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

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.

Timeline

Start

2017-09-18

Primary completion

2019-11-25

Completion

2020-03-25

Publications

• Background 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

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