DECREASE: Dapagliflozin Plus Exenatide on Central REgulation of Appetite in diabeteS typE 2

Sponsor
Amsterdam UMC, location VUmc (Other)
Overall Status
Completed
CT.gov ID
NCT03361098
Collaborator
AstraZeneca (Industry)
65
1
4
30.2
2.2

Study Details

Study Description

Brief Summary

This is a 16 week, phase 4, randomized and placebo controlled trial, investigating the separate and combined effects of Sodium Glucose coTransporter 2 (SGLT2) inhibition with dapagliflozin and Glucagon Like peptide-1 (GLP-1) receptor agonism with exenatide on food intake, body weight and the neural activity in the central satiety and reward circuits in response to food-related stimuli by blood oxygen level-dependent (BOLD) fMRI in obese type 2 diabetes patients. The investigators hypothesize that treatment with SGLT2 inhibitors is associated with alterations in central reward and satiety circuits in response to food related stimuli, leading to increased appetite and food intake. In addition, the investigators hypothesize that adding a GLP-1 receptor agonist to the treatment with an SGLT2 inhibitor may increase weight loss and prevent the increased food intake during treatment with SGLT2 inhibitors due to effects on neuronal activity of central satiety and reward circuits in response to food-related stimuli in obese patients with T2DM.

Condition or Disease Intervention/Treatment Phase
  • Drug: Dapagliflozin 10mg
  • Drug: Exenatide
  • Other: placebo exenatide
  • Other: placebo dapagliflozin
Phase 4

Detailed Description

The aim of this study is to investigate 1) the seperate and 2) combined actions of SGLT2 inhibition and GLP-1 receptor agonism on food intake, body weight and the activity within the central satiety and reward circuits in response to food-related stimuli and 3) wheter the combination with a GLP-1 receptor agonist can prevent the increased intake observed with SGLT2- inhibition treatment.

Methods: In four groups of obese patients with T2DM (n=16 per group), food intake and neuronal activity in relevant CNS circuits in response to food-related stimuli (using fMRI) will be investigated during 16 week treatment in a double blind placebo-controlled randomized trial with:1) SGLT2 inhibitor dapagliflozin 10 mg/day in combination with placebo GLP-1 receptor agonist exenatide twice daily, 2) GLP-1 receptor agonist exenatide twice daily in combination with placebo dapagliflozin, 3) combination of dapagliflozin 10 mg/day and exenatide twice daily, or 4) placebo dapagliflozin and placebo exenatide twice daily. To correlate changes in brain activity with subsequent feeding behavior, the investigators will measure food intake, self-reported hunger, satiety and mood, during a choice-buffet after the scanning.

Expected results: This project will gain insight into the CNS mechanisms underlying the the effects of seperate and combined treatment with SGLT2 inhibition and GLP-1 receptor agonism. Furthermore, this project will provide insight if combined treatment with a GLP-1 receptor agonist will prevent the increased intake, observed by treatment with an SGLT2 inhibitor, and if so, in the underlying (CNS) mechanisms. These findings may increase the understanding of the development of obesity and weight loss problems in obese and T2DM patients and may support the development of a balanced SGLT2 inhibitor/GLP-1 receptor agonist combination as a treatment strategy for obesity and T2DM.

Study Design

Study Type:
Interventional
Actual Enrollment :
65 participants
Allocation:
Randomized
Intervention Model:
Factorial Assignment
Masking:
Double (Participant, Investigator)
Masking Description:
Participants were treated in a double-dummy design. There was no difference in appearance between exenatide and placebo injections, or dapagliflozin and placebo tablets.
Primary Purpose:
Treatment
Official Title:
Combined Effects of SGLT2 Inhibition and GLP-1 Receptor Agonism on Food Intake, Body Weight and Central Satiety and Reward Circuits in Obese T2DM Patients
Actual Study Start Date :
Sep 18, 2017
Actual Primary Completion Date :
Nov 25, 2019
Actual Study Completion Date :
Mar 25, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: SGLT2 inhibitor + GLP-1 receptor agonist

dapagliflozin 10 mg tablet /day and exenatide twice daily subcutaneous injection (week 1-4; 5 microgram, week 5 -16; 10 microgram)

Drug: Dapagliflozin 10mg
Dapagliflozin 10mg oral tablet once daily
Other Names:
  • SGLT2 inhibitor ; Forxiga
  • Drug: Exenatide
    Exenatide 5 microgram b.i.d. week 1-4 Exenatide 10 microgram b.i.d. week 5-16
    Other Names:
  • GLP-1 receptor agonist ; Byetta
  • Active Comparator: GLP-1 receptor agonist (exenatide) and placebo

    GLP-1 receptor agonist exenatide twice daily in combination with placebo dapagliflozin

