title: Compensatory changes in energy balance during dapagliflozin treatment in type 2 diabetes mellitus: a randomised double-blind, placebo-controlled, cross-over trial (ENERGIZE)-study protocol.
abstract: Sodium glucose cotransporter 2 (SGLT2) inhibitors are effective blood-glucose-lowering medications with beneficial effects on body weight in patients with type 2 diabetes mellitus (T2DM). However, observed weight loss is less than that predicted from quantified glycosuria, suggesting a compensatory increase in energy intake or a decrease in energy expenditure. Studies using dual-energy X-ray absorptiometry (DEXA) have suggested most body weight change is due to loss of adipose tissue, but organ-specific changes in fat content (eg, liver, skeletal muscle) have not been determined. In this randomised, double-blind, placebo-controlled crossover study, we aim to study the compensatory changes in energy intake, eating behaviour and energy expenditure accompanying use of the SGLT2 inhibitor, dapagliflozin. Additionally, we aim to quantify changes in fat distribution using MRI, in liver fat using proton magnetic resonance spectroscopy (1H-MRS) and in central nervous system (CNS) responses to food images using blood oxygen level dependent (BOLD) functional MRI (fMRI).
  
  
  
  This outpatient study will evaluate the effect of dapagliflozin (10 mg), compared with placebo, on food intake and energy expenditure at 7 days and 12 weeks. 52 patients with T2DM will be randomised to dapagliflozin or placebo for short-term and long-term trial interventions in a within participants, crossover design. The primary outcome is the difference in energy intake during a test meal between dapagliflozin and placebo. Intake data are collected automatically using a customised programme operating a universal eating monitor (UEM). Secondary outcomes include (1) measures of appetite regulation including rate of eating, satiety quotient, appetite ratings (between and within meals), changes in CNS responses to food images measured using BOLD-fMRI, (2) measures of energy expenditure and (3) changes in body composition including changes in liver fat and abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT).
  
  
  
  This study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/0340) and is conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice (GCP).
  
  
  
  ISRCTN14818531. EUDRACT number 2013-004264-60.
authors.affiliation: Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.|Diabetes and Endocrinology Research Group, Clinical Sciences Centre, Aintree University Hospital NHS Foundation Trust, Liverpool, UK.
authors.forename: Surya Panicker
authors.initials: SP
authors.lastname: Rajeev
authors.affiliation: Diabetes and Endocrinology Research Group, Clinical Sciences Centre, Aintree University Hospital NHS Foundation Trust, Liverpool, UK.|Department of Musculoskeletal Biology II, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
authors.forename: Victoria S
authors.initials: VS
authors.lastname: Sprung
authors.affiliation: Department of Psychological Sciences, Institute of Psychology, Health and Society, University of Liverpool, Liverpool, UK.
authors.forename: Carl
authors.initials: C
authors.lastname: Roberts
authors.affiliation: Department of Psychological Sciences, Institute of Psychology, Health and Society, University of Liverpool, Liverpool, UK.
authors.forename: Jo A
authors.initials: JA
authors.lastname: Harrold
authors.affiliation: Department of Psychological Sciences, Institute of Psychology, Health and Society, University of Liverpool, Liverpool, UK.
authors.forename: Jason C G
authors.initials: JC
authors.lastname: Halford
authors.affiliation: Department of Psychological Sciences, Institute of Psychology, Health and Society, University of Liverpool, Liverpool, UK.
authors.forename: Andrej
authors.initials: A
authors.lastname: Stancak
authors.affiliation: Department of Psychological Sciences, Institute of Psychology, Health and Society, University of Liverpool, Liverpool, UK.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Boyland
authors.affiliation: Department of Musculoskeletal Biology II, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.|Magnetic Resonance and Image Analysis Research Centre (MARIARC), University of Liverpool, Liverpool, UK.
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Kemp
authors.affiliation: Diabetes and Endocrinology Research Group, Clinical Sciences Centre, Aintree University Hospital NHS Foundation Trust, Liverpool, UK.|Department of Musculoskeletal Biology II, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cuthbertson
authors.affiliation: Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.|Diabetes and Endocrinology Research Group, Clinical Sciences Centre, Aintree University Hospital NHS Foundation Trust, Liverpool, UK.
authors.forename: John P H
authors.initials: JP
authors.lastname: Wilding
mesh_terms: D000273:Adipose Tissue / Q000000981:diagnostic imaging / Q000473:pathology; D001559:Benzhydryl Compounds / Q000627:therapeutic use*; D001823:Body Composition; D050218:Body Fat Distribution; D001921:Brain / Q000000981:diagnostic imaging* / Q000503:physiopathology; D002153:Calorimetry, Indirect; D018592:Cross-Over Studies; D003463:Cues; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D004435:Eating; D004734:Energy Metabolism; D005247:Feeding Behavior; D005502:Food; D059907:Functional Neuroimaging; D005960:Glucosides / Q000627:therapeutic use*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D008099:Liver; D008279:Magnetic Resonance Imaging; D009929:Organ Size; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; C529054:dapagliflozin