Back to resultsDECREASE: Dapagliflozin Plus Exenatide on Central REgulation of Appetite in diabeteS typE 2 (DECREASE)
Primary Purpose
Type 2 Diabetes Mellitus, Obesity
Status
Completed
Phase
Phase 4
Locations
Netherlands
Study Type
Interventional
Intervention
Dapagliflozin 10mg
Exenatide
placebo exenatide
placebo dapagliflozin
Sponsored by
About this trial
This is an interventional treatment trial for Type 2 Diabetes Mellitus focused on measuring SGLT2 inhibition; dapagliflozin, GLP-1 receptor agonist; exenatide, Central satiety and reward circuits, bodyweight, brain
Eligibility Criteria
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
Sites / Locations
- Amsterdam UMC, location VU Medical Center
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Experimental
Active Comparator
Active Comparator
Placebo Comparator
Arm Label
SGLT2 inhibitor + GLP-1 receptor agonist
GLP-1 receptor agonist (exenatide) and placebo
SGLT2 inhibitor (dapagliflozin) and placebo
double placebo
Arm Description
dapagliflozin 10 mg tablet /day and exenatide twice daily subcutaneous injection (week 1-4; 5 microgram, week 5 -16; 10 microgram)
GLP-1 receptor agonist exenatide twice daily in combination with placebo dapagliflozin
SGLT2 inhibitor dapagliflozin 10 mg tablet /day in combination with placebo GLP-1 receptor agonist exenatide twice daily
placebo dapagliflozin and placebo exenatide twice daily
Outcomes
Primary Outcome Measures
Differences in neuronal activity in the central reward and satiety circuits in response to food-related stimuli by BOLD fMRI signal
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
Differences in neuronal activity in the central reward and satiety circuits in response to food-related stimuli by BOLD fMRI signal
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.
Feeding behaviour; ad libitum lunch buffet
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)
Feeding behaviour; ad libitum lunch buffet
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)
Self-reported hunger
Self-reported hunger, satiety and fullness and prospective food consumption will be rated on 100 mm visual analogue scales before and after the meal
Difference in resting energy expenditure measured by indirect calorimetry measurements
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)
Change in bodyweight (kg) and body mass index (kg/m2)
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)
Difference in bodycomposition measured by bio electrical impedance analysis and waist and hip circumference measurements (cm)
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)
Difference in resting brain activity by fMRI resting state measurements
Difference in resting brain activity by fMRI resting state measurements between groups (0-1.5, 0-16, 1.5-16)
Effect on cardiovascular autonomic balance by cardiovascular reflex test with finger plethysmography (Nexfin)
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)
Arterial stiffness: Pulse Wave analysis
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)
Renal measurements collecting 24 hour urine
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)
Laboratory parameters
Change in the plasma/serum biomarkers of metabolism, liver function, estimated renal function (eGFR), electrolytes, and haematocrit
Full Information
NCT ID
NCT03361098
First Posted
September 26, 2017
Last Updated
June 8, 2021
Sponsor
Amsterdam UMC, location VUmc
Collaborators
AstraZeneca
1. Study Identification
Unique Protocol Identification Number
NCT03361098
Brief Title
DECREASE: Dapagliflozin Plus Exenatide on Central REgulation of Appetite in diabeteS typE 2
Acronym
DECREASE
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
Study Type
Interventional
2. Study Status
Record Verification Date
June 2021
Overall Recruitment Status
Completed
Study Start Date
September 18, 2017 (Actual)
Primary Completion Date
November 25, 2019 (Actual)
Study Completion Date
March 25, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Amsterdam UMC, location VUmc
Collaborators
AstraZeneca
4. Oversight
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
Data Monitoring Committee
Yes
5. 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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes Mellitus, Obesity
Keywords
SGLT2 inhibition; dapagliflozin, GLP-1 receptor agonist; exenatide, Central satiety and reward circuits, bodyweight, brain
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Factorial Assignment
Masking
ParticipantInvestigator
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.
