Rationale, Design for the ASSET Study: A Prospective Randomized Study Comparing Empagliflozin’s Effect to Sitagliptin on Cardiac Fat Accumulation/Function in Patients with Type 2 Diabetes

INTRODUCTION: Ectopic fat accumulation has been found to play a pathophysiological role in insulin resistance, type 2 diabetes (T2DM), and coronary artery diseases. Findings from a number of previous studies suggest that sodium glucose cotransporter 2 (SGLT2) inhibitors reduce lipid accumulation, including myocardial and pericardial fat, while dipeptidyl peptidase 4 (DPP4) inhibitors suppress ectopic lipid accumulation and improve cardiac function. However, a clinical study that precisely explains and compares the efficacy of SGLT2 inhibitors and DPP4 inhibitors on cardiac fat accumulation has not been performed. Moreover, the association between cardiac fat accumulation and cardiac function or metabolic changes, such as tissue-specific insulin resistance, remains unclear. It is our intention to conduct the first study to assess the effects of empagliflozin compared to sitagliptin in reducing ectopic fat accumulation, specifically pericardial fat, and its association with improvement in cardiac function and tissue-specific insulin sensitivity. METHODS: We have designed a prospective, randomized open-label, and blinded-endpoint study with the intention to enroll 44 Japanese patients with T2DM. The patients are to be divided them into two groups, an empagliflozin group and an sitagliptin group, with the former to be supplemented with empagliflozin 10 mg and the latter to be supplemented with sitagliptin 100 mg, both groups for 12 weeks. The primary endpoint of the study is the change in the amount of pericardial fat. The secondary endpoints are the changes in the amount of intracellular fat in the myocardium, cardiac function, tissue-specific insulin sensitivity, fatty acid metabolism in myocardial tissue, assessed by parameters of iodine-123-β-methyl-iodophenyl pentadecanoic acid myocardial scintigraphy, blood and urine biomarkers, and lifestyle evaluation. PLANNED OUTCOMES: The results of this study will be available in 2020. The aim of this study is to provide an effective treatment strategy for patients with T2DM by considering cardiac fat accumulation, cardiac function, and insulin resistance. FUNDING: Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry: UMIN000026340.