Table 1

Study inclusion and exclusion criteria

INCLUSION CRITERIA
  • Males or females, age 18–65 years.

  • A clinical diagnosis of type 2 diabetes.

  • Glycosylated haemoglobin (HbA1c) ≥6.5% but ≤11% (48–97 mmol/mol).

  • Currently treated with either diet or any combination of metformin, DPP-IV inhibitors* and sulfonylureas (excluding patients treated with pioglitazone or insulin). *DPP-IV inhibitors will require wash out period of 4 weeks.

  • BMI 30–50 kg/m2.

  • Patients who are receiving the following medications must be on stable treatment regimen for a minimum of 2 months prior to screening:

    • Thyroid hormone replacement

    • Antidepressants


EXCLUSION CRITERIA
Medical History and Concurrent Diseases
  • Type 1 diabetes mellitus.

  • History of diabetic ketoacidosis or hyperosmolar non-ketotic coma.

  • Renal impairment: eGFR less than 60 mL/min/1.73 m2.

  • Familial renal glucosuria.

  • Clinically significant abnormal free T4 or patients needing initiation or adjustment of thyroid treatment according to the investigator.

  • Severe uncontrolled hypertension ≥180 mm Hg and/or diastolic ≥110 mm Hg.

  • Congestive heart failure class III-IV.

  • Recent (<6 months) myocardial infarction.

  • Known chronic liver disease (other than hepatic steatosis).

  • Significant cardiac dysrhythmias (including pacemaker or ICD).

  • Previous stroke.

  • History of seizures or unexplained syncope.

  • History of, or currently have, acute or chronic pancreatitis.

  • History of malignancy (with the exception of basal and squamous cell carcinoma of the skin) within the last 5 years.

  • History of medullary thyroid carcinoma or MEN2 (Multiple endocrine neoplasia type 2) or family history of medullary thyroid carcinoma or MEN2.

  • History of gastric bypass surgery or gastric banding surgery, or either procedure is planned during the time period of the study.

  • Patient, who in the judgement of the investigator, may be at risk of dehydration or volume depletion (hypovolaemia) that may affect the patient’s safety and/or the interpretation of efficacy or safety data.

  • Presence of any other medical condition that would, in the opinion of the investigator or their clinician, preclude safe participation in the study. This decision should be informed by dapagliflozin and exenatide precautions for use statements which will be provided to all clinicians and the research team.

  • Alcohol consumption in excess of 21 units/week females, 28 units/week males.

  • Current smoker (including electronic cigarettes) or having ceased smoking in the last 6 months.

  • Any history of a pacemaker or implantable cardioverter defibrillator (ICD).

  • Patients with a history of diabetic foot ulcers or previous (lower limb) digital amputations.

  • Patients currently taking part in a structured weight loss programme such as weight watchers or slimming world (excluding those on weight management programmes as part of their diabetes care).

  • Patients who score over 4 restraint subscale of the Dutch Eating Behaviour Questionnaire.

  • Patients who score over 27 on the Binge Eating Scale.

Physical and Laboratory Test Findings
  • ALT>3×upper limit of normal (ULN).

  • AST>3×ULN.

  • Bilirubin>2×ULN.

  • Haemoglobin ≤10.5 g/dL (≤105 g/L) for men; haemoglobin ≤9.5 g/dL (≤95 g/L) for women.

  • History of unexplained microscopic or macroscopic haematuria at screening, confirmed by follow-up sample a next scheduled visit, where according to the investigator a satisfactory evaluation of haematuria has not been conducted.

  • Weight <60 kg and >200 kg (due to DEXA limitations).

  • BMI <30 kg/m2 and >50 kg/m2.

  • Recent major change in body weight (>3 kg loss or gain in preceding month).


Allergies and Adverse Drug Reactions
  • Subjects with a history of any serious hypersensitivity reaction to GLP1-RA or SGLT2 inhibitor.

  • Participant should have no allergies against metacresol (the preservative in insulin vial).

  • History of anaphylaxis to food.

  • Known food allergies or food intolerance.

  • Known hypersensitivity to heparin.

  • Known hypersensitivity to intravenous catheter equipment.


Sex and Reproductive Status
  • Females of childbearing age who are not using adequate contraceptive methods or who are planning a pregnancy in the next 44 weeks (study duration plus 12 weeks).

  • Women who are pregnant or breast feeding.

  • Sexually active fertile men not using effective birth control if their partners are WOCBP.


Prohibited Treatments and/or Therapies
  • Diabetes treated with pioglitazone, SGLT2 inhibitors, GLP-1 analogues or insulin.

  • Treatment with SGLT2 inhibitor, GLP1 RA or subcutaneous insulin injections 3 months before screening.

  • Any weight loss medication (eg, orlistat) within 3 months prior to screening.

  • Use of any drug that might affect body weight or appetite (including antipsychotics or corticosteroids) within 3 months prior to screening.

  • Patients who are currently receiving a loop diuretic that cannot be discontinued.


Other Exclusion Criteria
  • Active or previous substance abuse or dependence.

  • Prisoners or subjects who are involuntarily incarcerated.

  • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.

  • Dislike >25% of the study foods.

  • Participation in other studies (within the past 30 days).


In situations where the patient has a contraindication to MR scanning, they will be randomised to the study but excluded from MR scanning only. The primary outcome measurement of fat mass can be derived from DEXA.
  • ALT, Alanine transaminase; AST, Aspartate transaminase; BMI, Body mass index; DEXA, dual-energy X-ray absorptiometry; eGFR, estimated glomerular filtration rate; GLP1-RA, glucagon-like peptide-1 receptor agonist; SGLT2i, sodium-glucose co-transporter 2 inhibitors; WOCBP, Women of childbearing potential.