Obesity, Type 2 Diabetes Mellitus
Conditions
Keywords
SGLT2 inhibition; dapagliflozin, GLP-1 receptor agonist; exenatide, Central satiety and reward circuits, bodyweight, brain
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.
Interventions
DRUGDapagliflozin 10mg
Dapagliflozin 10mg oral tablet once daily
DRUGExenatide
Exenatide 5 microgram b.i.d. week 1-4 Exenatide 10 microgram b.i.d. week 5-16
OTHERplacebo exenatide
placebo b.i.d. exenatide
OTHERplacebo dapagliflozin
placebo tablets dapagliflozin
Sponsors
AstraZeneca
Amsterdam UMC, location VUmc
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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) |
| 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) |
| 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) |
| 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) |
| 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) |
| 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. |
| 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) |
| 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 |
| 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) |
| 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) |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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. |
| Exploratory: Microbiome | Baseline and after 16 weeks | Fecal samples will be collected to determine the (change) microbiome |
| Safety outcome; vital signs | 16 weeks | Vital signs: pulse rate, bloodpressure, body temperature |
| 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 |
Countries
Netherlands
Outcome results
None listed