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

NCT05975528 | Unknown Phase 4 DMC

• 1 other identifier: 4-2022-1483
• Study Type: interventional
• Target: 92
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Diabetes Mellitus; Cellular Senescence; Sodium-Glucose Transporter 2 Inhibitors

Outcome Measures

Primary Outcomes (1)

• Changes of Cellular senescence markers

  Changes of cellular senescence markers (CD57+CD28- T cell, CD87+ monocyte) between SGLT2 inhibitor users and glimepiride users

  Changes from baseline to 3 months after use of SGLT2 inhibitors

Secondary Outcomes (13)

• Changes of Senescence-associated secretory phenotype

  Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors

• Changes of biochemistry profiles in blood (10^3/μL)

  Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors

• Changes of biochemistry profiles in blood (g/dL)

  Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors

• Changes of biochemistry profiles in blood (%)

  Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors

• Changes of biochemistry profiles in blood (mg/dL)

  Changes from baseline to 3 months/6 months after use of SGLT2 inhibitors

Study Arms (2)

SGLT2 inhibitor user

EXPERIMENTAL

Drug: SGLT2 inhibitor

Glimepiride user

ACTIVE COMPARATOR

Drug: Glimepiride

Interventions

SGLT2 inhibitor DRUG

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.

SGLT2 inhibitor user

Glimepiride DRUG

For non-SGLT2 inhibitor (glimepiride) administration period is 3 months, and then changed to the SGLT2 inhibitor another 3 months.

Glimepiride user

Eligibility Criteria

• Age: 50 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with type 2 diabetes who meet the diagnostic criteria of standard practice guidelines
• Age between 50 and 85
• Patients who signed the consent form
• Patients who meet at least one of the following as a high-risk group for cardiovascular disease:
• \) 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
• Adults 19 years of age or older who do not meet the diagnostic criteria for metabolic syndrome, diabetes, or hyperlipidemia
• Patients not taking medications related to diabetes or hyperlipidemia
• BMI less than 25kg/m2

You may not qualify if:

• Those who are unable to participate in clinical trials due to other researchers' judgment
• Those who cannot read the consent form
• Patients who refused to fill out the research participation consent form
• Breastfeeding or pregnant women
• Type 1 diabetes
• adrenal insufficiency, growth hormone deficiency, pituitary disease
• Patients who have undergone bariatric surgery within the past 2 years or gastrointestinal surgery that can cause chronic malabsorption
• Patients who have taken anti-obesity drugs within the past month or who have received other treatments that can cause weight changes
• Patients with blood diseases that can cause hemolysis or abnormal red blood cells
• Patients with active cancer or undergoing chemotherapy
• Patients with liver disease and cirrhosis who are taking antiviral drugs
• Patients with autoimmune disease taking steroids and immunosuppressants
• Organ transplant patients
• Taking antibiotics or NSAIDs within the last 2 weeks
• Patients with acute infections in previous 3 months including COVID-19

Sponsors & Collaborators

• Yonsei University: lead

Study Sites (1)

Yonsei University College of Medicine

Seoul, South Korea

RECRUITING

Related Publications (16)

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  PMID: 28577854 BACKGROUND

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  PMID: 26151266 BACKGROUND

• 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.

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• 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 BACKGROUND

• 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.

  PMID: 31542391 BACKGROUND

• 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 BACKGROUND

• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus

Interventions

Sodium-Glucose Transporter 2 Inhibitors; glimepiride

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Hypoglycemic Agents; Physiological Effects of Drugs

Study Officials

• Yong-ho Lee

  Department of Internal medicine, Yonsei University College of Medicine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Yong-ho Lee

CONTACT

02-2228-9143; YHOLEE@yuhs.ac

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2023
• First Posted: August 4, 2023
• Study Start: June 1, 2023
• Primary Completion: December 31, 2025
• Study Completion: December 31, 2025
• Last Updated: May 9, 2024

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

KR (1)