Cardiorenal protective effects of canagliflozin in CREDENCE according to glucose lowering.

Charytan, DM; Mahaffey, KW; Jardine, MJ; Cannon, CP; Neal, B; Lambers Heerspink, HJ; Agarwal, R; Bakris, GL; de Zeeuw, D; Levin, A; Pollock, C; Zhang, H; Zinman, B; Rosenthal, N; Perkovic, V; Di Tanna, GL; Yu, J; Rogers, K; Arnott, C; Wheeler, DC

Cardiorenal protective effects of canagliflozin in CREDENCE according to glucose lowering.

Charytan, DM Mahaffey, KW Jardine, MJ Cannon, CP Neal, B Lambers Heerspink, HJ Agarwal, R Bakris, GL de Zeeuw, D Levin, A Pollock, C Zhang, H Zinman, B Rosenthal, N Perkovic, V Di Tanna, GL Yu, J Rogers, K

Arnott, C Wheeler, DC

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Publisher:: BMJ
Publication Type:: Journal Article
Citation:: BMJ Open Diabetes Res Care, 2023, 11, (3), pp. e003270
Issue Date:: 2023-06

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Field	Value	Language
dc.contributor.author	Charytan, DM
dc.contributor.author	Mahaffey, KW
dc.contributor.author	Jardine, MJ
dc.contributor.author	Cannon, CP
dc.contributor.author	Neal, B
dc.contributor.author	Lambers Heerspink, HJ
dc.contributor.author	Agarwal, R
dc.contributor.author	Bakris, GL
dc.contributor.author	de Zeeuw, D
dc.contributor.author	Levin, A
dc.contributor.author	Pollock, C
dc.contributor.author	Zhang, H
dc.contributor.author	Zinman, B
dc.contributor.author	Rosenthal, N
dc.contributor.author	Perkovic, V
dc.contributor.author	Di Tanna, GL
dc.contributor.author	Yu, J
dc.contributor.author	Rogers, K https://orcid.org/0000-0001-5497-4298
dc.contributor.author	Arnott, C
dc.contributor.author	Wheeler, DC
dc.date.accessioned	2023-09-25T03:27:07Z
dc.date.available	2023-04-21
dc.date.available	2023-09-25T03:27:07Z
dc.date.issued	2023-06
dc.identifier.citation	BMJ Open Diabetes Res Care, 2023, 11, (3), pp. e003270
dc.identifier.issn	2052-4897
dc.identifier.issn	2052-4897
dc.identifier.uri	http://hdl.handle.net/10453/172267
dc.description.abstract	INTRODUCTION: Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain. RESEARCH DESIGN AND METHODS: We analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Effects on HbA1c were assessed using mixed models. Mediation of treatment effects by achieved glycemic control was analyzed using proportional hazards regression with and without adjustment for achieved HbA1c. End points included combined kidney or cardiovascular death, end-stage kidney disease or doubling of serum creatinine (primary trial outcome), and individual end point components. RESULTS: HbA1c lowering was modified by baseline estimated glomerular filtration rate (eGFR). For baseline eGFR 60-90, 45-59, and 30-44 mL/min/1.73 m2, overall HbA1c (canagliflozin vs placebo) decreased by -0.24%, -0.14%, and -0.08% respectively and likelihood of >0.5% decrease in HbA1c decreased with ORs of 1.47 (95% CI 1.27 to 1.67), 1.12 (0.94 to 1.33) and 0.99 (0.83 to 1.18), respectively. Adjustment for postbaseline HbA1c marginally attenuated canagliflozin effects on primary and kidney composite outcomes: unadjusted HR 0.67 (95% CI 0.57 to 0.80) and 0.66 (95% CI 0.53 to 0.81); adjusted for week 13 HbA1c, HR 0.71 (95% CI 0.060 to 0.84) and 0.68 (95% CI 0.55 to 0.83). Results adjusted for time-varying HbA1c or HbA1c as a cubic spline were similar and consistent with preserved clinical benefits across a range of excellent and poor glycemic control. CONCLUSIONS: The glycemic effects of canagliflozin are attenuated at lower eGFR but effects on kidney and cardiac end points are preserved. Non-glycemic effects may be primarily responsible for the kidney and cardioprotective benefits of canagliflozin.22.
dc.format	Print
dc.language	eng
dc.publisher	BMJ
dc.relation.ispartof	BMJ Open Diabetes Res Care
dc.relation.isbasedon	10.1136/bmjdrc-2022-003270
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1103 Clinical Sciences
dc.subject.classification	3202 Clinical sciences
dc.subject.classification	4206 Public health
dc.subject.mesh	Humans
dc.subject.mesh	Canagliflozin
dc.subject.mesh	Glucose
dc.subject.mesh	Glycated Hemoglobin
dc.subject.mesh	Kidney
dc.subject.mesh	Kidney Failure, Chronic
dc.subject.mesh	Sodium-Glucose Transporter 2 Inhibitors
dc.subject.mesh	Kidney
dc.subject.mesh	Humans
dc.subject.mesh	Kidney Failure, Chronic
dc.subject.mesh	Glucose
dc.subject.mesh	Canagliflozin
dc.subject.mesh	Sodium-Glucose Transporter 2 Inhibitors
dc.subject.mesh	Glycated Hemoglobin
dc.subject.mesh	Humans
dc.subject.mesh	Canagliflozin
dc.subject.mesh	Glucose
dc.subject.mesh	Glycated Hemoglobin
dc.subject.mesh	Kidney
dc.subject.mesh	Kidney Failure, Chronic
dc.subject.mesh	Sodium-Glucose Transporter 2 Inhibitors
dc.title	Cardiorenal protective effects of canagliflozin in CREDENCE according to glucose lowering.
dc.type	Journal Article
utslib.citation.volume	11
utslib.location.activity	England
utslib.for	1103 Clinical Sciences
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
utslib.copyright.status	open_access	*
dc.date.updated	2023-09-25T03:27:06Z
pubs.issue	3
pubs.publication-status	Published
pubs.volume	11
utslib.citation.issue	3

