Background: Interleukin-6 (IL-6) has emerged as a promising target for cardiovascular disease (CVD) prevention. Better understanding IL-6's contribution to CVD events in community-based, diverse cohorts and in clinically relevant subgroups will provide critical context about IL-6 inhibition for CVD prevention.
Objectives:To evaluate the association of circulating IL-6 concentrations with incident cardiovascular events and mortality using pooled data from large multi-ethnic prospective cohorts.
Methods: We harmonized individual-level participant data from 14 cohorts with blood IL-6 measurements and follow-up data on any of nine pre-specified outcomes: myocardial infarction, stroke, atrial fibrillation, heart failure (HF), total coronary heart disease (CHD), total CVD, all-cause mortality, CVD-specific mortality, and CHD-specific mortality. We used multivariable-adjusted Cox proportional hazards models to estimate hazard ratios (HRs). IL-6 was analyzed by quartiles and as a log-transformed continuous variable. Associations were then examined by age, prior CVD history, and in key cardiometabolic subgroups: by chronic kidney disease (CKD) status, diabetes status, high-sensitivity C-reactive protein (hsCRP) concentrations, and body mass index categories. Discrimination was evaluated by the area under the curve across four models: base, base + IL-6, base + hsCRP, and base + both markers.
Results: Among 59,396 participants, the median IL-6 concentration was 1.91 pg/mL. The mean age was 63.6 years (SD: 12.4). 67.6% were female, and 20.6% Black. The longest median follow-up time was 15.8 years (CVD-specific mortality). Higher IL-6 concentrations were associated with increased risk of all nine outcomes. The strongest association was observed for CHD-specific mortality, with an adjusted hazard ratio (HR) of 2.12 (95% CI: 1.88-2.39) in the highest compared to the lowest IL-6 quartile. The weakest association was for myocardial infarction (HR 1.45, 95% CI: 1.28-1.64). Findings were robust and consistent in all key subgroups. IL-6 alone demonstrated modest additive discrimination over hsCRP for stroke, HF, CVD, CHD, and mortality.
Conclusions: In this large harmonized, individual-level participant data analysis of prospective cohorts, higher IL-6 concentrations were strongly associated with nine cardiovascular and mortality outcomes after controlling for clinical covariates. Associations were robust across cardiometabolic subgroups, including CKD, diabetes, severe obesity, high hsCRP, and existing CVD.
Editors
Editor-in-Chief
Harlan M. Krumholz, MD, SM, FACC
CME Editor
Ragavendra R. Baliga, MD
Author
Michael J. Blaha, MD, MPH
Zhiqi Yao, MD, ScM
Important Dates
Date of Release: July 21, 2026
Term of Approval/Date of CME/MOC Expiration: July 20, 2027