Why the study?
Direct comparisons and potential additive effects of combining SGLT-2i and GLP1-RA in patients with T2DM and CKD remained unclear.
Does the addition of SGLT-2i, GLP1-RA, or their combination to RAASi therapy reduce mortality and adverse kidney events in patients with T2DM and CKD?
Cohort (n=19,139)
Yes
Does the addition of SGLT-2i, GLP1-RA, or their combination to RAASi therapy reduce mortality and adverse kidney events in patients with T2DM and CKD?
Answers are grounded in this paper and cite their sources.
In patients with T2DM and CKD, adding both an SGLT-2i and a GLP1-RA to baseline RAASi therapy is associated with a substantial reduction in all-cause mortality and major adverse kidney events compared to RAASi monotherapy.
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.
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Casper et al. (2026) conducted a cohort in Type 2 Diabetes Mellitus and Chronic Kidney Disease (n=19,139). Triple therapy (RAASi, SGLT-2i, and GLP1-RA) vs. RAASi monotherapy was evaluated on all-cause mortality (aHR 0.317, 95% CI 0.234-0.429).
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