title: 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.
  
  
  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.
authors.affiliation: General Medicine, San Lazzaro Hospital, Alba, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ferrannini
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hach
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Crowe
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Arjun
authors.initials: A
authors.lastname: Sanghvi
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Hall
authors.affiliation: CNR Institute of Clinical Physiology, Pisa, Italy ferranni@ifc.cnr.it.
authors.forename: Ele
authors.initials: E
authors.lastname: Ferrannini
mesh_terms: D000328:Adult; D001559:Benzhydryl Compounds / Q000008:administration & dosage*; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D005960:Glucosides / Q000008:administration & dosage*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism*; D015431:Weight Loss / Q000187:drug effects
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; C570240:empagliflozin