Energy Balance After Sodium-Glucose Cotransporter 2 Inhibition

Abstract

Objective: Sodium-glucose cotransporter 2 (SGLT2) inhibitors cause substantially less weight loss than expected from the energy excreted via glycosuria. Our aim was to analyze this phenomenon quantitatively.

Research design and methods: Eighty-six patients with type 2 diabetes (HbA1c 7.8 ± 0.8% [62 ± 9 mmol/mol], estimated glomerular filtration rate [eGFR] 89 ± 19 mL ⋅ min(-1) ⋅ 1.73 m(-2)) received empagliflozin (25 mg/day) for 90 weeks with frequent (n = 11) assessments of body weight, eGFR, and fasting plasma glucose (FPG). Time-dependent glucose filtration was calculated as the product of eGFR and FPG; time-dependent glycosuria was estimated from previous direct measurements. The relation of calorie-to-weight changes was estimated using a mathematical model of human energy metabolism that simulates the time course of weight change for a given change in calorie balance and calculates the corresponding energy intake changes.

Results: At week 90, weight loss averaged -3.2 ± 4.2 kg (corresponding to a median calorie deficit of 51 kcal/day [interquartile range (IQR) 112]). However, the observed calorie loss through glycosuria (206 kcal/day [IQR 90]) was predicted to result in a weight loss of -11.3 ± 3.1 kg, assuming no compensatory changes in energy intake. Thus, patients lost only 29 ± 41% of the weight loss predicted by their glycosuria; the model indicated that this difference was accounted for by a 13% (IQR 12) increase in calorie intake (269 kcal/day [IQR 258]) coupled with a 2% (IQR 5) increase in daily energy expenditure (due to diet-induced thermogenesis). This increased calorie intake was inversely related to baseline BMI (partial r = -0.34, P < 0.01) and positively to baseline eGFR (partial r = 0.29, P < 0.01).

Conclusions: Chronic glycosuria elicits an adaptive increase in energy intake. Combining SGLT2 inhibition with caloric restriction is expected to be associated with major weight loss.

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Figures

Figure 1

Time course of FPG concentrations, eGFR, renal glucose filtration rate, and urinary glucose excretion rate in 86 patients with T2DM treated with empagliflozin (25 mg/day) for 90 weeks. Plots are mean ± SEM.

Figure 2

Time course of observed and predicted (by glycosuria) weight loss in men and women with T2DM treated with empagliflozin (25 mg/day) for 90 weeks. Plots are mean ± SEM.

Figure 3

Calculated rates of energy intake and TDEE in men and women with T2DM treated with empagliflozin (25 mg/day) for 90 weeks. Plots are mean ± SEM averaged over the indicated time intervals.