Weight Loss Induced by Chronic Dapagliflozin Treatment Is Attenuated by Compensatory Hyperphagia in Diet‐Induced Obese (DIO) Rats

Dapagliflozin is a potent and selective sodium glucose cotransporter‐2 (SGLT2) inhibitor which promotes urinary glucose excretion and induces weight loss. Since metabolic compensation can offset a negative energy balance, we explored the potential for a compensatory physiological response to the weight loss induced by dapagliflozin. Dapagliflozin was administered (0.5–5 mpk; p.o.) to diet‐induced obese (DIO) rats with or without ad libitum access to food for 38 days. Along with inducing urinary glucose excretion, chronic administration of dapagliflozin dose‐dependently increased food and water intake relative to vehicle‐treated controls. Despite this, it reduced body weight by 4% (relative to controls) at the highest dose. The degree of weight loss was increased by an additional 9% if hyperphagia was prevented by restricting food intake to that of vehicle controls. Neither oxygen consumption (vO2) or the respiratory exchange ratio (RER) were altered by dapagliflozin treatment alone. Animals treated with dapagliflozin and pair‐fed to vehicle controls (5 mpk PF‐V) showed a reduction in RER and an elevation in nonfasting β‐hydroxybutyrate (BHBA) relative to ad libitum‐fed 5 mpk counterparts. Fasting BHBA was elevated in the 1 mpk, 5 mpk, and 5 mpk PF‐V groups. Serum glucose was reduced in the fasted, but not the unfasted state. Insulin was reduced in the non‐fasted state. These data suggest that in rodents, the persistent urinary glucose excretion induced by dapagliflozin was accompanied by compensatory hyperphagia, which attenuated the weight loss induced by SGLT2 inhibition. Therefore, it is possible that dapagliflozin‐induced weight loss could be enhanced with dietary intervention.