REAL-WORLD EFFECTIVENESS OF SEMAGLUTIDE AND SGLT-2I VS SGLT-2I ALONE ON KIDNEY AND CARDIOVASCULAR OUTCOMES IN PEOPLE WITH TYPE 2 DIABETES AND CHRONIC KIDNEY DISEASE

Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have both been shown to reduce the risk for clinically important kidney and cardiovascular outcomes in people with type 2 diabetes (T2D) and chronic kidney disease (CKD). Combination of these medications may provide additive benefits, but evidence is limited. This target trial emulation study aimed to investigate the potential additive effects of semaglutide and SGLT-2i vs SGLT-2i alone on kidney and cardiovascular outcomes in a real-world setting.

The Komodo Research Database (U.S. claims data linked with clinical and laboratory measurements; data cut: 2016–2024) was used to emulate a hypothetical target trial investigating the comparative effectiveness of semaglutide + SGLT-2i vs SGLT-2i alone, both on top of standard of care (defined as a renin-angiotensin system inhibitor and a glucose-lowering medication) in patients with a diagnosis of T2D and CKD (defined by an estimated glomerular filtration rate [eGFR] >25 and <60 mL/min/1.73m2). The primary outcome was major kidney disease events a composite of the onset of ≥40% reduction in eGFR from baseline, an eGFR <15 mL/min/1.73 m2, initiation of kidney replacement therapy (dialysis or kidney transplantation), or all-cause death. Secondary outcomes included 3-point major adverse cardiovascular events (3P-MACE, comprising nonfatal myocardial infarction, nonfatal stroke and all-cause death), hospitalization for heart failure, and all-cause death. Using a sequential trial design, patients were followed for 1 year, or until the occurrence of an outcome, treatment discontinuation, or end of the study period (31 December 2024), whichever occurred first. Targeted learning, specifically a sequential doubly robust estimator, coupled with an ensemble of parametric and data-adaptive machine learning models (super learning) was used to estimate the average treatment effect and adjust for 55 baseline and time-varying confounders. Missing covariate information was imputed using multiple imputations with chained equations. A range of subgroup and sensitivity analyses were performed.

Overall, 146,787 people were included, of which 8,718 (6.0%) were treated with semaglutide + SGLT-2i and 136,405 (94.0%) with SGLT-2i only at baseline. The median follow-up time for the primary outcome was 0.7 years (interquartile range: 0.3, 1.0). The adjusted 1-year risk of major kidney disease events was significantly lower with semaglutide + SGLT-2i (6.5%) vs SGLT-2i only (7.5%) (risk ratio [RR], 0.87 [95% CI: 0.85, 0.90], p<0.001) (Figure 1 and Table 1). A similar pattern was observed for the secondary endpoints 3P-MACE (2.7% vs 3.7%; RR, 0.74 [0.71, 0.77], p<0.001), hospitalization for heart failure (2.1% vs 2.9%; RR 0.74 [0.71, 0.77], p<0.001) and all-cause death (1.5% vs 2.0%; RR 0.75 [0.71, 0.79], p<0.001). In pre-specified sensitivity analyses, results were consistent when extending the follow-up to 2 years (risk ratio for primary outcome, 0.84 [0.82, 0.86], p<0.001) (Table 2). Negative control outcome analyses indicated no unmeasured confounding (RR for any fractures, 1.02 [0.95, 1.11], p=0.49).

This study suggests that combination therapy with semaglutide + SGLT-2i provides kidney and cardiovascular benefits compared with SGLT-2i alone among people with T2D and CKD.