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.2023.02.002Introduction 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
1. Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019;380(11):1022–1032.
2. Goldberg AC, Leiter LA, Stroes ESG, et al. Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom randomized clinical trial. JAMA. 2019;322(18):1780–1788.
3. Ballantyne CM, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study. Atherosclerosis. 2018;277:195–203.
4. Laufs U, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc. 2019;8(7):e011662.
5. Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1999;100(3):230–235.
6. Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA. 2001;286(1):64–70.
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