Cardiorenal and survival outcomes of GLP-1 receptor agonist and SGLT-2 inhibitor therapy in diabetic kidney disease: two stage-stratified real-world comparisons

Abstract

Abstract The comparative effectiveness of GLP-1 receptor agonists (GLP-1 RA) and SGLT-2 inhibitors (SGLT-2i), alone or in combination, for kidney protection in chronic kidney disease (CKD) remains unclear in real-world practice. We conducted a retrospective cohort study using the TriNetX global network from inception to up 11 th July 2025 including 736,212 adults with diabetes and CKD. We performed two separate, pre-specified comparisons stratified by baseline kidney function, each using 1:1 propensity score matching and each with its own comparator: in the preserved eGFR cohort, GLP-1 RA + SGLT-2i combination therapy versus SGLT-2i monotherapy (n = 142,372); and in the advanced CKD cohort, GLP-1 RA monotherapy versus standard care without either agent (n = 103,820). The two cohorts were analyzed independently and were not compared with each other; combination therapy was not evaluated in the advanced CKD cohort. Primary outcomes were major adverse kidney events (MAKE) and all-cause mortality. In the preserved eGFR cohort, combination therapy reduced MAKE by 27% (HR 0.73, 95% CI 0.69–0.77) and all-cause mortality by 46% (HR 0.54, 95% CI 0.50–0.58) compared to SGLT-2i monotherapy. The number needed to treat was 94 for MAKE prevention and 90 for mortality reduction. Combination therapy preserved 2.6 mL/min/1.73m 2 more eGFR at five years. In the advanced CKD cohort, GLP-1 RA monotherapy reduced all-cause mortality by 19% (HR 0.81, 95% CI 0.78–0.84) and major adverse cardiovascular events by 8% (HR 0.92, 95% CI 0.88–0.95) compared to standard care. Benefits were consistent across all subgroups (p-interaction = 0.18). Safety profiles favored GLP-1 RA-containing regimens with reduced amputation and pancreatitis risks. In two separate stage-stratified comparisons, GLP-1 RA plus SGLT-2i combination therapy was associated with greater kidney protection and lower mortality than SGLT-2i monotherapy in patients with preserved eGFR, and GLP-1 RA monotherapy was associated with lower mortality and fewer cardiovascular events than standard care in patients with advanced CKD. Because the two cohorts used different comparators and were not compared directly, these findings should not be interpreted as a single comparison of combination versus monotherapy across all stages of CKD.