Effect of Metformin versus Sodium Glucose Cotransporter-2 Inhibitors in Diabetic Patients with Chronic Kidney Disease: A Systematic Review

Abstract

Background:
Diabetic chronic kidney disease carries high risks of kidney failure and cardiovascular events, and clinicians frequently weigh metformin-based care against sodium–glucose cotransporter 2 inhibitor therapy for renoprotection.
Methods:
PubMed was searched from inception to August 2025 (English-language, human studies) for trials and cohort studies in adults with diabetes and chronic kidney disease evaluating metformin strategies and/or sodium–glucose cotransporter 2 inhibitors. Studies reporting kidney progression and cardiovascular or mortality outcomes were narratively synthesized (no meta-analysis).
Results:
Six studies were included: three randomized trials (n=4,304; n=4,401; n=6,609) and three population-based cohort studies (n=1,450; n=45,545; n=4,278). Sodium–glucose cotransporter 2 inhibitors reduced composite kidney outcomes in trials (hazard ratios 0.61 [95% confidence interval 0.51–0.72], 0.70 [0.59–0.82], and 0.72 [0.64–0.82]) and lowered kidney-related adverse events in advanced chronic kidney disease (odds ratio 0.48 [0.33–0.71]). In comparative cohorts, metformin plus sodium–glucose cotransporter 2 inhibitors reduced composite kidney outcomes (adjusted hazard ratio 0.65 [0.48–0.87]) and all-cause mortality (0.74 [0.64–0.84]) versus sodium–glucose cotransporter 2 inhibitors alone, with lower severe acute kidney injury (0.72 [0.54–0.96]) and metabolic acidosis (0.58 [0.40–0.83]); stopping metformin at stage 4 chronic kidney disease increased mortality (hazard ratio 1.26 [1.10–1.44]).
Conclusions:
Sodium–glucose cotransporter 2 inhibitors showed consistent kidney protection, while observational evidence supported continued metformin, especially in combination, when kidney-function–based safety monitoring is feasible in routine practice.