TY - JOUR
T1 - The sodium-glucose cotransporter-2 inhibitor canagliflozin does not increase risk of non-genital skin and soft tissue infections in people with type 2 diabetes mellitus
T2 - A pooled post hoc analysis from the CANVAS Program and CREDENCE randomized double-blind trials
AU - Kang, Amy
AU - Smyth, Brendan
AU - Neuen, Brendon L.
AU - Heerspink, Hiddo J.L.
AU - Di Tanna, Gian Luca
AU - Zhang, Hong
AU - Arnott, Clare
AU - Hockham, Carinna
AU - Agarwal, Rajiv
AU - Bakris, George
AU - Charytan, David M.
AU - de Zeeuw, Dick
AU - Greene, Tom
AU - Levin, Adeera
AU - Pollock, Carol
AU - Wheeler, David C.
AU - Mahaffey, Kenneth W.
AU - Perkovic, Vlado
AU - Jardine, Meg J.
N1 - Funding Information:
The CANVAS Program and CREDENCE studies were sponsored by Janssen Research and Development and were conducted collaboratively by the sponsor, an academic‐led steering committee, and an academic research organization, George Clinical. This post hoc analysis of the CANVAS Program and CREDENCE trials was not specifically funded. The funders were not involved in the design, analysis, reporting, or decision to submit this manuscript for publication. Amy Kang is supported by an National Health and Medical Research Council Postgraduate Scholarship (1150349) via the University of New South Wales and an Australian Government Research Training Program Fee Offset, and has received a George Institute Scholarship. Brendan Smyth is supported by the Jacquot Research Establishment Award from the Royal Australasian College of Physicians. We thank the participants in the trials and the study investigators, who are listed in the Data S2 , for the primary CANVAS Program and CREDENCE study publications.
Publisher Copyright:
© 2023 John Wiley & Sons Ltd.
PY - 2023/8
Y1 - 2023/8
N2 - Aims: To assess whether the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin affects risk of non-genital skin and soft tissue infections (SSTIs). Materials and methods: We performed a post hoc pooled individual participant analysis of the CANVAS Program and CREDENCE trials that randomized people with type 2 diabetes at high cardiovascular risk and/or with chronic kidney disease to either canagliflozin or placebo. Investigator-reported adverse events were assessed by two blinded authors following predetermined criteria for non-genital SSTIs. Risks of non-genital SSTIs, overall and within prespecified subgroups, and risk of non-genital fungal SSTIs, were analysed using Cox regression models. Factors associated with non-genital SSTIs were assessed using multivariable Cox regression models. Results: Overall, 903 of 14 531 participants (6%) experienced non-genital SSTIs over a median follow-up of 26 months. No difference was observed in non-genital SSTI rates between canagliflozin and placebo (24.0 events/1000 person-years vs. 23.9 events/1000 person-years, respectively; hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.85-1.11; P = 0.70), with consistent results across subgroups (all P interaction > 0.05). The risk of recurrent events and non-genital fungal infection also did not differ significantly between canagliflozin and placebo (HR 1.06, 95% CI 0.94-1.19 [P = 0.32] and HR 1.18, 95% CI 0.88-1.60 [P = 0.27], respectively). Baseline factors independently associated with non-genital SSTIs were younger age, male sex, higher body mass index, higher glycated haemoglobin, lower estimated glomerular filtration rate (eGFR), established peripheral vascular disease, and history of neuropathy. Conclusions: Canagliflozin did not affect risk of non-genital SSTIs or non-genital fungal SSTIs compared with placebo. These findings suggest that any SGLT2 inhibitor-mediated change in skin microenvironment is unlikely to have meaningful clinical consequences.
AB - Aims: To assess whether the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin affects risk of non-genital skin and soft tissue infections (SSTIs). Materials and methods: We performed a post hoc pooled individual participant analysis of the CANVAS Program and CREDENCE trials that randomized people with type 2 diabetes at high cardiovascular risk and/or with chronic kidney disease to either canagliflozin or placebo. Investigator-reported adverse events were assessed by two blinded authors following predetermined criteria for non-genital SSTIs. Risks of non-genital SSTIs, overall and within prespecified subgroups, and risk of non-genital fungal SSTIs, were analysed using Cox regression models. Factors associated with non-genital SSTIs were assessed using multivariable Cox regression models. Results: Overall, 903 of 14 531 participants (6%) experienced non-genital SSTIs over a median follow-up of 26 months. No difference was observed in non-genital SSTI rates between canagliflozin and placebo (24.0 events/1000 person-years vs. 23.9 events/1000 person-years, respectively; hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.85-1.11; P = 0.70), with consistent results across subgroups (all P interaction > 0.05). The risk of recurrent events and non-genital fungal infection also did not differ significantly between canagliflozin and placebo (HR 1.06, 95% CI 0.94-1.19 [P = 0.32] and HR 1.18, 95% CI 0.88-1.60 [P = 0.27], respectively). Baseline factors independently associated with non-genital SSTIs were younger age, male sex, higher body mass index, higher glycated haemoglobin, lower estimated glomerular filtration rate (eGFR), established peripheral vascular disease, and history of neuropathy. Conclusions: Canagliflozin did not affect risk of non-genital SSTIs or non-genital fungal SSTIs compared with placebo. These findings suggest that any SGLT2 inhibitor-mediated change in skin microenvironment is unlikely to have meaningful clinical consequences.
KW - canagliflozin
KW - clinical trial
KW - diabetes complications
KW - randomized trial
KW - SGLT2 inhibitor
KW - type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85158943243&partnerID=8YFLogxK
U2 - 10.1111/dom.15091
DO - 10.1111/dom.15091
M3 - Article
C2 - 37161691
AN - SCOPUS:85158943243
SN - 1462-8902
VL - 25
SP - 2151
EP - 2162
JO - Diabetes, Obesity and Metabolism
JF - Diabetes, Obesity and Metabolism
IS - 8
ER -