Rationale and design of the randomised controlled cross-over trial: Cardiovascular Effects of Empaglifozin in Diabetes Mellitus

Background Type 2 diabetes (T2D) is associated with an increased risk of cardiovascular (CV) disease. In patients with T2D and established CV disease, selective inhibitors of sodium–glucose cotransporter 2 (SGLT2) have been shown to decrease CV and all-cause mortality, and heart failure (HF) admissions. Utilising CV magnetic resonance imaging (CMR) and continuous glucose monitoring (CGM) by FreeStyle Libre Pro Sensor, we aim to explore the mechanisms of action which give Empagliflozin, an SGLT2 inhibitor, its beneficial CV effects and compare these to the effects of dipeptidyl peptidase-4 inhibitor Sitagliptin. Methods This is a single centre, open-label, cross-over trial conducted at the Leeds Teaching Hospitals NHS Trust. Participants are randomised for the order of treatment and receive three months therapy with Empagliflozin, and three months therapy with Sitagliptin sequentially. Twenty eight eligible T2D patients with established ischemic heart disease will be recruited. Patients undergo serial CMR scans on 3 visits, at week 0, week 12 and week 24 of the study.Discussion The primary outcome measure is the myocardial perfusion reserve in remote myocardium. The secondary outcome measures are myocardial fibrosis, ECV, aortic distensibility, LV/RV volume and function, and the relationship between glycemic markers and CV parameters.We hypothesize that Empaglifozin treatment is associated with improvements in myocardial blood flow and reductions in myocardial interstitial fibrosis, independent of CGM measured glycemic control in patients with T2D and established CV disease. Trial registration This study has full research ethics committee approval (REC: 18/YH/0190) and data collection is anticipated to finish in December 2021. This study was retrospectively registered at https://doi.org/10.1186/ISRCTN82391603 and monitored by the University of Leeds. The study results will be submitted for publication within 6 months of completion.