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

NCT ID: NCT03361098

Last Updated: 2021-06-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 65 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-18
• Study Completion Date: 2020-03-25

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.

Conditions

Type 2 Diabetes Mellitus; Obesity

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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)

Group Type: EXPERIMENTAL

Dapagliflozin 10mg

Intervention Type: DRUG

Dapagliflozin 10mg oral tablet once daily

Exenatide

Intervention Type: DRUG

Exenatide 5 microgram b.i.d. week 1-4 Exenatide 10 microgram b.i.d. week 5-16

GLP-1 receptor agonist (exenatide) and placebo

GLP-1 receptor agonist exenatide twice daily in combination with placebo dapagliflozin

Group Type: ACTIVE_COMPARATOR

Exenatide

Intervention Type: DRUG

Exenatide 5 microgram b.i.d. week 1-4 Exenatide 10 microgram b.i.d. week 5-16

placebo dapagliflozin

Intervention Type: OTHER

placebo tablets dapagliflozin

SGLT2 inhibitor (dapagliflozin) and placebo

SGLT2 inhibitor dapagliflozin 10 mg tablet /day in combination with placebo GLP-1 receptor agonist exenatide twice daily

Group Type: ACTIVE_COMPARATOR

Dapagliflozin 10mg

Intervention Type: DRUG

Dapagliflozin 10mg oral tablet once daily

placebo exenatide

Intervention Type: OTHER

placebo b.i.d. exenatide

double placebo

placebo dapagliflozin and placebo exenatide twice daily

Group Type: PLACEBO_COMPARATOR

placebo exenatide

Intervention Type: OTHER

placebo b.i.d. exenatide

placebo dapagliflozin

Intervention Type: OTHER

placebo tablets dapagliflozin

Interventions

Dapagliflozin 10mg

Dapagliflozin 10mg oral tablet once daily

Intervention Type: DRUG

Exenatide

Exenatide 5 microgram b.i.d. week 1-4 Exenatide 10 microgram b.i.d. week 5-16

Intervention Type: DRUG

placebo exenatide

placebo b.i.d. exenatide

Intervention Type: OTHER

placebo dapagliflozin

placebo tablets dapagliflozin

Intervention Type: OTHER

Other Intervention Names

SGLT2 inhibitor ; Forxiga; GLP-1 receptor agonist ; Byetta

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: collaborator

Amsterdam UMC, location VUmc

OTHER

Sponsor Role: lead

Responsible Party

RG IJzerman

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Richard G IJzerman, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Amsterdam UMC, location VUmc

Locations

Amsterdam UMC, location VU Medical Center

Amsterdam, North Holland, Netherlands

Countries

Netherlands

References

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.

Reference Type: BACKGROUND

PMID: 26815786 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26769912 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26672638 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26385462 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26331843 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26094857 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25071023 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24323912 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22402735 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26180105 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24463454 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28345814 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27651331 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20423700 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17566768 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26403227 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25943756 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28869249 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22332246 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35484607 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35134184 (View on PubMed)

Other Identifiers

DC2017DECREASE01

Identifier Type: -

Identifier Source: org_study_id