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    Clinical Trial Results:
    SGLT-2 Inhibitor Empagliflozin Effects on Appetite and Weight Regulation: A randomised double-blind placebo-controlled trial (SEESAW)

    Summary
    EudraCT number
    		 2015-001594-40
    Trial protocol
    		 GB  
    Global end of trial date
    30 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Aug 2020
    First version publication date
    27 Aug 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    UNOLE0526
    Additional study identifiers
    ISRCTN number
    		 ISRCTN82062639
    US NCT number
    		 NCT02798744
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Leicester
    Sponsor organisation address
    Research Governance Office, Academic Department, Leicester General Hospital, Leicester, United Kingdom, LE5 4PW
    Public contact
    Professor Melanie Davies , Leicester Diabetes Centre, +44 01162588973, melanie.davies@uhl-tr.nhs.uk
    Scientific contact
    Professor Melanie Davies , Leicester Diabetes Centre, +44 01162586481, melanie.davies@uhl-tr.nhs.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jul 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the cause for the discrepancy in predicted and observed weight loss with empagliflozin by measuring appetite hormone regulation.
    Protection of trial subjects
    All study participants were required to read a patient Information Sheet (PIS) about the trial (including trial treatments and any known side-effects) and sign an Informed Consent Form (ICF). Patients were monitored regularly throughout the trial duration.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Nov 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 68
    Worldwide total number of subjects
    68
    EEA total number of subjects
    68
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    34
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Sponsor Greenlight was issued on 18/11/2016. First Patient First Visit date was 04/01/2017 and Last Patient Last Visit date was 09/07/2017.

    Pre-assignment
    Screening details
    		 68 participants (44 men and 24 women) with type 2 diabetes, controlled via lifestyle or stable metformin therapy only, were enrolled into the study. 63 participants completed the study, of which primary outcome data was collected for 61 participants.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Empagliflozin (Jardiance™) and the placebo were formulated and supplied in identical tablet form sealed in identical medication packs by Boehringer Ingelheim and supplied to the third-party company ALMAC. ALMAC organised blinding, packaging and labelling of both Empagliflozin (Jardiance™) and the placebo. The finished stock was sent by ALMAC to the research site. The allocation to placebo or Empagliflozin (Jardiance™) was randomly assigned using an independent online computerised system.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Empagliflozin (Baseline)
    Arm description
    		 Empagliflozin (Jardiance™) 25mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin (Jardiance™)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage was 25mg once daily for Empagliflozin (Jardiance™), which is the maximum dose licensed for the treatment of Type 2 Diabetes in the UK.

    Arm title
    		 Empagliflozin plus ERD (Baseline)
    Arm description
    		 Empagliflozin (Jardiance™) 25mg once daily and energy restriction diet (ERD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin (Jardiance™)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage was 25mg once daily for Empagliflozin (Jardiance™), which is the maximum dose licensed for the treatment of Type 2 Diabetes in the UK.

    Arm title
    		 Placebo (baseline)
    Arm description
    		 The placebo was labelled as ‘25mg once daily’ to match the IMP.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Empagliflozin (Jardiance™)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage was 25mg once daily for Empagliflozin (Jardiance™), which is the maximum dose licensed for the treatment of Type 2 Diabetes in the UK.

    Investigational medicinal product name
    Placebo 25mg once daily
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Arm title
    		 Placebo plus ERD (baseline)
    Arm description
    		 Placebo and energy restriction diet (ERD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo 25mg once daily
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Number of subjects in period 1
    		Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline)
    Started
    17
    17
    17
    17
    Completed
    17
    17
    17
    17
    Period 2
    Period 2 title
    2 weeks
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    As before

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Empagliflozin (2 weeks)
    Arm description
    		 Empagliflozin (Jardiance™) 25mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin (Jardiance™)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage was 25mg once daily for Empagliflozin (Jardiance™), which is the maximum dose licensed for the treatment of Type 2 Diabetes in the UK.

    Arm title
    		 Empagliflozin plus ERD (2 weeks)
    Arm description
    		 Empagliflozin (Jardiance™) 25mg once daily and energy restriction diet (ERD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin (Jardiance™)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage was 25mg once daily for Empagliflozin (Jardiance™), which is the maximum dose licensed for the treatment of Type 2 Diabetes in the UK.

    Arm title
    		 Placebo (2 weeks)
    Arm description
    		 The placebo was labelled as ‘25mg once daily’ to match the IMP.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo 25mg once daily
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Arm title
    		 Placebo plus ERD (2 weeks)
    Arm description
    		 Placebo and energy restriction diet (ERD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo 25mg once daily
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Number of subjects in period 2
    		Empagliflozin (2 weeks) Empagliflozin plus ERD (2 weeks) Placebo (2 weeks) Placebo plus ERD (2 weeks)
    Started
    17
    17
    17
    17
    Completed
    17
    17
    17
    15
    Not completed
    0
    0
    0
    2
         Physician decision
    -
    -
    -
    1
         Lost to follow-up
    -
    -
    -
    1
    Period 3
    Period 3 title
    6 weeks
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    As above

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Empagliflozin (6 weeks)
    Arm description
    		 Empagliflozin (Jardiance™) 25mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin (Jardiance™)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage was 25mg once daily for Empagliflozin (Jardiance™), which is the maximum dose licensed for the treatment of Type 2 Diabetes in the UK.

    Arm title
    		 Empagliflozin plus ERD (6 weeks)
    Arm description
    		 Empagliflozin (Jardiance™) 25mg once daily and energy restriction diet (ERD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin (Jardiance™)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage was 25mg once daily for Empagliflozin (Jardiance™), which is the maximum dose licensed for the treatment of Type 2 Diabetes in the UK.

    Arm title
    		 Placebo (6 weeks)
    Arm description
    		 The placebo was labelled as ‘25mg once daily’ to match the IMP.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo 25mg once daily
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Arm title
    		 Placebo plus ERD (6 weeks)
    Arm description
    		 Placebo and energy restriction diet (ERD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo 25mg once daily
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Number of subjects in period 3
    		Empagliflozin (6 weeks) Empagliflozin plus ERD (6 weeks) Placebo (6 weeks) Placebo plus ERD (6 weeks)
    Started
    17
    17
    17
    15
    Completed
    17
    17
    17
    14
    Not completed
    0
    0
    0
    1
         Voluntary withdrawal
    -
    -
    -
    1
    Period 4
    Period 4 title
    12 weeks
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    As above

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Empagliflozin (12 weeks)
    Arm description
    		 Empagliflozin (Jardiance™) 25mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin (Jardiance™)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage was 25mg once daily for Empagliflozin (Jardiance™), which is the maximum dose licensed for the treatment of Type 2 Diabetes in the UK.

    Arm title
    		 Empagliflozin plus ERD (12 weeks)
    Arm description
    		 Empagliflozin (Jardiance™) 25mg once daily and energy restriction diet (ERD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin (Jardiance™)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage was 25mg once daily for Empagliflozin (Jardiance™), which is the maximum dose licensed for the treatment of Type 2 Diabetes in the UK.

    Arm title
    		 Placebo (12 weeks)
    Arm description
    		 The placebo was labelled as ‘25mg once daily’ to match the IMP.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo 25mg once daily
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Arm title
    		 Placebo plus ERD (12 weeks)
    Arm description
    		 Placebo and energy restriction diet (ERD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo 25mg once daily
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Number of subjects in period 4
    		Empagliflozin (12 weeks) Empagliflozin plus ERD (12 weeks) Placebo (12 weeks) Placebo plus ERD (12 weeks)
    Started
    17
    17
    17
    14
    Completed
    17
    17
    17
    14
    Period 5
    Period 5 title
    24 weeks
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    As above

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Empagliflozin (24 weeks)
    Arm description
    		 Empagliflozin (Jardiance™) 25mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin (Jardiance™)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage was 25mg once daily for Empagliflozin (Jardiance™), which is the maximum dose licensed for the treatment of Type 2 Diabetes in the UK.

    Arm title
    		 Empagliflozin plus ERD (24 weeks)
    Arm description
    		 Empagliflozin (Jardiance™) 25mg once daily and energy restriction diet (ERD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Empagliflozin (Jardiance™)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage was 25mg once daily for Empagliflozin (Jardiance™), which is the maximum dose licensed for the treatment of Type 2 Diabetes in the UK.

