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    Clinical Trial Results:
    The separate and combined effects of long-term GIP and GLP-1 receptor activation in patients with type 2 diabetes

    Summary
    EudraCT number
    		 2020-004774-22
    Trial protocol
    		 DK  
    Global end of trial date
    06 Jan 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jul 2026
    First version publication date
    03 Jul 2026
    Other versions
    Summary report(s)
    		 Helsted et al. 2026

    Trial information

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    Trial identification
    Sponsor protocol code
    GIP-SEMA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05078255
    WHO universal trial number (UTN)
    		 U1111-1259-1491
    Sponsors
    Sponsor organisation name
    Center for Clinical Metabolic Research
    Sponsor organisation address
    Gentofte Hospitalsvej 7, Hellerup, Denmark, 2900
    Public contact
    Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, +45 3867 2461, Asger.Lund.01@regionh.dk
    Scientific contact
    Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, +45 3867 2461, Asger.Lund.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
    30 Jun 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Jan 2025
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jan 2025
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The present study will evaluate the glucose-lowering effect (assessed by continuous glucose monitoring (CGM)) of the native hormone GIP in the context of pharmacological GLP-1 receptor activation in patients with type 2 diabetes. We hypothesise that long-term GLP-1 receptor agonism during concomitant GIP receptor agonism will disclose new physiological insights into glucose homeostasis and body weight regulation that may be used therapeutically in the future.
    Protection of trial subjects
    Subjects kept a trial diary where adverse effects were documented. At safety visits during the trial, the diary was assessed and a medical examination conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jan 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 61
    Worldwide total number of subjects
    61
    EEA total number of subjects
    61
    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)
    32
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between January 31, 2022, and September 4, 2024, we assessed 134 individuals for eligibility and enrolled 61 participants, who were randomly assigned to treatment regimens: 15 participants, placebo + placebo; 16 participants, placebo + GIP; 15 participants, semaglutide + placebo; 15 participants, semaglutide + GIP.

    Pre-assignment
    Screening details
    		 Inclusion criteria: 18-74 years of age; type 2 diabetes for at least six months; stable treatment with diet and exercise and/or any combination of stable treatment with metformin, sodium-glucose cotransporter 2 inhibitors, DPP-4 inhibitors, and sulphonylurea; glycated haemoglobin A1C of 6·5-10·5%; body mass index of 25-50 kg/m²; stable body weight.

    Period 1
    Period 1 title
    Baseline (before intervention)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study is a double-blinded, randomised (1:1:1:1), placebo-controlled, clinical trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1) placebo + placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    No treatment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Not assigned
    Routes of administration
    Not mentioned
    Dosage and administration details
    None - No treatment.

    Arm title
    		 2) placebo + GIP
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    No treatment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Not assigned
    Routes of administration
    Not mentioned
    Dosage and administration details
    None - No treatment.

    Arm title
    		 3) semaglutide + placebo
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    No treatment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Not assigned
    Routes of administration
    Not mentioned
    Dosage and administration details
    None - No treatment.

    Arm title
    		 4) semaglutide + GIP
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    No treatment
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Not assigned
    Routes of administration
    Not mentioned
    Dosage and administration details
    None - No treatment.

    Number of subjects in period 1
    		1) placebo + placebo 2) placebo + GIP 3) semaglutide + placebo 4) semaglutide + GIP
    Started
    15
    16
    15
    15
    Completed
    15
    16
    15
    15
    Period 2
    Period 2 title
    Overall trial
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    The study is a double-blinded, randomised (1:1:1:1), placebo-controlled, clinical trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1) placebo + placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    same as active

    Investigational medicinal product name
    saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    same as active comparator

    Arm title
    		 2) placebo + GIP
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    glucose-dependent insulinotropic polypeptide 1-42
    Investigational medicinal product code
    Other name
    GIP
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    16 pmol/kg/min continous subcutaneous infusion for six weeks

    Investigational medicinal product name
    saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    same as active

    Arm title
    		 3) semaglutide + placebo
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    semglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mg once weekly subcutaneous injection

    Arm title
    		 4) semaglutide + GIP
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    semglutide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    0.5 mg once weekly subcutaneous injection

    Investigational medicinal product name
    glucose-dependent insulinotropic polypeptide 1-42
    Investigational medicinal product code
    Other name
    GIP
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    16 pmol/kg/min continous subcutaneous infusion for six weeks

    Number of subjects in period 2
    		1) placebo + placebo 2) placebo + GIP 3) semaglutide + placebo 4) semaglutide + GIP
    Started
    15
    16
    15
    15
    Completed
    14
    8
    14
    15
    Not completed
    1
    8
    1
    0
         Consent withdrawn by subject
    1
    8
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline (before intervention)
    Reporting group description
    		 -

    Reporting group values
    		 Baseline (before intervention) Total
    Number of subjects
    		 61 61
    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)
    		 32 32
        From 65-84 years
    		 29 29
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 22 22
        Male
    		 39 39

