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

Charlotte C. van Ruiten; Dick J. Veltman; Anouk Schrantee; Liselotte van Bloemendaal; Frederik Barkhof; Mark H. H. Kramer; Max Nieuwdorp; Richard G. IJzerman

Disclosures

J Clin Endocrinol Metab. 2022;107(6):e2590-e2599. 

In This Article

Abstract and Introduction

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.

Introduction

The central nervous system (CNS) is the key regulator of food intake, as it receives and integrates a variety of hedonic, environmental, and homeostatic signals to produce an overall response of hunger or satiety. Altered brain reward responses to food stimuli may promote excessive eating, resulting in obesity and eventually type 2 diabetes.[1,2]

Functional magnetic resonance imaging (fMRI) can be used to noninvasively measure patterns of brain activity in response to specific stimuli. fMRI detects the blood-oxygen-level-dependent (BOLD) signal, which reflects changes in deoxyhemoglobin, driven by localized changes in cerebral blood flow and blood oxygenation, which are coupled to underlying neuronal activity (neurovascular coupling).[3] Task-based fMRI identifies brain regions that are functionally involved in specific task performance, for instance, presenting food pictures provides information about regions involved in the process of food evaluation. Although this is a reliable and widely used method, processing these cues involves a complex interconnected circuitry, and it is common that not all regions are simultaneously activated to a similar extent.

Studies using fMRI of the CNS found that compared with lean subjects, obese subjects with and without type 2 diabetes, have increased activation in reward processing areas such as the insula, striatum, and amygdala, in response to visual food cues.[4,5] These increased activations predict less weight loss during weight loss programs and predict future weight (re)gain.[6–8] The insula (taste perception, decision making, and interoception), limbic-striatal system (reward motivation), and the prefrontal and orbitofrontal cortex (reward evaluation and decision making) are part of a complex interconnected reward circuitry, and these areas are consistently shown to be involved in response to food cues).[5,9–14]

Because lifestyle-based weight loss strategies are often not effective in the long term, pharmacological approaches to assist weight loss are important. Two recently introduced drug classes for treatment of type 2 diabetes are sodium-glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs). Besides their effects on glucose regulation, both therapies are known to reduce body weight.[15,16]

The SGLT2is improve glycemic control in an insulin-independent manner by blocking glucose reabsorption in the renal proximal tubule, thereby enhancing urinary glucose excretion. Urinary glucose excretion induces chronic calorie loss, which leads to body weight reduction. However, the observed weight loss is consistently less than expected from the amount of urinary glucose excretion.[17,18] Around 50 to 85 g glucose per day, equivalent to ~ 300 kcal/day (1200 kJ/day), is excreted daily in SGLT2i treated patients with type 2 diabetes, which would result in a weight loss of ~7 to 10 kg in a year. However, observed weight loss with SGLT2is is only ~2 to 3 kg.[16] As studies showed that acute or chronic treatment with an SGLT2i does not alter energy expenditure,[17,18] the discrepancy between observed and expected weight loss implies that patients increased their energy intake. These findings are supported by studies in animals that showed compensatory hyperphagia in response to SGLT2 inhibition,[19,20] but studies in humans have not been performed. In order to optimize treatment, it is important to investigate this issue in humans and understand the mechanisms whereby SGLT2is might influence appetite regulation and food intake.

In addition to the effects of GLP-1RAs on glucose regulation, they also substantially reduce body weight.[15] The weight loss is mainly attributable to suppressed appetite signaling in the brain and increased satiety, which leads to a reduced food intake, via direct and indirect actions on the CNS.[13,21] Due to their effects on the CNS, adding a GLP-1RA to an SGLT2i may have beneficial effects, resulting in reduced food intake and greater reductions in body weight.[22] Three large studies showed that when GLP-1RAs are added to SGLT2is, the reductions in body weight loss and glucose were larger than with either therapy alone.[23–25] In addition, liraglutide blunted the SGLT2i-induced hyperphagia in rats.[20] Therefore, it could be suggested that the possible increased food intake during treatment with SGLT2i, may be prevented by GLP-1RAs via effects on the CNS. However, the effects of adding a GLP-1RA to an SGLT2i on central satiety and reward circuits and food intake in humans are unknown.

We thus investigated if treatment with the SGLT2i dapagliflozin induces alterations in central reward and satiety circuits in response to food-related stimuli in obese patients with type 2 diabetes. In addition, we investigated if adding the GLP-1RA exenatide to dapagliflozin could block this SGLT2i-induced increase in neuronal activity in a priori defined central reward and satiety centers in response to food-related stimuli. Additionally, we investigated the separate and combined effects of dapagliflozin and exenatide on food intake and appetite.

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