Rationale and design of the randomised controlled cross-over trial: Cardiovascular effects of empaglifozin in diabetes mellitus

Abstract

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 3 months therapy with Empagliflozin, and 3 months therapy with Sitagliptin sequentially. Twenty-eight eligible T2D patients with established ischaemic heart disease will be recruited. Patients undergo serial CMR scans on three visits.

Discussion: The primary outcome measure is the myocardial perfusion reserve in remote myocardium. We hypothesise 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.

Keywords: Empaglifozin; Type 2 diabetes; cardiovascular magnetic resonance imaging; continuous glucose monitoring.

Figure 1.

Potential molecular and macroscopic pathophysiological mechanisms leading to cardiac dysfunction in type 2 diabetes. In diabetes, insulin fails to suppress hormone sensitive lipase secretion in adipose tissue and very low-density lipoprotein secretion in the liver, leading to high circulating fatty acids.^, When fatty acid availability exceeds fatty acid oxidation rates, intramyocardial lipids accumulate. The subsequent lipotoxicity plays a role in the development of contractile dysfunction and observed in the diabetic heart. Moreover, inhibition of pyruvate dehydrogenase (due to the effects of pyruvate dehydrogenase kinase four induction and fatty acid derived acetyl-CoA) limits pyruvate oxidation. The dissociation of glycolysis and pyruvate oxidation in the diabetic heart results in the accumulation of glycolytic intermediates and glucotoxicity. Hyperglycemia, insulin resistance and hyperinsulinemia induce cardiac insulin resistance and metabolic disorders leading to mitochondrial dysfunction, oxidative stress, advanced glycation end products (AGEs), impairment of mitochondrial Ca²⁺ handling, inflammation, activation of renin–angiotensin–aldosterone system (RAAS), autonomic neuropathy, apoptosis and endothelial dysfunction. These pathophysiological abnormalities promote cardiac stiffness, hypertrophy, coronary microvascular dysfunction and fibrosis, resulting in cardiac diastolic dysfunction, systolic dysfunction and heart failure. Figure adapted from Jia et al.

Figure 2.

Study flow chart. Screening (Visits 1 and 2): Screening assessments will be performed over two visits and will include a review of medical history and concomitant medications, and a review of history of diabetes and complications. Screening tests will include blood tests for fasting serum glucose, insulin, full blood count (FBC), urea and electrolytes (U&E), glycated haemoglobin (HbA1c). The most recent clinical echocardiography report will be reviewed, and the Libre Pro Sensor fitting will be performed at this visit. Visit 3: First CMR assessments will be scheduled for the third study visit to the research centre (at least 2 months after myocardial infarction, revascularisation procedure or unstable angina episode). Prior to CMR imaging the Libre Pro Sensor will be removed and randomisation to one of the two medications will be undertaken. Visit 4: Blood tests including fasting serum glucose, insulin, FBC, U&E and HbA1c will be performed and a second Libre Pro Sensor will be fitted. Visit 5: The Libre Pro Sensor will be removed and the second CMR scan will be undertaken. Visit 6: Further blood tests including fasting serum glucose, insulin, FBC, U&E and HbA1 will be performed and the final Libre Pro Sensor will be fitted. Visit 7 (Final Visit): The Libre Pro Sensor will be removed and the final CMR scan will be performed.

Figure 3.

CMR protocol. LGE: late gadolinium enhancement; LV: left ventricular; RV: right ventricular; SA: short axis.