A <u>r</u>andomis<u>e</u>d, controlled, double blind <u>s</u>tudy to assess mechan<u>i</u>stic effects of combination therapy of dapag<u>li</u>flozin with <u>e</u>xenatide QW versus dapagliflozin alone i<u>n</u> obese patients with <u>t</u>ype 2 diabetes mellitus (RESILIENT): study protocol.

Abstract

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. 110 obese patients with diagnosed T2D (glycated haemoglobin, HbA_1c ≥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). 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. University of Liverpool. ISRCTN 52028580; EUDRACT number 2015-005242-60.