Effects of Bempedoic Acid on Markers of Inflammation and Lp(a)
- Bempedoic acid appears to consistently reduce LDL-C and hsCRP, in a pattern similar to that seen with statin therapy, suggesting it acts through a hepatic mechanism similar to but upstream from statins.
- Bempedoic acid-associated reductions in hsCRP appear to be independent of its effects on lipid levels.
- Bempedoic acid has the potential to be useful in patients with residual inflammatory risk or residual cholesterol risk. In light of recently published results from the CLEAR Outcomes trial, expanded indications for bempedoic acid for cardiovascular risk reduction might be anticipated in the future.
How does bempedoic acid affect inflammatory markers in patients with residual inflammatory risk?
The original CLEAR Harmony study enrolled patients on maximally tolerated statin therapy who had atherosclerotic cardiovascular disease (ASCVD) and/or heterogeneous familial hypercholesterolemia. Participants were randomized in 2:1 fashion to oral bempedoic acid 180 mg daily or placebo. Lipid parameters and high-sensitivity C-reactive protein (hsCRP) were assessed in all patients at both baseline and week 12. This secondary analysis of the CLEAR Harmony study assessed outcomes in the participants with residual inflammatory risk, characterized by baseline hsCRP level ≥2 mg/L. Additional evaluations of fibrinogen, interleukin-6 (IL-6), and lipoprotein(a) [Lp(a)] were performed.
This analysis included 817 patients with baseline hsCRP ≥2 mg/L, including 542 who received bempedoic acid and 275 who received placebo. Baseline characteristics were similar in both treatment groups and were similar to those of participants in the original CLEAR Harmony trial, with the exception of higher baseline hsCRP levels. Bempedoic acid reduced hsCRP levels at 12 weeks by a median of 1.66 mg/L. The placebo-corrected difference was –26.5% (95% confidence interval [CI], −34.8 to −18.4; p < 0.0001). Bempedoic acid did not significantly lower IL-6 or fibrinogen and had no clinically important impact on Lp(a).
Bempedoic acid reduced low-density lipoprotein cholesterol (LDL-C) at 12 weeks by a median of 20.8 mg/dL, with a placebo-corrected difference of –21.1% (95% CI, −23.7% to −18.5%; p < 0.0001). Placebo-corrected differences for other lipid parameters were −14.3% for non–high-density lipoprotein cholesterol (non–HDL-C), −12.8% for total cholesterol; −8.3% for HDL-C; −13.1% for apolipoprotein B; and 8.0% for triglycerides (p ≤ 0.0003 for all). The investigators observed minimal correlation between reductions in hsCRP and reductions in LDL-C.
Although bempedoic acid significantly lowered LDL-C and hsCRP, it did not significantly lower fibrinogen or IL-6, a pattern of findings similar to prior statin studies. In this trial, patients were receiving moderate- or high-intensity statin therapy; however, other bempedoic acid trials have shown similar reductions in hsCRP in patients not on statins. Data from this trial and others support the concept that bempedoic acid acts largely upstream in the same pathway as statins, reducing both LDL-C and hsCRP and that bempedoic acid-associated changes in hsCRP are independent of its effects on lipid levels. Bempedoic acid may prove to be a useful intervention for patients with residual cholesterol risk and residual inflammatory risk.
Bempedoic acid is currently approved by the US Food and Drug Administration as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional lowering of LDL-C. Expanded indications (i.e., for cardiovascular risk reduction in statin-intolerant patients with ASCVD or at high risk of ASCVD) for bempedoic acid might be anticipated in the future based on recently published results from the CLEAR Outcomes trial. Bempedoic acid has a low incidence of muscle-related adverse events, is supplied as a once-daily oral pill alone or in combination with ezetimibe, and can be taken with or without meals.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Advanced Lipid Testing, Homozygous Familial Hypercholesterolemia, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins
Keywords: Atherosclerosis, Apolipoproteins B, Cholesterol, LDL, Cholesterol, HDL, C-Reactive Protein, Dyslipidemias, Fibrinogen, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type III, Inflammation, Interleukin-6, Lipids, Lipoprotein(a), Patient Care Team, Primary Prevention, Risk Factors, Triglycerides
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