Association Between Metformin Use and Circulating Inflammatory Regulators: A Large-Scale Proteomic Analysis with Implications for HIV Immuno-metabolism

BackgroundRecent multiomic analyses identify metformin-inducible genes, such as DDIT4, as predictors of delayed HIV rebound, suggesting a "cell-extrinsic" role for low systemic inflammation in viral control. We sought to validate this inflammatory "cooling" in a large-scale human population. MethodsUsing Olink proteomics from the UK Biobank (N = 502,493), we evaluated associations between metformin use and inflammatory markers (IL-6, CXCL10, GZMB) in a diabetic cohort (N = 18,548). Stepwise regression was used to adjust for co-medications (statins) and glycemic control (HbA1c). ResultsMetformin use was associated with significantly lower levels of IL-6 (p = 0.0049) and CXCL10 (p < 0.001) after adjusting for age, BMI, and statin use. In exploratory analyses of participants with HIV (N = 61), metformin users showed directionally lower mean IL-6 and CXCL10. However, associations in the primary cohort were attenuated upon adjustment for HbA1c, indicating that metformins systemic anti-inflammatory effect is largely mediated by its metabolic efficacy. ConclusionsMetformin use is associated with a reduction in master regulators of inflammation, independent of common co-medications. These findings suggest that metformin promotes the systemic "cell-extrinsic" environment required for HIV control via its metabolic effects, providing a population-level substrate for the "block-and-lock" mechanisms observed in clinical cohorts.