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

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.

Timeline

Start

2023-06-01

Primary completion

2025-12-31

Completion

2025-12-31

Publications

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• 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.
• 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.
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• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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.
• Background 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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• Background 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.

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