Effectiveness of Adding GLP ‐1 Receptor Agonists to SGLT2 Inhibitor Therapy in Chronic Kidney Disease: A Population Based Study

Background Individually, sodium–glucose co‐transporter‐2 inhibitors (SGLT2i) and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have been shown to reduce major kidney and cardiovascular events in patients with chronic kidney disease (CKD). However, evidence supporting combined GLP‐1RA and SGLT2i therapy in this population remains limited. Methods We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, including adults with CKD treated with SGLT2i alone or SGLT2i with subsequent initiation of GLP‐1RA between June 2020 and December 2023. Propensity score matching (1:1) adjusted for demographics, comorbidities, medications, and laboratory values. The primary outcome was major adverse kidney events (MAKE); secondary outcomes included all‐cause mortality and major adverse cardiovascular events (MACE). Time‐to‐event analyses were performed using Cox proportional hazards models. Results Among 112 596 patients with CKD, 16460 received SGLT2i and GLP‐1RA combination therapy, and 96 136 received SGLT2i monotherapy. The matched cohort included 32 448 patients (16 224 per group). Over a median follow‐up of 12 months, the addition of a GLP‐1RA was associated with lower rates of the primary outcome of MAKE (HR 0.70; 95% CI 0.65–0.74; p < 0.001) compared with SGLT2i monotherapy. Combination therapy was also associated with lower risks of MACE (HR 0.83; 95% CI 0.78–0.87) and all‐cause mortality (HR 0.55; 95% CI 0.50–0.61). Benefits were consistent across CKD stages and diabetes status, with significantly more pronounced effects observed in patients with obesity, heart failure, and ischemic heart disease. Combination therapy was associated with increased gastrointestinal symptoms, genital infections, and retinopathy progression, but lower risks of volume‐depletion events and acute kidney injury. Conclusions In this real‐world CKD cohort, GLP‐1RA added to SGLT2i therapy was associated with substantial incremental reductions in kidney disease progression and cardiovascular events. These findings suggest an additive cardiorenal benefit, particularly in patients with obesity, supporting the evaluation of combination therapy in future randomised trials.