TY - JOUR
T1 - Interleukin-6 and Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes
T2 - New Insights From CANVAS
AU - Koshino, Akihiko
AU - Schechter, Meir
AU - Sen, Taha
AU - Vart, Priya
AU - Neuen, Brendon L.
AU - Neal, Bruce
AU - Arnott, Clare
AU - Perkovic, Vlado
AU - Ridker, Paul M.
AU - Tuttle, Katherine R.
AU - Hansen, Michael K.
AU - Heerspink, Hiddo J.L.
N1 - Funding Information:
T.S. is supported by the Biomarker Enterprise to Attack DKD (BEAt-DKD) project. The BEAt-DKD project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (IMI2 JU) under grant agreement no. 115974. IMI2 JU receives support from the European Union’s Horizon 2020 research and innovation program and the European Federation of Pharmaceutical Industries and Associations. K.R.T. is supported by National Institutes of Health research grants R01MD014712, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846, OT2HL161847, and UM1AI109568 and Centers for Disease Control and Prevention contract 75D301-21-P-12254.
Publisher Copyright:
© 2022 by the American Diabetes Association.
PY - 2022/11
Y1 - 2022/11
N2 - OBJECTIVE: The inflammatory cytokine interleukin-6 (IL-6) is associated with cardiovascular (CV) and kidney outcomes in various populations. However, data in patients with type 2 diabetes are limited. We assessed the association of IL-6 with CV and kidney outcomes in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and determined the effect of canagliflozin on IL-6.RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes at high CV risk were randomly assigned to canagliflozin or placebo. Plasma IL-6 was measured at baseline and years 1, 3, and 6. The composite CV outcome was nonfatal myocardial infarction, nonfatal stroke, or CV death; the composite kidney outcome was sustained ≥40% estimated glomerular filtration rate decline, end-stage kidney disease, or kidney-related death. Multi-variable-adjusted Cox proportional hazards regression was used to estimate the associations between IL-6 and the outcomes. The effect of canagliflozin on IL-6 over time was assessed with a repeated-measures mixed-effects model.RESULTS: The geometric mean IL-6 at baseline, available in 3,503 (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 CV 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 vs. placebo 4.4% [95% CI 1.3, 9.9; P = 0.01]). At year 1, each 25% lower level of IL-6 compared with baseline was associated with 7% (95% CI 1, 22) and 14% (95% CI 5, 22) lower risks for the CV and kidney outcome, respectively.CONCLUSIONS: In patients with type 2 diabetes at high CV risk, baseline IL-6 and its 1-year change were associated with CV and kidney outcomes. The effect of IL-6–lowering therapy on CV, kidney, and safety outcomes remains to be tested.
AB - OBJECTIVE: The inflammatory cytokine interleukin-6 (IL-6) is associated with cardiovascular (CV) and kidney outcomes in various populations. However, data in patients with type 2 diabetes are limited. We assessed the association of IL-6 with CV and kidney outcomes in the Canagliflozin Cardiovascular Assessment Study (CANVAS) and determined the effect of canagliflozin on IL-6.RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes at high CV risk were randomly assigned to canagliflozin or placebo. Plasma IL-6 was measured at baseline and years 1, 3, and 6. The composite CV outcome was nonfatal myocardial infarction, nonfatal stroke, or CV death; the composite kidney outcome was sustained ≥40% estimated glomerular filtration rate decline, end-stage kidney disease, or kidney-related death. Multi-variable-adjusted Cox proportional hazards regression was used to estimate the associations between IL-6 and the outcomes. The effect of canagliflozin on IL-6 over time was assessed with a repeated-measures mixed-effects model.RESULTS: The geometric mean IL-6 at baseline, available in 3,503 (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 CV 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 vs. placebo 4.4% [95% CI 1.3, 9.9; P = 0.01]). At year 1, each 25% lower level of IL-6 compared with baseline was associated with 7% (95% CI 1, 22) and 14% (95% CI 5, 22) lower risks for the CV and kidney outcome, respectively.CONCLUSIONS: In patients with type 2 diabetes at high CV risk, baseline IL-6 and its 1-year change were associated with CV and kidney outcomes. The effect of IL-6–lowering therapy on CV, kidney, and safety outcomes remains to be tested.
U2 - 10.2337/dc22-0866
DO - 10.2337/dc22-0866
M3 - Article
C2 - 36134918
AN - SCOPUS:85141364595
SN - 0149-5992
VL - 45
SP - 2644
EP - 2652
JO - Diabetes Care
JF - Diabetes Care
IS - 11
ER -