The impact of canagliflozin on the risk of neuropathy events: A post-hoc exploratory analysis of the CREDENCE trial

Jinlan Liao; Amy Kang; Chao Xia; Tamara Young; Gian Luca Di Tanna; Clare Arnott; Carol Pollock; Arun V Krishnan; Rajiv Agarwal; George Bakris; David M Charytan; Dick de Zeeuw; Hiddo J L Heerspink; Adeera Levin; Bruce Neal; David C Wheeler; Hong Zhang; Bernard Zinman; Kenneth W Mahaffey; Vlado Perkovic; Meg J Jardine; Brendan Smyth

doi:10.1016/j.diabet.2022.101331

The impact of canagliflozin on the risk of neuropathy events: A post-hoc exploratory analysis of the CREDENCE trial

Diabetes Metab. 2022 Jul;48(4):101331. doi: 10.1016/j.diabet.2022.101331. Epub 2022 Feb 13.

Authors

Jinlan Liao¹, Amy Kang², Chao Xia³, Tamara Young⁴, Gian Luca Di Tanna⁴, Clare Arnott⁵, Carol Pollock⁶, Arun V Krishnan⁷, Rajiv Agarwal⁸, George Bakris⁹, David M Charytan¹⁰, Dick de Zeeuw¹¹, Hiddo J L Heerspink¹¹, Adeera Levin¹², Bruce Neal¹³, David C Wheeler¹⁴, Hong Zhang¹⁵, Bernard Zinman¹⁶, Kenneth W Mahaffey¹⁷, Vlado Perkovic¹⁵, Meg J Jardine¹⁸, Brendan Smyth¹⁹

Affiliations

¹ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia; Department of Nephrology, Peking University Shenzhen Hospital, Shenzhen, China.
² The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia; Department of Renal Medicine, Prince of Wales Hospital, Sydney, New South Wales, Australia.
³ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia; Department of Radiology and Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China.
⁴ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia.
⁵ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney Medical School, Sydney, New South Wales, Australia.
⁶ Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; Royal North Shore Hospital, Sydney, New South Wales, Australia.
⁷ Prince of Wales Clinical School, University of New South Wales, Australia.
⁸ Indiana University School of Medicine and VA Medical Centre, Indianapolis, IN, USA.
⁹ Department of Medicine, University of Chicago Medicine, Chicago, IL, USA.
¹⁰ Nephrology Division, New York University Langone Medical Centre, New York University School of Medicine, New York, NY, USA.
¹¹ Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
¹² Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada.
¹³ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia; The Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia; Imperial College London, London, United Kingdom.
¹⁴ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia; Department of Renal Medicine, University College London Medical School, London, United Kingdom.
¹⁵ Renal Division of Peking University First Hospital, Beijing, China.
¹⁶ Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
¹⁷ Department of Medicine, Stanford Centre for Clinical Research, Stanford University School of Medicine, Stanford, CA, USA.
¹⁸ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia; Concord Repatriation General Hospital, Sydney, New South Wales, Australia; Department of Medicine, Stanford Centre for Clinical Research, Stanford University School of Medicine, Stanford, CA, USA.
¹⁹ The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia; NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia; Department of Renal Medicine, St George Hospital, Sydney, New South Wales, Australia. Electronic address: brendan.smyth@sydney.edu.au.

PMID: 35172198
DOI: 10.1016/j.diabet.2022.101331

Abstract

Aim: Canagliflozin reduces the risk, and progression, of diabetic kidney disease. We hypothesized that it may improve the microvascular complication of neuropathy.

Methods: The CREDENCE trial randomized participants with type 2 diabetes and kidney disease to canagliflozin 100 mg daily or placebo. Neuropathy events were defined post-hoc as any reported adverse event consistent with a peripheral or autonomic neuropathy event. The effect of canagliflozin and predictors of neuropathy events were estimated using Cox regression analysis. In sensitivity analyses the endpoint was restricted to sensorimotor polyneuropathy, diabetic neuropathy, and non-autonomic neuropathy events.

Results: Almost half (48.8%) of the 4401 participants had a diagnosis of neuropathy at baseline. Over a median of 2.45 years of follow up, 657 people experienced a neuropathy event (63.2 per 1000 patient-years). Independent factors associated with higher risk of experiencing neuropathy events were non-white race, younger age, higher glycated haemoglobin and lower estimated glomerular filtration rate. The incidence of neuropathy events was similar in people randomized to canagliflozin and placebo (334/2202 vs. 323/2199; HR 1.04, 95% CI 0.89 to 1.21, P = 0.66). Canagliflozin had no impact on sensorimotor polyneuropathy (HR 0.93, 95% CI 0.69 to 1.25, P = 0.63), diabetic neuropathy (HR 0.91, 95% CI 0.68 to 1.22, P = 0.52), or non-autonomic neuropathy (HR 1.03, 95% CI 0.87 to 1.21, P = 0.77). The lack of effect on neuropathy events was consistent in subgroup analyses.

Conclusion: Canagliflozin did not affect the risk of neuropathy events in the CREDENCE trial. Future large randomized studies with prespecified neuropathy endpoints are required to determine the impact of sodium glucose cotransporter 2 inhibitors on diabetic neuropathy.

Keywords: Adverse event; Diabetic kidney disease; Diabetic neuropathy; Randomized controlled trial; Sodium Glucose Co-transporter Inhibitors.

Publication types

Randomized Controlled Trial

MeSH terms

Canagliflozin / adverse effects
Cardiovascular Diseases* / epidemiology
Diabetes Mellitus, Type 2* / complications
Diabetes Mellitus, Type 2* / drug therapy
Diabetes Mellitus, Type 2* / epidemiology
Diabetic Nephropathies* / drug therapy
Diabetic Neuropathies* / drug therapy
Diabetic Neuropathies* / epidemiology
Humans
Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use

Substances

Sodium-Glucose Transporter 2 Inhibitors
Canagliflozin