Dapagliflozin and Prevention of Kidney Disease Among Patients With Type 2 Diabetes: Post Hoc Analyses From the DECLARE-TIMI 58 Trial

Abstract

Objective: In patients with moderate to severe albuminuric kidney disease, sodium-glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk.

Research design and methods: In the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was a sustained decline ≥40% in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and kidney-related death. Other outcomes included incidence of categorical eGFR decline of different thresholds and chronic (6 month to 4 year) or total (baseline to 4 year) eGFR slopes.

Results: Most participants were in the low-moderate KDIGO risk categories (n = 15,201 [90.3%]). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction = 0.97), including those at low risk (hazard ratio [HR] 0.54, 95% CI 0.38-0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR ≥60 mL/min/1.73 m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HRs 0.52, 0.57, 0.55, and 0.70, respectively; P < 0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m2/year; P < 0.0001).

Conclusions: Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease.

Trial registration: ClinicalTrials.gov NCT01730534.

© 2022 by the American Diabetes Association.

Figures

Figure 1

Cardiorenal and kidney-specific outcomes by KDIGO risk classification at baseline. The cardiorenal outcome was composed of confirmed eGFR decline of ≥40% from baseline to eGFR 2, new ESKD (defined as dialysis for 90 days or more, kidney transplantation, or sustained eGFR of <15 mL/min/1.73 m2), or death related to kidney failure or CV disease. The kidney-specific outcome was the same as the cardiorenal outcome except for CV-related death. HRs and 95% CIs were calculated using Cox proportional hazard models. Number of patients NNT to prevent one event during the study follow up was calculated based on the absolute risk reduction observed in the Kaplan-Meier (KM) estimates. eGFR was calculated by the CKD-EPI equation.

Figure 2

Confirmed categorical eGFR declines with dapagliflozin compared with placebo. HRs and 95% CIs were calculated using Cox proportional hazard regression models. eGFR was calculated by the CKD-EPI equation. All eGFR values are presented in mL/min/1.73 m2. KM, Kaplan-Meier.

Figure 3

Mean change in eGFR overall and by kidney-related subgroups in dapagliflozin compared with placebo. A: Acute and total slopes. B: Chronic slope. The total (baseline to 4 years) and chronic slopes (6 months to 4 years) are presented annually, while the acute slope (baseline to 6 months) is presented by 6 months. Mean eGFR slope was calculated for the entire population and by subgroups using a random-effects model analysis including the following covariates: baseline measurements stratification factors of baseline ASCVD category (established ASCVD or multiple risk factors for ASCVD) and the presence or absence of hematuria at baseline, treatment arm, visit and interaction terms of treatment and visit. All eGFR values are presented in mL/min/1.73 m2. UACR is presented as mg/g. eGFR slope is presented as least square (LS) mean estimators. MRF, multiple risk factors.

Figure 3

Mean change in eGFR overall and by kidney-related subgroups in dapagliflozin compared with placebo. A: Acute and total slopes. B: Chronic slope. The total (baseline to 4 years) and chronic slopes (6 months to 4 years) are presented annually, while the acute slope (baseline to 6 months) is presented by 6 months. Mean eGFR slope was calculated for the entire population and by subgroups using a random-effects model analysis including the following covariates: baseline measurements stratification factors of baseline ASCVD category (established ASCVD or multiple risk factors for ASCVD) and the presence or absence of hematuria at baseline, treatment arm, visit and interaction terms of treatment and visit. All eGFR values are presented in mL/min/1.73 m2. UACR is presented as mg/g. eGFR slope is presented as least square (LS) mean estimators. MRF, multiple risk factors.