Abstract:

INTRODUCTION: Relationships between glycemic-lowering effects of sodium glucose co-transporter 2 inhibitors and impact on kidney and cardiovascular outcomes are uncertain. RESEARCH DESIGN AND METHODS: We analyzed 4395 individuals with prebaseline and postbaseline hemoglobin A1c (HbA1c) randomized to canagliflozin (n=2193) or placebo (n=2202) in The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial. Effects on HbA1c were assessed using mixed models. Mediation of treatment effects by achieved glycemic control was analyzed using proportional hazards regression with and without adjustment for achieved HbA1c. End points included combined kidney or cardiovascular death, end-stage kidney disease or doubling of serum creatinine (primary trial outcome), and individual end point components. RESULTS: HbA1c lowering was modified by baseline estimated glomerular filtration rate (eGFR). For baseline eGFR 60-90, 45-59, and 30-44 mL/min/1.73 m2, overall HbA1c (canagliflozin vs placebo) decreased by -0.24%, -0.14%, and -0.08% respectively and likelihood of >0.5% decrease in HbA1c decreased with ORs of 1.47 (95% CI 1.27 to 1.67), 1.12 (0.94 to 1.33) and 0.99 (0.83 to 1.18), respectively. Adjustment for postbaseline HbA1c marginally attenuated canagliflozin effects on primary and kidney composite outcomes: unadjusted HR 0.67 (95% CI 0.57 to 0.80) and 0.66 (95% CI 0.53 to 0.81); adjusted for week 13 HbA1c, HR 0.71 (95% CI 0.060 to 0.84) and 0.68 (95% CI 0.55 to 0.83). Results adjusted for time-varying HbA1c or HbA1c as a cubic spline were similar and consistent with preserved clinical benefits across a range of excellent and poor glycemic control. CONCLUSIONS: The glycemic effects of canagliflozin are attenuated at lower eGFR but effects on kidney and cardiac end points are preserved. Non-glycemic effects may be primarily responsible for the kidney and cardioprotective benefits of canagliflozin.22.

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