Context: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) cause less weight loss than expected based on urinary calorie excretion. This may be explained by SGLT2i-induced alterations in central reward and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists are associated with reduced appetite and body weight, mediated by direct and indirect central nervous system (CNS) effects. Objective: We investigated the separate and combined effects of dapagliflozin and exenatide on the CNS in participants with obesity and type 2 diabetes. Methods: This was a 16-week, double-blind, randomized, placebo-controlled trial. Obese participants with type 2 diabetes (n = 64, age 63.5 ± 0.9 years, BMI 31.7 ± 0.6 kg/m2) were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice daily 10 μg with dapagliflozin-matched placebo, dapagliflozin and exenatide, or double placebo. Using functional MRI, the effects of treatments on CNS responses to viewing food pictures were assessed after 10 days and 16 weeks of treatment. Results: After 10 days, dapagliflozin increased, whereas exenatide decreased CNS activation in the left putamen. Combination therapy had no effect on responses to food pictures. After 16 weeks, no changes in CNS activation were observed with dapagliflozin, but CNS activation was reduced with dapagliflozin-exenatide in right amygdala. Conclusion: The early increase in CNS activation with dapagliflozin may contribute to the discrepancy between observed and expected weight loss. In combination therapy, exenatide blunted the increased CNS activation observed with dapagliflozin. These findings provide further insights into the weight-lowering mechanisms of SGLT2i and GLP-1 receptor agonists.
Original languageEnglish
Pages (from-to)E2590-E2599
JournalJournal of clinical endocrinology and metabolism
Issue number6
Publication statusPublished - 1 Jun 2022


  • GLP-1 receptor agonist
  • SGLT2 inhibitor
  • body weight
  • central nervous system
  • dapagliflozin
  • exenatide
  • functional neuroimaging
  • obesity
  • satiety and reward circuits
  • type 2 diabetes

Cite this