    Arm title
    		 Placebo (24 weeks)
    Arm description
    		 The placebo was labelled as ‘25mg once daily’ to match the IMP.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo 25mg once daily
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Arm title
    		 Placebo plus ERD (24 weeks)
    Arm description
    		 Placebo and energy restriction diet (ERD)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo 25mg once daily
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Number of subjects in period 5
    		Empagliflozin (24 weeks) Empagliflozin plus ERD (24 weeks) Placebo (24 weeks) Placebo plus ERD (24 weeks)
    Started
    17
    17
    17
    14
    Completed
    16
    17
    16
    14
    Not completed
    1
    0
    1
    0
         Adverse event, non-fatal
    -
    -
    1
    -
         Voluntary withdrawal
    1
    -
    -
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 68 68
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 34 34
        From 65-84 years
    		 34 34
        85 years and over
    		 0 0
    Age continuous
    The median age of the combined study population was 63 years
    Units: years
        median (full range (min-max))
    		 63 (39 to 74) -
    Gender categorical
    Units: Subjects
        Female
    		 24 24
        Male
    		 44 44
    Ethnicity
    Units: Subjects
        White
    		 49 49
        South Asian
    		 13 13
        Other
    		 6 6
    Smoking Status
    Units: Subjects
        Ex-smoker
    		 32 32
        Current smoker
    		 6 6
        Never smoker
    		 30 30
    Alcohol drinking status
    Units: Subjects
        Ex-drinker
    		 3 3
        Current drinker
    		 51 51
        Never drinker
    		 14 14
    Family History - Diabetes in Mother
    Units: Subjects
        No diabetes
    		 42 42
        Type 1 Diabetes
    		 2 2
        Type 2 Diabetes
    		 17 17
        Diabetes - type unknown
    		 3 3
        Not Reported
    		 4 4
    Family History - Diabetes in Father
    Units: Subjects
        No Diabetes
    		 45 45
        Type 1 Diabetes
    		 2 2
        Type 2 Diabetes
    		 11 11
        Diabetes - Type Unknown
    		 0 0
        Not reported
    		 10 10
    Family History - Diabetes in Siblings
    Units: Subjects
        No Diabetes
    		 38 38
        1 Sibling Diabetes
    		 13 13
        2 or more Siblings with Diabetes
    		 4 4
        Not reported
    		 13 13
    Family History - Diabetes in First Degree Relatives
    Units: Subjects
        No Diabetes
    		 40 40
        At least 1 Relative with Diabetes
    		 16 16
        Not Reported
    		 12 12
    Family History - Cardiovascular Disease
    Units: Subjects
        No
    		 23 23
        Yes
    		 43 43
        Unknown
    		 2 2
    Family History - Stroke
    Units: Subjects
        No
    		 39 39
        Yes
    		 24 24
        Unknown
    		 5 5
    Family History - High Blood Pressure
    Units: Subjects
        No
    		 16 16
        Yes
    		 36 36
        Unknown
    		 16 16
    Family History - High Cholesterol
    Units: Subjects
        No
    		 17 17
        Yes
    		 23 23
        Unknown
    		 28 28
    Family History - Gestational Diabetes
    Units: Subjects
        No
    		 42 42
        Yes
    		 0 0
        Unknown
    		 26 26
    Concomitant Medication
    Units: Subjects
        Yes
    		 56 56
        No
    		 12 12
    Medical History - Myocardial Infarction
    Units: Subjects
        No
    		 60 60
        Yes
    		 7 7
        Unknown
    		 1 1
    Medical History - Heart Valve Disease
    Units: Subjects
        No
    		 64 64
        Yes
    		 3 3
        Unknown
    		 1 1
    Medical History - Heart Failure
    Units: Subjects
        No
    		 67 67
        Yes
    		 0 0
        Unknown
    		 1 1
    Medical History - Atrial Fibrillation
    Units: Subjects
        No
    		 64 64
        Yes
    		 3 3
        Unknown
    		 1 1
    Medical History - Angina
    Units: Subjects
        No
    		 65 65
        Yes
    		 2 2
        Unknown
    		 1 1
    Medical History - Stroke
    Units: Subjects
        No
    		 66 66
        Yes
    		 1 1
        Unknown
    		 1 1
    Medical History - Angioplasty
    Units: Subjects
        No
    		 64 64
        Yes
    		 3 3
        Unknown
    		 1 1
    Medical History - Leg Angioplasty
    Units: Subjects
        No
    		 67 67
        Yes
    		 0 0
        Unknown
    		 1 1
    Medical History - Peripheral Vascular Disease
    Units: Subjects
        No
    		 67 67
        Yes
    		 0 0
        Unknown
    		 1 1
    Medical History - High Blood Pressure
    Units: Subjects
        No
    		 26 26
        Yes
    		 40 40
        Unknown
    		 2 2
    Medical History - High Cholesterol
    Units: Subjects
        No
    		 21 21
        Yes
    		 46 46
        Unknown
    		 1 1
    Medical History - Gestational Diabetes
    Units: Subjects
        N/A
    		 44 44
        No
    		 21 21
        Yes
    		 2 2
        Unknown
    		 1 1
    Medical History - Polycystic Ovaries
    Units: Subjects
        N/A
    		 44 44
        No
    		 21 21
        Yes
    		 2 2
        Unknown
    		 1 1
    Medical History - Thyroid Disorder
    Units: Subjects
        No
    		 63 63
        Yes
    		 4 4
        Unknown
    		 1 1
    Duration of Diabetes
    Units: Years
        median (full range (min-max))
    		 6 (0.58 to 15) -
    Average Systolic Blood Pressure
    Units: mmHg
        median (full range (min-max))
    		 127 (101 to 177) -
    Average Diastolic Blood Pressure
    Units: mmHg
        median (full range (min-max))
    		 77.5 (57 to 117.5) -
    Average Heart Rate
    Units: bpm
        median (full range (min-max))
    		 68.25 (43.5 to 96) -
    Weight
    Units: Kg
        median (full range (min-max))
    		 91 (59.5 to 146.6) -
    Body Mass Index
    Units: Kg^m2
        median (full range (min-max))
    		 31.8 (25 to 44.8) -
    Hip Circumference
    Units: cm
        median (full range (min-max))
    		 111.5 (93 to 147) -
    Waist Circumference
    Units: cm
        median (full range (min-max))
    		 110.9 (84 to 140) -
    Sodium
    Units: mmol/L
        median (full range (min-max))
    		 140 (136 to 144) -
    Potassium
    Units: mmol/L
        median (full range (min-max))
    		 4.3 (3.3 to 5.3) -
    Urea
    Units: mmol/L
        median (full range (min-max))
    		 5.8 (2.8 to 9.8) -
    Creatinine
    Units: umol/L
        median (full range (min-max))
    		 70.5 (49 to 102) -
    eGFR
    Units: ml/min/1.73m2
        median (full range (min-max))
    		 89 (67 to 90) -
    Albumin
    Units: g/L
        median (full range (min-max))
    		 45 (38 to 50) -
    Alkaline Phosphatase
    Units: iu/L
        median (full range (min-max))
    		 80 (35 to 126) -
    Alanine Transaminase
    Units: iu/L
        median (full range (min-max))
    		 25.5 (10 to 85) -
    Bilirubin
    Units: mg/dL
        median (full range (min-max))
    		 9 (4 to 23) -
    Total Cholesterol
    Units: mmol/L
        median (full range (min-max))
    		 4.1 (2.2 to 7) -
    Triglycerides
    Units: mmol/L
        least squares mean (full range (min-max))
    		 1.67 (0.51 to 3.54) -
    HDL Cholesterol
    Units: mmol/L
        median (full range (min-max))
    		 1.2 (0.7 to 2.2) -
    Total cholesterol:HDL ratio
    Units: none
        median (full range (min-max))
    		 3.4 (1.9 to 6.4) -
    LDL Cholesterol (calculated)
    Units: None
        median (full range (min-max))
    		 2 (0.8 to 4.8) -
    HbA1c
    Units: percentage
        median (full range (min-max))
    		 6.8 (6 to 8.2) -
    HbA1c
    Units: mmol/mol
        median (full range (min-max))
    		 51 (42 to 67) -

    End points

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    End points reporting groups
    Reporting group title
    Empagliflozin (Baseline)
    Reporting group description
    		 Empagliflozin (Jardiance™) 25mg once daily

    Reporting group title
    Empagliflozin plus ERD (Baseline)
    Reporting group description
    		 Empagliflozin (Jardiance™) 25mg once daily and energy restriction diet (ERD)

