xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05975528</url>
    </required_header>
    <id_info>
      <org_study_id>4-2022-1483</org_study_id>
      <nct_id>NCT05975528</nct_id>
    </id_info>
    <brief_title>Effect of Sodium-glucose Cotransporter-2 Inhibitor in Cellular Senescence in Patients With Cardiovascular Diseases or Type 2 Diabetes</brief_title>
    <official_title>Effect of Sodium-glucose Cotransporter-2 Inhibitor in Cellular Senescence in Patients With Cardiovascular Diseases or Advanced Type 2 Diabetes</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Yonsei University</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Yonsei University</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        Patients with type 2 diabetes (T2D) are more prevalent with aging-related comorbidities and&#xD;
        frailty, which leads to a shorter life expectancy than non-diabetic individuals and that this&#xD;
        excess mortality is largely attributable to cardiovascular causes.&#xD;
  &#xD;
        Therefore, since diabetes accelerates cellular senescence, attenuating aging process in&#xD;
        patients with T2D is expected to reduce progression of comorbidities and eventually increase&#xD;
        lifespan.&#xD;
  &#xD;
        According to previous studies, sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown&#xD;
        increased ketone bodies not only in blood but in various tissues including liver, kidney and&#xD;
        colon, which could lead to beneficial effects in metabolic diseases. Especially,&#xD;
        β-hydroxybutyrate (βHB) inhibits oxidative stress and reduces insulin resistance, which has a&#xD;
        positive effect on preventing cardio-renal-metabolic diseases and aging process in patients&#xD;
        with T2D.&#xD;
  &#xD;
        In this context, SGLT2 inhibitor can be a promising option to alleviate senescence process in&#xD;
        patients with T2D. However, despite the accumulating evidence that support anti-senescent&#xD;
        effect of SGLT2 inhibitor in preclinical models, no clinical study has investigated&#xD;
        association between SGLT2 inhibitor use and senescence patients with T2D.&#xD;
  &#xD;
        Thus, the objective of this study is to determine whether the use of SGLT2 inhibitor is&#xD;
        associated with anti-senescent effect in patients with T2D, which may expand the indications&#xD;
        of SGLT2 inhibitor other than glycemic control.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        &lt;Study design&gt;&#xD;
  &#xD;
          -  Prospective study : Patients with type 2 diabetes who started antidiabetics for the&#xD;
             first time or were taking antidiabetics (metformin-based monotherapy or 2- or 3- agent&#xD;
             therapy), requiring additional glycemic control by either SGLT2 inhibitor and non-SGLT2&#xD;
             inhibitor(sulfonylurea) are enrolled in this study.&#xD;
  &#xD;
          -  Drug administration period: Total 180 days, but non-SGLT2 inhibitor administration&#xD;
             period is 3 months, and then changed to the SGLT2 inhibitor another 3 months. Health&#xD;
             people are also recruited for comparison with patients with T2D.&#xD;
  &#xD;
          -  Drug administration: For the SGLT2 inhibitor group, empagliflozin 10mg or dapagliflozin&#xD;
             10mg once daily is administered. For the non-SGLT2 inhibitor group (minimum glimepiride&#xD;
             1mg) was administered depending of the patient's glycemic status and hypoglycemic risk.&#xD;
  &#xD;
        &lt; Study methods&gt;&#xD;
  &#xD;
          1. After explaining the contents of the study and obtaining consent during hospitalization&#xD;
             or outpatient visit, 20ml of additional whole blood is additionally obtained when blood&#xD;
             is collected for routine medical purpose. Also, for those agreed to participate in the&#xD;
             study, albuminuria and proteinuria are measured and the remaining specimens (5ml) are&#xD;
             stored.&#xD;
  &#xD;
          2. Among all patients participating in the study, blood and urine samples should be&#xD;
             collected to measure the following parameters in each visit (1~3): fasting glucose,&#xD;
             fasting insulin, fasting c-peptide, HbA1c, beta-hydroxybutyrate, free fatty&#xD;
             acid-fasting, postprandial 90 min glucose/insulin/c-peptide, BUN, creatinine, eGFR, AST,&#xD;
             ALT, ALP, GGT, total bilirubin, total protein, albumin, uric acid, total cholesterol,&#xD;
             triglyceride, HDL, LDL, WBC, hemoglobin, hematocrit, platelet, c-reactive protein,&#xD;
