Effects of semaglutide and dapagliflozin on natriuretic peptides in type 2 diabetes: a randomized comparative study

Background/Introduction Type 2 diabetes (T2D) is associated with a substantially increased risk of heart failure, partly mediated by myocardial stress and neurohormonal activation. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) both improve cardiovascular outcomes in T2D, but their comparative effects on heart failure and cardiac stress pathways remain incompletely understood. Purpose To compare the longitudinal effects of the GLP-1 RA semaglutide and the SGLT2i dapagliflozin on plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations in patients with T2D. NT-proBNP is a well-established biomarker of myocardial wall stress and prognostic risk. Methods Post hoc analysis of a prospective, open-label randomised clinical trial that recruited participants between 2020 and 2022 and followed them for 6 months. NT-proBNP was measured in blood samples collected at baseline and after 6 months. Participants with type 2 diabetes on metformin monotherapy, recruited at a single centre, were randomised in a 1:1 ratio to treatment with semaglutide or dapagliflozin. Changes over time in NT-proBNP were analysed using Tobit regression to account for left-censoring. Between-group differences were assessed using mixed-effects models adjusted for relevant covariates. Results A total of 75 participants received semaglutide and 92 received dapagliflozin (mean age 66 years; 31% women; mean HbA1c 53 mmol/mol). Baseline NT-proBNP levels were overall low (median 77 ng/L, interquartile range 55–138) and below the limit of quantification in 25% of participants. During the 6-month follow-up, NT-proBNP declined significantly by 7% in the semaglutide group (p=0.01), whereas it increased by 20% in the dapagliflozin group (p=0.07). A significant time-by-treatment interaction was observed, indicating that the magnitude of change in NT-proBNP differed between the treatment groups. Conclusions In patients with T2D without heart failure, treatment with semaglutide but not dapagliflozin was associated with a reduction in NT-proBNP over 6 months, independent of renal function, body mass index, and other known determinants of NT-proBNP. These findings suggest that glucose-lowering therapies may exert distinct influences on myocardial stress pathways, with potential implications for heart failure risk modulation.NT-proBNP levels at baseline and follow-up.Longitudinal trajectories by treatment group.