    Reporting group title
    Placebo (baseline)
    Reporting group description
    		 The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Reporting group title
    Placebo plus ERD (baseline)
    Reporting group description
    		 Placebo and energy restriction diet (ERD)
    Reporting group title
    Empagliflozin (2 weeks)
    Reporting group description
    		 Empagliflozin (Jardiance™) 25mg once daily

    Reporting group title
    Empagliflozin plus ERD (2 weeks)
    Reporting group description
    		 Empagliflozin (Jardiance™) 25mg once daily and energy restriction diet (ERD)

    Reporting group title
    Placebo (2 weeks)
    Reporting group description
    		 The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Reporting group title
    Placebo plus ERD (2 weeks)
    Reporting group description
    		 Placebo and energy restriction diet (ERD)
    Reporting group title
    Empagliflozin (6 weeks)
    Reporting group description
    		 Empagliflozin (Jardiance™) 25mg once daily

    Reporting group title
    Empagliflozin plus ERD (6 weeks)
    Reporting group description
    		 Empagliflozin (Jardiance™) 25mg once daily and energy restriction diet (ERD)

    Reporting group title
    Placebo (6 weeks)
    Reporting group description
    		 The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Reporting group title
    Placebo plus ERD (6 weeks)
    Reporting group description
    		 Placebo and energy restriction diet (ERD)
    Reporting group title
    Empagliflozin (12 weeks)
    Reporting group description
    		 Empagliflozin (Jardiance™) 25mg once daily

    Reporting group title
    Empagliflozin plus ERD (12 weeks)
    Reporting group description
    		 Empagliflozin (Jardiance™) 25mg once daily and energy restriction diet (ERD)

    Reporting group title
    Placebo (12 weeks)
    Reporting group description
    		 The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Reporting group title
    Placebo plus ERD (12 weeks)
    Reporting group description
    		 Placebo and energy restriction diet (ERD)
    Reporting group title
    Empagliflozin (24 weeks)
    Reporting group description
    		 Empagliflozin (Jardiance™) 25mg once daily

    Reporting group title
    Empagliflozin plus ERD (24 weeks)
    Reporting group description
    		 Empagliflozin (Jardiance™) 25mg once daily and energy restriction diet (ERD)

    Reporting group title
    Placebo (24 weeks)
    Reporting group description
    		 The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Reporting group title
    Placebo plus ERD (24 weeks)
    Reporting group description
    		 Placebo and energy restriction diet (ERD)

    Primary: Total PYY AUC

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    End point title
    		 Total PYY AUC
    End point description
    Change in total PYY AUC during mixed meal tolerance test
    End point type
    Primary
    End point timeframe
    0, 2, 6, 12 and 24 weeks
    End point values
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline) Empagliflozin (2 weeks) Empagliflozin plus ERD (2 weeks) Placebo (2 weeks) Placebo plus ERD (2 weeks) Empagliflozin (6 weeks) Empagliflozin plus ERD (6 weeks) Placebo (6 weeks) Placebo plus ERD (6 weeks) Empagliflozin (12 weeks) Empagliflozin plus ERD (12 weeks) Placebo (12 weeks) Placebo plus ERD (12 weeks) Empagliflozin (24 weeks) Empagliflozin plus ERD (24 weeks) Placebo (24 weeks) Placebo plus ERD (24 weeks)
    Number of subjects analysed
    15 [1]
    17
    15 [2]
    14 [3]
    15 [4]
    17
    16 [5]
    14 [6]
    16 [7]
    16 [8]
    16 [9]
    13 [10]
    15 [11]
    16 [12]
    16 [13]
    14 [14]
    15 [15]
    17
    15 [16]
    14 [17]
    Units: pg/mL
        arithmetic mean (standard deviation)
    146.2 ± 49.2
    134.4 ± 46.8
    143.5 ± 67.0
    157.4 ± 57.6
    153.6 ± 55.2
    141.3 ± 51.2
    143.9 ± 44.2
    159.7 ± 39.9
    159.3 ± 57.2
    140.2 ± 43.4
    150.2 ± 66.1
    154.2 ± 29.5
    176.2 ± 60.6
    143.6 ± 55.6
    136.1 ± 63.7
    149.5 ± 43.3
    165.8 ± 56.2
    141.2 ± 39.4
    146.4 ± 69.7
    149.6 ± 36.3
    Notes
    [1] - Complete case analysis: 1 x withdrawn, 1 x data not available
    [2] - Complete case analysis: 1 x withdrawn, 1 x data not available
    [3] - Complete case analysis: 3 x withdrawn
    [4] - Complete case analysis: 1 x withdrawn, 1 x data not available
    [5] - Complete case analysis: 1 x data not available
    [6] - Complete case analysis: 3 x withdrawn
    [7] - Complete case analysis: 1 x data not available
    [8] - 1 x did not attend
    [9] - Complete case analysis: 1 x data not available
    [10] - Complete case analysis: 3 x withdrawn, 1 x data not available
    [11] - Complete case analysis: 2 x data not available
    [12] - 1 x data not available
    [13] - Complete case analysis: 1 x data not available
    [14] - Complete case analysis: 3 x withdrawn
    [15] - Complete case analysis: 1 x withdrawn, 1 x data not available
    [16] - Complete case analysis: 1 x withdrawn, 1 x data not available
    [17] - Complete case analysis: 3 x withdrawn
    Statistical analysis title
    		 GLM - placebo plus ERD vs placebo @24wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Placebo plus ERD (24 weeks)
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4 [18]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -8.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.58
         upper limit
    		 11.4
    Notes
    [18] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin (24 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.179 [19]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    13.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.13
         upper limit
    		 32.97
    Notes
    [19] - Not significant
    Statistical analysis title
    		 GLM - empa plus ERD vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin plus ERD (24 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.92 [20]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.01
         upper limit
    		 19.95
    Notes
    [20] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Placebo plus ERD (12 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.772 [21]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    3.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20
         upper limit
    		 26.94
    Notes
    [21] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin (12 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003 [22]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    34.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.38
         upper limit
    		 57.29
    Notes
    [22] - Significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 12wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 12 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin plus ERD (12 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.177 [23]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    15.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.04
         upper limit
    		 38.19
    Notes
    [23] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Placebo plus ERD (6 weeks)
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.521 [24]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -6.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.17
         upper limit
    		 14.27
    Notes
    [24] - Not Significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin (6 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.498 [25]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    6.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.02
         upper limit
    		 26.8
    Notes
    [25] - Not Significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 6wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 6 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin plus ERD (6 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.738 [26]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    3.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.65
         upper limit
    		 23.51
    Notes
    [26] - Not Significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Placebo plus ERD (2 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.511 [27]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    7.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.97
         upper limit
    		 30.09
    Notes
    [27] - Not Significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin (2 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.406 [28]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    9.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.67
         upper limit
    		 31.32
    Notes
    [28] - Not Significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 2wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 2 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin plus ERD (2 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.711 [29]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    4.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.35
         upper limit
    		 25.42
    Notes
    [29] - Not Significant