             urinalysis with microscopy. In addition, the following tests including liver fibroscan&#xD;
             and body composition tests are conducted to check for diabetic complications.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">August 2023</start_date>
    <completion_date type="Anticipated">December 31, 2025</completion_date>
    <primary_completion_date type="Anticipated">December 31, 2025</primary_completion_date>
    <phase>Phase 4</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Changes of Cellular senescence markers</measure>
      <time_frame>Changes from baseline to 3 months after use of SGLT2 inhibitors</time_frame>
      <description>Changes of cellular senescence markers (CD57+CD28- T cell, CD87+ monocyte) between SGLT2 inhibitor users and glimepiride users</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Changes of Senescence-associated secretory phenotype</measure>
      <time_frame>Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors</time_frame>
      <description>SASP (Senescence-associated secretory phenotype) : IL-1/6, TNFa, MCP-1</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes of Short physical performance battery score</measure>
      <time_frame>Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes of biochemistry profiles in blood (10^3/μL)</measure>
      <time_frame>Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors</time_frame>
      <description>- Changes in Biochemistry profiles in blood WBC count (10^3/μL), Platelet counts (10^3/μL)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes of biochemistry profiles in blood (g/dL)</measure>
      <time_frame>Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors</time_frame>
      <description>- Changes in Biochemistry profiles in blood Hemoglobin (g/dL)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes of biochemistry profiles in blood (%)</measure>
      <time_frame>Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors</time_frame>
      <description>- Changes in Biochemistry profiles in blood Hematocrit (%), HbA1c (%)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes of biochemistry profiles in blood (mg/dL)</measure>
      <time_frame>Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors</time_frame>
      <description>- Changes in Biochemistry profiles in blood Creatinine (mg/dL), Total cholesterol (mg/dL), Triglyceride (mg/dL), HDL-cholesterol (mg/dL), Fasting glucose (mg/dL)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes of biochemistry profiles in blood (IU/L)</measure>
      <time_frame>Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors</time_frame>
      <description>- Changes in Biochemistry profiles in blood AST (IU/L), ALT (IU/L), γ-Glutamyl transferase (IU/L)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes of biochemistry profiles in blood (mg/L)</measure>
      <time_frame>Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors</time_frame>
      <description>- Changes in Biochemistry profiles in blood C-Reactive Protein(mg/L)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes of biochemistry profiles in blood (μEq/L)</measure>
      <time_frame>Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors</time_frame>
      <description>- Changes in Biochemistry profiles in blood Free fatty acid-Fasting (μEq/L)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes of biochemistry profiles in blood (μU/mL)</measure>
      <time_frame>Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors</time_frame>
      <description>- Changes in Biochemistry profiles in blood Fasting Insulin (μU/mL)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes of biochemistry profiles in blood (mmol/L)</measure>
      <time_frame>Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors</time_frame>
      <description>- Changes in Biochemistry profiles in blood Beta-hydroxybutyrate (mmol/L)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes of body composition using Inbody (kg)</measure>
      <time_frame>Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors</time_frame>
      <description>Changes of body composition using Inbody: Skeletal muscle mass (kg) Body fat mass (kg) Right arm muscle mass (kg) Left arm muscle mass (kg) Trunk muscle mass (kg) Right leg muscle mass (kg) Left leg muscle mass (kg)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes of body composition using Inbody (cm)</measure>
      <time_frame>Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors</time_frame>
