Cardiac effects of dapagliflozin in diabetic rats with subacute exposure

Yıl 2022, Cilt: 52 Sayı: 1, 8 - 13, 28.04.2022

Tugce Boran Bahar Ulus Karaca Ayça Karagöz Köroğlu Engin Kaptan Feriha Ercan Gül Özhan

https://doi.org/10.26650/IstanbulJPharm.2022.1038546

Öz

Background and Aims: Dapagliflozin (DAPA) is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of type 2 diabetes mellitus (T2DM) as a monotherapy or combination therapy with other antidiabetic medicines. The Food and Drug Administration (FDA) recently approved DAPA to minimize the risk of hospitalization due to heart failure in patients with T2DM because of its antihypertensive and antihyperglycemic activities. However, further study of DAPA is necessary to ensure the safety of patients.
Methods: T2DM was induced by streptozotocin (STZ) injection (35 mg/kg b.w. i.p.) in male rats that were fed a high-fat diet for two weeks before STZ injection. The diabetic rats were exposed to 10 mg/kg DAPA by oral gavage during sub-acute treat- ment. Total cholesterol levels and oxidative stress parameters were evaluated. Heart tissues were histologically examined, and cardiac troponin T (cTnT) levels were measured.
Results: DAPA has the potential to inhibit diabetes-induced oxidative stress and morphologic damage to heart tissue, and increased cTnT levels of the heart, which is important for cardiac contractility.
Conclusion: DAPA might have a protective effect on the heart at a 10 mg/kg oral dose; however, further experimental and clinical studies are required to clarify the cardio-protective potential of DAPA.

