Type 2 Diabetes MellitusPhase 4DECREASENCT03361098
DECREASE: Dapagliflozin Plus Exenatide on Central REgulation of Appetite in diabeteS typE 2
A Phase 4 study testing Dapagliflozin 10mg and Exenatide in people with Type 2 Diabetes Mellitus and Obesity, run by Amsterdam UMC, location VUmc at 1 site in Netherlands.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Type 2 Diabetes Mellitus, Obesity
- What is being tested?
- Dapagliflozin 10mg and Exenatide
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 65 participants
- Where
- 1 siteNetherlands
- Study dates
- 18 Sep 2017to 25 Mar 2020
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
Who cannot join
- 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)
Show all 30Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Amsterdam UMC, location VU Medical Center
Amsterdam, North Holland, 1081 HV
About this study
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
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.
Read the 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.
- Conditions
- Type 2 Diabetes Mellitus, Obesity
- Being tested
- Dapagliflozin 10mg, Exenatide, placebo exenatide, placebo dapagliflozin
- Keywords
- SGLT2 inhibition; dapagliflozin, GLP-1 receptor agonist; exenatide, Central satiety and reward circuits, bodyweight, brain
- Medical subject headings
- Diabetes Mellitus, Type 2, Obesity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dapagliflozin 10mgDrug
Also called SGLT2 inhibitor ; Forxiga
Dapagliflozin 10mg oral tablet once daily
ExenatideDrug
Also called GLP-1 receptor agonist ; Byetta
Exenatide 5 microgram b.i.d. week 1-4 Exenatide 10 microgram b.i.d. week 5-16
placebo exenatideOther
placebo b.i.d. exenatide
placebo dapagliflozinOther
placebo tablets dapagliflozin
| Study group | Role | What they receive |
|---|---|---|
| SGLT2 inhibitor + GLP-1 receptor agonist | Experimental | dapagliflozin 10 mg tablet /day and exenatide twice daily subcutaneous injection (week 1-4; 5 microgram, week 5 -16; 10 microgram) Receives: Drug: Dapagliflozin 10mg; Drug: Exenatide |
| GLP-1 receptor agonist (exenatide) and placebo | Active comparator | GLP-1 receptor agonist exenatide twice daily in combination with placebo dapagliflozin Receives: Drug: Exenatide; Other: placebo dapagliflozin |
| SGLT2 inhibitor (dapagliflozin) and placebo | Active comparator | SGLT2 inhibitor dapagliflozin 10 mg tablet /day in combination with placebo GLP-1 receptor agonist exenatide twice daily Receives: Drug: Dapagliflozin 10mg; Other: placebo exenatide |
| double placebo | Placebo comparator | placebo dapagliflozin and placebo exenatide twice daily Receives: Other: placebo exenatide; Other: placebo dapagliflozin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: at baseline, after 10 days and after 16 weeks
Secondary outcomes (12)
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.
Measured: at baseline, after 10 days and after 16 weeks
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)
Measured: at baseline, after 10 days and after 16 weeks
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)
Measured: at baseline, after 10 days and after 16 weeks
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
Measured: at baseline, after 10 days and after 16 weeks
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)
Measured: at baseline, after 10 days and after 16 weeks
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)
Measured: 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)
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)
Measured: at baseline, after 10 days and after 16 weeks
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)
Measured: at baseline, after 10 days and after 16 weeks
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)
Measured: at baseline, after 10 days and after 16 weeks
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)
Measured: at baseline, after 10 days and after 16 weeks
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)
Measured: at baseline, after 10 days and after 16 weeks
Laboratory parameters
Change in the plasma/serum biomarkers of metabolism, liver function, estimated renal function (eGFR), electrolytes, and haematocrit
Measured: at baseline, after 10 days and after 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Dec 2017
- Study start18 Sep 2017
- Primary completion25 Nov 2019
- Study completion25 Mar 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (21)Papers the sponsor has linked to this study.
- Other trials for Type 2 Diabetes MellitusStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 65 participants (actual)
Sponsor and investigators
- Lead sponsor
- Amsterdam UMC, location VUmc
- Sponsor type
- University, hospital or other
- Collaborators
- AstraZeneca
- Responsible party
- Principal investigator, RG IJzerman, Amsterdam UMC, location VUmc
- Investigators
- Richard G IJzerman, MD PhD, Principal investigator, Amsterdam UMC, location VUmc
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03361098
- Sponsor's protocol ID
- DC2017DECREASE01
- Acronym
- DECREASE
- Status last verified
- Jun 2021
- First submitted
- 26 Sep 2017
- Last updated
- 11 Jun 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data that underlie the results, after de-identification
Publications
van Bloemendaal L, Ijzerman RG, Ten Kulve JS, Barkhof F, Diamant M, Veltman DJ, van Duinkerken E. Alterations in white matter volume and integrity in obesity and type 2 diabetes. Metab Brain Dis. 2016 Jun;31(3):621-9. doi: 10.1007/s11011-016-9792-3. Epub 2016 Jan 27.
