Abstract 140: Plasma Interleukin-6 Levels And Cardiovascular Events In The Cirt Trial: Consistent Associations For Incident Coronary, Cerebrovascular, And Peripheral Artery Disease

Introduction: Inflammation is causally related to atherothrombosis. Interleukin-1β (IL-1β) and interleukin-18 (IL-18) require NLRP3 inflammasome for activation and have downstream effects on interleukin-6 (IL-6), a marker previously associated with high risk of coronary artery and cerebrovascular disease (CCVD). However, data pertaining to peripheral artery disease (PAD) are sparse and could offer druggable targets in this disease. Methods: We conducted a prospective cohort study of 4248 patients with type 2 diabetes or metabolic syndrome and prior coronary artery disease who participated in the NIH-funded Cardiovascular Inflammation Reduction Trial (CIRT). Participants were followed for up to 5 years for incident CCVD and symptomatic PAD events. Randomized treatment with low-dose methotrexate (vs. placebo) had no effect on event rates or plasma levels of inflammatory biomarkers. Baseline levels of IL-1β, IL-18, and IL-6 were tested for association with incident vascular events. Kaplan-Meier curves and Cox proportional hazards models (adjusted for traditional risk factors) were estimated. Results: In multivariable adjusted analyses, hazard ratios for the lowest (referent) to highest baseline quartiles of IL-6 were 1.0, 1.5, 1.8, and 2.0 (p-trend <0.001) and 1.0, 1.2, 2.5, and 2.0 (p-trend = 0.04) for incident CCVD (N=349) and PAD (N=87), respectively. Baseline IL-6 levels above vs. below the median (2.50 pg/ml) were associated with a 56% increased risk of CCVD (HR 1.56, 95% CI 1.26-1.93) and a 113% increased risk PAD (HR 2.13, 95% CI 1.36-3.32) (Figure 1). Baseline levels of IL-1β and IL-18 did not associate with incident CCVD or PAD. Conclusion: In this contemporary cohort of secondary prevention patients, elevated IL-6 was associated with both incident CCVD and PAD. These data support exploration of direct IL-6 inhibition for PAD prevention, a strategy currently being pursued to reduce risk of coronary artery and cerebrovascular disease.