    Secondary: Acylated ghrelin AUC

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    End point title
    		 Acylated ghrelin AUC
    End point description
    Change in acylated ghrelin AUC during mixed meal tolerance test
    End point type
    Secondary
    End point timeframe
    0, 2, 6, 12 and 24 weeks
    End point values
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline) Empagliflozin (2 weeks) Empagliflozin plus ERD (2 weeks) Placebo (2 weeks) Placebo plus ERD (2 weeks) Empagliflozin (6 weeks) Empagliflozin plus ERD (6 weeks) Placebo (6 weeks) Placebo plus ERD (6 weeks) Empagliflozin (12 weeks) Empagliflozin plus ERD (12 weeks) Placebo (12 weeks) Placebo plus ERD (12 weeks) Empagliflozin (24 weeks) Empagliflozin plus ERD (24 weeks) Placebo (24 weeks) Placebo plus ERD (24 weeks)
    Number of subjects analysed
    16
    17
    16
    14
    14
    17
    16
    14
    16
    16
    16
    13
    15
    16
    16
    14
    15
    17
    15
    14
    Units: pg/mL
        arithmetic mean (standard deviation)
    43.2 ± 39.0
    53 ± 56.1
    35.4 ± 33.8
    41.2 ± 80.3
    42.6 ± 39.9
    52.3 ± 58.1
    33.4 ± 28.4
    83.8 ± 214.2
    42.6 ± 39.5
    47.3 ± 46.9
    28.8 ± 21.6
    98.8 ± 261.1
    61.3 ± 71.0
    64.3 ± 59.1
    38.4 ± 38.5
    79.3 ± 202.9
    42.3 ± 50.7
    57.4 ± 49.4
    50.6 ± 51.0
    58.9 ± 126.3
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Placebo plus ERD (24 weeks)
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.765 [30]
    Method
    		 Generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    3.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.69
         upper limit
    		 24.06
    Notes
    [30] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin (24 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.187 [31]
    Method
    		 Generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -13.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -34.26
         upper limit
    		 6.68
    Notes
    [31] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 24wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 24 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin plus ERD (24 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.185 [32]
    Method
    		 Generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -13.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.47
         upper limit
    		 6.47
    Notes
    [32] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Placebo plus ERD (12 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.049 [33]
    Method
    		 Generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    32.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 64.92
    Notes
    [33] - Not significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)
    Statistical analysis title
    		 GLM - empa vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin (12 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.81 [34]
    Method
    		 Generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    3.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.88
         upper limit
    		 35.67
    Notes
    [34] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 12wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 12 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin plus ERD (12 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.538 [35]
    Method
    		 Generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -9.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.35
         upper limit
    		 21.58
    Notes
    [35] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Placebo plus ERD (6 weeks)
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02 [36]
    Method
    		 Generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    61.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.67
         upper limit
    		 112.79
    Notes
    [36] - Not significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)
    Statistical analysis title
    		 GLM - empa vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin (6 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.965 [37]
    Method
    		 Generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -1.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49.68
         upper limit
    		 47.52
    Notes
    [37] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 6wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 6 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin plus ERD (6 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.775 [38]
    Method
    		 Generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -7.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -55.92
         upper limit
    		 41.69
    Notes
    [38] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Placebo plus ERD (2 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.037 [39]
    Method
    		 Generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    42.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.65
         upper limit
    		 83.12
    Notes
    [39] - Not significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)
    Statistical analysis title
    		 GLM - empa vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin (2 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.874 [40]
    Method
    		 Generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -3.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -43.4
         upper limit
    		 36.89
    Notes
    [40] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 2wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 2 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin plus ERD (2 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.586 [41]
    Method
    		 Generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -10.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -49.12
         upper limit
    		 27.75
    Notes
    [41] - Not significant

    Secondary: GLP-1 AUC

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    End point title
    		 GLP-1 AUC
    End point description
    Change in GLP-1 AUC during mixed meal tolerance test
    End point type
    Secondary
    End point timeframe
    0, 2, 6, 12 and 24 weeks
    End point values
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline) Empagliflozin (2 weeks) Empagliflozin plus ERD (2 weeks) Placebo (2 weeks) Placebo plus ERD (2 weeks) Empagliflozin (6 weeks) Empagliflozin plus ERD (6 weeks) Placebo (6 weeks) Placebo plus ERD (6 weeks) Empagliflozin (12 weeks) Empagliflozin plus ERD (12 weeks) Placebo (12 weeks) Placebo plus ERD (12 weeks) Empagliflozin (24 weeks) Empagliflozin plus ERD (24 weeks) Placebo (24 weeks) Placebo plus ERD (24 weeks)
    Number of subjects analysed
    16
    17
    16
    14
    15
    17
    16
    14
    16
    16
    16
    13
    15
    16
    16
    14
    15
    17
    15
    14
    Units: pmol/L
        arithmetic mean (standard deviation)
    47.9 ± 15.1
    43.1 ± 11.5
    45.5 ± 10.6
    46.3 ± 12.4
    52.7 ± 13.7
    48.3 ± 18.1
    44.0 ± 9.1
    47.5 ± 12.3
    50.8 ± 14.1
    45.6 ± 14.8
    44.3 ± 13.1
    45.8 ± 13.5
    54.0 ± 17.6
    47.0 ± 17.4
    44.2 ± 10.6
    44.0 ± 14.5
    49.9 ± 10.9
    43.8 ± 13.3
    46.1 ± 11.9
    47.0 ± 13.7
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Placebo plus ERD (24 weeks)
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.657 [42]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.14
         upper limit
    		 6.56
    Notes
    [42] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin (24 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.25 [43]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    3.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.17
         upper limit
    		 8.32
    Notes
    [43] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 24wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 24 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin plus ERD (24 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.896 [44]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.77
         upper limit
    		 5.45
    Notes
    [44] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Placebo plus ERD (12 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.976 [45]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.61
         upper limit
    		 7.38
    Notes
    [45] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin (12 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.055 [46]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    7.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 14.57
    Notes
    [46] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 12wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 12 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin plus ERD (12 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.163 [47]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    5.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.09
         upper limit
    		 12.38
    Notes
    [47] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Placebo plus ERD (6 weeks)
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.922 [48]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.12
         upper limit
    		 5.66
    Notes
    [48] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin (6 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.093 [49]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    4.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.73
         upper limit
    		 9.42
    Notes
    [49] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 6wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 6 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin plus ERD (6 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.257 [50]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    2.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.14
         upper limit
    		 8.01
    Notes
    [50] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Placebo plus ERD (2 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28 [51]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    3.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.73
         upper limit
    		 9.43
    Notes
    [51] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin (2 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.049 [52]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    6.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 11.99
    Notes
    [52] - Not significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 2wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 2 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin plus ERD (2 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.028 [53]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 12.28
    Notes
    [53] - Not significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)

    Secondary: Hunger - VAS

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    End point title
    		 Hunger - VAS
    End point description
    Change in Hunger AUC (measured using visual analogue scale - (VAS)) during mixed meal tolerance test
    End point type
    Secondary
    End point timeframe
    0, 2, 6, 12 and 24 weeks
    End point values
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline) Empagliflozin (2 weeks) Empagliflozin plus ERD (2 weeks) Placebo (2 weeks) Placebo plus ERD (2 weeks) Empagliflozin (6 weeks) Empagliflozin plus ERD (6 weeks) Placebo (6 weeks) Placebo plus ERD (6 weeks) Empagliflozin (12 weeks) Empagliflozin plus ERD (12 weeks) Placebo (12 weeks) Placebo plus ERD (12 weeks) Empagliflozin (24 weeks) Empagliflozin plus ERD (24 weeks) Placebo (24 weeks) Placebo plus ERD (24 weeks)
    Number of subjects analysed
    17
    17
    17
    17
    15
    17
    16
    15
    16
    16
    17
    14
    15
    17
    17
    14
    14
    17
    16
    14
    Units: mm
        arithmetic mean (standard deviation)
    36.5 ± 19.8
    29.0 ± 18.8
    29.3 ± 21.5
    24.0 ± 16.3
    38.1 ± 18.3
    29.6 ± 20.9
    27.3 ± 17.6
    24.6 ± 17.9
    35.3 ± 23.1
    32.5 ± 19.7
    32.3 ± 21.2
    23.8 ± 20.2
    30.7 ± 20.2
    29.8 ± 23.9
    28.2 ± 18.3
    33.3 ± 23.2
    41.6 ± 19.4
    36.0 ± 24.9
    31.2 ± 18.4
    26.5 ± 18.7
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Placebo plus ERD (24 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.645 [54]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.12
         upper limit
    		 8.13
    Notes
    [54] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin (24 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.199 [55]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    6.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.67
         upper limit
    		 17.58
    Notes
    [55] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 24wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 24 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin plus ERD (24 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.495 [56]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    3.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.53
         upper limit
    		 13.51
    Notes
    [56] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Placebo plus ERD (12 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.225 [57]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    8.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.08
         upper limit
    		 21.57
    Notes
    [57] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin (12 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.898 [58]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.87
         upper limit
    		 12.17
    Notes
    [58] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 12wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 12 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin plus ERD (12 weeks)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.793 [59]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    1.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.81
         upper limit
    		 14.15
    Notes
    [59] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Placebo plus ERD (6 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42 [60]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -5.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.74
         upper limit
    		 7.39
    Notes
    [60] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin (6 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.999 [61]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.07
         upper limit
    		 12.06
    Notes
    [61] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 6wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 6 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin plus ERD (6 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.913 [62]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.63
         upper limit
    		 11.3
    Notes
    [62] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Placebo plus ERD (2 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.937 [63]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.46
         upper limit
    		 10.26
    Notes
    [63] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin (2 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.266 [64]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    5.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.27
         upper limit
    		 15.47
    Notes
    [64] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 2wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 2 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin plus ERD (2 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.745 [65]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    1.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.86
         upper limit
    		 10.99
    Notes
    [65] - Not significant

