A Four‐Week Treatment With Dapagliflozin Is Associated With a Reduction in Insulin‐Stimulated Renal Cortical Glucose Uptake: A Post Hoc Analysis From a Pilot Study

Introduction and objective: Treatment with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) reduces the risk of both cardiovascular and renal outcomes in type 2 diabetes (T2D). The specific mechanism by which this happens has not yet been clarified. Recent findings indicate that, in obese individuals, the kidney exhibits lower 18-fluorodeoxyglucose ([18F]-FDG) uptake rates compared to lean individuals, possibly due to insulin resistance. This post hoc analysis from our pilot study DAPAHeart aims to evaluate changes in cortical renal [18F]-FDG uptake in T2D patients following short-term treatment with dapagliflozin. Methods: In our DAPAHeart trial, a single-centre, 4-week, prospective, double-blind, controlled study, we enrolled T2D patients with stable coronary artery disease and preserved glomerular filtration rates. Participants were randomly assigned in a 1:1 ratio to receive either dapagliflozin (10 mg daily) or a placebo. PET scans using [18F]-FDG were performed during a hyperinsulinemic-euglycemic clamp (HEC) to measure regional FDG uptake before and after the 4-week treatment with SGLT-2i. Results: After 4 weeks of treatment, the between-group comparison (Mann-Whitney U test on change-from-baseline values) did not reach statistical significance for any SUV parameter. Nevertheless, a consistent directional pattern in renal standardised uptake value (SUV) was noted across all parameters, with reductions observed in the dapagliflozin group and stable or slightly increased values in the placebo group. The within-group analysis revealed a significant reduction in SUV_peak in the dapagliflozin group (p = 0.028), while no significant change was detected in the placebo group. Conclusion: Although the primary between-group comparison did not reach statistical significance, likely due to the limited sample size (n = 7 per group), a consistent directional pattern was observed across all renal SUV parameters, with reductions in the dapagliflozin group and stable or slightly increased values in the placebo group. These findings suggest decreased glucose uptake in an insulin-stimulated state (HEC) in the dapagliflozin group. Although the causes of this reduction require further investigation, these preliminary findings support the hypothesis that SGLT-2 inhibition may reduce tubular energy requirements and glucose uptake, potentially contributing to the preservation of kidney function.