Bempedoic acid reduces hs-CRP, but not fibrinogen and IL-6 in patients with residual inflammatory risk

Effects of bempedoic acid on CRP, IL-6, fibrinogen and lipoprotein(a) in patients with residual inflammatory risk: A secondary analysis of the CLEAR harmony trial

Literature - Ridker PM, Lei L, Ray KK, et al. - J Clin Lipidol. 2023 Feb 14;S1933-2874(23)00032-6. doi: 10.1016/j.jacl.2023.02.002

Introduction and methods

Background

As bempedoic acid, an oral inhibitor of ATP citrate lyase, reduces LDL-c and also hs-CRP [1-6], it is a potential therapeutic option for patients with residual cholesterol or inflammatory risk. However, the mechanisms underlying its possible anti-inflammatory effects are uncertain.

Aim of the study

The authors examined the impact of bempedoic acid on fibrinogen and IL-6 and the relationships between bempedoic acid–associated changes in biomarkers (including lipids and lipoproteins) in patients with ASCVD and/or heterozygous familial hypercholesterolemia (HeFH) who were receiving maximal tolerated statin therapy and had residual inflammatory risk.

Methods

This was a secondary biomarker analysis of the multicenter, randomized, placebo-controlled CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen) Harmony trial. In this analysis, 817 patients with ASCVD and/or HeFH on maximally tolerated statin therapy who had residual inflammatory risk (defined as baseline hs-CRP ≥2 mg/L) were included who had been randomized (2:1 ratio) to bempedoic acid 180 mg once daily or matching placebo.

Change from baseline to 12 weeks in plasma levels of LDL-c, non–HDL-c, total cholesterol (TC), HDL-c, apoB, triglycerides, hs-CRP, fibrinogen, IL-6, and Lp(a) was measured.

Main results

From baseline to 12 weeks, the median reduction in LDL-c levels was 20.8 mg/dL in the bempedoic acid group (n=542) and 1.5 mg/dL in the placebo group (n=275) (placebo-corrected median group difference: −21.1%; 95%CI: −23.7% to −18.5%; P<0.0001).
The placebo-corrected difference for non–HDL-c was –14.3% (95%CI: –16.8% to –11.9%; P<0.0001), for TC –12.8% (–14.8% to –10.8%; P<0.0001), for HDL-c –8.3% (–10.1% to –6.6%; P<0.0001), for apoB –13.1% (–15.5% to –10.6%; P<0.0001), for triglycerides 8.0% (3.7%–12.5%; P=0.0003), and for hs-CRP –26.5% (–34.8% to –18.4%; P<0.0001).
Compared with placebo, bempedoic acid did not lower levels of fibrinogen (placebo-corrected difference: 2.1%; 95%CI: –2.0% to 6.4%; P=0.32) or IL-6 (–3.7%; –11.5% to 4.3%; P=0.36), and the treatment effect on Lp(a) was deemed to have no clinically important impact (2.4%; 0.0%–4.8%; P=0.011).
Bempedoic acid–associated changes in hs-CRP showed no correlation with bempedoic acid–associated changes in any of the lipid fractions (all r<0.05 ), except for a weak correlation with HDL-c (r=–0.12; P=0.006).

Conclusion

In this secondary biomarker analysis of the CLEAR Harmony trial, bempedoic acid reduced levels of LDL-c and hs-CRP compared with placebo in patients with ASCVD and/or HeFH and residual inflammatory risk but had no effect on the inflammatory markers fibrinogen and IL-6. In addition, the bempedoic acid–associated reduction in hs-CRP did not correlate with the LDL-c reduction observed in the bempedoic acid group.

According to the authors, their “study, taken together with earlier work, suggest that bempedoic acid—acting upstream of statins—likely has LDL-lowering and anti-inflammatory effects through a similar hepatic mechanism.” They therefore believe that bempedoic acid may be useful to treat patients with residual inflammatory risk or residual cholesterol risk.

References

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Find this article online at J Clin Lipidol.