Dr Brendon Neuen1, Mr Robert Fletcher1, Associate Professor Clare Arnott1,2,3, Dr Muthiah Vadagunathan4, Professor Vlado Perkovic5, Professor Meg Jardine6, Professor Bruce Neal1, Professor Kenneth Mahaffey7, Professor Hiddo Heerspink8, Professor Carol Pollock9
1The George Institute For Global Health, Newtown, Australia, 2Department of Cardiology, Royal Prince Alfred Hospital, Camperdown, Australia, 3Sydney Medical School, University of Sydney, Camperdown, Australia, 4Brigham and Women’s Hospital, Harvard Medical School, Boston, United States, 5Faculty of Medicine, UNSW Sydney, Kensington, Australia, 6NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Australia, 7Department of Medicine, Stanford Center for Clinical Research, Stanford University School of Medicine, Stanford, United States, 8Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands, 9Kolling Institute, University of Sydney, St Leonards, Australia
Aim
To evaluate the efficacy and safety of canagliflozin according to loop and thiazide diuretic use in people with type 2 diabetes and chronic kidney disease (CKD), and the impact of canagliflozin on diuretic use over time.
Background
Loop and thiazide diuretics are used commonly in CKD to manage hypertension and/or volume overload. It is uncertain whether the efficacy or safety of canagliflozin is modified by diuretics, and if canagliflozin affects diuretic use over time.
Methods
We conducted a post-hoc analysis of the CREDENCE trial, which randomised individuals with type 2 diabetes and CKD to canagliflozin or placebo. Cox regression models were used to evaluate treatment effects by baseline diuretic use and effects on diuretic initiation and discontinuation after randomisation.
Results
Of 4,401 participants, 955 (21.7%) and 1252 (28.4%) received loop and thiazide diuretics respectively at baseline. Canagliflozin reduced the risk of kidney failure, doubling of serum creatinine, cardiovascular or renal death (HR 0.70, 95% CI 0.59-0.82) irrespective of loop or thiazide diuretic use (P-interaction 0.18 and 0.77, respectively), with similarly consistent effects for heart failure or cardiovascular death (HR 0.69, 95% CI 0.57-0.83; all P-interaction >0.20). No increased risk of acute kidney injury or volume depletion was observed across diuretic subgroups (all P-interaction >0.05). Loop diuretic discontinuation was infrequent (16.2%) and not affected by canagliflozin (HR 1.19, 95% 0.87-1.64). In those who were diuretic-naïve, canagliflozin delayed the initiation of loop diuretics after randomization (HR 0.60, 95% CI 0.51-0.72).
Conclusions
In people with type 2 diabetes and CKD, canagliflozin safely reduces the risk of kidney and cardiovascular outcomes irrespective of diuretic use and reduces new initiation of loop diuretics over time.
Biography:
Dr Brendon Neuen is an nephrology registrar and NHMRC funded research fellow at The George Institute for Global Health, having trained in Sydney and Oxford.
He is an internationally recognised expert on SGLT2 inhibitors and serves as the founding Secretariat of the SGLT2 Meta-analysis Cardiorenal Trialists Consortium, which brings together data from all completed SGLT2 inhibitor trials.
His work has directly informed over a dozen international and national guidelines, scientific statements and position papers that define best practice for the care of people with diabetes and CKD, including the American Diabetes Association Standards of Care and the KDIGO Guidelines.