Limited Impact of Sodium-Glucose Cotransporter-2 Inhibitors on Appetite and Body Weight: Evidence From Clinical and Rodent Studies

Background: The effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on appetite and food intake remains unclear. This study investigated the effects of SGLT2 inhibitors on appetite, food craving, and body weight in patients with type 2 diabetes and diabetic rat models. Methods: Thirty-four participants were randomized to receive either dapagliflozin or sitagliptin for 24 weeks. The primary endpoint was body weight changes from baseline; secondary outcomes included food intake, appetite and related hormone changes, and glycemic control. For rodent study, Otsuka Long-Evans Tokushima Fatty (OLETF) rats treated with empagliflozin for 12 weeks to evaluate chronic effect on food intake and appetite-related gene expression. Results: Weight reduction in the dapagliflozin group was lower than expected, with a 1.99 kg difference at 24 weeks (P < 0.001). Leptin levels significantly decreased in the dapagliflozin group, but food intake and appetite scores showed no differences between the groups. Consistent with the human study, food intake at 12 weeks of empagliflozin treatment in OLETF rats showed no difference from the controls, while increased intake during the first 3 weeks in the empagliflozin group. Conclusion: Sustained SGLT2 inhibitor treatment does not cause compensatory appetite increase after weight stabilization. Furthermore, it does not stimulate appetite or affect appetite-regulating molecules, thereby supporting its metabolic safety with respect to energy intake. This finding suggests that less-than-expected weight loss with SGLT2 inhibitors may result from mechanisms other than sustained changes in appetite or food intake.