The impact of metformin on kidney disease progression and mortality in diabetic patients using SGLT2 inhibitors: a real-world cohort study

Background: Selecting the optimal first-line therapy for type 2 diabetes is essential for achieving glycemic control and providing cardio-renal protection, though the combined benefits of metformin with SGLT2 inhibitors, remain uncertain. Methods: This retrospective cohort study analyzed data from Clalit Health Services (2016–2021), to compare outcome in adults with type 2 diabetes treated with SGLT2 inhibitors alone versus in combination with metformin. Propensity score matching was applied to balance baseline characteristics between groups. Primary outcomes were a composite kidney outcome (40% decline in eGFR, or progression to ESRD), and all-cause mortality. Safety outcomes included hospitalizations, acute kidney injury and metabolic acidosis. Results: The study included 45,545 patients, with 6774 patients in each group following propensity score matching. The median follow-up time was 1166 days. Combination therapy with metformin and SGLT2 inhibitors was associated with significantly reduced risk of all-cause mortality (aHR 0.74, 95% CI 0.64–0.84), and composite kidney outcomes (aHR 0.65 95% CI 0.48–0.87) even after accounting for mortality as a competing risk (aHR 0.67; 95% CI 0.5–0.9). Furthermore, combination therapy was associated with reduced risks of hospitalization (aHR 0.93 95% CI 0.87–0.99), severe acute kidney injury events (aHR 0.72 95% CI 0.54–0.96) and metabolic acidosis events (aHR 0.58 95% CI 0.4–0.83), compared with SGLT2 inhibitors alone. Conclusions: Patients receiving combination therapy with metformin and SGLT2 inhibitors showed significantly reduced risks of kidney disease progression and mortality compared to those treated with SGLT2 inhibitors alone. These findings support the use of metformin with SGLT2 inhibitors as a first-line treatment strategy for type 2 diabetes irrespective of glycemic control or cardio-renal risk factors.