      <description>Changes of body composition using Inbody: Weight circumference (cm) Hip circumference (cm)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes of body composition using Inbody (cm2)</measure>
      <time_frame>Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors</time_frame>
      <description>Changes of body composition using Inbody: Visceral fat area (cm2)</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">87</enrollment>
    <condition>Diabetes Mellitus</condition>
    <condition>Cellular Senescence</condition>
    <condition>Sodium-Glucose Transporter 2 Inhibitors</condition>
    <arm_group>
      <arm_group_label>SGLT2 inhibitor user</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
    </arm_group>
    <arm_group>
      <arm_group_label>Glimepiride user</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>SGLT2 inhibitor</intervention_name>
      <description>For the SGLT2 inhibitor group, total drug adminstration days are 180 days, but non-SGLT2 inhibitor administration period is 3 months, and then changed to the SGLT2 inhibitor another 3 months.&#xD;
  For the SGLT2 inhibitor group, empagliflozin 10mg or dapagliflozin 10mg once daily is administered.</description>
      <arm_group_label>SGLT2 inhibitor user</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Glimepiride</intervention_name>
      <description>For non-SGLT2 inhibitor (glimepiride) administration period is 3 months, and then changed to the SGLT2 inhibitor another 3 months.</description>
      <arm_group_label>Glimepiride user</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          &lt;Inclusion criteria for patients with type 2 diabetes and high risk cardiovascular disease&gt;&#xD;
  &#xD;
            1. Patients with type 2 diabetes who meet the diagnostic criteria of standard practice&#xD;
               guidelines&#xD;
  &#xD;
            2. Age between 50 and 85&#xD;
  &#xD;
            3. Patients who signed the consent form&#xD;
  &#xD;
            4. Patients who meet at least one of the following as a high-risk group for&#xD;
               cardiovascular disease:&#xD;
  &#xD;
          1) History of myocardial infarction, within the last 3 months 2) Imaging proven coronary&#xD;
          artery disease (2 or more coronary arteries or left main coronary artery disease) 3)&#xD;
          History of ischemic or hemorrhagic cerebrovascular disease within the last 3 months 4)&#xD;
          Imaging proven obstructive peripheral arterial disease 5) Intima media thickness more than&#xD;
          0.9mm or observed plaque 6) estimated glomerular filtration rate between 30-60 7) BMI more&#xD;
          than 25kg/m2 accompanied two or more of the following are present: hypertension, current&#xD;
          smoker, imaging proven steatohepatitis, alanine aminotransferase more than 40IU/L&#xD;
  &#xD;
          &lt;Inclusion criteria for healthy people&gt;&#xD;
  &#xD;
            1. Adults 19 years of age or older who do not meet the diagnostic criteria for metabolic&#xD;
               syndrome, diabetes, or hyperlipidemia&#xD;
  &#xD;
            2. Patients not taking medications related to diabetes or hyperlipidemia&#xD;
  &#xD;
            3. BMI less than 25kg/m2&#xD;
  &#xD;
          &lt;Exclusion criteria&gt;&#xD;
  &#xD;
            1. Those who are unable to participate in clinical trials due to other researchers'&#xD;
               judgment&#xD;
  &#xD;
            2. Those who cannot read the consent form&#xD;
  &#xD;
            3. Patients who refused to fill out the research participation consent form&#xD;
  &#xD;
            4. Breastfeeding or pregnant women&#xD;
  &#xD;
            5. Type 1 diabetes&#xD;
  &#xD;
            6. adrenal insufficiency, growth hormone deficiency, pituitary disease&#xD;
  &#xD;
            7. Patients who have undergone bariatric surgery within the past 2 years or&#xD;
               gastrointestinal surgery that can cause chronic malabsorption&#xD;
  &#xD;
            8. Patients who have taken anti-obesity drugs within the past month or who have received&#xD;
               other treatments that can cause weight changes&#xD;
  &#xD;
            9. Patients with blood diseases that can cause hemolysis or abnormal red blood cells&#xD;
  &#xD;
           10. Patients with active cancer or undergoing chemotherapy&#xD;
  &#xD;
           11. Patients with liver disease and cirrhosis who are taking antiviral drugs&#xD;
  &#xD;
           12. Patients with autoimmune disease taking steroids and immunosuppressants&#xD;
  &#xD;
           13. Organ transplant patients&#xD;
  &#xD;
           14. Taking antibiotics or NSAIDs within the last 2 weeks&#xD;
  &#xD;