    Secondary: Fullness - VAS

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    End point title
    		 Fullness - VAS
    End point description
    Change in Fullness AUC (measured using visual analogue scale - (VAS)) during mixed meal tolerance test
    End point type
    Secondary
    End point timeframe
    0, 2, 6, 12 and 24 weeks
    End point values
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline) Empagliflozin (2 weeks) Empagliflozin plus ERD (2 weeks) Placebo (2 weeks) Placebo plus ERD (2 weeks) Empagliflozin (6 weeks) Empagliflozin plus ERD (6 weeks) Placebo (6 weeks) Placebo plus ERD (6 weeks) Empagliflozin (12 weeks) Empagliflozin plus ERD (12 weeks) Placebo (12 weeks) Placebo plus ERD (12 weeks) Empagliflozin (24 weeks) Empagliflozin plus ERD (24 weeks) Placebo (24 weeks) Placebo plus ERD (24 weeks)
    Number of subjects analysed
    17
    17
    17
    17
    16
    17
    16
    15
    17
    16
    17
    14
    16
    17
    17
    14
    15
    17
    16
    14
    Units: mm
        arithmetic mean (standard deviation)
    50.6 ± 22.7
    54.1 ± 22.3
    50.5 ± 24.1
    59.3 ± 20.1
    56.3 ± 17.2
    53.8 ± 19.5
    50.9 ± 27.8
    59.8 ± 23.4
    61.7 ± 21.4
    54.0 ± 21.3
    52.0 ± 25.0
    54.2 ± 28.9
    56.7 ± 23.0
    49.4 ± 28.8
    56.4 ± 24.3
    59.0 ± 25.0
    53.4 ± 18.0
    51.8 ± 22.8
    53.9 ± 22.2
    61.7 ± 24.0
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Placebo plus ERD (24 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.479 [66]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    4.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.09
         upper limit
    		 17.24
    Notes
    [66] - not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin (24 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86 [67]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.4
         upper limit
    		 11.19
    Notes
    [67] - not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 24wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 24 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin plus ERD (24 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.608 [68]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -3.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.05
         upper limit
    		 8.8
    Notes
    [68] - not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Placebo plus ERD (12 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.903 [69]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.91
         upper limit
    		 15.81
    Notes
    [69] - not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin (12 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.971 [70]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.73
         upper limit
    		 16.33
    Notes
    [70] - not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 12wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 12 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin plus ERD (12 weeks)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.292 [71]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -8.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.33
         upper limit
    		 7.32
    Notes
    [71] - not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 6weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Placebo plus ERD (6 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.768 [72]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -2.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.41
         upper limit
    		 13.59
    Notes
    [72] - not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin (6 weeks)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.205 [73]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    9.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.26
         upper limit
    		 24.55
    Notes
    [73] - not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 6wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 6 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin plus ERD (6 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.882 [74]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.03
         upper limit
    		 16.33
    Notes
    [74] - not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Placebo plus ERD (2 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.769 [75]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    2.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.52
         upper limit
    		 15.59
    Notes
    [75] - not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin (2 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.356 [76]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    6.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.88
         upper limit
    		 19.13
    Notes
    [76] - not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 2wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 2 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin plus ERD (2 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.972 [77]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.65
         upper limit
    		 13.11
    Notes
    [77] - not significant

    Secondary: Satisfaction - VAS

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    End point title
    		 Satisfaction - VAS
    End point description
    Change in Satisfaction AUC (measured using visual analogue scale - (VAS)) during mixed meal tolerance test
    End point type
    Secondary
    End point timeframe
    0, 2, 6, 12 and 24 weeks
    End point values
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline) Empagliflozin (2 weeks) Empagliflozin plus ERD (2 weeks) Placebo (2 weeks) Placebo plus ERD (2 weeks) Empagliflozin (6 weeks) Empagliflozin plus ERD (6 weeks) Placebo (6 weeks) Placebo plus ERD (6 weeks) Empagliflozin (12 weeks) Empagliflozin plus ERD (12 weeks) Placebo (12 weeks) Placebo plus ERD (12 weeks) Empagliflozin (24 weeks) Empagliflozin plus ERD (24 weeks) Placebo (24 weeks) Placebo plus ERD (24 weeks)
    Number of subjects analysed
    17
    17
    17
    17
    16
    17
    16
    15
    17
    16
    17
    14
    16
    17
    17
    14
    15
    17
    16
    14
    Units: mm
        arithmetic mean (standard deviation)
    48.6 ± 20.0
    55.6 ± 16.7
    54.0 ± 21.8
    59.1 ± 20.0
    58.8 ± 16.6
    52.6 ± 21.0
    51.7 ± 22.1
    62.3 ± 23.0
    62.4 ± 21.2
    50.6 ± 25.2
    53.3 ± 23.6
    53.7 ± 27.2
    65.5 ± 18.8
    51.1 ± 27.7
    57.0 ± 23.8
    61.2 ± 23.0
    54.5 ± 16.1
    50.8 ± 24.0
    56.6 ± 21.0
    63.4 ± 24.1
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Placebo plus ERD (24 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.369 [78]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    5.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7
         upper limit
    		 18.86
    Notes
    [78] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin (24 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.903 [79]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.89
         upper limit
    		 13.46
    Notes
    [79] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 24wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 24 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin plus ERD (24 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.383 [80]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -5.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.69
         upper limit
    		 6.79
    Notes
    [80] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Placebo plus ERD (12 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.79 [81]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    2.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.54
         upper limit
    		 17.8
    Notes
    [81] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin (12 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.134 [82]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    11.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.56
         upper limit
    		 26.64
    Notes
    [82] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 12wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 12 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin plus ERD (12 weeks)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.387 [83]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -6.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.31
         upper limit
    		 8.25
    Notes
    [83] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Placebo plus ERD (6 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.772 [84]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -2.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.56
         upper limit
    		 13.79
    Notes
    [84] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin (6 weeks)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.132 [85]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    11.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.54
         upper limit
    		 26.93
    Notes
    [85] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 6wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 6 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin plus ERD (6 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.757 [86]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -2.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.86
         upper limit
    		 12.99
    Notes
    [86] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Placebo plus ERD (2 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.306 [87]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    6.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.9
         upper limit
    		 18.82
    Notes
    [87] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin (2 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.075 [88]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    10.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.12
         upper limit
    		 23.07
    Notes
    [88] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 2wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 2 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin plus ERD (2 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.986 [89]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.75
         upper limit
    		 11.96
    Notes
    [89] - Not significant

    Secondary: PFC - VAS

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    End point title
    		 PFC - VAS
    End point description
    Change in Prospective Food Consumption (PFC) AUC (measured using visual analogue scale - (VAS)) during mixed meal tolerance test
    End point type
    Secondary
    End point timeframe
    0, 2, 6, 12 and 24 weeks
    End point values
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline) Empagliflozin (2 weeks) Empagliflozin plus ERD (2 weeks) Placebo (2 weeks) Placebo plus ERD (2 weeks) Empagliflozin (6 weeks) Empagliflozin plus ERD (6 weeks) Placebo (6 weeks) Placebo plus ERD (6 weeks) Empagliflozin (12 weeks) Empagliflozin plus ERD (12 weeks) Placebo (12 weeks) Placebo plus ERD (12 weeks) Empagliflozin (24 weeks) Empagliflozin plus ERD (24 weeks) Placebo (24 weeks) Placebo plus ERD (24 weeks)
    Number of subjects analysed
    17
    17
    17
    17
    16
    17
    16
    15
    17
    16
    17
    14
    16
    17
    17
    14
    15
    17
    16
    14
    Units: mm
        arithmetic mean (standard deviation)
    46.9 ± 20.9
    35.5 ± 21.0
    41.9 ± 21.5
    28.7 ± 17.7
    41.1 ± 19.6
    36.0 ± 18.9
    38.0 ± 23.3
    29.0 ± 18.2
    40.4 ± 23.5
    36.3 ± 20.8
    40.8 ± 24.9
    33.7 ± 23.3
    36.8 ± 24.9
    35.5 ± 25.8
    32.8 ± 20.6
    34.9 ± 21.8
    44.3 ± 19.1
    39.0 ± 24.8
    39.1 ± 18.5
    31.2 ± 20.6
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Placebo plus ERD (24 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.976
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.66
         upper limit
    		 10.34
    Statistical analysis title
    		 GLM - empa vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin (24 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.652
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.71
         upper limit
    		 12.31
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 24wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 24 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin plus ERD (24 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.513
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    3.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.49
         upper limit
    		 12.99
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Placebo plus ERD (12 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.222
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    9.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.62
         upper limit
    		 24.21
    Statistical analysis title
    		 GLM - empa vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin (12 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.924
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.28
         upper limit
    		 14.63
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 12wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 12 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin plus ERD (12 weeks)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.368
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    6.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.45
         upper limit
    		 20.1
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Placebo plus ERD (6 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.911
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.82
         upper limit
    		 14.11
    Statistical analysis title
    		 GLM - empa vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin (6 weeks)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.679
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -2.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.6
         upper limit
    		 10.82
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 6wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 6 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin plus ERD (6 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.732
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -2.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.41
         upper limit
    		 11.53
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Placebo plus ERD (2 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.745
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -1.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.23
         upper limit
    		 9.47
    Statistical analysis title
    		 GLM - empa vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin (2 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.607
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -2.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.78
         upper limit
    		 8.06
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 2wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 2 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin plus ERD (2 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.95
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.34
         upper limit
    		 11.02

