The Effect of Dapagliflozin on Albuminuria in DECLARE-TIMI 58

Abstract

Objective: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk.

Research design and methods: DECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to <30, ≥30 to ≤300, and >300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and cardiovascular or renal death; specific renal outcome included all except cardiovascular death.

Results: Baseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with >15 to <30 mg/g, 4,030 (23.93%) with 30-300 mg/g, and 1,169 (6.94%) with >300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across all UACR and eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35-1.56], P < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g (P < 0.0125, P interaction = 0.033), and the renal-specific outcome was reduced for all UACR subgroups (P < 0.05, P interaction = 0.480).

Conclusions: In DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease.

Trial registration: ClinicalTrials.gov NCT01730534.

© 2021 by the American Diabetes Association.

Figures

Figure 1

Change in UACR over time by treatment arm at baseline, 6 months, and 1, 2, 3, and 4 years in the group of patients with baseline UACR ≤15 mg/g (A), baseline UACR >15 to <30 mg/g (B), baseline UACR ≥30 to ≤300 mg/g (C) and baseline UACR >300 mg/g (D), and in the group of patients with baseline eGFR ≥90 mL/min/1.73 m2 (E), baseline eGFR <90 to ≥60 mL/min/1.73 m2 (F), and baseline eGFR <60 mL/min/1.73 m2 (G). Shown are point estimates and 95% confidence intervals of geometric mean back-transformed to the original scale.

Figure 1

Change in UACR over time by treatment arm at baseline, 6 months, and 1, 2, 3, and 4 years in the group of patients with baseline UACR ≤15 mg/g (A), baseline UACR >15 to <30 mg/g (B), baseline UACR ≥30 to ≤300 mg/g (C) and baseline UACR >300 mg/g (D), and in the group of patients with baseline eGFR ≥90 mL/min/1.73 m2 (E), baseline eGFR <90 to ≥60 mL/min/1.73 m2 (F), and baseline eGFR <60 mL/min/1.73 m2 (G). Shown are point estimates and 95% confidence intervals of geometric mean back-transformed to the original scale.

Figure 2

Change in confirmed sustained categorical UACR (mg/g) from baseline (BL) to EOT in dapagliflozin vs. placebo arm. A: Improvement in UACR categories. B: Deterioration in UACR categories.

Figure 3

Treatment effect of dapagliflozin vs. placebo on composite cardiorenal and renal-specific outcomes according to baseline UACR categories of ≤15, >15 to 300 mg/g. Cox model with stratification factor (baseline hematuria status and eASCVD or MRF status). KM, Kaplan-Meier.