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

NCT03361098 | Completed Phase 4 DMC

• 1 other identifier: DC2017DECREASE01
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 1

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.

Conditions

Type 2 Diabetes Mellitus; Obesity

Keywords

SGLT2 inhibition; dapagliflozin; GLP-1 receptor agonist; exenatide; Central satiety and reward circuits; bodyweight; brain

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (12)

• 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

• Feeding behaviour; ad libitum lunch buffet

  at baseline, after 10 days and after 16 weeks

• Feeding behaviour; ad libitum lunch buffet

  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

Other Outcomes (5)

• Safety outcomes; Adverse events

  +/- 21 weeks

• Safety outcome; vital signs

  16 weeks

• Exploratory objective: Cerebral perfusion assessed by Arterial Spin Labeling

  16 weeks

Study Arms (4)

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)

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

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

Drug: Dapagliflozin 10mg; Other: placebo exenatide

double placebo

PLACEBO COMPARATOR

placebo dapagliflozin and placebo exenatide twice daily

Other: placebo exenatide; Other: placebo dapagliflozin

Interventions

Dapagliflozin 10mg DRUG

Dapagliflozin 10mg oral tablet once daily

Also known as: SGLT2 inhibitor ; Forxiga

SGLT2 inhibitor (dapagliflozin) and placebo; SGLT2 inhibitor + GLP-1 receptor agonist

Exenatide DRUG

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

Also known as: GLP-1 receptor agonist ; Byetta

GLP-1 receptor agonist (exenatide) and placebo; SGLT2 inhibitor + GLP-1 receptor agonist

placebo exenatide OTHER

placebo b.i.d. exenatide

SGLT2 inhibitor (dapagliflozin) and placebo; double placebo

placebo dapagliflozin OTHER

placebo tablets dapagliflozin

GLP-1 receptor agonist (exenatide) and placebo; double placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead
• AstraZeneca: collaborator

Study Sites (1)

Amsterdam UMC, location VU Medical Center

Amsterdam, North Holland, 1081 HV, Netherlands

Location

Related Publications (21)

• 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.

  PMID: 26815786 BACKGROUND

• 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.

  PMID: 26769912 BACKGROUND

• 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.

  PMID: 26672638 BACKGROUND

• 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.

  PMID: 26385462 BACKGROUND

• 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.

  PMID: 26331843 BACKGROUND

• 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.

  PMID: 26094857 BACKGROUND

• 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.

  PMID: 25071023 BACKGROUND

• 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.

  PMID: 24323912 BACKGROUND

• 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.

  PMID: 22402735 BACKGROUND

• 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.

  PMID: 26180105 BACKGROUND

• 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.

  PMID: 24463454 BACKGROUND

• 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.

  PMID: 28345814 BACKGROUND

• 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.

  PMID: 27651331 BACKGROUND

• 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.

  PMID: 20423700 BACKGROUND

• 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.

  PMID: 17566768 BACKGROUND

• 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.

  PMID: 26403227 BACKGROUND

• 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.

  PMID: 25943756 BACKGROUND

• 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.

  PMID: 28869249 BACKGROUND

• 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.

  PMID: 22332246 BACKGROUND

• 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.

  PMID: 35484607 DERIVED

• 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.

  PMID: 35134184 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Obesity

Interventions

dapagliflozin; Sodium-Glucose Transporter 2 Inhibitors; Exenatide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Hypoglycemic Agents; Physiological Effects of Drugs; Peptides; Amino Acids, Peptides, and Proteins; Venoms; Complex Mixtures; Toxins, Biological; Biological Factors

Study Officials

• Richard G IJzerman, MD PhD

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Participants were treated in a double-dummy design. There was no difference in appearance between exenatide and placebo injections, or dapagliflozin and placebo tablets.
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 26, 2017
• First Posted: December 4, 2017
• Study Start: September 18, 2017
• Primary Completion: November 25, 2019
• Study Completion: March 25, 2020
• Last Updated: June 11, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF, CSR
• Time Frame: Beginning 3 months and ending 2 years following article publication
• Access Criteria: Researchers who provide a methodologically sound proposal

Locations

NL (1)