Large meta-analysis on anti-inflammatory effect of lipid-lowering therapies
In a meta-analysis of 53 RCTs, statins, bempedoic acid, ezetimibe, and omega-3 fatty acids lowered circulating CRP levels, irrespective of changes in LDL-C or triglycerides.
This summary is based on the publication of Xie S, Galimberti F, Olmastroni E, et al. - Effect of lipid-lowering therapies on C-reactive protein levels: a comprehensive meta-analysis of randomized controlled trials. Cardiovasc Res. 2024 Feb 19:cvae034 [Online ahead of print]. doi: 10.1093/cvr/cvae034
Introduction and methods
Background
Observational studies have shown increased hs-CRP levels are associated with elevated CVD risk in individuals with or with no history of CVD [1]. At the same time, RCTs on lipid-lowering therapies (LLTs) have demonstrated that patients who met both the LDL-c target (<70 mg/dL) and CRP target (<2 mg/L) had better clinical outcomes than those meeting neither target [2,3]. The question is whether LLTs have an anti-inflammatory effect and how this is related to the lipid-lowering effect of these drugs.
Aim of the study
The authors assessed the effect of several LLTs on circulating CRP levels and whether this effect is associated with the reduction of levels of LDL-c or triglycerides.
Methods
The authors conducted a meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines that included 171,668 subjects from 53 RCTs (phase 2, 3, or 4), with each an intervention duration >3 weeks and sample size (for both intervention and control group) >100 subjects. In these trials, the effect of LLTs (statins, ezetimibe, omega-3 fatty acids, fibrates, PCSK9 inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, and/or bempedoic acid) on CRP levels was compared with that of placebo.
Main results
- Compared with placebo, CRP levels were decreased by statins (absolute mean difference: –0.65 mg/L; 95%CI: –0.87 to –0.43; relative CRP change from baseline: –17.31%), bempedoic acid (–0.43 mg/L; 95%CI: –0.67 to –0.20; –20.02%), ezetimibe (–0.28 mg/L; 95%CI: –0.48 to –0.08; –3.19%), and omega-3 fatty acids (–0.27 mg/L; 95%CI: –0.52 to –0.01; –12.83%).
- Fibrates did not lead to a significant CRP reduction (absolute mean difference: –0.40 mg/L; 95%CI: –1.17 to 0.38; relative CRP change from baseline: –10.28%).
- In contrast, a slight CRP increase was observed for PCSK9 inhibitors (absolute mean difference: 0.11 mg/L; 95%CI: 0.07–0.14; relative CRP change from baseline: 5.99%), while CETP inhibitors resulted in a small but nonsignificant rise in CRP levels (0.10 mg/L; 95%CI: 0.00–0.21; 6.98%).
- In subgroup analyses stratified by type of prevention (primary vs. secondary) or baseline CRP level, a significant difference in CRP reduction was only seen for patients treated with statins versus placebo who had a baseline CRP level ≥3 mg/L (absolute mean difference: –1.05 mg/L; 95%CI: –1.29 to –0.82) compared with those with baseline CRP <3 mg/L (absolute mean difference: –0.43 mg/L; 95%CI: –0.50 to –0.36; P<0.01).
- Mixed-effects meta-regression analyses adjusted for age, sex, and intervention duration did not show a significant correlation between changes in CRP and LDL-c or triglycerides for any of the LLTs with a significant effect on CRP levels, except for omega-3 fatty acids (slope for adjusted model: 0.0879 and 0.0371, respectively; both P<0.0001). However, after removal of 1 trial (REDUCE-IT) from the analyses, both correlations were no longer statistically significant.
Conclusion
In this meta-analysis of 53 RCTs investigating the anti-inflammatory effect of 7 main LLTs, statins, bempedoic acid, ezetimibe, and omega-3 fatty acids lowered circulating CRP levels, irrespective of changes in LDL-c or triglycerides. PCSK9 inhibitors slightly increased CRP levels, while fibrates and CETP inhibitors did not have a significant effect.
The authors conclude “[f]urther investigation is required to clearly demonstrate how this potential anti-inflammatory action may influence cardiovascular protection, and whether new therapies targeting inflammation pathways (as the recently approved colchicine) could be added to lipid treatment and used to help reducing cardiovascular risk in selected groups of individuals.”
References
1. Ballantyne CM. Clinical Lipidology: A Companion to Braunwald’s Heart Disease - 2nd Edition. Canada, Elsevier, 2014:138. Available from https://www.elsevier.com/books/clinical-lipidology-a-companion-to-braunwalds-heart-disease/ballantyne/978-0-323-28786-9
2. Ridker PM, Cannon CP, Morrow D, et al. C-Reactive Protein Levels and Outcomes after Statin Therapy. N Engl J Med. 2005;352(1):20-28. doi:10.1056/NEJMoa042378
3. Bohula EA, Giugliano RP, Cannon CP, et al. Achievement of Dual Low-Density Lipoprotein Cholesterol and High-Sensitivity C-Reactive Protein Targets More Frequent With the Addition of Ezetimibe to Simvastatin and Associated With Better Outcomes in IMPROVE-IT. Circulation. 2015;132(13):1224-1233. doi:10.1161/CIRCULATIONAHA.115.018381