           15. Patients with acute infections in previous 3 months including COVID-19&#xD;
  &#xD;
           16. Previous use of GLP-1 receptor agonist, thiazolidinedione, SGLT2 inhibitor&#xD;
  &#xD;
           17. Patients with severe hyperglycemia (HbA1c &gt; 10%)&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>50 Years</minimum_age>
      <maximum_age>85 Years</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Yong-ho Lee</last_name>
      <role>Principal Investigator</role>
      <affiliation>Department of Internal medicine, Yonsei University College of Medicine</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Yong-ho Lee</last_name>
      <phone>02-2228-9143</phone>
      <email>YHOLEE@yuhs.ac</email>
    </overall_contact>
    <location>
      <facility>
        <name>Yonsei University College of Medicine</name>
        <address>
          <city>Seoul</city>
          <country>Korea, Republic of</country>
        </address>
      </facility>
      <contact>
        <last_name>Yong-ho Lee</last_name>
        <phone>02-2228-9143</phone>
        <email>YHOLEE@yuhs.ac</email>
      </contact>
    </location>
    <location_countries>
      <country>Korea, Republic of</country>
    </location_countries>
    <reference>
      <citation>Wen CP, Chang CH, Tsai MK, Lee JH, Lu PJ, Tsai SP, Wen C, Chen CH, Kao CW, Tsao CK, Wu X. Diabetes with early kidney involvement may shorten life expectancy by 16 years. Kidney Int. 2017 Aug;92(2):388-396. doi: 10.1016/j.kint.2017.01.030. Epub 2017 Jun 1.</citation>
      <PMID>28577854</PMID>
    </reference>
    <reference>
      <citation>Emerging Risk Factors Collaboration; Di Angelantonio E, Kaptoge S, Wormser D, Willeit P, Butterworth AS, Bansal N, O'Keeffe LM, Gao P, Wood AM, Burgess S, Freitag DF, Pennells L, Peters SA, Hart CL, Haheim LL, Gillum RF, Nordestgaard BG, Psaty BM, Yeap BB, Knuiman MW, Nietert PJ, Kauhanen J, Salonen JT, Kuller LH, Simons LA, van der Schouw YT, Barrett-Connor E, Selmer R, Crespo CJ, Rodriguez B, Verschuren WM, Salomaa V, Svardsudd K, van der Harst P, Bjorkelund C, Wilhelmsen L, Wallace RB, Brenner H, Amouyel P, Barr EL, Iso H, Onat A, Trevisan M, D'Agostino RB Sr, Cooper C, Kavousi M, Welin L, Roussel R, Hu FB, Sato S, Davidson KW, Howard BV, Leening MJ, Leening M, Rosengren A, Dorr M, Deeg DJ, Kiechl S, Stehouwer CD, Nissinen A, Giampaoli S, Donfrancesco C, Kromhout D, Price JF, Peters A, Meade TW, Casiglia E, Lawlor DA, Gallacher J, Nagel D, Franco OH, Assmann G, Dagenais GR, Jukema JW, Sundstrom J, Woodward M, Brunner EJ, Khaw KT, Wareham NJ, Whitsel EA, Njolstad I, Hedblad B, Wassertheil-Smoller S, Engstrom G, Rosamond WD, Selvin E, Sattar N, Thompson SG, Danesh J. Association of Cardiometabolic Multimorbidity With Mortality. JAMA. 2015 Jul 7;314(1):52-60. doi: 10.1001/jama.2015.7008. Erratum In: JAMA. 2015 Sep 15;314(11):1179. Leening, Maarten [corrected to Leening, Maarten J G].</citation>
      <PMID>26151266</PMID>
    </reference>
    <reference>
      <citation>Palmer AK, Gustafson B, Kirkland JL, Smith U. Cellular senescence: at the nexus between ageing and diabetes. Diabetologia. 2019 Oct;62(10):1835-1841. doi: 10.1007/s00125-019-4934-x. Epub 2019 Aug 27.</citation>
      <PMID>31451866</PMID>
    </reference>
    <reference>
      <citation>Palmer AK, Xu M, Zhu Y, Pirtskhalava T, Weivoda MM, Hachfeld CM, Prata LG, van Dijk TH, Verkade E, Casaclang-Verzosa G, Johnson KO, Cubro H, Doornebal EJ, Ogrodnik M, Jurk D, Jensen MD, Chini EN, Miller JD, Matveyenko A, Stout MB, Schafer MJ, White TA, Hickson LJ, Demaria M, Garovic V, Grande J, Arriaga EA, Kuipers F, von Zglinicki T, LeBrasseur NK, Campisi J, Tchkonia T, Kirkland JL. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell. 2019 Jun;18(3):e12950. doi: 10.1111/acel.12950. Epub 2019 Mar 25.</citation>
      <PMID>30907060</PMID>
    </reference>
    <reference>
      <citation>Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, Herrmann SM, Jensen MD, Jia Q, Jordan KL, Kellogg TA, Khosla S, Koerber DM, Lagnado AB, Lawson DK, LeBrasseur NK, Lerman LO, McDonald KM, McKenzie TJ, Passos JF, Pignolo RJ, Pirtskhalava T, Saadiq IM, Schaefer KK, Textor SC, Victorelli SG, Volkman TL, Xue A, Wentworth MA, Wissler Gerdes EO, Zhu Y, Tchkonia T, Kirkland JL. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019 Sep;47:446-456. doi: 10.1016/j.ebiom.2019.08.069. Epub 2019 Sep 18. Erratum In: EBioMedicine. 2020 Feb;52:102595.</citation>
      <PMID>31542391</PMID>
    </reference>
    <reference>
      <citation>Kim JH, Lee M, Kim SH, Kim SR, Lee BW, Kang ES, Cha BS, Cho JW, Lee YH. Sodium-glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter-organ crosstalk. Diabetes Obes Metab. 2019 Apr;21(4):801-811. doi: 10.1111/dom.13577. Epub 2018 Dec 4.</citation>