    Drug: Exenatide
    Exenatide 5 microgram b.i.d. week 1-4 Exenatide 10 microgram b.i.d. week 5-16
    Other Names:
  • GLP-1 receptor agonist ; Byetta
  • Other: placebo dapagliflozin
    placebo tablets dapagliflozin

    Active Comparator: SGLT2 inhibitor (dapagliflozin) and placebo

    SGLT2 inhibitor dapagliflozin 10 mg tablet /day in combination with placebo GLP-1 receptor agonist exenatide twice daily

    Drug: Dapagliflozin 10mg
    Dapagliflozin 10mg oral tablet once daily
    Other Names:
  • SGLT2 inhibitor ; Forxiga
  • Other: placebo exenatide
    placebo b.i.d. exenatide

    Placebo Comparator: double placebo

    placebo dapagliflozin and placebo exenatide twice daily

    Other: placebo exenatide
    placebo b.i.d. exenatide

    Other: placebo dapagliflozin
    placebo tablets dapagliflozin

    Outcome Measures

    Primary Outcome Measures

    1. Differences in neuronal activity in the central reward and satiety circuits in response to food-related stimuli by BOLD fMRI signal [at baseline, after 10 days and after 16 weeks]

      Differences in neuronal activity in the central reward and satiety circuits in response to food related stimuli by BOLD fMRI signal compared to baseline and 16 weeks of treatment between the exenatide + dapagliflozine, exenatide +placebo, dapagliflozin+placebo and double placebo arms.

    Secondary Outcome Measures

    1. Differences in neuronal activity in the central reward and satiety circuits in response to food-related stimuli by BOLD fMRI signal [at baseline, after 10 days and after 16 weeks]

      Differences in neuronal activity in the central reward and satiety circuits in response to food related stimuli by BOLD fMRI signal compared to baseline and 1.5 weeks of treatment and 1.5 and 16 weeks of treatment between the exenatide + dapagliflozine, exenatide +placebo, dapagliflozin+placebo and double placebo arms.

    2. Feeding behaviour; ad libitum lunch buffet [at baseline, after 10 days and after 16 weeks]

      Feeding behaviour, measured as quantitative (kcal) changes in food choice, during an ad libitum lunch buffet will be compared between the groups (at baseline and 1,5 week, baseline and 16 weeks and 1.5 and 16 weeks of treatment)

    3. Feeding behaviour; ad libitum lunch buffet [at baseline, after 10 days and after 16 weeks]

      Feeding behaviour, measured as qualitative (energy density as well as nutrient composition;carbohydrate/fat/protein) changes in food choice, during an ad libitum lunch buffet will be compared between the groups (at baseline and 1,5 week, baseline and 16 weeks and 1.5 and 16 weeks of treatment)

    4. Self-reported hunger [at baseline, after 10 days and after 16 weeks]

      Self-reported hunger, satiety and fullness and prospective food consumption will be rated on 100 mm visual analogue scales before and after the meal

    5. Difference in resting energy expenditure measured by indirect calorimetry measurements [at baseline, after 10 days and after 16 weeks]

      Difference in resting energy expenditure measured by indirect calorimetry measurements between the groups (baseline and 16 weeks, baseline and 1.5 weeks and 1.5 and 16 weeks of treatment)

    6. Change in bodyweight (kg) and body mass index (kg/m2) [at baseline, after 10 days and after 16 weeks]

      Change in bodyweight (kg) and body mass index (kg/m2) between the groups ( at baseline and 1,5 week, baseline and 16 weeks, 1.5 week and 16 weeks)

    7. Difference in bodycomposition measured by bio electrical impedance analysis and waist and hip circumference measurements (cm) [at baseline, after 10 days and after 16 weeks]

      Difference in bodycomposition measured by bio electrical impedance analysis and waist and hip circumference measurements (cm) between the groups (0-1.5, 0-16, 1.5-16)

    8. Difference in resting brain activity by fMRI resting state measurements [at baseline, after 10 days and after 16 weeks]

      Difference in resting brain activity by fMRI resting state measurements between groups (0-1.5, 0-16, 1.5-16)

    9. Effect on cardiovascular autonomic balance by cardiovascular reflex test with finger plethysmography (Nexfin) [at baseline, after 10 days and after 16 weeks]

      Effect on cardiovascular autonomic balance by cardiovascular reflex test with finger plethysmography (Nexfin) measuring bloodpressure, hartfrequency, ECG between the groups (0-16, 0-1.5, 1.5-16)

    10. Arterial stiffness: Pulse Wave analysis [at baseline, after 10 days and after 16 weeks]

      Arterial stiffness: Pulse Wave analysis will be assessed using the Sphygmocor system, a non-invasive system using applanation tonometry between the groups (0-16, 0-1.5, 1.5-16)

