Effects of SGLT2 inhibition and GLP-1 receptor agonism on the regulation of food intake and body weight: illuminating the role of the brain

Previous studies found that people with obesity and type 2 diabetes, compared with lean individuals, have increased brain responses to food pictures, and reduced brain activation in response to the actual receipt of food, which results in more craving for food, while the receipt of food is less rewarding, which contributes to overeating. This thesis provides evidence that SGLT2 inhibitors can affect the central regulation of food intake in people with obesity and type 2 diabetes. We found that dapagliflozin further increased brain activation in areas regulating satiety and reward in response to food cues, paralleled by increases in carbohydrate intake and appetite scores. Together, this may contribute to the difference between observed and expected weight loss with SGLT2i treatment. This thesis confirmed previous findings that GLP-1RAs alters food-related brain responses after short-term treatment. Interestingly, we also found these GLP-1RA effects on the brain after 16 weeks of treatment. Importantly, when exenatide was combined with dapagliflozin, the dapagliflozin-induced increase in brain responses to food cues after 10 days, was not observed anymore, and after 16 weeks, even a reduced brain activation in response to food cues was observed, which may contribute to more weight loss with the combination of SGLT2i and GLP-1RA. In response to low-calorie food pictures, dapagliflozin was associated with reduced brain activation, exenatide with increased brain activation, while the combination of both showed no effect on brain activation. This suggest that that the possible induced hyperphagia with dapagliflozin treatment may be specific for high-calorie/sweet foods. This may have clinical consequences as a specific decreased preference for low-calorie foods, in combination with the previously found preference for high-calorie foods, may hamper the weight loss of SGLT2i. Eating behavior, especially emotional eating, and to a lesser extent external eating, was associated with a reduced efficacy of GLP-1RA treatment effect on brain activation, whereas restraint eating was associated with increased efficacy of GLP-1RA treatment. Eating behavior may be assessed if weight loss with GLP-1RA treatment is less than expected. The dapagliflozin-induced plasma volume contraction contributes to the measured blood pressure reduction after short-term treatment, while a reduction in SNS activity may contribute to longer-term blood pressure reduction. Combination therapy with dapagliflozin and exenatide resulted in the largest decrease in blood pressure. However, as the effect on plasma volume was comparable to dapagliflozin monotherapy, and SNS activity was not reduced, other mechanisms are likely to contribute to the blood pressure lowering effect of this combination, and needs further investigation. The combination of exenatide and dapagliflozin resulted in a larger reduction in albuminuria, eGFR, KIM-1, and metabolic risk factors compared to either therapy alone or placebo. Together, these findings provide further insight in the appetite and weight lowering mechanisms, mechanisms underlying the blood pressure, and kidney effects of SGLT2i and GLP-1RAs alone and in combination, and may lead to further development of treatment strategies for obesity and type 2 diabetes.