      <PMID>30407726</PMID>
    </reference>
    <reference>
      <citation>Han YM, Ramprasath T, Zou MH. beta-hydroxybutyrate and its metabolic effects on age-associated pathology. Exp Mol Med. 2020 Apr;52(4):548-555. doi: 10.1038/s12276-020-0415-z. Epub 2020 Apr 8.</citation>
      <PMID>32269287</PMID>
    </reference>
    <reference>
      <citation>Cunnane SC, Courchesne-Loyer A, St-Pierre V, Vandenberghe C, Pierotti T, Fortier M, Croteau E, Castellano CA. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease. Ann N Y Acad Sci. 2016 Mar;1367(1):12-20. doi: 10.1111/nyas.12999. Epub 2016 Jan 14.</citation>
      <PMID>26766547</PMID>
    </reference>
    <reference>
      <citation>Sedej S. Ketone bodies to the rescue for an aging heart? Cardiovasc Res. 2018 Jan 1;114(1):e1-e2. doi: 10.1093/cvr/cvx218. No abstract available.</citation>
      <PMID>29293913</PMID>
    </reference>
    <reference>
      <citation>Sebastian-Valverde M, Pasinetti GM. The NLRP3 Inflammasome as a Critical Actor in the Inflammaging Process. Cells. 2020 Jun 26;9(6):1552. doi: 10.3390/cells9061552.</citation>
      <PMID>32604771</PMID>
    </reference>
    <reference>
      <citation>Camell CD, Gunther P, Lee A, Goldberg EL, Spadaro O, Youm YH, Bartke A, Hubbard GB, Ikeno Y, Ruddle NH, Schultze J, Dixit VD. Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis. Cell Metab. 2019 Dec 3;30(6):1024-1039.e6. doi: 10.1016/j.cmet.2019.10.006. Epub 2019 Nov 14.</citation>
      <PMID>31735593</PMID>
    </reference>
    <reference>
      <citation>Kim SR, Lee SG, Kim SH, Kim JH, Choi E, Cho W, Rim JH, Hwang I, Lee CJ, Lee M, Oh CM, Jeon JY, Gee HY, Kim JH, Lee BW, Kang ES, Cha BS, Lee MS, Yu JW, Cho JW, Kim JS, Lee YH. SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nat Commun. 2020 May 1;11(1):2127. doi: 10.1038/s41467-020-15983-6.</citation>
      <PMID>32358544</PMID>
    </reference>
    <reference>
      <citation>Madonna R, Barachini S, Moscato S, Ippolito C, Mattii L, Lenzi C, Balistreri CR, Zucchi R, De Caterina R. Sodium-glucose cotransporter type 2 inhibitors prevent ponatinib-induced endothelial senescence and disfunction: A potential rescue strategy. Vascul Pharmacol. 2022 Feb;142:106949. doi: 10.1016/j.vph.2021.106949. Epub 2021 Nov 26.</citation>
      <PMID>34843980</PMID>
    </reference>
    <reference>
      <citation>Trnovska J, Svoboda P, Pelantova H, Kuzma M, Kratochvilova H, Kasperova BJ, Dvorakova I, Rosolova K, Malinska H, Huttl M, Markova I, Oliyarnyk O, Melcova M, Skop V, Mraz M, Stemberkova-Hubackova S, Haluzik M. Complex Positive Effects of SGLT-2 Inhibitor Empagliflozin in the Liver, Kidney and Adipose Tissue of Hereditary Hypertriglyceridemic Rats: Possible Contribution of Attenuation of Cell Senescence and Oxidative Stress. Int J Mol Sci. 2021 Sep 30;22(19):10606. doi: 10.3390/ijms221910606.</citation>
      <PMID>34638943</PMID>
    </reference>
    <reference>
      <citation>Madonna R, Doria V, Minnucci I, Pucci A, Pierdomenico DS, De Caterina R. Empagliflozin reduces the senescence of cardiac stromal cells and improves cardiac function in a murine model of diabetes. J Cell Mol Med. 2020 Nov;24(21):12331-12340. doi: 10.1111/jcmm.15699. Epub 2020 Sep 17.</citation>
      <PMID>32940423</PMID>
    </reference>
    <reference>
      <citation>Sugizaki T, Zhu S, Guo G, Matsumoto A, Zhao J, Endo M, Horiguchi H, Morinaga J, Tian Z, Kadomatsu T, Miyata K, Itoh H, Oike Y. Treatment of diabetic mice with the SGLT2 inhibitor TA-1887 antagonizes diabetic cachexia and decreases mortality. NPJ Aging Mech Dis. 2017 Sep 8;3:12. doi: 10.1038/s41514-017-0012-0. eCollection 2017.</citation>
      <PMID>28900540</PMID>
    </reference>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>June 13, 2023</study_first_submitted>
    <study_first_submitted_qc>August 1, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 4, 2023</study_first_posted>
    <last_update_submitted>August 1, 2023</last_update_submitted>
    <last_update_submitted_qc>August 1, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 4, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Cardiovascular Diseases</mesh_term>
      <mesh_term>Diabetes Mellitus</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Glimepiride</mesh_term>
      <mesh_term>Sodium-Glucose Transporter 2 Inhibitors</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05975528
  org study id: 4-2022-1483
  nct id: NCT05975528
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  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.
