Brown, Emily, Wilton, Moon M 
ORCID: 0000-0003-4052-7918, Sprung, Victoria S ORCID: 0000-0002-2666-4986, Harrold, Joanne A ORCID: 0000-0002-0899-4586, Halford, Jason CG ORCID: 0000-0003-1629-3189, Stancak, Andrej ORCID: 0000-0003-3323-3305, Burgess, Malcolm, Howarth, Elaine, Umpleby, A Margot, Kemp, Graham J ORCID: 0000-0002-8324-9666 et al (show 2 more authors)
(2021)
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.
BMJ open, 11 (7).
e045663-e045663.
Abstract
<h4>Introduction</h4>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.<h4>Methods and analysis</h4>110 obese patients with diagnosed T2D (glycated haemoglobin, HbA<sub>1c</sub> ≥48 mmol/mol) will be treated for 32 weeks with dapagliflozin (10 mg once daily either alone or in combination with exenatide QW (2 mg 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) <i>energy balance</i> (energy intake and energy expenditure measured by indirect calorimetry); (2) <i>appetite</i> (between and within meals) and satiety quotient; (3) <i>body composition</i> including visceral adipose tissue, subcutaneous adipose tissue, liver and pancreatic fat. Exploratory outcome measures include <i>metabolic changes</i> in hepatic and peripheral insulin sensitivity (using a two-stage hyperinsulinaemic, euglycaemic clamp), <i>central nervous system responses</i> to food images using blood oxygen level-dependent (BOLD) functional MRI (fMRI) and <i>changes in cardiovascular function</i> (using transthoracic echocardiography, cardiac MR and duplex ultrasonography).<h4>Ethics and dissemination</h4>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.<h4>Trial sponsor</h4>University of Liverpool.<h4>Trial registration number</h4>ISRCTN 52028580; EUDRACT number 2015-005242-60.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | general diabetes, general endocrinology, cardiology |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences Faculty of Health and Life Sciences > Institute of Population Health |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 02 Aug 2021 08:06 |
| Last Modified: | 18 Jan 2023 21:34 |
| DOI: | 10.1136/bmjopen-2020-045663 |
| Open Access URL: | https://en.x-mol.com/paper/article/141757788545571... |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3131817 |
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