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: A pooled post hoc analysis from the CANVAS Program and CREDENCE randomized double-blind trials

Amy Kang; Brendan Smyth; Brendon L Neuen; Hiddo J L Heerspink; Gian Luca Di Tanna; Hong Zhang; Clare Arnott; Carinna Hockham; Rajiv Agarwal; George Bakris; David M Charytan; Dick de Zeeuw; Tom Greene; Adeera Levin; Carol Pollock; David C Wheeler; Kenneth W Mahaffey; Vlado Perkovic; Meg J Jardine

doi:10.1111/dom.15091

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: A pooled post hoc analysis from the CANVAS Program and CREDENCE randomized double-blind trials

Diabetes Obes Metab. 2023 Aug;25(8):2151-2162. doi: 10.1111/dom.15091. Epub 2023 May 10.

Authors

Amy Kang^{1

2

3}, Brendan Smyth^{1

4

5}, Brendon L Neuen¹, Hiddo J L Heerspink^{1

6}, Gian Luca Di Tanna¹, Hong Zhang⁷, Clare Arnott^{1

8}, Carinna Hockham¹, Rajiv Agarwal⁹, George Bakris¹⁰, David M Charytan¹¹, Dick de Zeeuw⁶, Tom Greene¹², Adeera Levin¹³, Carol Pollock^{14

15}, David C Wheeler¹⁶, Kenneth W Mahaffey¹⁷, Vlado Perkovic^{1

2}, Meg J Jardine^{1

4

18}

Affiliations

¹ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
² University of New South Wales, Sydney, New South Wales, Australia.
³ Department of Nephrology, Prince of Wales Hospital, Sydney, New South Wales, Australia.
⁴ NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia.
⁵ Department of Renal Medicine, St George Hospital, Sydney, New South Wales, Australia.
⁶ Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
⁷ Renal Division of Peking University First Hospital, Beijing, China.
⁸ Department of Cardiology, Royal Prince Alfred Hospital, Sydney Medical School, Sydney, New South Wales, Australia.
⁹ Indiana University School of Medicine and VA Medical Center, Indianapolis, Indiana, USA.
¹⁰ Department of Medicine, University of Chicago Medicine, Chicago, Illinois, USA.
¹¹ Nephrology Division, New York University Langone Medical Center, New York University School of Medicine, New York, New York, USA.
¹² University of Utah, Salt Lake City, Utah, USA.
¹³ Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁴ Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
¹⁵ Royal North Shore Hospital, Sydney, New South Wales, Australia.
¹⁶ Department of Renal Medicine, University College London Medical School, London, UK.
¹⁷ Stanford Centre for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
¹⁸ Concord Repatriation General Hospital, Sydney, New South Wales, Australia.

PMID: 37161691
DOI: 10.1111/dom.15091

Abstract

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.

Keywords: SGLT2 inhibitor; canagliflozin; clinical trial; diabetes complications; randomized trial; type 2 diabetes.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Canagliflozin / adverse effects
Cardiovascular Diseases* / complications
Diabetes Mellitus, Type 2* / chemically induced
Diabetes Mellitus, Type 2* / complications
Diabetes Mellitus, Type 2* / drug therapy
Glucose / therapeutic use
Humans
Male
Sodium
Sodium-Glucose Transporter 2 Inhibitors* / adverse effects
Soft Tissue Infections* / chemically induced

Substances

Canagliflozin
Sodium-Glucose Transporter 2 Inhibitors
Glucose
Sodium