Allocation
Randomized
Enrollment
65 (Actual)
8. Arms, Groups, and Interventions
Arm Title
SGLT2 inhibitor + GLP-1 receptor agonist
Arm Type
Experimental
Arm Description
dapagliflozin 10 mg tablet /day and exenatide twice daily subcutaneous injection (week 1-4; 5 microgram, week 5 -16; 10 microgram)
Arm Title
GLP-1 receptor agonist (exenatide) and placebo
Arm Type
Active Comparator
Arm Description
GLP-1 receptor agonist exenatide twice daily in combination with placebo dapagliflozin
Arm Title
SGLT2 inhibitor (dapagliflozin) and placebo
Arm Type
Active Comparator
Arm Description
SGLT2 inhibitor dapagliflozin 10 mg tablet /day in combination with placebo GLP-1 receptor agonist exenatide twice daily
Arm Title
double placebo
Arm Type
Placebo Comparator
Arm Description
placebo dapagliflozin and placebo exenatide twice daily
Intervention Type
Drug
Intervention Name(s)
Dapagliflozin 10mg
Other Intervention Name(s)
SGLT2 inhibitor ; Forxiga
Intervention Description
Dapagliflozin 10mg oral tablet once daily
Intervention Type
Drug
Intervention Name(s)
Exenatide
Other Intervention Name(s)
GLP-1 receptor agonist ; Byetta
Intervention Description
Exenatide 5 microgram b.i.d. week 1-4 Exenatide 10 microgram b.i.d. week 5-16
Intervention Type
Other
Intervention Name(s)
placebo exenatide
Intervention Description
placebo b.i.d. exenatide
Intervention Type
Other
Intervention Name(s)
placebo dapagliflozin
Intervention Description
placebo tablets dapagliflozin
Primary Outcome Measure Information:
Title
Differences in neuronal activity in the central reward and satiety circuits in response to food-related stimuli by BOLD fMRI signal
Description
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.
Time Frame
at baseline, after 10 days and after 16 weeks
Secondary Outcome Measure Information:
Title
Differences in neuronal activity in the central reward and satiety circuits in response to food-related stimuli by BOLD fMRI signal
Description
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.
Time Frame
at baseline, after 10 days and after 16 weeks
Title
Feeding behaviour; ad libitum lunch buffet
Description
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)
Time Frame
at baseline, after 10 days and after 16 weeks
Title
Feeding behaviour; ad libitum lunch buffet
Description
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)
Time Frame
at baseline, after 10 days and after 16 weeks
Title
Self-reported hunger
Description
Self-reported hunger, satiety and fullness and prospective food consumption will be rated on 100 mm visual analogue scales before and after the meal
Time Frame
at baseline, after 10 days and after 16 weeks
Title
Difference in resting energy expenditure measured by indirect calorimetry measurements
Description
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)
Time Frame
at baseline, after 10 days and after 16 weeks
Title
Change in bodyweight (kg) and body mass index (kg/m2)
Description
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)
Time Frame
at baseline, after 10 days and after 16 weeks
Title
Difference in bodycomposition measured by bio electrical impedance analysis and waist and hip circumference measurements (cm)
Description
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)
Time Frame
at baseline, after 10 days and after 16 weeks
Title
Difference in resting brain activity by fMRI resting state measurements
Description
Difference in resting brain activity by fMRI resting state measurements between groups (0-1.5, 0-16, 1.5-16)
Time Frame
at baseline, after 10 days and after 16 weeks
Title
Effect on cardiovascular autonomic balance by cardiovascular reflex test with finger plethysmography (Nexfin)
Description
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)
Time Frame
at baseline, after 10 days and after 16 weeks
Title
Arterial stiffness: Pulse Wave analysis
Description
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)
Time Frame
at baseline, after 10 days and after 16 weeks
Title
Renal measurements collecting 24 hour urine
Description
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)
Time Frame
at baseline, after 10 days and after 16 weeks
Title
Laboratory parameters
Description
Change in the plasma/serum biomarkers of metabolism, liver function, estimated renal function (eGFR), electrolytes, and haematocrit
Time Frame
at baseline, after 10 days and after 16 weeks
Other Pre-specified Outcome Measures:
Title
Safety outcomes; Adverse events
Description
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
Time Frame
+/- 21 weeks
Title
Safety outcome; vital signs
Description
Vital signs: pulse rate, bloodpressure, body temperature
Time Frame
16 weeks
Title
Exploratory objective: Cerebral perfusion assessed by Arterial Spin Labeling
Description
Cerebral perfusion assessed by Arterial Spin Labeling between groups (0-1.5,0-16, 1.5-16)
Time Frame
16 weeks
Title
Exploratory objective: measurement of hormones
Description
blood will be collected to have the opportunity to perform measurements of hormones such as leptin, cortisol, ghrelin.
Time Frame
16 weeks
Title
Exploratory: Microbiome
Description
Fecal samples will be collected to determine the (change) microbiome
Time Frame
Baseline and after 16 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Richard G IJzerman, MD PhD
Organizational Affiliation
Amsterdam UMC, location VUmc
Official's Role
Principal Investigator
Facility Information:
Facility Name
Amsterdam UMC, location VU Medical Center
City
Amsterdam
State/Province
Noord-Holland
ZIP/Postal Code
1081 HV
Country
Netherlands
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual participant data that underlie the results, after de-identification
IPD Sharing Time Frame
Beginning 3 months and ending 2 years following article publication
IPD Sharing Access Criteria
Researchers who provide a methodologically sound proposal
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DECREASE: Dapagliflozin Plus Exenatide on Central REgulation of Appetite in diabeteS typE 2
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