The impact of canagliflozin on the risk of neuropathy events: A post-hoc exploratory analysis of the CREDENCE trial - 27/07/22

Doi : 10.1016/j.diabet.2022.101331

Jinlan Liao ^a,^b,^{^{1
Co-principal authors}}, Amy Kang ^a,^c,^{^{1
Co-principal authors}}, Chao Xia ^a,^d, Tamara Young ^a, Gian Luca Di Tanna ^a, Clare Arnott ^a,^e, Carol Pollock ^f,^g, Arun V. Krishnan ^h, Rajiv Agarwal ⁱ, George Bakris ^j, David M. Charytan ^k, Dick de Zeeuw ^l, Hiddo J.L. Heerspink ^l, Adeera Levin ^m, Bruce Neal ^a,^n,^o, David C. Wheeler ^a,^p, Hong Zhang ^q, Bernard Zinman ^r, Kenneth W. Mahaffey ^s, Vlado Perkovic ^q, Meg J Jardine ^a,^t,^s, Brendan Smyth ^a,^u,^v,^⁎
^a The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
^b Department of Nephrology, Peking University Shenzhen Hospital, Shenzhen, China
^c Department of Renal Medicine, Prince of Wales Hospital, Sydney, New South Wales, Australia
^d Department of Radiology and Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
^e Department of Cardiology, Royal Prince Alfred Hospital, Sydney Medical School, Sydney, New South Wales, Australia
^f Kolling Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
^g Royal North Shore Hospital, Sydney, New South Wales, Australia
^h Prince of Wales Clinical School, University of New South Wales, Australia
ⁱ Indiana University School of Medicine and VA Medical Centre, Indianapolis, IN, USA
^j Department of Medicine, University of Chicago Medicine, Chicago, IL, USA
^k Nephrology Division, New York University Langone Medical Centre, New York University School of Medicine, New York, NY, USA
^l Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
^m Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada
ⁿ The Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia
^o Imperial College London, London, United Kingdom
^p Department of Renal Medicine, University College London Medical School, London, United Kingdom
^q Renal Division of Peking University First Hospital, Beijing, China
^r Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Canada
^s Department of Medicine, Stanford Centre for Clinical Research, Stanford University School of Medicine, Stanford, CA, USA
^t Concord Repatriation General Hospital, Sydney, New South Wales, Australia
^u NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia
^v Department of Renal Medicine, St George Hospital, Sydney, New South Wales, Australia

^⁎Corresponding author at: NHMRC Clinical Trials Centre, University of Sydney, Medical Foundation Building, 92-94 Parramatta Road, Camperdown NSW 2050, Australia.NHMRC Clinical Trials CentreUniversity of SydneyMedical Foundation Building, 92-94 Parramatta RoadCamperdownNSW2050Australia

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.

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

Plan

Introduction

Methods

Neuropathy adverse events

Statistical analysis

Results

Baseline characteristics and neuropathy events

Primary outcome, sensitivity analyses and subgroup analyses

Predictors of neuropathy events

See Appendix in supplementary material associated with this article on line.

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Vol 48 - N° 4

Article 101331- juillet 2022 Retour au numéro

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The impact of canagliflozin on the risk of neuropathy events: A post-hoc exploratory analysis of the CREDENCE trial - 27/07/22

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