Which randomized trials have evaluated SGLT‑2 inhibitors in adults with stage 2–4 chronic kidney disease and albuminuria?

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Last updated: February 19, 2026 • View editorial policy

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Major Randomized Trials of SGLT2 Inhibitors in Adults with Stage 2–4 CKD and Albuminuria

The DAPA-CKD and CREDENCE trials represent the highest-quality evidence for SGLT2 inhibitors in adults with chronic kidney disease and albuminuria, demonstrating robust renal and cardiovascular protection across CKD stages 2–4.

Primary Trials with Dedicated Renal Outcomes

DAPA-CKD Trial (Dapagliflozin)

  • DAPA-CKD enrolled 4,304 adults with CKD stages 2–4 (eGFR 25–75 mL/min/1.73 m²) and albuminuria (UACR 200–5,000 mg/g), with 68% having type 2 diabetes and 32% having CKD without diabetes 1, 2.

  • The trial demonstrated a 39% reduction in the primary composite endpoint of ≥50% sustained eGFR decline, end-stage kidney disease, or cardiovascular/renal death (HR 0.61,95% CI 0.51–0.72) 3, 1.

  • Kidney-specific outcomes improved by 44% (HR 0.56,95% CI 0.45–0.68), including sustained eGFR decline, end-stage kidney disease, or renal death 3, 1.

  • Cardiovascular death or heart failure hospitalization was reduced by 29% (HR 0.71,95% CI 0.55–0.92), and all-cause mortality decreased by 31% (HR 0.69,95% CI 0.53–0.88) 3, 1.

  • At baseline, 44% of participants had eGFR 30–45 mL/min/1.73 m² and 15% had eGFR <30 mL/min/1.73 m², with median UACR of 950 mg/g and 97% receiving ACE inhibitors or ARBs 1.

CREDENCE Trial (Canagliflozin)

  • CREDENCE randomized 4,401 adults with type 2 diabetes, eGFR 30–90 mL/min/1.73 m² (mean 56 mL/min/1.73 m²), and UACR 300–5,000 mg/g (mean albuminuria >900 mg/day) 3.

  • The trial was stopped early due to a 30% reduction in the primary composite endpoint of chronic dialysis ≥30 days, kidney transplantation, sustained eGFR <15 mL/min/1.73 m², doubling of serum creatinine sustained ≥30 days, or cardiovascular/renal death 3.

  • ESKD development was reduced by 32%, and cardiovascular death or heart failure hospitalization decreased by 31% 3.

  • Background therapy included ACE inhibitors or ARBs in >99% of participants, demonstrating additive benefit to renin-angiotensin system blockade 3.

Cardiovascular Outcome Trials with Renal Secondary Endpoints

EMPA-REG OUTCOME (Empagliflozin)

  • Empagliflozin reduced incident or worsening nephropathy by 39% (composite of UACR >300 mg/g, doubling of serum creatinine, ESKD, or death from ESKD) in patients with type 2 diabetes and established cardiovascular disease 3.

  • The risk of doubling serum creatinine with eGFR ≤45 mL/min/1.73 m² was reduced by 44% 3.

CANVAS Program (Canagliflozin)

  • Canagliflozin reduced progression of albuminuria by 27% and the composite of eGFR reduction, ESKD, or renal/cardiovascular death by 40% 3.

DECLARE-TIMI 58 (Dapagliflozin)

  • Among 17,160 patients with type 2 diabetes, dapagliflozin reduced hospitalization for heart failure by 27% (HR 0.73,95% CI 0.61–0.88) and the composite of heart failure hospitalization or cardiovascular death by 17% (HR 0.83,95% CI 0.73–0.95) 1.

  • Mean baseline eGFR was 85.2 mL/min/1.73 m², with 23.5% having microalbuminuria (UACR 30–300 mg/g) and 6.8% having macroalbuminuria (UACR >300 mg/g) 1.

Recent Meta-Analysis Evidence

SMART-C Meta-Analysis (2025)

  • Pooled analysis of 10 randomized trials with 70,361 participants demonstrated that SGLT2 inhibitors reduce CKD progression by 38% (HR 0.62,95% CI 0.57–0.68) regardless of baseline eGFR or albuminuria 4.

  • Benefits were consistent across all eGFR subgroups: HR 0.61 for eGFR ≥60 mL/min/1.73 m², HR 0.57 for eGFR 45–60, HR 0.64 for eGFR 30–45, and HR 0.71 for eGFR <30 mL/min/1.73 m² 4.

  • Protection extended to patients with minimal albuminuria: HR 0.58 for UACR ≤30 mg/g, HR 0.74 for UACR 30–300 mg/g, and HR 0.57 for UACR >300 mg/g 4.

  • Kidney failure alone was reduced by 34% (HR 0.66,95% CI 0.58–0.75), supporting routine use across the full spectrum of kidney function 4.

Guideline Integration of Trial Evidence

  • The 2024 BMJ guideline panel systematically reviewed all available randomized trial evidence and provides risk-stratified recommendations accounting for variable prognoses of adults with CKD 5.

  • KDIGO 2022 guidelines position SGLT2 inhibitors as first-line therapy based on 11 published clinical trials, with strong recommendations for patients with eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g 6.

  • The 2023 ADA Standards of Care explicitly recommend SGLT2 inhibitors for slowing CKD progression independent of glycemic control needs, based on the totality of cardiovascular outcome trials and dedicated renal trials 3.

Common Pitfalls in Trial Interpretation

  • Do not restrict SGLT2 inhibitors to patients with diabetes alone—DAPA-CKD demonstrated identical benefits in the 32% of participants without diabetes 1, 2.

  • Do not withhold therapy in stage 4 CKD—15% of DAPA-CKD participants had eGFR <30 mL/min/1.73 m², and meta-analysis confirms benefit down to eGFR 20 mL/min/1.73 m² 1, 4.

  • Do not discontinue due to the expected early eGFR dip of 2–5 mL/min/1.73 m²—this hemodynamic change is reversible and followed by long-term renal protection 7.

References

2
Research

Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial.

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2020

6
Guideline

SGLT2 Inhibitors in Heart Failure, CKD, and Diabetes

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

7
Guideline

Dapagliflozin Dosing and Safety Considerations

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

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This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.