{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T19:53:14Z","timestamp":1765828394100,"version":"3.48.0"},"reference-count":29,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T00:00:00Z","timestamp":1626652800000},"content-version":"unspecified","delay-in-days":18,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","award":["ESR-14-10188"],"award-info":[{"award-number":["ESR-14-10188"]}],"id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2021,6,28]]},"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The newer glucose-lowering therapies for type 2 diabetes (T2D), the glucagon-like peptide-1 receptor agonists (GLP1-RAs) and the sodium-glucose co-transporter 2 inhibitors (SGLT2i), have additional clinical benefits beyond improving glycaemic control; promoting weight loss, addressing associated cardiovascular risk factors and reducing macrovascular and microvascular complications. Considering their independent mechanisms of actions, there is a potential for significant synergy with combination therapy, yet limited data exist. This 32-week randomised, double-blind, placebo-controlled trial will gain mechanistic insight into the effects of coadministration of exenatide QW, a weekly subcutaneous GLP1-RA, with dapagliflozin, a once daily oral SGLT2i, on the dynamic, adaptive changes in energy balance, total, regional and organ-specific fat mass and multiorgan insulin sensitivity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>\n                      110 obese patients with diagnosed T2D (glycated haemoglobin, HbA\n                      <jats:sub>1c<\/jats:sub>\n                      \u226548 mmol\/mol) will be treated for 32 weeks with dapagliflozin (10\u2009mg once daily either alone or in combination with exenatide QW (2\u2009mg once weekly); active treatments will be compared with a control group (placebo tablet and sham injection). The primary objective of the study is to compare the adjusted mean reduction in total body fat mass (determined by dual-energy X-ray absorptiometry, DEXA) from baseline following 32 weeks of treatment with exenatide QW and dapagliflozin versus dapagliflozin alone compared with control (placebo). Secondary outcome measures include changes in (1)\n                      <jats:italic>energy balance<\/jats:italic>\n                      (energy intake and energy expenditure measured by indirect calorimetry); (2)\n                      <jats:italic>appetite<\/jats:italic>\n                      (between and within meals) and satiety quotient; (3)\n                      <jats:italic>body composition<\/jats:italic>\n                      including visceral adipose tissue, subcutaneous adipose tissue, liver and pancreatic fat. Exploratory outcome measures include\n                      <jats:italic>metabolic changes<\/jats:italic>\n                      in hepatic and peripheral insulin sensitivity (using a two-stage hyperinsulinaemic, euglycaemic clamp),\n                      <jats:italic>central nervous system responses<\/jats:italic>\n                      to food images using blood oxygen level-dependent (BOLD) functional MRI (fMRI) and\n                      <jats:italic>changes in cardiovascular function<\/jats:italic>\n                      (using transthoracic echocardiography, cardiac MR and duplex ultrasonography).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>This study has been approved by the North West Liverpool Central Research Ethics Committee (14\/NW\/1147) and is conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice. Results from the study will be published in peer-reviewed scientific and open access journals and\/or presented at scientific conferences and summarised for distribution to the participants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial sponsor<\/jats:title>\n                    <jats:p>University of Liverpool.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>ISRCTN 52028580; EUDRACT number 2015-005242-60.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2020-045663","type":"journal-article","created":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T12:09:45Z","timestamp":1626782985000},"page":"e045663","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":9,"title":["A randomised, controlled, double blind study to assess mechanistic effects of combination therapy of dapagliflozin with exenatide QW versus dapagliflozin alone in obese patients with type 2 diabetes mellitus (RESILIENT): study protocol"],"prefix":"10.1136","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1097-0580","authenticated-orcid":false,"given":"Emily","family":"Brown","sequence":"first","affiliation":[{"name":"Metabolism and Nutrition Research Group, University Hospital Aintree, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK"},{"name":"Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moon M","family":"Wilton","sequence":"additional","affiliation":[{"name":"Department of Psychology, Institute of Population Health, University of Liverpool, Liverpool, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2666-4986","authenticated-orcid":false,"given":"Victoria S","family":"Sprung","sequence":"additional","affiliation":[{"name":"Research Institute for Sport & Exercise Sciences, Liverpool John Moores University, Liverpool, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanne A","family":"Harrold","sequence":"additional","affiliation":[{"name":"Department of Psychology, Institute of Population Health, University of Liverpool, Liverpool, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason C G","family":"Halford","sequence":"additional","affiliation":[{"name":"School of Psychology, University of Leeds, Leeds, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrej","family":"Stancak","sequence":"additional","affiliation":[{"name":"Department of Psychology, Institute of Population Health, University of Liverpool, Liverpool, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malcolm","family":"Burgess","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Hospital Aintree, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elaine","family":"Howarth","sequence":"additional","affiliation":[{"name":"Liverpool Clinical Trials Centre, Institute of Population Health, University of