Effect of Sodium-glucose Cotransporter-2 Inhibitor in Cellular Senescence in Patients With Cardiovascular Diseases or Type 2 Diabetes

Overview

Patients with type 2 diabetes (T2D) are more prevalent with aging-related comorbidities and frailty, which leads to a shorter life expectancy than non-diabetic individuals and that this excess mortality is largely attributable to cardiovascular causes. Therefore, since diabetes accelerates cellular senescence, attenuating aging process in patients with T2D is expected to reduce progression of comorbidities and eventually increase lifespan. According to previous studies, sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown increased ketone bodies not only in blood but in various tissues including liver, kidney and colon, which could lead to beneficial effects in metabolic diseases. Especially, β-hydroxybutyrate (βHB) inhibits oxidative stress and reduces insulin resistance, which has a positive effect on preventing cardio-renal-metabolic diseases and aging process in patients with T2D. In this context, SGLT2 inhibitor can be a promising option to alleviate senescence process in patients with T2D. However, despite the accumulating evidence that support anti-senescent effect of SGLT2 inhibitor in preclinical models, no clinical study has investigated association between SGLT2 inhibitor use and senescence patients with T2D. Thus, the objective of this study is to determine whether the use of SGLT2 inhibitor is associated with anti-senescent effect in patients with T2D, which may expand the indications of SGLT2 inhibitor other than glycemic control.

\<Study design\> * Prospective study : Patients with type 2 diabetes who started antidiabetics for the first time or were taking antidiabetics (metformin-based monotherapy or 2- or 3- agent therapy), requiring additional glycemic control by either SGLT2 inhibitor and non-SGLT2 inhibitor(sulfonylurea) are enrolled in this study. * Drug administration period: Total 180 days, but non-SGLT2 inhibitor administration period is 3 months, and then changed to the SGLT2 inhibitor another 3 months. Health people are also recruited for comparison with patients with T2D. * Drug administration: For the SGLT2 inhibitor group, empagliflozin 10mg or dapagliflozin 10mg once daily is administered. For the non-SGLT2 inhibitor group (minimum glimepiride 1mg) was administered depending of the patient's glycemic status and hypoglycemic risk. * Glimepiride and gliclazide, both belonging to the sulfonylurea class, can be administered interchangeably. * Additionally, medication dosages may be adjusted based on blood glucose and test results, and DPP4 inhibitors may be added according to medical judgment, following the guidelines of the Korean Diabetes Association. \< Study methods\> 1. After explaining the contents of the study and obtaining consent during hospitalization or outpatient visit, 20ml of additional whole blood is additionally obtained when blood is collected for routine medical purpose. Also, for those agreed to participate in the study, albuminuria and proteinuria are measured and the remaining specimens (5ml) are stored. 2. Among all patients participating in the study, blood and urine samples should be collected to measure the following parameters in each visit (1\~3): fasting glucose, fasting insulin, fasting c-peptide, HbA1c, beta-hydroxybutyrate, free fatty acid-fasting, postprandial 90 min glucose/insulin/c-peptide, BUN, creatinine, eGFR, AST, ALT, ALP, GGT, total bilirubin, total protein, albumin, uric acid, total cholesterol, triglyceride, HDL, LDL, WBC, hemoglobin, hematocrit, platelet, c-reactive protein, urinalysis with microscopy. In addition, the following tests including liver fibroscan (Incorporation of fibroscan conducted up to 3 months before/after registration for reference and use during registration) and body composition tests are conducted to check for diabetic complications.