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

Abstract

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 m2, 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 (Pheterogeneity=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 (Pheterogeneity=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.

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

Copyright © 2021 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

For all kidney-related efficacy outcomes, the relative benefits of canagliflozin were consistent across all urine albumin-to-creatinine ratio (UACR) categories. For kidney-related adverse events, a greater relative risk reduction was observed in higher UACR categories. For all kidney-related outcomes, absolute benefits were greatest in individuals with higher levels of UACR. 95% CI, 95% confidence interval; HR, hazard ratio.

Figure 2.

For all cardiovascular-related efficacy outcomes and all-cause mortality, the relative and absolute benefits of canagliflozin were consistent across UACR categories.

Figure 3.

The relative reduction in albuminuria was greater in individuals with a lower baseline UACR, while the absolute reduction was greater in individuals with a higher UACR. het, heterogeneity.

Figure 4.

After an acute drop in eGFR between treatment commencement and week 3 in all baseline categories of albuminuria, canagliflozin attenuated annual eGFR decline from week 3 to last available measurement in every albuminuria subgroup. The absolute reduction in chronic eGFR slope was greatest in individuals with a UACR of >1000 to <3000 mg/g. SE, standard error.