Comparative Effectiveness of Combination Therapy in Patients with Chronic Kidney Disease and Diabetes mellitus Type 2 using Real World Data

BACKGROUND AND HYPOTHESIS: Diabetes mellitus type 2 (T2DM) is the primary driver of chronic kidney disease (CKD). Renin-angiotensin-aldosterone system inhibitors (RAASi) represent basic therapy for CKD in T2DM. Recent studies demonstrated renal benefits of sodium glucose cotransporter 2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA), but data on direct comparisons and potential additive effects of their combination remain unclear. METHODS: Using data from the US Collaborative Network in TriNetX, we analyzed patients with T2DM, CKD, and eGFR between 20-60 mL/min. A target-trial emulation with propensity score matching evaluated different drug combinations in first-user design versus RAASi monotherapy. Primary endpoint was all-cause mortality. Secondary outcomes included a composite endpoint of all-cause mortality and major adverse kidney events (MAKE), and MAKE as a distinct endpoint. MAKE was defined as CKD stage 5, end-stage renal disease, eGFR <15 mL/min, or need for renal replacement therapy. Kaplan-Meier analysis was used for survival analysis. RESULTS: We identified n= 19,139 patients with T2DM, an eGFR between 20-60mL/min and already established RAASi treatment. RAASi combined with SGLT-2i (aHR 0.602, 95% CI 0.528-0.686) or GLP1-RA (aHR 0.597, 95% CI 0.507-0.702) reduced mortality compared to RAASi monotherapy. Triple therapy showed the greatest mortality reduction (aHR 0.317, 95% CI 0.234-0.429). Secondary endpoints favored dual therapy over RAASi monotherapy, with triple therapy providing the strongest risk reduction for both composite endpoint (aHR 0.414, 95% CI 0.328-0.524) and MAKE (aHR 0.509, 95% CI 0.374-0.693). CONCLUSION: SGLT-2i and GLP1-RA independently improve outcomes in T2DM patients on RAASi treatment. Triple therapy was associated with lower risk for mortality and renal outcomes.