Inflammation and Cholesterol as Predictors of CV Events

Quick Takes

  • In this study of statin-intolerant patients participating in the CLEAR-Outcomes trial to assess the value of bempedoic acid in atherosclerotic CVD, inflammation assessed by hs-CRP predicted risk for future CV events and particularly CV death more strongly than hyperlipidemia assessed by LDL-C.
  • Among the nonstatins that effectively lower LDL-C, PCSK9 inhibitors, ezetimibe, and bile acid sequestrants have anti-atherosclerotic and anti-inflammatory effects, but only bempedoic acid lowers hs-CRP significantly.
  • Of interest is that bempedoic acid reduced CV events at all levels of hs-CRP rather than the threshold of >2 mg/dL, as was arbitrarily used in the JUPITER and LoDoCo trials.

Study Questions:

Is residual inflammatory risk assessed by high-sensitivity C-reactive protein (hs-CRP) as strong a predictor of future cardiovascular events (CVEs) as is residual risk assessed by low-density lipoprotein cholesterol (LDL-C)?


The multinational CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-lnhibiting Regimen) trial randomly allocated 13,970 statin-intolerant patients to 180 mg of oral bempedoic acid daily or matching placebo and followed them for a four-component composite of incident myocardial infarction, stroke, coronary revascularization, or CV death, and for all-cause mortality. Quartiles of increasing baseline hs-CRP and LDL-C were assessed as predictors of future adverse events after adjustment for traditional risk factors and randomized treatment assignment.


Compared with placebo, bempedoic acid reduced median hs-CRP by 21.6% and mean LDL-C levels by 21.1% at 6 months. Baseline hs-CRP was significantly associated with the primary composite endpoint of major CVEs (highest to lowest quartile); (hazard ratio [HR], 1.43 [95% Cl, 1.24-1.65]), CV mortality (HR, 2.00 [95% Cl, 1.53-2.61]), and all-cause mortality (HR, 2.21 [95% Cl, 1.79-2.73]). By contrast, the relationship of baseline LDL-C quartile (highest vs. lowest) to future events was smaller in magnitude for the primary composite CV endpoint (HR, 1.19 [95% Cl, 1.04-1.37]) and neutral for CV mortality (HR, 0.90 [95% Cl, 0.70-1.17]) and all-cause mortality (HR, 0.95 [95% Cl, 0.78-1.16]). Risks were high for those with elevated hs-CRP irrespective of LDL-C level. Bempedoic acid demonstrated similar efficacy in reducing CVEs across all levels of hs-CRP and LDL-C.


Among contemporary statin-intolerant patients, inflammation assessed by hs-CRP predicted risk for future CVEs and death more strongly than hyperlipidemia assessed by LDL-C. Compared with placebo, bempedoic acid had similar efficacy for reducing CV risk across hs-CRP and LDL-C strata.


The study lends further support regarding the value of lowering hs-CRP to reduce CVEs in persons with atherosclerotic CVD on statins as had been demonstrated with low-dose colchicine combined with statins when hs-CRP is >2 mg/dL.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Prevention

Keywords: Cholesterol, LDL, C-Reactive Protein, Inflammation

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