Clinical trial NCT03361098: DECREASE: Dapagliflozin Plus Exenatide on Central REgulation of Appetite in diabeteS typE 2
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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type 2 Diabetes Mellitus
Obesity
Keywords: SGLT2 inhibition; dapagliflozin
GLP-1 receptor agonist; exenatide
Central satiety and reward circuits
bodyweight
brain
Lead sponsor: Amsterdam UMC, location VUmc
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2017-12-04
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Differences in neuronal activity in the central reward and satiety circuits in response to food-related stimuli by BOLD fMRI signal
timeFrame: at baseline, after 10 days and after 16 weeks
Secondary outcomes:
measure: Differences in neuronal activity in the central reward and satiety circuits in response to food-related stimuli by BOLD fMRI signal
timeFrame: at baseline, after 10 days and after 16 weeks
measure: Feeding behaviour; ad libitum lunch buffet
timeFrame: at baseline, after 10 days and after 16 weeks
measure: Feeding behaviour; ad libitum lunch buffet
timeFrame: at baseline, after 10 days and after 16 weeks
measure: Self-reported hunger
timeFrame: at baseline, after 10 days and after 16 weeks
measure: Difference in resting energy expenditure measured by indirect calorimetry measurements
timeFrame: at baseline, after 10 days and after 16 weeks
measure: Change in bodyweight (kg) and body mass index (kg/m2)
timeFrame: at baseline, after 10 days and after 16 weeks
measure: Difference in bodycomposition measured by bio electrical impedance analysis and waist and hip circumference measurements (cm)
timeFrame: at baseline, after 10 days and after 16 weeks
measure: Difference in resting brain activity by fMRI resting state measurements
timeFrame: at baseline, after 10 days and after 16 weeks
measure: Effect on cardiovascular autonomic balance by cardiovascular reflex test with finger plethysmography (Nexfin)
timeFrame: at baseline, after 10 days and after 16 weeks
measure: Arterial stiffness: Pulse Wave analysis
timeFrame: at baseline, after 10 days and after 16 weeks
measure: Renal measurements collecting 24 hour urine
timeFrame: at baseline, after 10 days and after 16 weeks
measure: Laboratory parameters
timeFrame: at baseline, after 10 days and after 16 weeks
Other outcomes:
measure: Safety outcomes; Adverse events
timeFrame: +/- 21 weeks
measure: Safety outcome; vital signs
timeFrame: 16 weeks
measure: Exploratory objective: Cerebral perfusion assessed by Arterial Spin Labeling
timeFrame: 16 weeks
measure: Exploratory objective: measurement of hormones
timeFrame: 16 weeks
measure: Exploratory: Microbiome
timeFrame: Baseline and after 16 weeks
Locations:
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location VU Medical Center
state: Noord-Holland
Study officials:
affiliation: Amsterdam UMC, location VUmc
name: Richard G IJzerman, MD PhD
role: PRINCIPAL_INVESTIGATOR
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