Effect of Interleukin-6 Pathway Inhibition on Apolipoprotein A1 and Apolipoprotein B: A Meta-Analysis
Underlined: presenting author
Background
Elevated interleukin-6 (IL-6) is an established independent risk factor for coronary heart disease. apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) outperform conventional lipids as cardiovascular risk markers, reflecting antiatherogenic HDL and atherogenic LDL/VLDL burden, respectively. IL-6 pathway inhibition, via receptor blockade or ligand inhibition, is increasingly used in patients with elevated cardiovascular risk, yet paradoxically raises apolipoprotein levels despite reducing inflammation. Given this inconsistently controlled evidence, we performed a meta-analysis quantifying the pooled effect of IL-6 pathway inhibition on ApoA1 and ApoB.
Methods
PubMed, EBSCOhost, and the Cochrane Library were systematically searched for randomized controlled trials (RCTs) and observational studies evaluating IL-6 pathway inhibitors in adults with rheumatoid arthritis or elevated cardiovascular risk. The primary outcomes were change in ApoA1 and ApoB from baseline to follow-up. Studies were stratified a priori by design—RCT versus single-arm cohort—to account for the substantial methodological heterogeneity in comparator structure across the available literature. Mean differences (MD) with 95% confidence intervals (CI) were pooled using random-effects models (REML). Between-study heterogeneity was assessed using the I² statistic. All analyses were performed in RStudio using the meta package.
Results
Six studies met inclusion criteria (2 RCTs, 4 single-arm cohorts; total n=199), evaluating tocilizumab (n=5 studies) and ziltivekimab (n=1 study). Random-effects pooling demonstrated a significant increase in ApoA1 (MD +10.21 mg/dL, 95% CI 2.36–18.06; I²=86%) and ApoB (MD +11.08 mg/dL, 95% CI 6.29–15.88; I²=32%) following IL-6 pathway inhibition. Effect estimates were directionally consistent and did not differ significantly between RCT and single-arm subgroups for either ApoA1 (+7.36 vs. +11.79 mg/dL; p=0.55) or ApoB (+10.58 vs. +11.69 mg/dL; p=0.82), suggesting the finding is robust across differing levels of methodological rigor, despite substantial heterogeneity, particularly for ApoA1.
Discussion & Conclusion
IL-6 pathway inhibition is associated with a significant, consistent increase in both ApoA1 and ApoB across randomized and observational evidence. Because these two markers carry opposing atherogenic implications, the net effect of IL-6 blockade on cardiovascular risk cannot be inferred from apolipoprotein changes alone. These findings support incorporating apolipoprotein monitoring in patients receiving IL-6 pathway inhibitors and underscore the need for dedicated cardiovascular outcome trials to clarify the clinical significance of this lipid paradox.