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

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.

Eligibility Criteria:
\<Inclusion criteria for patients with type 2 diabetes and high risk cardiovascular disease\>

1. Patients with type 2 diabetes who meet the diagnostic criteria of standard practice guidelines
2. Age between 50 and 85
3. Patients who signed the consent form
4. Patients who meet at least one of the following as a high-risk group for cardiovascular disease:

1) History of myocardial infarction, within the last 3 months 2) Imaging proven coronary artery disease (2 or more coronary arteries or left main coronary artery disease) 3) History of ischemic or hemorrhagic cerebrovascular disease within the last 3 months 4) Imaging proven obstructive peripheral arterial disease 5) Intima media thickness more than 0.9mm or observed plaque 6) estimated glomerular filtration rate between 30-60 7) BMI more than 25kg/m2 accompanied two or more of the following are present: hypertension, current smoker, imaging proven steatohepatitis, alanine aminotransferase more than 40IU/L

\<Inclusion criteria for healthy people\>

1. Adults 19 years of age or older who do not meet the diagnostic criteria for metabolic syndrome, diabetes, or hyperlipidemia
2. Patients not taking medications related to diabetes or hyperlipidemia
3. BMI less than 25kg/m2

\<Exclusion criteria\>

1. Those who are unable to participate in clinical trials due to other researchers' judgment
2. Those who cannot read the consent form
3. Patients who refused to fill out the research participation consent form
4. Breastfeeding or pregnant women
5. Type 1 diabetes
6. adrenal insufficiency, growth hormone deficiency, pituitary disease
7. Patients who have undergone bariatric surgery within the past 2 years or gastrointestinal surgery that can cause chronic malabsorption
8. Patients who have taken anti-obesity drugs within the past month or who have received other treatments that can cause weight changes
9. Patients with blood diseases that can cause hemolysis or abnormal red blood cells
10. Patients with active cancer or undergoing chemotherapy
11. Patients with liver disease and cirrhosis who are taking antiviral drugs
12. Patients with autoimmune disease taking steroids and immunosuppressants
13. Organ transplant patients
14. Taking antibiotics or NSAIDs within the last 2 weeks
15. Patients with acute infections in previous 3 months including COVID-19
16. Previous use of GLP-1 receptor agonist, thiazolidinedione, SGLT2 inhibitor
17. Patients with severe hyperglycemia (HbA1c \> 10%)