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    Clinical Trial Results:
    The impact of liraglutide on glucose tolerance and the risk of type 2 diabetes in women with previous gestational diabetes mellitus

    Summary
    EudraCT number
    		 2012-001371-37
    Trial protocol
    		 DK  
    Global end of trial date
    04 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jun 2021
    First version publication date
    25 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GDM-TREAT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Steno Diabetes Center Copenhagen
    Sponsor organisation address
    Gentofte Hospitalsvej 1, Hellerup, Denmark, 2900
    Public contact
    Center for diabetesforskning, Gentofte Hospital, University of Copenhagen, 45 38672461, emilie.skytte.andersen@regionh.dk
    Scientific contact
    Center for diabetesforskning, Gentofte Hospital, University of Copenhagen, 61685006 38672461, emilie.skytte.andersen@regionh.dk
    Sponsor organisation name
    Steno Diabetes Center Copenhagen
    Sponsor organisation address
    Gentofte Hospitalsvej 1, Hellerup, Denmark, 2900
    Public contact
    Tina Vilsbøll, Steno Diabetes Center Copenhagen, 0045 40940825, tina.vilsboell.01@regionh.dk
    Scientific contact
    Tina Vilsbøll, Steno Diabetes Center Copenhagen, 0045 40940825, tina.vilsboell.01@regionh.dk
    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
    19 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the effect of the glucagon-like peptide-1 receptor agonist liraglutide on patophysiological characteristics and the risk of type 2 diabetes mellitus in women with previous gestational diabetes mellitus (GDM).
    Protection of trial subjects
    This study is not considered as having any ethical problems. The treatment is associated with minimal discomfort for the participating patients comprising blood sample collection, daily injection of liraglutide (Victoza®) or placebo in the subcutis of the abdomen, in the thigh or the upper arm. Common adverse events are mild to moderate transient gastrointestinal symptoms (nausea, vomiting and diarrhoea) affecting around 10-15% of treated patients and headache. The injection is practically pain-free but may leave a small haemorrhage. This will resolve on its own. Less commonly, the patients may experience stomach pain, constipation, fever, reflux, gastritis, dizziness, tiredness and upper airway infection. Uncommon adverse events comprise struma (in patients with existing thyroid adenoma) and angioedema (very uncommon 0.05%). When collecting blood, some patients may experience minor discomfort when the needle penetrates the skin and rarely a small bleeding occurs. The amount of blood collected during the entire study period is a maximum of 1800 ml (during 5 years) and only patients with a normal blood percent will be included. Severe systemic AEs are not expected. Dexa scanning will be performed three times during the study with the object of determining the distribution of bone and adipose tissue. Such an examination results in a modest radiation dosis (approximately equivalent to 2-3 times the dose received from a dental X-ray). Dexa scanning takes 15 minutes and is a painless procedure with no expected side effects. The patients will receive thorough verbal and written information about the risk of developing the mentioned AEs. Verbal and written informed consent will be obtained from patients prior to participation in accordance with current rules. It will be emphasized in the declaration of consent that participation in the project is voluntary and that patients may withdraw their consent to participate at any time without providing a reason and wit
    Background therapy
    		 Liraglutide (Victoza®) is supplied in pens for injection containing 18 mg of the GLP-1 agonist liraglutide in 3 ml sterile water with disodiumphosphate and propylenglycol, and phenol for conservation (pH 8.15). Commercial pens will be used and the information given in the packaging will be applicable. The initial daily dose will be 0.6 mg for one week, thereafter, the dose will be titrated once-weekly (by 0.6 mg) up to 1.8 mg (after 2 weeks) for the remaining treatment period. Patients who do not tolerate injections of liraglutide 1.8 mg will be allowed to continue on the maximally tolerated dose. The injection is administered once daily in the morning. The maximal plasma concentration is reached 8-12 hours after s.c. injection (21). The half-life in plasma is approximately 13 hours and the duration of effect is 24 hours. The placebo pens contain the same as the Victoza® pens except from the GLP-1 analogue and are administered in the same way and volume as liraglutide. The placebo pens are specially prepared for this study and will be used in the study only.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Aug 2012
    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
    Denmark: 105
    Worldwide total number of subjects
    105
    EEA total number of subjects
    105
    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)
    105
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Women with previous gestational diabetes mellitus were invited to participate in the study (n=2418). They were recruited from the three major obstetric departmens in the Capital region of Denmark. All eligible women (n=121) were screened between september 2012 and august 2014 and 105 women were randomised.