    Secondary: Body weight

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    End point title
    		 Body weight
    End point description
    Change in body weight
    End point type
    Secondary
    End point timeframe
    0, 2, 6, 12 and 24 weeks
    End point values
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline) Empagliflozin (2 weeks) Empagliflozin plus ERD (2 weeks) Placebo (2 weeks) Placebo plus ERD (2 weeks) Empagliflozin (6 weeks) Empagliflozin plus ERD (6 weeks) Placebo (6 weeks) Placebo plus ERD (6 weeks) Empagliflozin (12 weeks) Empagliflozin plus ERD (12 weeks) Placebo (12 weeks) Placebo plus ERD (12 weeks) Empagliflozin (24 weeks) Empagliflozin plus ERD (24 weeks) Placebo (24 weeks) Placebo plus ERD (24 weeks)
    Number of subjects analysed
    17
    17
    17
    17
    17
    17
    17
    15
    17
    16
    17
    14
    16
    17
    17
    14
    16
    17
    16
    14
    Units: kg
        arithmetic mean (standard deviation)
    89.1 ± 18.9
    90.2 ± 16.2
    96.5 ± 17.9
    95.8 ± 21.1
    88.3 ± 18.7
    88.6 ± 16.1
    96.4 ± 17.6
    92.4 ± 20.9
    87.9 ± 18.5
    88.5 ± 15.2
    96.5 ± 17.7
    90.7 ± 20.7
    87.0 ± 19.0
    85.8 ± 16.1
    96.4 ± 17.1
    90.0 ± 23.0
    86.3 ± 18.2
    84.5 ± 16.5
    95.6 ± 17.8
    92.4 ± 19.7
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Placebo plus ERD (24 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.191 [90]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -1.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.79
         upper limit
    		 0.76
    Notes
    [90] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin (24 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.049 [91]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -2.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.45
         upper limit
    		 -0.01
    Notes
    [91] - Not significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 24wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 24 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin plus ERD (24 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [92]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -5.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.79
         upper limit
    		 -3.44
    Notes
    [92] - Significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Placebo plus ERD (12 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.048 [93]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -4.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.7
         upper limit
    		 -0.04
    Notes
    [93] - Not significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)
    Statistical analysis title
    		 GLM - empa vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin (12 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.333 [94]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.34
         upper limit
    		 2.14
    Notes
    [94] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 12wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 12 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin plus ERD (12 weeks)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.029 [95]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -4.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.74
         upper limit
    		 -0.48
    Notes
    [95] - Not significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Placebo plus ERD (6 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.042 [96]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.34
         upper limit
    		 -0.04
    Notes
    [96] - Significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin (6 weeks)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011 [97]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.54
         upper limit
    		 -0.34
    Notes
    [97] - Significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 6wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 6 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin plus ERD (6 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [98]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -3.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.39
         upper limit
    		 -2.17
    Notes
    [98] - Significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Placebo plus ERD (2 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.135 [99]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.24
         upper limit
    		 0.17
    Notes
    [99] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin (2 weeks)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.031 [100]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.44
         upper limit
    		 -0.07
    Notes
    [100] - Not significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 2wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 2 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin plus ERD (2 weeks)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [101]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -1.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.19
         upper limit
    		 -0.83
    Notes
    [101] - Significant

    Secondary: Fat mass - DEXA

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    End point title
    		 Fat mass - DEXA
    End point description
    Change in fat mass (measured using DEXA)
    End point type
    Secondary
    End point timeframe
    0 and 24 weeks
    End point values
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline) Empagliflozin (24 weeks) Empagliflozin plus ERD (24 weeks) Placebo (24 weeks) Placebo plus ERD (24 weeks)
    Number of subjects analysed
    17
    17
    17
    17
    16
    17
    16
    14
    Units: kg
        arithmetic mean (standard deviation)
    34.8 ± 8.3
    35.0 ± 10.5
    37.4 ± 10.5
    36.4 ± 10.2
    33.9 ± 8.3
    30.6 ± 9.5
    36.9 ± 10.2
    32.8 ± 9.1
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Placebo plus ERD (24 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.033 [102]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -1.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.72
         upper limit
    		 -0.16
    Notes
    [102] - Not significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)
    Statistical analysis title
    		 GLM - empa vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin (24 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.264 [103]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.71
         upper limit
    		 0.74
    Notes
    [103] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 24wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 24 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin plus ERD (24 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [104]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -4.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.76
         upper limit
    		 -2.36
    Notes
    [104] - Significant

    Secondary: Lean mass - DEXA

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    End point title
    		 Lean mass - DEXA
    End point description
    Change in lean mass (measured using DEXA)
    End point type
    Secondary
    End point timeframe
    0 and 24 weeks
    End point values
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline) Empagliflozin (24 weeks) Empagliflozin plus ERD (24 weeks) Placebo (24 weeks) Placebo plus ERD (24 weeks)
    Number of subjects analysed
    17
    17
    17
    17
    16
    17
    16
    14
    Units: kg
        arithmetic mean (standard deviation)
    51.1 ± 13.0
    52.2 ± 11.1
    55.6 ± 9.9
    55.7 ± 11.5
    49.5 ± 12.4
    51.1 ± 10.8
    55.5 ± 9.8
    56.2 ± 11.3
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo plus ERD (24 weeks) v Placebo (24 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.428 [105]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 1.18
    Notes
    [105] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin (24 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [106]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.23
         upper limit
    		 -0.6
    Notes
    [106] - Significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 24wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 24 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin plus ERD (24 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [107]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.4
         upper limit
    		 -0.8
    Notes
    [107] - Significant

