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
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 65
- 试验地点
- 1
- 主要终点
- Differences in neuronal activity in the central reward and satiety circuits in response to food-related stimuli by BOLD fMRI signal
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
盲法说明
Participants were treated in a double-dummy design. There was no difference in appearance between exenatide and placebo injections, or dapagliflozin and placebo tablets.
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
研究组 & 干预措施
SGLT2 inhibitor (dapagliflozin) and placebo
SGLT2 inhibitor dapagliflozin 10 mg tablet /day in combination with placebo GLP-1 receptor agonist exenatide twice daily
干预措施: placebo exenatide (Other)
double placebo
placebo dapagliflozin and placebo exenatide twice daily
干预措施: placebo exenatide (Other)
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)
干预措施: Dapagliflozin 10mg (Drug)
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)
干预措施: Exenatide (Drug)
GLP-1 receptor agonist (exenatide) and placebo
GLP-1 receptor agonist exenatide twice daily in combination with placebo dapagliflozin
干预措施: Exenatide (Drug)
GLP-1 receptor agonist (exenatide) and placebo
GLP-1 receptor agonist exenatide twice daily in combination with placebo dapagliflozin
干预措施: placebo dapagliflozin (Other)
SGLT2 inhibitor (dapagliflozin) and placebo
SGLT2 inhibitor dapagliflozin 10 mg tablet /day in combination with placebo GLP-1 receptor agonist exenatide twice daily
干预措施: Dapagliflozin 10mg (Drug)
double placebo
placebo dapagliflozin and placebo exenatide twice daily
干预措施: placebo dapagliflozin (Other)
结局指标
主要结局
Differences in neuronal activity in the central reward and satiety circuits in response to food-related stimuli by BOLD fMRI signal
时间窗: 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.
次要结局
- Change in bodyweight (kg) and body mass index (kg/m2)(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)(at baseline, after 10 days and after 16 weeks)
- Self-reported hunger(at baseline, after 10 days and after 16 weeks)
- Difference in resting energy expenditure measured by indirect calorimetry measurements(at baseline, after 10 days and after 16 weeks)
- Difference in resting brain activity by fMRI resting state measurements(at baseline, after 10 days and after 16 weeks)
- Laboratory parameters(at baseline, after 10 days and after 16 weeks)
- Feeding behaviour; ad libitum lunch buffet(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(at baseline, after 10 days and after 16 weeks)
- Effect on cardiovascular autonomic balance by cardiovascular reflex test with finger plethysmography (Nexfin)(at baseline, after 10 days and after 16 weeks)
- Arterial stiffness: Pulse Wave analysis(at baseline, after 10 days and after 16 weeks)
- Renal measurements collecting 24 hour urine(at baseline, after 10 days and after 16 weeks)
研究者
RG IJzerman
Principal Investigator
Amsterdam UMC, location VUmc