Anahtar Kelimeler

Dapagliflozin, SGLT2 inhibitor, Type 2 diabetes mellitus, Cardio-protection

Destekleyen Kurum

Research Fund of Istanbul University

Proje Numarası

Project No: TDK-2018-31064

Kaynakça

• SGLT2 inhibitor against diabetic cardiomyopathy in type 2 dia- betic rats: possible underlying mechanisms. Biomedicines, 8(3), 43. https://doi.org/10.3390/biomedicines8030043
• Inzucchi, S. E., Zinman, B., Wanner, C., Ferrari, R., Fitchett, D., Hantel, S., ... Johansen, O. E. (2015). SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome tri- als. Diabetes and Vascular Disease Research, 12(2), 90-100. https:// doi.org/10.1177/1479164114559852
• Jankowski, M., Bissonauth, V., Gao, L., Gangal, M., Wang, D., Da- nalache, B., ... Gutkowska, J. (2010). Anti-inflammatory effect of oxytocin in rat myocardial infarction. Basic Research in Cardiol- ogy, 105(2), 205-218. https://doi.org/10.1007/s00395-009-0076-5
• Kato, E.T., Silverman, M.G., Mosenzon, O., Zelniker, T.A., Cahn, A., Furtado, R.H., ... Wiviott, S.D. (2019). Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circula- tion, 139(22), 2528-2536. https://doi.org/10.1161/CIRCULA- TIONAHA.119.040130
• Kelly, K.J. (2020, January 3). Dapagliflozin approved to reduce risk for heart failure hospitalization in type 2 diabetes. Retrieved from https://www.jwatch.org/fw115953/2019/10/22/dapagliflozin- approved-reduce-risk-heart-failure.
• Kıngır, Z.B., Kumral, Z.N.Ö., Çam, M.E., Çilingir, Ö.T., Şekerler, T., Er- can, F., ... Okuyan, B. (2019). Effects of dapagliflozin in experimen- tal sepsis model in rats. Turkish Journal of Trauma & Emergency Surgery, 25(3), 213-221.
• Liro, A. (1985). Variation in weights of body and internal organs of the field mouse in a gradient of urban habitats. Acta Therio- logica, 30(24), 359-377.
• Liu, Q., Wang, S., & Cai, L. (2014). Diabetic cardiomyopathy and its mechanisms: role of oxidative stress and damage. Journal of Dia- betes Investigation, 5(6), 623-634. https://doi.org/10.1111/jdi.12250
• Lorenzo-Almorós, A., Tuñón, J., Orejas, M., Cortés, M., Egido, J., & Lorenzo, Ó. (2017). Diagnostic approaches for diabetic cardio- myopathy. Cardiovascular Diabetology, 16(1), 1-14. https://doi. org/10.1186/s12933-017-0506-x
• Ptaszynska, A., Hardy, E., Johnsson, E., Parikh, S., & List, J. (2013). Effects of dapagliflozin on cardiovascular risk factors. Post- graduate Medicine, 125(3), 181-189. https://doi.org/10.3810/ pgm.2013.05.2667
• Rebolledo-Solleiro, D., & Fernández-Guasti, A. (2018). Influence of sex and estrous cycle on blood glucose levels, body weight gain, and depressive-like behavior in streptozotocin-induced diabetic rats. Physiology & Behavior, 194, 560567. https://doi.org/10.1016/j. physbeh.2018.06.033
• Reed, J.W. (2016). Impact of sodium–glucose cotransporter 2 inhibitors on blood pressure. Vascular Health and Risk Manage- ment, 12, 393. https://doi.org/10.2147/VHRM.S111991
• Reilly, T.P., Graziano, M.J., Janovitz, E.B., Dorr, T.E., Fairchild, C., Lee, F., ... Tirmenstein, M. (2014). Carcinogenicity risk assessment sup- ports the chronic safety of dapagliflozin, an inhibitor of sodium– glucose co-transporter 2, in the treatment of type 2 diabetes mellitus. Diabetes Therapy, 5(1), 73-96. https://doi.org/10.1007/ s13300-014-0053-3
• Sehnert, A.J., Huq, A., Weinstein, B.M., Walker, C., Fishman, M., & Stainier, D.Y. (2002).Cardiac troponin T is essential in sarcomere as- sembly and cardiac contractility. Nature Genetics, 31(1), 106-110. https://doi.org/10.1038/ng875
• Singh, V.P., Le, B., Khode, R., Baker, K.M., & Kumar, R. (2008). Intracel- lular angiotensin II production in diabetic rats is correlated with cardiomyocyte apoptosis, oxidative stress, and cardiac fibrosis. Di- abetes, 57(12), 3297-3306. https://doi.org/10.2337/db08-0805
• Skovsø, S. (2014). Modeling type 2 diabetes in rats using high fat diet and streptozotocin. Journal of Diabetes Investigation, 5(4), 349-358. https://doi.org/10.1111/jdi.12235
• Tanajak, P., Sa-Nguanmoo, P., Sivasinprasasn, S., Thummasorn, S., Siri-Angkul, N., Chattipakorn, S.C., & Chattipakorn, N. (2018). Car- dioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia-reperfusion injury. Journal of Endocrinology, 236(2), 69- 84. https://doi.org/10.1530/JOE-17-0457
• Thomson, S.C., Rieg, T., Miracle, C., Mansoury, H., Whaley, J., Vallon, V., & Singh, P. (2012). Acute and chronic effects of SGLT2 block- ade on glomerular and tubular function in the early diabetic rat. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 302(1), R75-R83. https://doi.org/10.1152/ ajpregu.00357.2011
• Tiwari, B.K., Pandey, K.B., Abidi, A.B., & Rizvi, S.I. (2013). Markers of oxidative stress during diabetes mellitus. Journal of Biomark- ers, 2013. https://doi.org/10.1155/2013/378790
• Wallace, K.B., Hausner, E., Herman, E., Holt, G.D., Macgregor, J.T., Metz, A.L., ... York, M. J. (2004). Serum troponins as biomarkers of drug-induced cardiac toxicity. Toxicologic Pathology, 32(1), 106- 121. https://doi.org/10.1080/01926230490261302
• Wei, W., Liu, Q., Tan, Y., Liu, L., Li, X., & Cai, L. (2009). Oxidative stress, diabetes, and diabetic complications. Hemoglobin, 33(5), 370-377. https://doi.org/10.3109/03630260903212175
• Wiviott, S.D., Raz, I., Bonaca, M.P., Mosenzon, O., Kato, E.T., Cahn, A., ... Sabatine, M.S. (2019). Dapagliflozin and cardiovascular out- comes in type 2 diabetes. New England Journal of Medicine, 380(4), 347-357. https://doi.org/10.1056/NEJMoa1812389
• Zhang, M., Zhang, H., Liu, C., Li, X., Ling, M., Wang, Z., & Xing, Y. (2018). Myocardial protective effects of nicorandil on rats with type 2 diabetic cardiomyopathy. Medical Science Monitor Basic Re- search, 24, 141. https://doi.org/10.12659/MSMBR.910974