    End points

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    End points reporting groups
    Reporting group title
    1) placebo + placebo
    Reporting group description
    		 -

    Reporting group title
    2) placebo + GIP
    Reporting group description
    		 -

    Reporting group title
    3) semaglutide + placebo
    Reporting group description
    		 -

    Reporting group title
    4) semaglutide + GIP
    Reporting group description
    		 -
    Reporting group title
    1) placebo + placebo
    Reporting group description
    		 -

    Reporting group title
    2) placebo + GIP
    Reporting group description
    		 -

    Reporting group title
    3) semaglutide + placebo
    Reporting group description
    		 -

    Reporting group title
    4) semaglutide + GIP
    Reporting group description
    		 -

    Primary: Change in 14-day mean glucose levels

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    End point title
    		 Change in 14-day mean glucose levels
    End point description
    For the primary endpoint, mean changes of sensor-detected glucose from baseline to end-of-treatment for the two primary comparisons were similar. The effects of treatment with GIP regarding mean sensor-detected glucose from baseline to end-of-treatment were estimated to 0·80 mmol/L (97·5% CI 0·18 to 1·80, p=0·13) (placebo + GIP vs. placebo + placebo) and 0·05 mmol/L (97·5% CI -0·85 to 0·95, p=1·00) (semaglutide + GIP vs. semaglutide + placebo), respectively.
    End point type
    Primary
    End point timeframe
    The primary endpoint is change in 14-day mean glucose levels (assessed by blinded CGM) during the last 14 days of the intervention period as compared to 14-day mean glucose levels during the last 14 days of the run-in period.
    End point values
    		 1) placebo + placebo 2) placebo + GIP 3) semaglutide + placebo 4) semaglutide + GIP 1) placebo + placebo 2) placebo + GIP 3) semaglutide + placebo 4) semaglutide + GIP
    Number of subjects analysed
    15
    15
    15
    15
    15
    16
    15
    15
    Units: mmol/L
        arithmetic mean (standard deviation)
    9.1 ( 2.4 )
    8.4 ( 1.7 )
    8.3 ( 1.2 )
    8.8 ( 1.3 )
    8.4 ( 1.6 )
    8.9 ( 1.6 )
    6.5 ( 0.5 )
    6.8 ( 1.4 )
    Statistical analysis title
    		 constrained linear mixed model
    Comparison groups
    4) semaglutide + GIP v 1) placebo + placebo v 2) placebo + GIP v 3) semaglutide + placebo
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 ≤ 97.5
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Secondary: Secondary endpoints - Glycaemic variability

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    End point title
    		 Secondary endpoints - Glycaemic variability
    End point description
    For glycaemic variability (coefficient of variance of CGM measurements), time in glycaemic ranges, HbA1C, body weight, waist circumference, systolic blood pressure, and heart rate there were no differences regarding the two primary comparisons.
    End point type
    Secondary
    End point timeframe
    Glycaemic variability will be assessed by 14-day coefficient of variance (CV) of glucose levels (assessed by CGM) during the last 14 days of the intervention period as compared to 14-day CV of glucose levels during the last 14 days of the run-in period.
    End point values
    		 1) placebo + placebo 2) placebo + GIP 3) semaglutide + placebo 4) semaglutide + GIP 1) placebo + placebo 2) placebo + GIP 3) semaglutide + placebo 4) semaglutide + GIP
    Number of subjects analysed
    15
    16
    15
    15
    15
    16
    15
    15
    Units: %
        number (not applicable)
    22
    22
    21
    22
    22
    21
    18
    20
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall trial
    Adverse event reporting additional description
    The most common adverse event was injection site reaction to the GIP infusion. The injection site reaction was an inflammatory response localised to the injection site, characterised by redness, swelling, itching, and soreness. The severity of the reaction varied between participants but was generally mild to moderate.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Placebo + placebo
    Reporting group description
    		 -

    Reporting group title
    Placebo + GIP
    Reporting group description
    		 -

    Reporting group title
    Semaglutide + placebo
    Reporting group description
    		 -

    Reporting group title
    Semaglutide + GIP
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo + placebo Placebo + GIP Semaglutide + placebo Semaglutide + GIP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo + placebo Placebo + GIP Semaglutide + placebo Semaglutide + GIP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 15 (53.33%)
    9 / 16 (56.25%)
    11 / 15 (73.33%)
    12 / 15 (80.00%)
    General disorders and administration site conditions
    Injection site reaction to pump
         subjects affected / exposed
    2 / 15 (13.33%)
    7 / 16 (43.75%)
    2 / 15 (13.33%)
    11 / 15 (73.33%)
         occurrences all number
    3
    11
    6
    25
    Gastrointestinal disorders
    Any gastrointestinal adverse event
         subjects affected / exposed
    8 / 15 (53.33%)
    9 / 16 (56.25%)
    11 / 15 (73.33%)
    12 / 15 (80.00%)
         occurrences all number
    24
    22
    81
    59

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/42173109
    http://www.ncbi.nlm.nih.gov/pubmed/36849212
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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