Interleukin-6 and Cardiovascular and Kidney Outcomes in Patients with Type 2 Diabetes: New Insights from CANVAS

   Objective: The inflammatory cytokine interleukin-6 (IL-6) is associated with cardiovascular and kidney outcomes in various populations. However, data in patients with type 2 diabetes is limited. We assessed the association of IL-6 with cardiovascular and kidney outcomes in the CANVAS trial and determined the effect of canagliflozin on IL-6. Research Design and Methods: Patients with type 2 diabetes at high cardiovascular risk were randomly assigned to canagliflozin or placebo. Plasma IL-6 was measured at baseline and year 1, 3, and 6. The composite cardiovascular outcome was non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death; the composite kidney outcome was sustained ≥40% eGFR decline, end-stage kidney disease, or kidney-related death. Multivariable adjusted Cox proportional hazard regression was used to estimate the associations between IL-6 and outcomes. The effect of canagliflozin on IL-6 over time was assessed with a repeated measures mixed effect model. Results: The geometric mean IL-6 at baseline, available in 3503 (80.2%) participants, was 1.7 pg/mL. Each doubling of baseline IL-6 was associated with 14% (95%CI 4, 24) and 21% (95%CI 1, 45) increased risk of cardiovascular and kidney outcomes, respectively. Over 6 years, IL-6 increased by 5.8% (95% CI 3.4, 8.3) in the placebo group. Canagliflozin modestly attenuated the IL-6 increase (absolute percentage difference versus placebo 4.4% [95% CI 1.3, 9.9; p=0.01]). At year 1, each 25% lower level of IL-6 compared to baseline was associated with 7% (95%CI 1, 22) and 14% (95%CI 5, 22) lower risks for the cardiovascular and kidney outcome, respectively.   Conclusions/interpretation: In patients with type 2 diabetes at high cardiovascular risk, baseline IL-6 and its 1-year change were associated with cardiovascular and kidney outcomes.  The effect of IL-6 lowering therapy on cardiovascular, kidney, and safety outcomes remains to be tested.  </p