A Target Trial Emulation Study of SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Combination Therapy in Preventing Kidney Failure in Type 2 Diabetes

Key Points Compared with glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors were associated with a lower risk of kidney failure among individuals with type 2 diabetes. Use of combination SGLT2 inhibitor and glucagon-like peptide-1 receptor agonist was infrequent but associated with lower kidney failure risk in high-risk individuals. Providers should prioritize SGLT2 inhibitors in patients with type 2 diabetes to prevent progression to kidney failure. Background The relative effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for kidney protection, both individually and in combination, is incompletely understood. We sought to compare associations of GLP-1 receptor agonists, SGLT2 inhibitors, and both medications in combination with incident kidney failure among individuals with type 2 diabetes. Methods We conducted a target trial emulation study with new user, active comparator design using deidentified electronic health records data from Optum Labs Data Warehouse. We included adults with type 2 diabetes who were prescribed a GLP-1 receptor agonist, SGLT2 inhibitor, or both between January 1, 2015, and June 29, 2024. We estimated the association of medication class with incident kidney failure using inverse probability of treatment weighted Cox proportional hazards regression models in both intention-to-treat and as-treated methodologies. Results There were 504,151 individuals with 2965 kidney failure events during a median 2.35 (interquartile range 1.09–4.32) years of follow-up. Average prescription duration was 0.69 years for GLP-1 receptor agonists, 0.62 years for SGLT2 inhibitors, and 0.44 years for combination therapy. In the intention-to-treat analysis, compared with GLP-1 receptor agonists, the risk of kidney failure was significantly lower with SGLT2 inhibitors (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.73 to 0.91) but no different with combination therapy (HR, 0.72; 95% CI, 0.45 to 1.15). The results were similar in the as-treated model. Among individuals with CKD or heart failure, the risk of kidney failure was significantly lower with combination therapy compared with GLP-1 receptor agonists (HR, 0.54; 95% CI, 0.30 to 0.97). Conclusions SGLT2 inhibitors were associated with a lower risk of kidney failure compared to GLP-1 receptor agonists. Among high-risk patients with type 2 diabetes and CKD or heart failure, combination therapy may further reduce the risk of kidney failure.