    Secondary: REE

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    End point title
    		 REE
    End point description
    Change in resting energy expenditure (REE) (measured using indirect calorimetry)
    End point type
    Secondary
    End point timeframe
    0, 2, 6, 12 and 24 weeks
    End point values
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline) Empagliflozin (2 weeks) Empagliflozin plus ERD (2 weeks) Placebo (2 weeks) Placebo plus ERD (2 weeks) Empagliflozin (6 weeks) Empagliflozin plus ERD (6 weeks) Placebo (6 weeks) Placebo plus ERD (6 weeks) Empagliflozin (12 weeks) Empagliflozin plus ERD (12 weeks) Placebo (12 weeks) Placebo plus ERD (12 weeks) Empagliflozin (24 weeks) Empagliflozin plus ERD (24 weeks) Placebo (24 weeks) Placebo plus ERD (24 weeks)
    Number of subjects analysed
    17
    17
    17
    17
    17
    17
    16
    15
    16
    16
    16
    14
    17
    17
    16
    14
    16
    17
    15
    13
    Units: kcal/day
        arithmetic mean (standard deviation)
    1469.9 ± 375.1
    1391.8 ± 408.4
    1500.5 ± 399.0
    1605.0 ± 423.5
    1461.8 ± 399.5
    1443.8 ± 269.5
    1528.8 ± 381.6
    1570.6 ± 431.5
    1484.5 ± 400.2
    1338.0 ± 429.9
    1611.9 ± 477.4
    1599.2 ± 430.4
    1467.6 ± 364.9
    1402.0 ± 377.6
    1537.1 ± 393.1
    1547.5 ± 359.9
    1446.5 ± 385.9
    1397.7 ± 362.5
    1606.6 ± 335.4
    1667.2 ± 402.8
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Placebo plus ERD (24 weeks)
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.545 [108]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -58.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -249.44
         upper limit
    		 131.71
    Notes
    [108] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin (24 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.143 [109]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -133.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -311.28
         upper limit
    		 44.84
    Notes
    [109] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 24wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 24 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin plus ERD (24 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05 [110]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -176.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -351.85
         upper limit
    		 -0.21
    Notes
    [110] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Placebo plus ERD (12 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.361 [111]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -72.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -228.17
         upper limit
    		 83.09
    Notes
    [111] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin (12 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.534 [112]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -46.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -193.31
         upper limit
    		 100.21
    Notes
    [112] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 12wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 12 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin plus ERD (12 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.493 [113]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -51.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -199.06
         upper limit
    		 95.81
    Notes
    [113] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 6weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Placebo plus ERD (6 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.633 [114]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -62.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -317.62
         upper limit
    		 193.15
    Notes
    [114] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin (6 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.385 [115]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -108.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -353.86
         upper limit
    		 136.47
    Notes
    [115] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 6wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 6 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin plus ERD (6 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.045 [116]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -250.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -495.64
         upper limit
    		 -5.79
    Notes
    [116] - Not significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Placebo plus ERD (2 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.958 [117]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -5.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -199.79
         upper limit
    		 189.33
    Notes
    [117] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin (2 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.62 [118]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -47.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -235.22
         upper limit
    		 140.15
    Notes
    [118] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 2wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 2 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin plus ERD (2 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.875 [119]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -15.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -203.6
         upper limit
    		 173.46
    Notes
    [119] - Not significant

    Secondary: Physical activity - Daily steps

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    End point title
    		 Physical activity - Daily steps
    End point description
    Change in daily steps (measured using wrist-worn accelerometer)
    End point type
    Secondary
    End point timeframe
    0, 6, 12 and 24 weeks
    End point values
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline) Empagliflozin (6 weeks) Empagliflozin plus ERD (6 weeks) Placebo (6 weeks) Placebo plus ERD (6 weeks) Empagliflozin (12 weeks) Empagliflozin plus ERD (12 weeks) Placebo (12 weeks) Placebo plus ERD (12 weeks) Empagliflozin (24 weeks) Empagliflozin plus ERD (24 weeks) Placebo (24 weeks) Placebo plus ERD (24 weeks)
    Number of subjects analysed
    17
    17
    17
    17
    16
    15
    17
    10
    16
    16
    17
    13
    15
    14
    16
    13
    Units: steps/day
        arithmetic mean (standard deviation)
    5952.1 ± 2283.8
    5819.0 ± 2402.0
    5347.6 ± 2213.9
    5155.7 ± 2335.8
    5255.4 ± 1614.2
    6503.8 ± 2563.1
    6384.0 ± 3188.4
    6064.4 ± 2992.8
    5838.1 ± 1708.3
    6261.3 ± 2500.5
    5549.0 ± 2251.1
    6435.5 ± 3159.9
    5234.2 ± 1650.0
    6722.4 ± 2924.9
    5822.4 ± 2312.4
    6355.1 ± 2239.4
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Placebo plus ERD (24 weeks)
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.363 [120]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    604.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -697.64
         upper limit
    		 1905.9
    Notes
    [120] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin (24 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.209 [121]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -799.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2046.99
         upper limit
    		 447.07
    Notes
    [121] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 24wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 24 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin plus ERD (24 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.375 [122]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    573.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -694.97
         upper limit
    		 1842.79
    Notes
    [122] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Placebo plus ERD (12 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.339 [123]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    507.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -531.65
         upper limit
    		 1546.02
    Notes
    [123] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin (12 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.737 [124]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -167.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1144.49
         upper limit
    		 809.94
    Notes
    [124] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 12wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 24 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin plus ERD (12 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.919 [125]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    50.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -922.41
         upper limit
    		 1022.73
    Notes
    [125] - Not significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Placebo plus ERD (6 weeks)
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.628 [126]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -318.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1607.36
         upper limit
    		 970.59
    Notes
    [126] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin (6 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.018 [127]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -1410.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2580.31
         upper limit
    		 -241.24
    Notes
    [127] - Not significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 6wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 6 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin plus ERD (6 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.454 [128]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -436.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1580.43
         upper limit
    		 707.03
    Notes
    [128] - Not significant

    Secondary: HbA1c

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    End point title
    		 HbA1c
    End point description
    Change in HbA1c
    End point type
    Secondary
    End point timeframe
    0, 2, 6, 12 and 24 weeks
    End point values
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline) Empagliflozin (2 weeks) Empagliflozin plus ERD (2 weeks) Placebo (2 weeks) Placebo plus ERD (2 weeks) Empagliflozin (6 weeks) Empagliflozin plus ERD (6 weeks) Placebo (6 weeks) Placebo plus ERD (6 weeks) Empagliflozin (12 weeks) Empagliflozin plus ERD (12 weeks) Placebo (12 weeks) Placebo plus ERD (12 weeks) Empagliflozin (24 weeks) Empagliflozin plus ERD (24 weeks) Placebo (24 weeks) Placebo plus ERD (24 weeks)
    Number of subjects analysed
    17
    17
    17
    17
    14
    17
    17
    13
    15
    14
    16
    13
    16
    17
    16
    14
    16
    17
    16
    14
    Units: percent
        arithmetic mean (standard deviation)
    6.9 ± 0.8
    6.8 ± 0.5
    7.1 ± 0.6
    6.9 ± 0.5
    6.8 ± 0.7
    6.7 ± 0.5
    7.0 ± 0.5
    6.8 ± 0.4
    6.6 ± 0.5
    6.5 ± 0.4
    6.9 ± 0.6
    6.5 ± 0.5
    6.4 ± 0.4
    6.3 ± 0.4
    6.9 ± 0.6
    6.5 ± 0.8
    6.6 ± 0.4
    6.5 ± 0.5
    7.1 ± 0.7
    6.8 ± 0.9
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Placebo plus ERD (24 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.626 [129]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.47
         upper limit
    		 0.28
    Notes
    [129] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin (24 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.041 [130]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.74
         upper limit
    		 -0.02
    Notes
    [130] - Not significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 24wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 24 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin plus ERD (24 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.021 [131]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.78
         upper limit
    		 -0.06
    Notes
    [131] - Not significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Placebo plus ERD (12 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06 [132]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.72
         upper limit
    		 0.01
    Notes
    [132] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin (12 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009 [133]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.82
         upper limit
    		 -0.12
    Notes
    [133] - Significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 12wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 12 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin plus ERD (12 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006 [134]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.84
         upper limit
    		 -0.14
    Notes
    [134] - Significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Placebo plus ERD (6 weeks)
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015 [135]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.44
         upper limit
    		 -0.05
    Notes
    [135] - Significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin (6 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008 [136]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 -0.07
    Notes
    [136] - Significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 6wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 6 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin plus ERD (6 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [137]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 -0.12
    Notes
    [137] - Significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Placebo plus ERD (2 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.034 [138]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 -0.01
    Notes
    [138] - Not significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)
    Statistical analysis title
    		 GLM - empa vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin (2 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.221 [139]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.04
    Notes
    [139] - Not significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 2wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 2 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin plus ERD (2 weeks)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.058 [140]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 0
    Notes
    [140] - Not significant

