Abstract Details

Title Synergistic and Distinct Central Effects of Dapagliflozin and Exenatide on Brain Networks Intrinsic Connectivity in Obesity and Type 2 Diabetes: A Randomized Controlled Trial

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P1 - Poster Session 1 (8:00 AM-9:00 AM)

Poster/Presentation
Number 13-001

Objective To investigate the separate and combined effects of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide and the sodium-glucose cotransporter-2 inhibitor (SGLT2i) dapagliflozin on resting-state functional connectivity (rs-FC) of cerebral networks that regulate body weight and eating behavior in patients with obesity and type 2 diabetes (T2DM).

Background Neural dysregulation of appetite and reward contributes to obesity and T2DM. GLP-1RAs and SGLT2is improve metabolic outcomes and interact with distinct brain circuits, but their effects on the intrinsic connectivity of appetite- and reward-related networks have remained incompletely characterized.

Design/Methods In this 16-week, randomized, double-blind, placebo-controlled trial (1:1:1:1 ratio), 57 participants with T2DM and obesity (mean age 63±7 years; 72% male) received dapagliflozin 10mg, exenatide 10µg BID, combination therapy, or double placebo. Resting-state fMRI was obtained at baseline, 10 days, and 16 weeks. Voxel-wise, family-wise error (FWE)-corrected analyses compared groups vs. placebo, and connectivity changes were correlated with anthropometric and metabolic outcomes.

Results At baseline, there were no differences in connectivity. At 10 days, dapagliflozin reduced connectivity in the ventral tegmental area within the limbic network (P_FWE<0.05), correlating with weight loss (ρ=0.29, P=0.026). Combination therapy increased connectivity in the right middle frontal gyrus within the mouth sensorimotor network (P_FWE<0.05; ρ=–0.27, P=0.045), fully mediating body fat reduction (b=–0.252, 95% CI [–0.535, –0.0054]). At 16 weeks, exenatide increased right anterior cingulate cortex connectivity within the subgenual reward network (P_FWE<0.05), linked to reductions in HbA1c (ρ=–0.46, P=0.013) and body fat percent (ρ=–0.33, P=0.013). The combination group showed lower right hippocampal limbic intrinsic connectivity (P_FWE<0.05), correlating with greater weight loss (ρ=0.31, P=0.019).

Conclusions Dapagliflozin and exenatide exert distinct yet complementary central effects. While dapagliflozin initially attenuates “bottom-up” midbrain-limbic reward signaling, exenatide later enhances “top-down” cortical control of behavior. Combination therapy synchronously modulates the mouth sensorimotor and limbic circuits, targeting multiple components of eating behavior, thus promote weight loss and metabolic improvement.

Authors/Disclosures
Jonadab Dos Santos Silva, MD, PhD PRESENTER	Dr. Dos Santos Silva has nothing to disclose.
Charlotte van Ruiten (Amsterdam University Medical Center, Vrije University Medical Center (VUmc))	No disclosure on file
Richard IJzerman, MD, PhD	Dr. IJzerman has nothing to disclose.
Eelco van Duinkerken, PhD	Mr. van Duinkerken has nothing to disclose.

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