily or placebo for 52 weeks, with safety as the primary outcome and LDL-C reduction as the principal efficacy measure.

Bempedoic acid reduced LDL-C by 18.1% versus placebo at 12 weeks, with the effect sustained through 52 weeks. Non-HDL-C was reduced by 13.3%, ApoB by 11.9%, and hs-CRP by 21.5% — the last finding consistent with a potential anti-inflammatory mechanism independent of LDL-C reduction. On the safety side, overall and serious adverse events were similar between groups, and critically, muscle-related events were not increased — addressing the key concern given bempedoic acid’s mechanism (upstream of the enzyme that statins inhibit in the cholesterol synthesis pathway; it is not activated in skeletal muscle).

However, gout occurred more frequently with bempedoic acid (1.2% vs 0.3%), a finding attributable to bempedoic acid’s effect on uric acid metabolism. This safety signal became more prominent in subsequent larger analyses.

CLEAR Harmony established bempedoic acid’s safety and LDL-C–lowering profile on top of statins. The subsequent CLEAR Outcomes trial established its cardiovascular benefit in statin-intolerant patients. Together, these trials define bempedoic acid as an effective non-statin lipid-lowering agent with a specific clinical niche.

We rate the evidence strong. A rigorous phase 3 safety and efficacy trial establishing bempedoic acid as a safe LDL-C–lowering addition to maximally tolerated statin therapy without excess muscle toxicity.