    Pre-assignment
    Screening details
    		 The women were fasting (10 hours) including water, coffea, medication and tobacco. We meassured height, waist, hip-circumference, weight, Blodd pressure, urine , basic blood sampling and medical history was obtained.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Women with previous GDM randomised to recieve placebo injection with saline during the first double-blinded year of the study. The placebo pens was specially prepared for this study and was only used in the study.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    s
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Plascebo injections with saline in 1.8 mg

    Arm title
    		 Liraglutide
    Arm description
    		 Overweight women with previous gestational diabetes mellitus taken injections with active liraglutide 1.8 mg . Liraglutide (Victoza®) is supplied in pens for injection containing 18 mg of the GLP-1 agonist liraglutide in 3 ml sterile water with disodiumphosphate and propylenglycol, and phenol for conservation (pH 8.15). Commercial pens will be used and the information given in the packaging will be applicable. The initial daily dose will be 0.6 mg for one week, thereafter, the dose will be titrated once-weekly (by 0.6 mg) up to 1.8 mg (after 2 weeks) for the remaining treatment period. Patients who do not tolerate injections of liraglutide 1.8 mg will be allowed to continue on the maximally tolerated dose. The injection is administered once daily in the morning. The maximal plasma concentration is reached 8-12 hours after s.c. injection. The half-life in plasma is approximately 13 hours and the duration of effect is 24 hours.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Victoza
    Investigational medicinal product code
    Other name
    s
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Liraglutide (Victoza®) is supplied in pens for injection containing 18 mg of the GLP-1 agonist liraglutide in 3 ml sterile water with disodiumphosphate and propylenglycol, and phenol for conservation (pH 8.15). Commercial pens will be used and the information given in the packaging will be applicable. The initial daily dose will be 0.6 mg for one week, thereafter, the dose will be titrated once-weekly (by 0.6 mg) up to 1.8 mg (after 2 weeks) for the remaining treatment period. Patients who do not tolerate injections of liraglutide 1.8 mg will be allowed to continue on the maximally tolerated dose. The injection is administered once daily in the morning. The maximal plasma concentration is reached 8-12 hours after s.c. injection. The half-life in plasma is approximately 13 hours and the duration of effect is 24 hours.

    Number of subjects in period 1
    		Placebo Liraglutide
    Started
    55
    50
    Completed
    40
    28
    Not completed
    15
    22
         fear of adverse events
    -
    1
         Adverse event, non-fatal
    -
    2
         Other diseases
    2
    -
         Unknown
    2
    -
         Pregnancy
    -
    3
         type 2 diabetes
    1
    -
         unknown reason
    -
    5
         diseases not related to study drug
    -
    7
         Lack of compliance
    2
    -
         Lost to follow-up
    3
    1
         Personal issues
    5
    3
    Period 2
    Period 2 title
    5 year follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    the double-blinding stopped after one year after randomisation. the following 4 years have been open-labelled and unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    s
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Plascebo injections with saline in 1.8 mg

    Arm title
    		 Liraglutide
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Victoza
    Investigational medicinal product code
    Other name
    s
    Pharmaceutical forms
    Dispersion for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Liraglutide (Victoza®) is supplied in pens for injection containing 18 mg of the GLP-1 agonist liraglutide in 3 ml sterile water with disodiumphosphate and propylenglycol, and phenol for conservation (pH 8.15). Commercial pens will be used and the information given in the packaging will be applicable. The initial daily dose will be 0.6 mg for one week, thereafter, the dose will be titrated once-weekly (by 0.6 mg) up to 1.8 mg (after 2 weeks) for the remaining treatment period. Patients who do not tolerate injections of liraglutide 1.8 mg will be allowed to continue on the maximally tolerated dose. The injection is administered once daily in the morning. The maximal plasma concentration is reached 8-12 hours after s.c. injection. The half-life in plasma is approximately 13 hours and the duration of effect is 24 hours.

    Number of subjects in period 2
    		Placebo Liraglutide
    Started
    40
    28
    Completed
    40
    28

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Women with previous GDM randomised to recieve placebo injection with saline during the first double-blinded year of the study. The placebo pens was specially prepared for this study and was only used in the study.

    Reporting group title
    Liraglutide
    Reporting group description
    		 Overweight women with previous gestational diabetes mellitus taken injections with active liraglutide 1.8 mg . Liraglutide (Victoza®) is supplied in pens for injection containing 18 mg of the GLP-1 agonist liraglutide in 3 ml sterile water with disodiumphosphate and propylenglycol, and phenol for conservation (pH 8.15). Commercial pens will be used and the information given in the packaging will be applicable. The initial daily dose will be 0.6 mg for one week, thereafter, the dose will be titrated once-weekly (by 0.6 mg) up to 1.8 mg (after 2 weeks) for the remaining treatment period. Patients who do not tolerate injections of liraglutide 1.8 mg will be allowed to continue on the maximally tolerated dose. The injection is administered once daily in the morning. The maximal plasma concentration is reached 8-12 hours after s.c. injection. The half-life in plasma is approximately 13 hours and the duration of effect is 24 hours.

