The effects of canagliflozin on gout in type 2 diabetes: a post-hoc analysis of the CANVAS Program

JingWei Li; Sunil V Badve; Zien Zhou; Anthony Rodgers; Richard Day; Richard Oh; Mary Lee; Vlado Perkovic; Dick de Zeeuw; Kenneth W Mahaffey; Greg Fulcher; David R Matthews; Bruce Neal

doi:10.1016/S2665-9913(19)30078-5

The effects of canagliflozin on gout in type 2 diabetes: a post-hoc analysis of the CANVAS Program

Lancet Rheumatol. 2019 Dec;1(4):e220-e228. doi: 10.1016/S2665-9913(19)30078-5.

Authors

JingWei Li¹, Sunil V Badve², Zien Zhou³, Anthony Rodgers⁴, Richard Day⁵, Richard Oh⁶, Mary Lee⁶, Vlado Perkovic⁷, Dick de Zeeuw⁸, Kenneth W Mahaffey⁹, Greg Fulcher¹⁰, David R Matthews¹¹, Bruce Neal¹²

Affiliations

¹ Department of Cardiology, People's Liberation Army General Hospital, Beijing, China; Department of Cardiology, Xinqiao Hospital, Army Military Medical University, Chongqing, China; The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia.
² The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia; Department of Renal Medicine, St George Hospital, Sydney, NSW, Australia.
³ The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia; Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia.
⁵ St Vincent's Hospital Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
⁶ Janssen Research & Development, LLC, Raritan, NJ, USA.
⁷ The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia; The Royal North Shore Hospital, Sydney, NSW, Australia.
⁸ Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
⁹ Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ The Royal North Shore Hospital, Sydney, NSW, Australia.
¹¹ Oxford Centre for Diabetes, Endocrinology and Metabolism and Harris Manchester College, University of Oxford, Oxford, UK.
¹² The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia; The Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia; Department of Epidemiology and Biostatistics, Imperial College London, London, UK. Electronic address: bneal@georgeinstitute.org.au.

PMID: 38229378
DOI: 10.1016/S2665-9913(19)30078-5

Abstract

Background: Sodium glucose co-transporter 2 inhibitors have been shown to reduce serum urate concentration. The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program integrated data from two similarly designed, randomised, double-blind, placebo-controlled trials (CANVAS and CANVAS-Renal) assessing the cardiovascular and renal safety of canagliflozin compared with placebo in patients with type 2 diabetes. In this post-hoc analysis, we aimed to investigate the effect of canagliflozin compared with placebo on gout in the CANVAS Program.

Methods: In the CANVAS Program, individuals with type 2 diabetes and an elevated risk of cardiovascular disease were randomly assigned to receive either canagliflozin (100 or 300 mg) or placebo. In this post-hoc analysis, we assessed the effects of canagliflozin versus placebo on serum urate concentration using mixed linear models and the occurrence of either an adverse event attributed to gout flare or the commencement of a drug for gout using Kaplan-Meier analysis with Cox proportional hazards models to determine a hazard ratio (HR) and 95% CIs. All analyses were done according to the principle of intention to treat, and there was no imputation for missing data.

Findings: 10 142 participants were included in analyses. At baseline, mean age was 63 years (SD 8), 3633 (36%) participants were female, mean serum urate concentration was 348·9 μmol/L (95·5), and 471 (5%) of participants had a history of gout. Mean follow-up was 3·6 years (SD 2·0) and mean serum urate concentration was -23·3 μmol/L (95% CI -25·4 to -21·3) lower in participants treated with canagliflozin than in those who received placebo, equating to a 6·7% reduction in serum urate (percentage difference -6·7%, 95% CI -7·3 to -6·1). During follow-up, 80 individuals reported an episode of gout flare and 147 commenced a drug for gout. The occurrence of gout flare or the need for treatment for gout was lower in participants treated with canagliflozin than in those who received placebo (HR 0·53, 95% CI 0·40-0·71; p<0·0001). The proportional reduction for gout flare adverse events (2·0 patients with an event per 1000 patient-years in the canagliflozin group vs 2·6 patients with an event per 1000 patient-years in the placebo group; 0·64, 95% CI 0·41-0·99; p=0·046) was similar in size to that for commencement of a drug for gout (3·3 vs 5·4 patients with an event per 1000 patient-years; 0·52, 0·38-0·72; p<0·0001) and hyperuricaemia (1·8 vs 2·5 patients with an event per 1000 patient-years; 0·59, 0·37-0·93; p=0·023).

Interpretation: In this post-hoc analysis, compared with placebo, canagliflozin reduced serum urate concentration and also reduced events related to gout flare among patients with type 2 diabetes. A trial explicitly designed to test the effects of sodium glucose co-transporter 2 inhibition on gout is required to confirm these observations.

Funding: Janssen Research & Development.