    Secondary: Fasting plasma glucose

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    End point title
    		 Fasting plasma glucose
    End point description
    Change in fasting plasma glucose
    End point type
    Secondary
    End point timeframe
    0, 2, 6, 12 and 24 weeks
    End point values
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline) Empagliflozin (2 weeks) Empagliflozin plus ERD (2 weeks) Placebo (2 weeks) Placebo plus ERD (2 weeks) Empagliflozin (6 weeks) Empagliflozin plus ERD (6 weeks) Placebo (6 weeks) Placebo plus ERD (6 weeks) Empagliflozin (12 weeks) Empagliflozin plus ERD (12 weeks) Placebo (12 weeks) Placebo plus ERD (12 weeks) Empagliflozin (24 weeks) Empagliflozin plus ERD (24 weeks) Placebo (24 weeks) Placebo plus ERD (24 weeks)
    Number of subjects analysed
    17
    17
    17
    17
    16
    16
    17
    14
    17
    15
    17
    12
    15
    16
    17
    13
    16
    17
    16
    13
    Units: mmol/L
        arithmetic mean (standard deviation)
    6.4 ± 1.1
    6.6 ± 1.1
    7.3 ± 1.4
    6.8 ± 1.3
    5.9 ± 1.0
    5.6 ± 0.8
    6.9 ± 1.3
    6.4 ± 1.0
    5.6 ± 1.1
    5.4 ± 0.5
    6.9 ± 1.2
    6.5 ± 1.1
    5.6 ± 0.8
    5.5 ± 0.6
    7.0 ± 1.0
    6.7 ± 1.1
    5.6 ± 0.8
    5.3 ± 0.6
    6.9 ± 1.4
    6.5 ± 1.2
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo plus ERD (24 weeks) v Placebo (24 weeks)
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.872 [141]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.63
         upper limit
    		 0.53
    Notes
    [141] - Not significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 24wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 24 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin (24 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [142]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.44
         upper limit
    		 -0.31
    Notes
    [142] - Significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 24wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 24 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (24 weeks) v Empagliflozin plus ERD (24 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [143]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.78
         upper limit
    		 -0.69
    Notes
    [143] - Significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Placebo plus ERD (12 weeks)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.923 [144]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.61
         upper limit
    		 0.55
    Notes
    [144] - Not Significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 12wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 12 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin (12 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [145]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.57
         upper limit
    		 -0.42
    Notes
    [145] - Significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 12wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 12 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (12 weeks) v Empagliflozin plus ERD (12 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [146]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 -0.69
    Notes
    [146] - Significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Placebo plus ERD (6 weeks)
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.305 [147]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.73
         upper limit
    		 0.23
    Notes
    [147] - Not Significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 6wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 6 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin (6 weeks)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [148]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.22
         upper limit
    		 -0.32
    Notes
    [148] - Significant
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 6wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 6 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (6 weeks) v Empagliflozin plus ERD (6 weeks)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [149]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.51
         upper limit
    		 -0.59
    Notes
    [149] - Significant
    Statistical analysis title
    		 GLM – placebo plus ERD vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of placebo plus diet vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Placebo plus ERD (2 weeks)
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.503 [150]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 0.26
    Notes
    [150] - Not Significant
    Statistical analysis title
    		 GLM - empa vs placebo @ 2wks
    Statistical analysis description
    Complete case generalized linear model analyses of empagliflozin 25mg vs placebo at 2 weeks; using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin (2 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.026 [151]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.83
         upper limit
    		 -0.05
    Notes
    [151] - Not Significant (note application of Holm's Sequential Bonferroni procedure to adjust for multiple comparisons)
    Statistical analysis title
    		 GLM – empa plus ERD vs placebo @ 2wks
    Statistical analysis description
    Generalized linear model analyses of empagliflozin 25mg plus ERD vs placebo at 2 weeks, using models with normal distribution, identity link and adjusted for randomization stratification factors (sex and BMI) and baseline value of outcome. Statistical significance was determined using Holm's Sequential Bonferroni procedure.
    Comparison groups
    Placebo (2 weeks) v Empagliflozin plus ERD (2 weeks)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [152]
    Method
    		 generalised linear model
    Parameter type
    		 adjusted beta co-efficient
    Point estimate
    -0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.12
         upper limit
    		 -0.35
    Notes
    [152] - Significant

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Randomisation to 5 days post last dose (up to 25 weeks).
    Adverse event reporting additional description
    At each visit the study Investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the study Investigator was recorded, irrespective if the relation to study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Empagliflozin (Baseline)
    Reporting group description
    		 Empagliflozin (Jardiance™) 25mg once daily

    Reporting group title
    Empagliflozin plus ERD (Baseline)
    Reporting group description
    		 Empagliflozin (Jardiance™) 25mg once daily and energy restriction diet (ERD)

    Reporting group title
    Placebo (baseline)
    Reporting group description
    		 The placebo was labelled as ‘25mg once daily’ to match the IMP.

    Reporting group title
    Placebo plus ERD (baseline)
    Reporting group description
    		 Placebo and energy restriction diet (ERD)

    Serious adverse events
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    1 / 17 (5.88%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    General disorders and administration site conditions
    Pyrexia
    Additional description: Participant reported two hospital admissions for the investigation and treatment of pyrexia. Minimal information provided to the study team.
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Exacerbation of Asthma
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Empagliflozin (Baseline) Empagliflozin plus ERD (Baseline) Placebo (baseline) Placebo plus ERD (baseline)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 17 (35.29%)
    7 / 17 (41.18%)
    8 / 17 (47.06%)
    8 / 17 (47.06%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    Thirst
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Productive cough
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Depressed mood
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Fibula fracture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Fall (Mechanical)
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    Head injury
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Muscle strain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Splinter
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Thermal burn
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dizziness postural
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Presyncope
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    0
    1
    Blood and lymphatic system disorders
    Normocytic anaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Eye swelling
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lacrimination increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Visual impairment
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    3 / 17 (17.65%)
         occurrences all number
    0
    0
    1
    3
    Constipation
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Toothache
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 17 (11.76%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dysuria
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Micturition urgency
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Joint swelling
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Plantar fasciitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 17 (0.00%)
    2 / 17 (11.76%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 17 (17.65%)
    2 / 17 (11.76%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
         occurrences all number
    3
    2
    1
    0
    Viral infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Gout
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Iron deficiency
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 17 (5.88%)
    0 / 17 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Apr 2016
    Protocol Amendment:- Amendment to the stratification criteria to remove ‘sex’. Update to safety reporting procedures following the receipt of a Direct Healthcare Professional Communication report (dated 21st March 2016) regarding diabetic ketoacidosis and the use of Empagliflozin. Exclusion criteria updated to reflect safety information and diabetic ketoacidosis included as an Adverse Events of Special Interest.
    29 Jun 2016
    Protocol Amendment:- Inclusion and exclusion criteria amended to widen HbA1c range and increase upper age limit. Change to breakfast standardisation; standardised breakfast meal to represent 33.3% of daily energy requirement as opposed to 30%. Clarification provided regarding the timing of samples collected at visits 1-5; 1 fasting sample and 6 samples after the standardised breakfast meal. Change to wording in section 8.5 (investigations) which references the timing of indirect calorimetry assessment; assessment performed at visit 1 not visit 0. Change to the timing of provision of baseline activity monitors to participants; monitors to be given at visit 0 not visit 1. Study measures added to table 1 (scheduled of assessments) for clarity. Clarification providing regarding the visit window between visit 0 and visit 1. Boehringer Ingelheim added to the reporting procedure for SAE. Additional recruitment activity in primary care added to recruitment strategy section. Minor amendment to randomisation and code breaking section to change description of placebo/IMP from ‘capsules’ to ‘tablets’.
    29 Sep 2016
    Protocol Amendment:- Removal of study contact details from the front cover of the protocol. Change of name from Project Management Committee to Trial Management Group. Trial Summary updated to more accurately reflect visit length. Exclusion criteria updated to allow any future emerging safety concerns to be addressed without compromising participant safety. Treatment Management section updated to include information on acute kidney injury. Amendment to the number and timing of blood samples collected during study visits 1-5. Addition of information regarding storage of blood samples for future research.
    08 Feb 2017
    Protocol Amendment:- Exclusion criteria amended to exclude rotating day/night shift workers, as well as to allow investigators to use clinical judgement in assessing excessive alcohol consumption. Addition of increased Lower Limb Amputation to the section on Adverse Events of Special Interest (AESI). Addition of a follow-up telephone call within 1 week (+/-3days) of medication completion to capture any potential Adverse Events during the drug wash-out period. Amendment to recruitment strategy allowing for more strategies to be adopted. Amendment to the visit window in which screening bloods results can be used from 6 to 3 months prior to study visit. Clarification of the use of indirect calorimeter for determining participants’ daily energy requirement. Amendment to the time required for inclinometer wear from 8 to 9 days.
    20 Mar 2018
    Protocol Amendment:- Visit window for visits 1-5 and end of study telephone call amended (widened to +/-5 days) to allow flexibility with appointment booking and reduce protocol deviations. Amendment to the wording within the 24 hour Meal Standardisation section to reflect current practice; all participants will consume a standardised evening meal provided to them at least 10 hours before their visit. Amendment to the physical activity section to allow for flexibility with provision of monitors. The study team chose to avoid these holiday periods, as it is not habitual behaviour.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None
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