TY - JOUR
T1 - Combination therapy with exenatide decreases the dapagliflozin-induced changes in brain responses to anticipation and consumption of palatable food in patients with type 2 diabetes
T2 - A randomized controlled trial
AU - van Ruiten, Charlotte C.
AU - Veltman, Dick J.
AU - Wijdeveld, Madelief
AU - ten Kulve, Jennifer S.
AU - Kramer, Mark H.H.
AU - Nieuwdorp, Max
AU - IJzerman, Richard G.
N1 - Funding Information: This work was funded by an investigator initiated grant from AstraZeneca (ESR‐16‐11865). The funder had no role in the study design, data analyses or interpretation, or drafting of the manuscript, nor in the decision to submit the manuscript for publication. Funding information Funding Information: information This work was funded by an investigator initiated grant from AstraZeneca (ESR-16-11865). The funder had no role in the study design, data analyses or interpretation, or drafting of the manuscript, nor in the decision to submit the manuscript for publication.The authors thank Ton Schweigmann (Department of Radiology and Nuclear Medicine, VU University Medical Center) Renée de Meijer, Jeanette Boerop and Ingrid Knuffman for their assistance during the test visits, as well as the participants in this study. Funding Information: RGIJ is principal investigator of studies sponsored by research grants from AstraZeneca, Eli Lilly & Co. and Novo Nordisk. Trough MHHK, the Amsterdam University Medical Center, location VUmc, received research grants from AstraZeneca, Boehringer Ingelheim, Novo Nordisk and Sanofi‐Aventis. MN is supported by a personal ZONMW VICI grant 2020 [09150182010020] and received an unrestricted grant from AstraZeneca and serves on the Scientific Advisory Board of Caelus Pharmaceuticals, the Netherlands and Kaleido, USA. All authors declare they have not received any fees personally in connection with the roles described above, as all honoraria were paid to their employer (Amsterdam University Medical Center, location VUmc). No other potential conflicts of interest relevant to this article are reported. CCvR, DJV, MW and JStK declare that they have no competing interests. Publisher Copyright: © 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.
PY - 2022/8
Y1 - 2022/8
N2 - Aims: Sodium-glucose cotransporter-2 inhibitors induce less weight loss than expected. This may be explained by sodium-glucose cotransporter-2 inhibitor-induced alterations in central reward- and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists reduce appetite and body weight because of direct and indirect effects on the brain. We investigated the separate and combined effects of dapagliflozin and exenatide on the brain in response to the anticipation and consumption of food in people with obesity and type 2 diabetes. Materials and Methods: As part of a larger study, this was a 16 week, double-blind, randomized, placebo-controlled trial. Subjects with obesity and type 2 diabetes were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice-daily 10 μg with dapagliflozin-matched placebo, dapagliflozin plus exenatide, or double placebo. Using functional magnetic resonance imaging, the effects of treatments on brain responses to the anticipation of food and food receipt were assessed after 10 days and 16 weeks. Results: After 10 days, dapagliflozin increased activation in right amygdala and right caudate nucleus in response to the anticipation of food, and tended to decrease activation in right amygdala in response to actual food receipt. After 16 weeks, no changes in brain activation were observed with dapagliflozin. Dapagliflozin plus exenatide reduced activation in right caudate nucleus and amygdala to the anticipation of food, and decreased activation in the right amygdala in response to food receipt after 16 weeks. Conclusions: The dapagliflozin-induced changes in brain activation may contribute to the discrepancy between observed and expected weight loss with dapagliflozin. Exenatide blunted the dapagliflozin-induced changes in brain activation, which may contribute to the additional weight loss with combined treatment.
AB - Aims: Sodium-glucose cotransporter-2 inhibitors induce less weight loss than expected. This may be explained by sodium-glucose cotransporter-2 inhibitor-induced alterations in central reward- and satiety circuits, leading to increased appetite and food intake. Glucagon-like peptide-1 receptor agonists reduce appetite and body weight because of direct and indirect effects on the brain. We investigated the separate and combined effects of dapagliflozin and exenatide on the brain in response to the anticipation and consumption of food in people with obesity and type 2 diabetes. Materials and Methods: As part of a larger study, this was a 16 week, double-blind, randomized, placebo-controlled trial. Subjects with obesity and type 2 diabetes were randomized (1:1:1:1) to dapagliflozin 10 mg with exenatide-matched placebo, exenatide twice-daily 10 μg with dapagliflozin-matched placebo, dapagliflozin plus exenatide, or double placebo. Using functional magnetic resonance imaging, the effects of treatments on brain responses to the anticipation of food and food receipt were assessed after 10 days and 16 weeks. Results: After 10 days, dapagliflozin increased activation in right amygdala and right caudate nucleus in response to the anticipation of food, and tended to decrease activation in right amygdala in response to actual food receipt. After 16 weeks, no changes in brain activation were observed with dapagliflozin. Dapagliflozin plus exenatide reduced activation in right caudate nucleus and amygdala to the anticipation of food, and decreased activation in the right amygdala in response to food receipt after 16 weeks. Conclusions: The dapagliflozin-induced changes in brain activation may contribute to the discrepancy between observed and expected weight loss with dapagliflozin. Exenatide blunted the dapagliflozin-induced changes in brain activation, which may contribute to the additional weight loss with combined treatment.
KW - GLP-1 receptor agonist
KW - SGLT2 inhibitor
KW - central regulation of appetite
KW - dapagliflozin
KW - exenatide
KW - functional neuroimaging
KW - obesity
KW - type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85130334363&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/dom.14732
DO - https://doi.org/10.1111/dom.14732
M3 - Article
C2 - 35491524
SN - 1462-8902
VL - 24
SP - 1588
EP - 1597
JO - Diabetes, Obesity and Metabolism
JF - Diabetes, Obesity and Metabolism
IS - 8
ER -