PubMed 26815786Ten Kulve JS, Veltman DJ, van Bloemendaal L, Groot PF, Ruhe HG, Barkhof F, Diamant M, Ijzerman RG. Endogenous GLP1 and GLP1 analogue alter CNS responses to palatable food consumption. J Endocrinol. 2016 Apr;229(1):1-12. doi: 10.1530/JOE-15-0461. Epub 2016 Jan 14.
PubMed 26769912Ten Kulve JS, van Bloemendaal L, Balesar R, IJzerman RG, Swaab DF, Diamant M, la Fleur SE, Alkemade A. Decreased Hypothalamic Glucagon-Like Peptide-1 Receptor Expression in Type 2 Diabetes Patients. J Clin Endocrinol Metab. 2016 May;101(5):2122-9. doi: 10.1210/jc.2015-3291. Epub 2015 Dec 16.
PubMed 26672638ten Kulve JS, Veltman DJ, van Bloemendaal L, Barkhof F, Deacon CF, Holst JJ, Konrad RJ, Sloan JH, Drent ML, Diamant M, IJzerman RG. Endogenous GLP-1 mediates postprandial reductions in activation in central reward and satiety areas in patients with type 2 diabetes. Diabetologia. 2015 Dec;58(12):2688-98. doi: 10.1007/s00125-015-3754-x. Epub 2015 Sep 18.
PubMed 26385462van Bloemendaal L, Veltman DJ, ten Kulve JS, Drent ML, Barkhof F, Diamant M, IJzerman RG. Emotional eating is associated with increased brain responses to food-cues and reduced sensitivity to GLP-1 receptor activation. Obesity (Silver Spring). 2015 Oct;23(10):2075-82. doi: 10.1002/oby.21200. Epub 2015 Aug 31.
PubMed 26331843van Bloemendaal L, Veltman DJ, Ten Kulve JS, Groot PF, Ruhe HG, Barkhof F, Sloan JH, Diamant M, Ijzerman RG. Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans. Diabetes Obes Metab. 2015 Sep;17(9):878-86. doi: 10.1111/dom.12506. Epub 2015 Jul 22.
PubMed 26094857van Bloemendaal L, IJzerman RG, Ten Kulve JS, Barkhof F, Konrad RJ, Drent ML, Veltman DJ, Diamant M. GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes. 2014 Dec;63(12):4186-96. doi: 10.2337/db14-0849. Epub 2014 Jul 28.
PubMed 25071023van Bloemendaal L, Ten Kulve JS, la Fleur SE, Ijzerman RG, Diamant M. Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS. J Endocrinol. 2014 Mar 7;221(1):T1-16. doi: 10.1530/JOE-13-0414. Print 2014 Apr.
PubMed 24323912Devenny JJ, Godonis HE, Harvey SJ, Rooney S, Cullen MJ, Pelleymounter MA. Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats. Obesity (Silver Spring). 2012 Aug;20(8):1645-52. doi: 10.1038/oby.2012.59. Epub 2012 Mar 8.
PubMed 22402735Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy Balance After Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015 Sep;38(9):1730-5. doi: 10.2337/dc15-0355. Epub 2015 Jul 15.
PubMed 26180105Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014 Feb;124(2):499-508. doi: 10.1172/JCI72227. Epub 2014 Jan 27.
PubMed 24463454Lundkvist P, Pereira MJ, Katsogiannos P, Sjostrom CD, Johnsson E, Eriksson JW. Dapagliflozin once daily plus exenatide once weekly in obese adults without diabetes: Sustained reductions in body weight, glycaemia and blood pressure over 1 year. Diabetes Obes Metab. 2017 Sep;19(9):1276-1288. doi: 10.1111/dom.12954. Epub 2017 May 31.
PubMed 28345814Frias JP, Guja C, Hardy E, Ahmed A, Dong F, Ohman P, Jabbour SA. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016 Dec;4(12):1004-1016. doi: 10.1016/S2213-8587(16)30267-4. Epub 2016 Sep 16.
PubMed 27651331Frank S, Laharnar N, Kullmann S, Veit R, Canova C, Hegner YL, Fritsche A, Preissl H. Processing of food pictures: influence of hunger, gender and calorie content. Brain Res. 2010 Sep 2;1350:159-66. doi: 10.1016/j.brainres.2010.04.030. Epub 2010 Apr 25.
