Kidney, Cardiovascular, and Safety Outcomes of Canagliflozin according to Baseline Albuminuria: A CREDENCE Secondary Analysis.

Publisher: Wolters Kluwer Health Country of Publication: United States NLM ID: 101271570 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1555-905X (Electronic) Linking ISSN: 15559041 NLM ISO Abbreviation: Clin J Am Soc Nephrol Subsets: MEDLINE

Publication: 2023- : Hagerstown, MD : Wolters Kluwer Health
Original Publication: Washington, D.C. : American Society of Nephrology, c2005-

Albuminuria/*urine ; Canagliflozin/*therapeutic use ; Cardiovascular Diseases/*prevention & control ; Diabetes Mellitus, Type 2/*drug therapy ; Diabetes Mellitus, Type 2/*urine ; Kidney Diseases/*prevention & control ; Sodium-Glucose Transporter 2 Inhibitors/*therapeutic use; Aged ; Cardiovascular Diseases/etiology ; Diabetes Mellitus, Type 2/complications ; Double-Blind Method ; Female ; Humans ; Kidney Diseases/etiology ; Male ; Middle Aged

Background and Objectives: The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial.
Design, Setting, Participants, & Measurements: The study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to <90 ml/min per 1.73 m ² , and UACR of >300 to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g ( n =2348), >1000 to <3000 mg/g ( n =1547), and ≥3000 mg/g ( n =506). In addition, we examined the effects of canagliflozin on UACR itself, eGFR slope, and the intermediate outcomes of glycated hemoglobin, body weight, and systolic BP.
Results: Overall, higher UACR was associated with higher rates of kidney and cardiovascular events. Canagliflozin reduced efficacy outcomes for all UACR levels, with no evidence that relative benefits varied between levels. For example, canagliflozin reduced the primary composite outcome by 24% (hazard ratio [HR], 0.76; 95% confidence interval [95% CI], 0.56 to 1.04) in the lowest UACR subgroup, 28% (HR, 0.72; 95% CI, 0.56 to 0.93) in the UACR subgroup >1000 to <3000 mg/g, and 37% (HR, 0.63; 95% CI, 0.47 to 0.84) in the highest subgroup ( P heterogeneity =0.55). Absolute risk reductions for kidney outcomes were greater in participants with higher baseline albuminuria; the number of primary composite events prevented across ascending UACR categories were 17 (95% CI, 3 to 38), 45 (95% CI, 9 to 81), and 119 (95% CI, 35 to 202) per 1000 treated participants over 2.6 years ( P heterogeneity =0.02). Rates of kidney-related adverse events were lower with canagliflozin, with a greater relative reduction in higher UACR categories.
Conclusions: Canagliflozin safely reduces kidney and cardiovascular events in people with type 2 diabetes and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥3000 mg/g.
Clinical Trial Registry Name and Registration Number: ClinicalTrials.gov: CREDENCE, NCT02065791.
Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_22_CJN15260920_final.mp3.
(Copyright © 2021 by the American Society of Nephrology.)

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Keywords: SGLT2 inhibitors; albuminuria; canagliflozin; cardiovascular system; chronic kidney disease progression; diabetes; randomized controlled trials

ClinicalTrials.gov NCT02065791

0 (Sodium-Glucose Transporter 2 Inhibitors)
0SAC974Z85 (Canagliflozin)

Date Created: 20210223 Date Completed: 20220103 Latest Revision: 20230421

20240628

PMC8011002

10.2215/CJN.15260920

33619120