Study Protocol for the TIGHTEN Study Comparing the Effects of Tofogliflozin and Glimepiride on Skeletal Muscle Mass in Patients with Type 2 Diabetes without Obesity: A Prospective, Multicenter, Open-Label, Randomized, Parallel Group Trial in Japan.

INTRODUCTION: Although sodium-glucose cotransporter 2 (SGLT2) inhibitors are associated with a lower risk of hypoglycemia, they may result in weight reduction, and provide additional benefits for cardiovascular disease, chronic kidney disease, and heart failure. However, their use in Japanese individuals with type 2 diabetes (T2D)-many of whom are older and without obesity-raises concerns regarding sarcopenia. This study aims to investigate the impact of the SGLT2 inhibitor tofogliflozin, compared with sulfonylurea glimepiride, on skeletal muscle mass in patients with T2D without obesity. METHODS: This study is a prospective, multicenter, open-label, randomized, parallel group, comparative trial. Adult Japanese patients with T2D with a body mass index of < 25 kg/m2 and a glycated hemoglobin (HbA1c) level of 7.0 to < 10.0% will be randomly assigned in a 1:1 ratio to receive tofogliflozin (20 mg orally/day) or glimepiride (0.5-4 mg orally/day) for 24 weeks. The primary endpoint is the change in total skeletal muscle mass to total body weight ratio from baseline to 24 weeks. The key secondary endpoints include the percentage change in total skeletal muscle mass to total body weight ratio and the change or percentage change in skeletal muscle mass index from baseline to 24 weeks. In total, 56 participants were calculated to be required, considering a dropout rate 15%, a two-sided alpha of 0.05, and a power of 0.9. PLANNED OUTCOMES: Participant recruitment commenced in April 2024 and concluded in June 2025. The complete findings of this study are anticipated to be published in 2027. We expect that the results will elucidate the impact of SGLT2 inhibitors on skeletal muscle mass in individuals with T2D without obesity, thereby addressing concerns related to sarcopenia. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCT) (No. jRCTs041240011); registered 10 April 2024, https://jrct.mhlw.go.jp/en-latest-detail/jRCTs041240011 .