Interleukin-6 and Cardiovascular Outcomes in Patients with Type 2 Diabetes: A Post Hoc Analysis of CANVAS Trial

Introduction: The sodium glucose co-transporter 2 inhibitor (SGLT2i) canagliflozin (CANA) reduced cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) at high CV risk in the CANVAS Program. CANA has been shown to reduce markers of inflammation in small clinical studies. Higher interleukin-6 (IL-6) levels, a key inflammatory mediator, are associated with increased CV risk. We assessed the association between IL-6 and CV outcomes in patients with T2D and determined the effects of CANA on IL-6 levels over time. Methods: Patients were randomly assigned to CANA (100 or 300 mg/day) or placebo. Plasma IL-6 was measured at baseline and 1, 3, and 6 years after randomization. Outcomes were a composite CV endpoint of non-fatal myocardial infarction, non-fatal stroke, or CV death; a composite of CV death or heart failure hospitalization (hHF) ; or hHF alone. Multivariable adjusted Cox proportional hazard regression model was used to estimate the associations between baseline IL-6 and CV outcomes. The effect of CANA versus placebo on IL-6 levels over time was assessed with a repeated measures mixed effect model. Results: Of 4,330 CANVAS trial participants, 3,503 (80.9%) had available IL-6 measurements at baseline. In multivariable adjusted models, each doubling of baseline IL-6 was associated with 14% (95% CI 4-24%) , 24% (13-37%) , or 35% (16-57%) increased risk for the composite CV endpoint, CV death or hHF, or hHF alone, respectively (all p<0.01) . Compared with placebo, CANA reduced IL-6 levels by 4.4% (95% CI 1.3-9.9%; p=0.01) during follow-up. The proportion of the effect of CANA on the composite CV, CV death or hHF, and hHF endpoints explained by the change in IL-6 was 16.5% (p=0.02) , 28.5% (p=0.34) , and 11.4% (p=0.05) , respectively. Conclusion: In patients with T2D at high CV risk, increased IL-6 is associated with a higher risk of CV outcomes. CANA reduced IL-6 levels over time which may partly explain its protective effect. Disclosure A.Koshino: None. M.Schechter: None. T.Sen: None. B.Neuen: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Consultant; Bayer AG, Other Relationship; Janssen Research & Development, LLC. C.Arnott: Other Relationship; Amgen Inc. V.Perkovic: Advisory Panel; Astellas Pharma Inc., Baxter, DURECT Corporation, Merck & Co., Inc., Metavant Sciences, Mundipharma, Relypsa Inc., Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Bristol-Myers Squibb Company, Dimerix, Eli Lilly and Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Novo Nordisk, Novo Nordisk, Otsuka America Pharmaceutical, Inc., Pfizer Inc., Sanofi, Servier Laboratories, Tricida, Inc., UpToDate. M.K.Hansen: Employee; Janssen Research & Development, LLC. H.L.Heerspink: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Chinook Therapeutics Inc., CSL Behring, Gilead Sciences, Inc., Goldfinch Bio, Inc., Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Mundipharma, Traveere Pharmaceuticals, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S.