DECREASE: Dapagliflozin Plus Exenatide on Central REgulation of Appetite in diabeteS typE 2 (DECREASE)

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.

Study Overview

• Status: Completed
• Conditions: Obesity; Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Dapagliflozin 10mg; Drug: Exenatide; Other: placebo dapagliflozin; Other: placebo exenatide

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 Type: Interventional
• Enrollment (Actual): 65
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands, 1081 HV
      • Amsterdam UMC, Location VU Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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)	Drug: Dapagliflozin 10mg; Dapagliflozin 10mg oral tablet once daily; Other Names: SGLT2 inhibitor ; Forxiga; Drug: Exenatide; Exenatide 5 microgram b.i.d. week 1-4 Exenatide 10 microgram b.i.d. week 5-16; Other Names: GLP-1 receptor agonist ; Byetta
Active Comparator: GLP-1 receptor agonist (exenatide) and placebo; GLP-1 receptor agonist exenatide twice daily in combination with placebo dapagliflozin	Drug: Exenatide; Exenatide 5 microgram b.i.d. week 1-4 Exenatide 10 microgram b.i.d. week 5-16; Other Names: GLP-1 receptor agonist ; Byetta; Other: placebo dapagliflozin; placebo tablets dapagliflozin
Active Comparator: SGLT2 inhibitor (dapagliflozin) and placebo; SGLT2 inhibitor dapagliflozin 10 mg tablet /day in combination with placebo GLP-1 receptor agonist exenatide twice daily	Drug: Dapagliflozin 10mg; Dapagliflozin 10mg oral tablet once daily; Other Names: SGLT2 inhibitor ; Forxiga; Other: placebo exenatide; placebo b.i.d. exenatide
Placebo Comparator: double placebo; placebo dapagliflozin and placebo exenatide twice daily	Other: placebo dapagliflozin; placebo tablets dapagliflozin; Other: placebo exenatide; placebo b.i.d. exenatide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	at baseline, after 10 days and after 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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)	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)	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	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)	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)	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)	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)	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)	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)	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)	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	at baseline, after 10 days and after 16 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety outcomes; Adverse events	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	+/- 21 weeks
Safety outcome; vital signs	Vital signs: pulse rate, bloodpressure, body temperature	16 weeks
Exploratory objective: Cerebral perfusion assessed by Arterial Spin Labeling	Cerebral perfusion assessed by Arterial Spin Labeling between groups (0-1.5,0-16, 1.5-16)	16 weeks
Exploratory objective: measurement of hormones	blood will be collected to have the opportunity to perform measurements of hormones such as leptin, cortisol, ghrelin.	16 weeks
Exploratory: Microbiome	Fecal samples will be collected to determine the (change) microbiome	Baseline and after 16 weeks

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Richard G IJzerman, MD PhD, Amsterdam UMC, location VUmc

Publications and helpful links

General Publications

• Lundkvist 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.
• Ferrannini 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. Erratum In: J Clin Invest. 2014 Apr 1;124(4):1868.
• Ferrannini 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.
• Frias 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. Erratum In: Lancet Diabetes Endocrinol. 2017 Dec;5(12 ):e8.
• Devenny 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.
• 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.
• Ten 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.
• Ten 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.
• ten 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.
• van 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.
• van 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.
• van 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.
• van 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.
• Frank 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.
• Rothemund 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.
• Rajeev SP, Cuthbertson DJ, Wilding JP. Energy balance and metabolic changes with sodium-glucose co-transporter 2 inhibition. Diabetes Obes Metab. 2016 Feb;18(2):125-34. doi: 10.1111/dom.12578. Epub 2015 Dec 10.
• Muskiet MH, Tonneijck L, Smits MM, Kramer MH, Heerspink HJ, van Raalte DH. Pleiotropic effects of type 2 diabetes management strategies on renal risk factors. Lancet Diabetes Endocrinol. 2015 May;3(5):367-81. doi: 10.1016/S2213-8587(15)00030-3.
• Muskiet MHA, Tonneijck L, Smits MM, van Baar MJB, Kramer MHH, Hoorn EJ, Joles JA, van Raalte DH. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol. 2017 Oct;13(10):605-628. doi: 10.1038/nrneph.2017.123. Epub 2017 Sep 4.
• Murdaugh DL, Cox JE, Cook EW 3rd, Weller RE. fMRI reactivity to high-calorie food pictures predicts short- and long-term outcome in a weight-loss program. Neuroimage. 2012 Feb 1;59(3):2709-21. doi: 10.1016/j.neuroimage.2011.10.071.
• van Ruiten CC, Smits MM, Kok MD, Serne EH, van Raalte DH, Kramer MHH, Nieuwdorp M, IJzerman RG. Mechanisms underlying the blood pressure lowering effects of dapagliflozin, exenatide, and their combination in people with type 2 diabetes: a secondary analysis of a randomized trial. Cardiovasc Diabetol. 2022 Apr 28;21(1):63. doi: 10.1186/s12933-022-01492-x.
• van Ruiten CC, Veltman DJ, Schrantee A, van Bloemendaal L, Barkhof F, Kramer MHH, Nieuwdorp M, IJzerman RG. Effects of Dapagliflozin and Combination Therapy With Exenatide on Food-Cue Induced Brain Activation in Patients With Type 2 Diabetes. J Clin Endocrinol Metab. 2022 May 17;107(6):e2590-e2599. doi: 10.1210/clinem/dgac043.

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2017
• Primary Completion (Actual): November 25, 2019
• Study Completion (Actual): March 25, 2020

Study Registration Dates

• First Submitted: September 26, 2017
• First Submitted That Met QC Criteria: November 27, 2017
• First Posted (Actual): December 4, 2017

Study Record Updates

• Last Update Posted (Actual): June 11, 2021
• Last Update Submitted That Met QC Criteria: June 8, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: brain; SGLT2 inhibition; dapagliflozin; GLP-1 receptor agonist; exenatide; Central satiety and reward circuits; bodyweight
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Obesity Agents; Incretins; Dapagliflozin; Exenatide; Sodium-Glucose Transporter 2 Inhibitors
• Other Study ID Numbers: DC2017DECREASE01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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
• IPD Sharing Supporting Information Type: Study Protocol; Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• 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