  
        < 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
             and body composition tests are conducted to check for diabetic complications.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  measure: Changes of Cellular senescence markers
  time frame: Changes from baseline to 3 months after use of SGLT2 inhibitors
  description: Changes of cellular senescence markers (CD57+CD28- T cell, CD87+ monocyte) between SGLT2 inhibitor users and glimepiride users
  measure: Changes of Senescence-associated secretory phenotype
  time frame: Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors
  description: SASP (Senescence-associated secretory phenotype) : IL-1/6, TNFa, MCP-1
  measure: Changes of Short physical performance battery score
  time frame: Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors
  measure: Changes of biochemistry profiles in blood (10^3/μL)
  time frame: Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors
  description: - Changes in Biochemistry profiles in blood WBC count (10^3/μL), Platelet counts (10^3/μL)
  measure: Changes of biochemistry profiles in blood (g/dL)
  time frame: Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors
  description: - Changes in Biochemistry profiles in blood Hemoglobin (g/dL)
  measure: Changes of biochemistry profiles in blood (%)
  time frame: Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors
  description: - Changes in Biochemistry profiles in blood Hematocrit (%), HbA1c (%)
  measure: Changes of biochemistry profiles in blood (mg/dL)
  time frame: Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors
  description: - Changes in Biochemistry profiles in blood Creatinine (mg/dL), Total cholesterol (mg/dL), Triglyceride (mg/dL), HDL-cholesterol (mg/dL), Fasting glucose (mg/dL)
  measure: Changes of biochemistry profiles in blood (IU/L)
  time frame: Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors
  description: - Changes in Biochemistry profiles in blood AST (IU/L), ALT (IU/L), γ-Glutamyl transferase (IU/L)
  measure: Changes of biochemistry profiles in blood (mg/L)
  time frame: Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors
  description: - Changes in Biochemistry profiles in blood C-Reactive Protein(mg/L)
  measure: Changes of biochemistry profiles in blood (μEq/L)
  time frame: Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors
  description: - Changes in Biochemistry profiles in blood Free fatty acid-Fasting (μEq/L)
  measure: Changes of biochemistry profiles in blood (μU/mL)
  time frame: Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors
  description: - Changes in Biochemistry profiles in blood Fasting Insulin (μU/mL)
  measure: Changes of biochemistry profiles in blood (mmol/L)
  time frame: Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors
  description: - Changes in Biochemistry profiles in blood Beta-hydroxybutyrate (mmol/L)
  measure: Changes of body composition using Inbody (kg)
  time frame: Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors
  description: Changes of body composition using Inbody: Skeletal muscle mass (kg) Body fat mass (kg) Right arm muscle mass (kg) Left arm muscle mass (kg) Trunk muscle mass (kg) Right leg muscle mass (kg) Left leg muscle mass (kg)
  measure: Changes of body composition using Inbody (cm)
  time frame: Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors
  description: Changes of body composition using Inbody: Weight circumference (cm) Hip circumference (cm)
  measure: Changes of body composition using Inbody (cm2)
  time frame: Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors
  description: Changes of body composition using Inbody: Visceral fat area (cm2)
  arm group label: SGLT2 inhibitor user
  arm group type: Experimental
  arm group label: Glimepiride user
  arm group type: Active Comparator
  intervention type: Drug
  intervention name: SGLT2 inhibitor
  description: For the SGLT2 inhibitor group, total drug adminstration days are 180 days, but non-SGLT2 inhibitor administration period is 3 months, and then changed to the SGLT2 inhibitor another 3 months.