    Reporting group values
    		 Placebo Liraglutide Total
    Number of subjects
    		 55 50 105
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 55 50 105
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.3 ( 4.9 ) 38.5 ( 4.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 55 50 105
        Male
    		 0 0 0
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 86.2 ( 10.6 ) 90.5 ( 19.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Women with previous GDM randomised to recieve placebo injection with saline during the first double-blinded year of the study. The placebo pens was specially prepared for this study and was only used in the study.

    Reporting group title
    Liraglutide
    Reporting group description
    		 Overweight women with previous gestational diabetes mellitus taken injections with active liraglutide 1.8 mg . Liraglutide (Victoza®) is supplied in pens for injection containing 18 mg of the GLP-1 agonist liraglutide in 3 ml sterile water with disodiumphosphate and propylenglycol, and phenol for conservation (pH 8.15). Commercial pens will be used and the information given in the packaging will be applicable. The initial daily dose will be 0.6 mg for one week, thereafter, the dose will be titrated once-weekly (by 0.6 mg) up to 1.8 mg (after 2 weeks) for the remaining treatment period. Patients who do not tolerate injections of liraglutide 1.8 mg will be allowed to continue on the maximally tolerated dose. The injection is administered once daily in the morning. The maximal plasma concentration is reached 8-12 hours after s.c. injection. The half-life in plasma is approximately 13 hours and the duration of effect is 24 hours.
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Liraglutide
    Reporting group description
    		 -

    Primary: Glucose tolerance

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    End point title
    		 Glucose tolerance
    End point description
    End point type
    Primary
    End point timeframe
    Glucose tolerance meassured as Area unde the curve for the 75g oral glucose tolerance test. We calculated the between group difference from baseline to 5-year to evaluate the effect from treatment with liraglutide and reported as differences from baseline
    End point values
    		 Placebo Liraglutide
    Number of subjects analysed
    40
    28
    Units: mmol/L*min
    arithmetic mean (confidence interval 95%)
        glucose tolerance
    123 (46.6 to 199)
    -69.2 (-160 to 21.6)
    Statistical analysis title
    		 Constrained liniar mixed model
    Comparison groups
    Placebo v Liraglutide
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Body weight

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    End point title
    		 Body weight
    End point description
    End point type
    Secondary
    End point timeframe
    Body weight was assesed at baseline and at five years follow-up. We calculated the between group difference from baseline to 5-year to evaluate the effect from treatment with liraglutide and reported as differences from baseline
    End point values
    Number of subjects analysed
    Units: kg
    arithmetic mean (confidence interval 95%)
        kg
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    We assesed adverse events throughout the complete study period, beeing from beginning of the randomisation to end of trial for each individual.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 No dictionary
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Liraglutide
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Liraglutide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 55 (0.00%)
    0 / 50 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo Liraglutide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 55 (45.45%)
    40 / 50 (80.00%)
    Nervous system disorders
    Fatigue
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 55 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    4
    Headache
         subjects affected / exposed
    4 / 55 (7.27%)
    4 / 50 (8.00%)
         occurrences all number
    4
    4
    General disorders and administration site conditions
    Marks on injection site
         subjects affected / exposed
    15 / 55 (27.27%)
    9 / 50 (18.00%)
         occurrences all number
    15
    9
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    9 / 55 (16.36%)
    23 / 50 (46.00%)
         occurrences all number
    9
    23
    Vomiting
         subjects affected / exposed
    0 / 55 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    Decreased appetite
         subjects affected / exposed
    3 / 55 (5.45%)
    6 / 50 (12.00%)
         occurrences all number
    3
    6
    Obstipation
         subjects affected / exposed
    2 / 55 (3.64%)
    8 / 50 (16.00%)
         occurrences all number
    2
    8
    Diarrhoea
         subjects affected / exposed
    5 / 55 (9.09%)
    5 / 50 (10.00%)
         occurrences all number
    5
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    The dropout rate is a limitation.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33036179
    http://www.ncbi.nlm.nih.gov/pubmed/28364253
    http://www.ncbi.nlm.nih.gov/pubmed/27810989
    http://www.ncbi.nlm.nih.gov/pubmed/24176797
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