American Diabetes Association
2022_06_22_IL-6_in_CANVAS_revised_ESM.pdf (772.5 kB)

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

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posted on 2022-09-22, 00:10 authored by Akihiko Koshino, Meir Schechter, Taha Sen, Priya Vart, Brendon L. Neuen, Bruce Neal, Clare Arnott, Vlado Perkovic, Paul M. Ridker, Katherine R. Tuttle, Michael K. Hansen, Hiddo J.L. Heerspink


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.


The CANVAS trial and biomarker measurements were funded by Janssen Research & Development. The CANVAS trial was done as a collaboration between the funder, an academic steering committee and an academic research organization, The George Institute. The funder was involved in the study design, data collection, data analysis, data interpretation and writing of the report.


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