  For the SGLT2 inhibitor group, empagliflozin 10mg or dapagliflozin 10mg once daily is administered.
  arm group label: SGLT2 inhibitor user
  intervention type: Drug
  intervention name: Glimepiride
  description: For non-SGLT2 inhibitor (glimepiride) administration period is 3 months, and then changed to the SGLT2 inhibitor another 3 months.
  arm group label: Glimepiride user
  criteria: 
  gender: All
  minimum age: 50 Years
  maximum age: 85 Years
  healthy volunteers: Accepts Healthy Volunteers
  last name: Yong-ho Lee
  role: Principal Investigator
  affiliation: Department of Internal medicine, Yonsei University College of Medicine
  last name: Yong-ho Lee
  phone: 02-2228-9143
  email: YHOLEE@yuhs.ac
  facility: 
  contact: 
  country: Korea, Republic of
  citation: Wen CP, Chang CH, Tsai MK, Lee JH, Lu PJ, Tsai SP, Wen C, Chen CH, Kao CW, Tsao CK, Wu X. Diabetes with early kidney involvement may shorten life expectancy by 16 years. Kidney Int. 2017 Aug;92(2):388-396. doi: 10.1016/j.kint.2017.01.030. Epub 2017 Jun 1.
  PMID: 28577854
  citation: Emerging Risk Factors Collaboration; Di Angelantonio E, Kaptoge S, Wormser D, Willeit P, Butterworth AS, Bansal N, O'Keeffe LM, Gao P, Wood AM, Burgess S, Freitag DF, Pennells L, Peters SA, Hart CL, Haheim LL, Gillum RF, Nordestgaard BG, Psaty BM, Yeap BB, Knuiman MW, Nietert PJ, Kauhanen J, Salonen JT, Kuller LH, Simons LA, van der Schouw YT, Barrett-Connor E, Selmer R, Crespo CJ, Rodriguez B, Verschuren WM, Salomaa V, Svardsudd K, van der Harst P, Bjorkelund C, Wilhelmsen L, Wallace RB, Brenner H, Amouyel P, Barr EL, Iso H, Onat A, Trevisan M, D'Agostino RB Sr, Cooper C, Kavousi M, Welin L, Roussel R, Hu FB, Sato S, Davidson KW, Howard BV, Leening MJ, Leening M, Rosengren A, Dorr M, Deeg DJ, Kiechl S, Stehouwer CD, Nissinen A, Giampaoli S, Donfrancesco C, Kromhout D, Price JF, Peters A, Meade TW, Casiglia E, Lawlor DA, Gallacher J, Nagel D, Franco OH, Assmann G, Dagenais GR, Jukema JW, Sundstrom J, Woodward M, Brunner EJ, Khaw KT, Wareham NJ, Whitsel EA, Njolstad I, Hedblad B, Wassertheil-Smoller S, Engstrom G, Rosamond WD, Selvin E, Sattar N, Thompson SG, Danesh J. Association of Cardiometabolic Multimorbidity With Mortality. JAMA. 2015 Jul 7;314(1):52-60. doi: 10.1001/jama.2015.7008. Erratum In: JAMA. 2015 Sep 15;314(11):1179. Leening, Maarten [corrected to Leening, Maarten J G].
  PMID: 26151266
  citation: Palmer AK, Gustafson B, Kirkland JL, Smith U. Cellular senescence: at the nexus between ageing and diabetes. Diabetologia. 2019 Oct;62(10):1835-1841. doi: 10.1007/s00125-019-4934-x. Epub 2019 Aug 27.
  PMID: 31451866
  citation: Palmer AK, Xu M, Zhu Y, Pirtskhalava T, Weivoda MM, Hachfeld CM, Prata LG, van Dijk TH, Verkade E, Casaclang-Verzosa G, Johnson KO, Cubro H, Doornebal EJ, Ogrodnik M, Jurk D, Jensen MD, Chini EN, Miller JD, Matveyenko A, Stout MB, Schafer MJ, White TA, Hickson LJ, Demaria M, Garovic V, Grande J, Arriaga EA, Kuipers F, von Zglinicki T, LeBrasseur NK, Campisi J, Tchkonia T, Kirkland JL. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell. 2019 Jun;18(3):e12950. doi: 10.1111/acel.12950. Epub 2019 Mar 25.
  PMID: 30907060
  citation: Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, Herrmann SM, Jensen MD, Jia Q, Jordan KL, Kellogg TA, Khosla S, Koerber DM, Lagnado AB, Lawson DK, LeBrasseur NK, Lerman LO, McDonald KM, McKenzie TJ, Passos JF, Pignolo RJ, Pirtskhalava T, Saadiq IM, Schaefer KK, Textor SC, Victorelli SG, Volkman TL, Xue A, Wentworth MA, Wissler Gerdes EO, Zhu Y, Tchkonia T, Kirkland JL. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019 Sep;47:446-456. doi: 10.1016/j.ebiom.2019.08.069. Epub 2019 Sep 18. Erratum In: EBioMedicine. 2020 Feb;52:102595.