PubMed 20423700Rothemund Y, Preuschhof C, Bohner G, Bauknecht HC, Klingebiel R, Flor H, Klapp BF. Differential activation of the dorsal striatum by high-calorie visual food stimuli in obese individuals. Neuroimage. 2007 Aug 15;37(2):410-21. doi: 10.1016/j.neuroimage.2007.05.008. Epub 2007 May 18.
PubMed 17566768
Study at a glance
From the registry record, last updated by the sponsor on 11 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03361098
- Acronym / sponsor ID
- DECREASE / DC2017DECREASE01
- Conditions
- Type 2 Diabetes Mellitus, Obesity
- Keywords
- SGLT2 inhibition; dapagliflozin, GLP-1 receptor agonist; exenatide, Central satiety and reward circuits, bodyweight, brain
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 65 participants (actual)
- Lead sponsor
- Amsterdam UMC, location VUmcUniversity, hospital or other
- Collaborators
- AstraZeneca
- Study start
- 18 Sep 2017 (actual)
- Primary completion
- 25 Nov 2019 (actual)
- Study completion
- 25 Mar 2020 (actual)
- First posted
- 4 Dec 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- Double blind (participant, investigator)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| SGLT2 inhibitor + GLP-1 receptor agonist | Experimental | Drug: Dapagliflozin 10mg, Drug: Exenatidedapagliflozin 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) and placebo | Active comparator | Drug: Exenatide, Other: placebo dapagliflozinGLP-1 receptor agonist exenatide twice daily in combination with placebo dapagliflozin |
| SGLT2 inhibitor (dapagliflozin) and placebo | Active comparator | Drug: Dapagliflozin 10mg, Other: placebo exenatideSGLT2 inhibitor dapagliflozin 10 mg tablet /day in combination with placebo GLP-1 receptor agonist exenatide twice daily |
| double placebo | Placebo comparator | Other: placebo exenatide, Other: placebo dapagliflozinplacebo dapagliflozin and placebo exenatide twice daily |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (30 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Dapagliflozin 10mgAlso: SGLT2 inhibitor ; ForxigaDapagliflozin 10mg oral tablet once daily | Drug | SGLT2 inhibitor (dapagliflozin) and placebo, SGLT2 inhibitor + GLP-1 receptor agonist |
| ExenatideAlso: GLP-1 receptor agonist ; ByettaExenatide 5 microgram b.i.d. week 1-4 Exenatide 10 microgram b.i.d. week 5-16 | Drug | GLP-1 receptor agonist (exenatide) and placebo, SGLT2 inhibitor + GLP-1 receptor agonist |
| placebo exenatideplacebo b.i.d. exenatide | Other | SGLT2 inhibitor (dapagliflozin) and placebo, double placebo |
| placebo dapagliflozinplacebo tablets dapagliflozin | Other | GLP-1 receptor agonist (exenatide) and placebo, double placebo |
Primary outcome
Differences in neuronal activity in the central reward and satiety circuits in response to food-related stimuli by BOLD fMRI signal
Time frame: 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.
12 secondary outcomes
Differences in neuronal activity in the central reward and satiety circuits in response to food-related stimuli by BOLD fMRI signal
Time frame: at baseline, after 10 days and after 16 weeks
Feeding behaviour; ad libitum lunch buffet
Time frame: at baseline, after 10 days and after 16 weeks
Feeding behaviour; ad libitum lunch buffet
Time frame: at baseline, after 10 days and after 16 weeks
Self-reported hunger
Time frame: at baseline, after 10 days and after 16 weeks
Difference in resting energy expenditure measured by indirect calorimetry measurements
Time frame: at baseline, after 10 days and after 16 weeks
Change in bodyweight (kg) and body mass index (kg/m2)
Time frame: 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)
Time frame: at baseline, after 10 days and after 16 weeks
Difference in resting brain activity by fMRI resting state measurements
Time frame: at baseline, after 10 days and after 16 weeks
Effect on cardiovascular autonomic balance by cardiovascular reflex test with finger plethysmography (Nexfin)
Time frame: at baseline, after 10 days and after 16 weeks
Arterial stiffness: Pulse Wave analysis
Time frame: at baseline, after 10 days and after 16 weeks
Renal measurements collecting 24 hour urine
Time frame: at baseline, after 10 days and after 16 weeks
Laboratory parameters
Time frame: at baseline, after 10 days and after 16 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Jun 2021.
- Background: PubMed 26815786van Bloemendaal L, Ijzerman RG, Ten Kulve JS, Barkhof F, Diamant M, Veltman DJ, van Duinkerken E. Alterations in white matter volume and integrity in obesity and type 2 diabetes. Metab Brain Dis. 2016 Jun;31(3):621-9. doi: 10.1007/s11011-016-9792-3. Epub 2016 Jan 27.
