Early changes in renal function do not appear to mediate cardiovascular risk with dapagliflozin plus semaglutide: a real-world observational hypothesis-generating cohort study.

BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome links heart failure (HF), myocardial infarction (MI), kidney disease, diabetes, and obesity. SGLT2 inhibitors and GLP-1 receptor agonists improve cardiovascular and renal outcomes, but mechanisms underlying combination therapy remain uncertain. We assessed whether early changes in estimated glomerular filtration rate (ΔeGFR) mediate the association between dapagliflozin plus semaglutide and HF/MI-related outcomes. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study of 376 adults prescribed dapagliflozin, with or without semaglutide, at a Saudi tertiary hospital (2020-2024). Inverse probability of treatment weighting and causal mediation analysis evaluated whether ΔeGFR mediated treatment-outcome associations during 90-365days of follow-up. RESULTS: Combination therapy was not associated with a statistically significant difference in recorded HF/MI-related clinical status (adjusted RR 0.787; 95% bootstrap CI 0.320-1.813;  = 0.516). ΔeGFR showed minimal mediation (indirect RR 1.013; 95% CI 0.901-1.165). IPTW analyses yielded similar neutral findings (composite RR 1.12; 95% CI 0.47-2.66). CONCLUSIONS: Early ΔeGFR showed little evidence of mediating HF/MI-related risk differences between combination therapy and dapagliflozin alone. Because outcomes were not independently adjudicated, these secondary findings are exploratory. Larger prospective studies are needed.