    11. Renal measurements collecting 24 hour urine [at baseline, after 10 days and after 16 weeks]

      Renal measurements collecting 24 hour urine; glucose excretion (0-1.5, 0-16, 1.5-16), creatinine clearance (0-1.5, 0-16, 1.5-16), tubular function; sodium excretion and urinary pH (0-1.5, 0-16, 1.5-16), renal damage markers albumin/creatinine ratio (0-1.5, 0-16, 1.5-16)

    12. Laboratory parameters [at baseline, after 10 days and after 16 weeks]

      Change in the plasma/serum biomarkers of metabolism, liver function, estimated renal function (eGFR), electrolytes, and haematocrit

    Other Outcome Measures

    1. Safety outcomes; Adverse events [+/- 21 weeks]

      Occurence of adverse events (as reported by the patient) starting at the informed consent untill 30 days after administration of the last dose of study medication

    2. Safety outcome; vital signs [16 weeks]

      Vital signs: pulse rate, bloodpressure, body temperature

    3. Exploratory objective: Cerebral perfusion assessed by Arterial Spin Labeling [16 weeks]

      Cerebral perfusion assessed by Arterial Spin Labeling between groups (0-1.5,0-16, 1.5-16)

    4. Exploratory objective: measurement of hormones [16 weeks]

      blood will be collected to have the opportunity to perform measurements of hormones such as leptin, cortisol, ghrelin.

    5. Exploratory: Microbiome [Baseline and after 16 weeks]

      Fecal samples will be collected to determine the (change) microbiome

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 75 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Age 18-75 years

    • BMI 27-40 kg/m2

    • Stable bodyweight (<5% reported change during the previous 3 months).

    • Diagnosed with T2DM > 3 months prior to screening

    • Treatment with metformin and/or sulphonylurea at a stable dose for at least 3 months.

    • HbA1c 7.0-10% for patients treated with metformin

    • HbA1c 7.5-10% for patients treated with metformin and/ or sulphonylurea

    • For women: post menopausal (excluding possible menstruation cycle effects)

    Exclusion Criteria:
    • GLP-1 based therapies, DDP-4 inhibitors, SGLT-2 inhibitors, thiazolidinediones or insulin within 3 months before screening

    • Weight-lowering agents within 3 months before screening.

    • Congestive heart failure (NYHA II-IV)

    • Chronic renal failure (glomerular filtration rate < 45 mL/min/1.73m2 per Modification of Diet in Renal Disease (MDRD))

    • Liver disease

    • History of gastrointestinal disorders (including gastroparese, pancreatitis and cholelithiasis)

    • Patients with MEN2 syndrome or history or family history of medullary thyroid carcinoma

    • Neurological illness

    • Malignancy (except for basal cell carcinoma)

    • History of major heart disease

    • History of major renal disease

    • Pregnancy or breast feeding

    • Implantable devices

    • Substance abuse

    • Addiction

    • Alcohol abuse (defined as: for men > 21 units/week, for women >14 units/week)

    • Smoking/ nicotine abuse (defined as: daily smoking / a daily use of nicotine)

    • Contra-indication for MRI, such as claustrophobia or pacemaker

    • psychiatric illnesses; mood disorders, eating disorders, anxiety disorders, schizophrenia and other psychotic disorders, dissociative disorders, somatoform disorders, delirium, dementia and other cognitive disorders

    • Chronic use of centrally acting agents or glucocorticoids within 2 weeks immediately prior to screening

    • Use of cytostatic or immune modulatory agents

    • History of allergy for exenatide or other GLP-1 RA

    • Participation in other studies

    • Individuals who have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry

    • Individuals who are investigator site personnel, directly affiliated with the study, or are immediate family of investigator site personnel directly affiliated with the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.

    • Individuals who have previously completed or withdrawn from this study or any other study investigating GLP-1 receptor agonist or dipeptidyl peptidase (DPP)-4 within 6 months

    • Visual disability, not correctable with glasses or contact lens

    • Individuals who, in the opinion of the investigator, are unsuitable in any other way to participate in this study

    • Poor commandment of the Dutch language or any (mental) disorder that precludes full understanding the purpose, instruction and hence participation in the study

    • Further exclusion criteria will be in compliance with the EMeA SPC of exenatide and dapagliflozin

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Amsterdam UMC, location VU Medical Center Amsterdam Noord-Holland Netherlands 1081 HV

    Sponsors and Collaborators

    • Amsterdam UMC, location VUmc
    • AstraZeneca

    Investigators

    • Principal Investigator: Richard G IJzerman, MD PhD, Amsterdam UMC, location VUmc

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    RG IJzerman, Principal Investigator, Amsterdam UMC, location VUmc
    ClinicalTrials.gov Identifier:
    NCT03361098
    Other Study ID Numbers:
    • DC2017DECREASE01
    First Posted:
    Dec 4, 2017
    Last Update Posted:
    Jun 11, 2021
    Last Verified:
    Jun 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    No
    Keywords provided by RG IJzerman, Principal Investigator, Amsterdam UMC, location VUmc
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jun 11, 2021