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

Abstract

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.

Combating the dual burden: therapeutic targeting of common pathways in obesity and type 2 diabetes

“…Although substantial progress has been achieved in preclinical studies, the putative success and safety of coagonist therapy for the treatment of patients with obesity and T2DM remains uncertain and requires extensive additional clinical validation 110 . Another potential future option is a SGLT-2 inhibitor/GLP1-RA combination in an attempt to weaken the compensatory "overeating" mechanism observed with SGLT-2 inhibition 91 .…”

Weight Management in Type 2 Diabetes: Current and Emerging Approaches to Treatment

“…Although increased glucose excretion contributes to the weight loss observed with SGLT2 inhibitor treatment, weight reduction is often limited to ,4 kg after even 52 weeks of treatment (55). This attenuation of weight loss may occur because SGLT2 inhibitor-induced glycosuria is accompanied by compensatory hyperphagia, as demonstrated in animal studies (63) and suggested by human studies (64,65 59 kg) (55,66). When used in combination therapy, dapagliflozin and canagliflozin were associated with an increased risk of genital tract infections, whereas dapagliflozin was also associated with a modest increased risk of UTI.…”

Age-related changes in the diurnal variation of ketogenesis in patients with type 2 diabetes and relevance to hypoglycemic medications

“…However, it is obvious that strict carbohydrate restriction up-regulates lipolysis and ketogenesis. Similarly, the administration of an SGLT-2 inhibitor, which enhances urinary glucose excretion, resulted in a carbohydrate shortage and increased ketogenesis in rats [33]. Therefore, ketogenesis has a greater physiological and pathological effect on patients with a low-carbohydrate diet and those who are given SGLT-2 inhibitors.…”