Effects of Dapagliflozin and Combination Therapy With Exenatide on Food-Cue Induced Brain Activation in Patients With Type 2 Diabetes.

Abstract

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.

• Authors: Charlotte C van Ruiten, Dick J Veltman, Anouk Schrantee, Liselotte van Bloemendaal, Frederik Barkhof, Mark H H Kramer, Max Nieuwdorp, Richard G IJzerman
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 107 Issue 6 Pg. e2590-e2599 (05 17 2022) ISSN: 1945-7197 [Electronic] United States
• PMID: 35134184 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.

Chemical References

• Benzhydryl Compounds
• Blood Glucose
• Glucosides
• Glycated Hemoglobin A
• Hypoglycemic Agents
• Sodium-Glucose Transporter 2 Inhibitors
• dapagliflozin
• Exenatide

Topics

• Benzhydryl Compounds
• Blood Glucose
• Brain (diagnostic imaging)
• Cues
• Diabetes Mellitus, Type 2 (complications, drug therapy)
• Double-Blind Method
• Exenatide
• Glucosides
• Glycated Hemoglobin (analysis)
• Humans
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Middle Aged
• Obesity (complications, drug therapy)
• Sodium-Glucose Transporter 2 Inhibitors (therapeutic use)
• Weight Loss