Energy Balance After Sodium–Glucose Cotransporter 2 Inhibition

Abstract

OBJECTIVESodium–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 METHODSEighty-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.RESULTSAt 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).CONCLUSIONSChronic glycosuria elicits an adaptive increase in energy intake. Combining SGLT2 inhibition with caloric restriction is expected to be associated with major weight loss.

Metabolic consequences of acute and chronic empagliflozin administration in treatment-naive and metformin pretreated patients with type 2 diabetes

“…Thus, both the Met and TN patients reproduced the complex metabolic adaptation to pharmacologically induced glycosuria that was observed in this cohort as a whole [20] and has also been reported for other members of the SGLT2 inhibitor class [21]. The compensatory increase in EGP that occurs with empagliflozin treatment may attenuate the reduction in hyperglycaemia that would be predicted from the increase in UGE, although increases in food intake may also contribute [33]. The observed shift in substrate oxidation from carbohydrate to fat is consistent with the weight loss that has been observed in clinical trials of empagliflozin [14].…”

Pharmacological Approaches in the Treatment and Maintenance of Weight Loss

“…This attenuation of weight loss may occur because SGLT-2 inhibitor-induced glycosuria is accompanied by compensatory hyperphagia, as demonstrated in animal studies (53) and suggested by human studies (59). A potential future option is a SGLT-2 inhibitor/GLP-1 receptor agonist combination (59). The effect of GLP-1 receptor agonists on satiety may weaken the compensatory "overeating" mechanism observed with SGLT-2 inhibition and enhance weight loss by SGLT-2 inhibitors (60).…”

“…While increased glucose excretion contributes to the weight loss observed with SGLT-2 inhibitor treatment, weight reduction is often limited to ,4 kg after even 52 weeks of treatment (54). This attenuation of weight loss may occur because SGLT-2 inhibitor-induced glycosuria is accompanied by compensatory hyperphagia, as demonstrated in animal studies (53) and suggested by human studies (59). A potential future option is a SGLT-2 inhibitor/GLP-1 receptor agonist combination (59).…”

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.…”