  PMID: 31542391
  citation: Kim JH, Lee M, Kim SH, Kim SR, Lee BW, Kang ES, Cha BS, Cho JW, Lee YH. Sodium-glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter-organ crosstalk. Diabetes Obes Metab. 2019 Apr;21(4):801-811. doi: 10.1111/dom.13577. Epub 2018 Dec 4.
  PMID: 30407726
  citation: Han YM, Ramprasath T, Zou MH. beta-hydroxybutyrate and its metabolic effects on age-associated pathology. Exp Mol Med. 2020 Apr;52(4):548-555. doi: 10.1038/s12276-020-0415-z. Epub 2020 Apr 8.
  PMID: 32269287
  citation: Cunnane SC, Courchesne-Loyer A, St-Pierre V, Vandenberghe C, Pierotti T, Fortier M, Croteau E, Castellano CA. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease. Ann N Y Acad Sci. 2016 Mar;1367(1):12-20. doi: 10.1111/nyas.12999. Epub 2016 Jan 14.
  PMID: 26766547
  citation: Sedej S. Ketone bodies to the rescue for an aging heart? Cardiovasc Res. 2018 Jan 1;114(1):e1-e2. doi: 10.1093/cvr/cvx218. No abstract available.
  PMID: 29293913
  citation: Sebastian-Valverde M, Pasinetti GM. The NLRP3 Inflammasome as a Critical Actor in the Inflammaging Process. Cells. 2020 Jun 26;9(6):1552. doi: 10.3390/cells9061552.
  PMID: 32604771
  citation: Camell CD, Gunther P, Lee A, Goldberg EL, Spadaro O, Youm YH, Bartke A, Hubbard GB, Ikeno Y, Ruddle NH, Schultze J, Dixit VD. Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis. Cell Metab. 2019 Dec 3;30(6):1024-1039.e6. doi: 10.1016/j.cmet.2019.10.006. Epub 2019 Nov 14.
  PMID: 31735593
  citation: Kim SR, Lee SG, Kim SH, Kim JH, Choi E, Cho W, Rim JH, Hwang I, Lee CJ, Lee M, Oh CM, Jeon JY, Gee HY, Kim JH, Lee BW, Kang ES, Cha BS, Lee MS, Yu JW, Cho JW, Kim JS, Lee YH. SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nat Commun. 2020 May 1;11(1):2127. doi: 10.1038/s41467-020-15983-6.
  PMID: 32358544
  citation: Madonna R, Barachini S, Moscato S, Ippolito C, Mattii L, Lenzi C, Balistreri CR, Zucchi R, De Caterina R. Sodium-glucose cotransporter type 2 inhibitors prevent ponatinib-induced endothelial senescence and disfunction: A potential rescue strategy. Vascul Pharmacol. 2022 Feb;142:106949. doi: 10.1016/j.vph.2021.106949. Epub 2021 Nov 26.
  PMID: 34843980
  citation: Trnovska J, Svoboda P, Pelantova H, Kuzma M, Kratochvilova H, Kasperova BJ, Dvorakova I, Rosolova K, Malinska H, Huttl M, Markova I, Oliyarnyk O, Melcova M, Skop V, Mraz M, Stemberkova-Hubackova S, Haluzik M. Complex Positive Effects of SGLT-2 Inhibitor Empagliflozin in the Liver, Kidney and Adipose Tissue of Hereditary Hypertriglyceridemic Rats: Possible Contribution of Attenuation of Cell Senescence and Oxidative Stress. Int J Mol Sci. 2021 Sep 30;22(19):10606. doi: 10.3390/ijms221910606.
  PMID: 34638943
  citation: Madonna R, Doria V, Minnucci I, Pucci A, Pierdomenico DS, De Caterina R. Empagliflozin reduces the senescence of cardiac stromal cells and improves cardiac function in a murine model of diabetes. J Cell Mol Med. 2020 Nov;24(21):12331-12340. doi: 10.1111/jcmm.15699. Epub 2020 Sep 17.
  PMID: 32940423
  citation: Sugizaki T, Zhu S, Guo G, Matsumoto A, Zhao J, Endo M, Horiguchi H, Morinaga J, Tian Z, Kadomatsu T, Miyata K, Itoh H, Oike Y. Treatment of diabetic mice with the SGLT2 inhibitor TA-1887 antagonizes diabetic cachexia and decreases mortality. NPJ Aging Mech Dis. 2017 Sep 8;3:12. doi: 10.1038/s41514-017-0012-0. eCollection 2017.
  PMID: 28900540
  responsible party type: Sponsor
  mesh term: Cardiovascular Diseases
  mesh term: Diabetes Mellitus
  mesh term: Glimepiride
  mesh term: Sodium-Glucose Transporter 2 Inhibitors
  sharing ipd: No