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Theranostics 2021; 11(9):4502-4515. doi:10.7150/thno.54498 This issue Cite

Review

Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to pre-clinical and clinical therapeutics

Zhenghong Liu¹, Xiaoxuan Ma¹, Iqra Ilyas¹, Xueying Zheng¹, Sihui Luo¹, Peter J. Little^2,3, Danielle Kamato³, Amirhossein Sahebkar^4,5, Weiming Wu⁶, Jianping Weng^1✉, Suowen Xu^1✉

1. Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
2. Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, QLD 4575, Australia.
3. School of Pharmacy, Pharmacy Australia Centre of Excellence, the University of Queensland, Woolloongabba, Queensland 4102, Australia.
4. Halal Research Center of IRI, FDA, Tehran, Iran.
5. Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad. Iran.
6. Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, China.

✉ Corresponding authors: Suowen Xu, PhD, E-mail: sxu1984edu.cn; ORCID: 0000-0002-5488-5217; Jianping Weng, MD, PhD, E-mail: wengjpedu.cn; ORCID: 0000-0002-7889-1697.

Abstract

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are new oral drugs for the therapy of patients with type 2 diabetes mellitus (T2DM). Research in the past decade has shown that drugs of the SGLT2i class, such as empagliflozin, canagliflozin, and dapagliflozin, have pleiotropic effects in preventing cardiovascular diseases beyond their favorable impact on hyperglycemia. Of clinical relevance, recent landmark cardiovascular outcome trials have demonstrated that SGLT2i reduce major adverse cardiovascular events, hospitalization for heart failure, and cardiovascular death in T2DM patients with/without cardiovascular diseases (including atherosclerotic cardiovascular diseases and various types of heart failure). The major pharmacological action of SGLT2i is through inhibiting glucose re-absorption in the kidney and thus promoting glucose excretion. Studies in experimental models of atherosclerosis have shown that SGLT2i ameliorate the progression of atherosclerosis by mechanisms including inhibition of vascular inflammation, reduction in oxidative stress, reversing endothelial dysfunction, reducing foam cell formation and preventing platelet activation. Here, we summarize the anti-atherosclerotic actions and mechanisms of action of SGLT2i, with an aim to emphasize the clinical utility of this class of agents in preventing the insidious cardiovascular complications accompanying diabetes.

Keywords: SGLT2 inhibitors, diabetes, atherosclerosis, therapy, cardiovascular complications

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