Liverpool, Liverpool, Merseyside, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A Margot","family":"Umpleby","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, University of Surrey, Guildford, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graham J","family":"Kemp","sequence":"additional","affiliation":[{"name":"Liverpool Magnetic Resonance Imaging Centre (LiMRIC), University of Liverpool, Liverpool, UK"},{"name":"Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John PH","family":"Wilding","sequence":"additional","affiliation":[{"name":"Metabolism and Nutrition Research Group, University Hospital Aintree, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK"},{"name":"Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel J","family":"Cuthbertson","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK"},{"name":"Department of Psychology, Institute of Population Health, University of Liverpool, Liverpool, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2021,7,20]]},"reference":[{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.1","DOI":"10.14423\/SMJ.0000000000000214"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.2","DOI":"10.1038\/clpt.2008.250"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.3","DOI":"10.2337\/dc08-1863"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.4","DOI":"10.1016\/j.mce.2008.08.012"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.5","DOI":"10.1172\/JCI990"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.6","DOI":"10.1210\/jc.86.9.4382"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.7","DOI":"10.1172\/JCI72227"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.8","DOI":"10.1172\/JCI70704"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.9","DOI":"10.1038\/nm.3828"},{"key":"2025121511440377000_11.7.e045663.10","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1038\/oby.2012.59","article-title":"Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats","volume":"20","author":"Devenny","year":"2012","journal-title":"Obesity"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.11","DOI":"10.2337\/dc15-0355"},{"key":"2025121511440377000_11.7.e045663.12","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1016\/S2213-8587(16)30267-4","article-title":"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","volume":"4","author":"Fr\u00edas","year":"2016","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2025121511440377000_11.7.e045663.13","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/S2213-8587(18)30023-8","article-title":"Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial","volume":"6","author":"Ludvik","year":"2018","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2025121511440377000_11.7.e045663.14","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/S2213-8587(19)30066-X","article-title":"Semaglutide once Weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (sustain 9): a randomised, placebo-controlled trial","volume":"7","author":"Zinman","year":"2019","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2025121511440377000_11.7.e045663.15","first-page":"R764","article-title":"Energy metabolism rate equation for fasting and postabsorptive subjects","volume":"244","author":"Ben-Porat","year":"1983","journal-title":"Am J Physiol"},{"key":"2025121511440377000_11.7.e045663.16","first-page":"R1347","article-title":"Reappraisal of the Weir equation for calculation of metabolic rate","volume":"258","author":"Mansell","year":"1990","journal-title":"Am J Physiol"},{"key":"2025121511440377000_11.7.e045663.17","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.diabres.2014.06.006","article-title":"Combinational therapy with metformin and sodium-glucose cotransporter inhibitors in management of type 2 diabetes: systematic review and meta-analyses","volume":"105","author":"Zhang","year":"2014","journal-title":"Diabetes Res Clin Pract"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.18","DOI":"10.1007\/BF00280883"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.19","DOI":"10.1016\/0022-3999(85)90010-8"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.20","DOI":"10.1038\/ijo.2009.107"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.21","DOI":"10.1006\/appe.2001.0414"},{"key":"2025121511440377000_11.7.e045663.22","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1038\/ejcn.2015.57","article-title":"Preliminary validation and principal components analysis of the control of eating questionnaire (CoEQ) for the experience of food craving","volume":"69","author":"Dalton","year":"2015","journal-title":"Eur J Clin Nutr"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.23","DOI":"10.1002\/1098-108X(198602)5:2<295::AID-EAT2260050209>3.0.CO;2-T"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.24","DOI":"10.1016\/j.jada.2009.05.006"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.25","DOI":"10.1042\/CS20150447"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.26","DOI":"10.1152\/ajpheart.00471.2010"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.27","DOI":"10.1016\/j.jpeds.2011.05.019"},{"key":"2025121511440377000_11.7.e045663.28","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/ijo.2015.151","article-title":"Metabolically healthy and unhealthy obesity: differential effects on myocardial function according to metabolic syndrome, rather than obesity","volume":"40","author":"Dobson","year":"2016","journal-title":"Int J Obes"},{"doi-asserted-by":"publisher","key":"2025121511440377000_11.7.e045663.29","DOI":"10.1523\/JNEUROSCI.4682-05.2006"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2020-045663","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T19:44:16Z","timestamp":1765827856000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2020-045663"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7]]},"references-count":29,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7,20]]},"published-print":{"date-parts":[[2021,7]]}},"alternative-id":["10.1136\/bmjopen-2020-045663"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2020-045663","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"type":"print","value":"2044-6055"},{"type":"electronic","value":"2044-6055"}],"subject":[],"published":{"date-parts":[[2021,7]]}}}