- Background: PubMed 26769912Ten Kulve JS, Veltman DJ, van Bloemendaal L, Groot PF, Ruhe HG, Barkhof F, Diamant M, Ijzerman RG. Endogenous GLP1 and GLP1 analogue alter CNS responses to palatable food consumption. J Endocrinol. 2016 Apr;229(1):1-12. doi: 10.1530/JOE-15-0461. Epub 2016 Jan 14.
- Background: PubMed 26672638Ten Kulve JS, van Bloemendaal L, Balesar R, IJzerman RG, Swaab DF, Diamant M, la Fleur SE, Alkemade A. Decreased Hypothalamic Glucagon-Like Peptide-1 Receptor Expression in Type 2 Diabetes Patients. J Clin Endocrinol Metab. 2016 May;101(5):2122-9. doi: 10.1210/jc.2015-3291. Epub 2015 Dec 16.
- Background: PubMed 26385462ten Kulve JS, Veltman DJ, van Bloemendaal L, Barkhof F, Deacon CF, Holst JJ, Konrad RJ, Sloan JH, Drent ML, Diamant M, IJzerman RG. Endogenous GLP-1 mediates postprandial reductions in activation in central reward and satiety areas in patients with type 2 diabetes. Diabetologia. 2015 Dec;58(12):2688-98. doi: 10.1007/s00125-015-3754-x. Epub 2015 Sep 18.
- Background: PubMed 26331843van Bloemendaal L, Veltman DJ, ten Kulve JS, Drent ML, Barkhof F, Diamant M, IJzerman RG. Emotional eating is associated with increased brain responses to food-cues and reduced sensitivity to GLP-1 receptor activation. Obesity (Silver Spring). 2015 Oct;23(10):2075-82. doi: 10.1002/oby.21200. Epub 2015 Aug 31.
- Background: PubMed 26094857van Bloemendaal L, Veltman DJ, Ten Kulve JS, Groot PF, Ruhe HG, Barkhof F, Sloan JH, Diamant M, Ijzerman RG. Brain reward-system activation in response to anticipation and consumption of palatable food is altered by glucagon-like peptide-1 receptor activation in humans. Diabetes Obes Metab. 2015 Sep;17(9):878-86. doi: 10.1111/dom.12506. Epub 2015 Jul 22.
- Background: PubMed 25071023van Bloemendaal L, IJzerman RG, Ten Kulve JS, Barkhof F, Konrad RJ, Drent ML, Veltman DJ, Diamant M. GLP-1 receptor activation modulates appetite- and reward-related brain areas in humans. Diabetes. 2014 Dec;63(12):4186-96. doi: 10.2337/db14-0849. Epub 2014 Jul 28.
- Background: PubMed 24323912van Bloemendaal L, Ten Kulve JS, la Fleur SE, Ijzerman RG, Diamant M. Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS. J Endocrinol. 2014 Mar 7;221(1):T1-16. doi: 10.1530/JOE-13-0414. Print 2014 Apr.
- Background: PubMed 22402735Devenny JJ, Godonis HE, Harvey SJ, Rooney S, Cullen MJ, Pelleymounter MA. Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats. Obesity (Silver Spring). 2012 Aug;20(8):1645-52. doi: 10.1038/oby.2012.59. Epub 2012 Mar 8.
- Background: PubMed 26180105Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy Balance After Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015 Sep;38(9):1730-5. doi: 10.2337/dc15-0355. Epub 2015 Jul 15.
- Background: PubMed 24463454Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014 Feb;124(2):499-508. doi: 10.1172/JCI72227. Epub 2014 Jan 27.
- Background: PubMed 28345814Lundkvist P, Pereira MJ, Katsogiannos P, Sjostrom CD, Johnsson E, Eriksson JW. Dapagliflozin once daily plus exenatide once weekly in obese adults without diabetes: Sustained reductions in body weight, glycaemia and blood pressure over 1 year. Diabetes Obes Metab. 2017 Sep;19(9):1276-1288. doi: 10.1111/dom.12954. Epub 2017 May 31.
- Individual participant dataSharing planned: Yes. Individual participant data that underlie the results, after de-identification
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Richard G IJzerman, MD PhD principal investigator
Amsterdam UMC, location VUmc
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Dapagliflozin 10mg and Exenatide in people with Type 2 Diabetes Mellitus and Obesity, run by Amsterdam UMC, location VUmc at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Differences in neuronal activity in the central reward and satiety circuits in response to food-related stimuli by BOLD fMRI signal (time frame: at baseline, after 10 days and after 16 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03361098, which also lists 21 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jun 2021.