See article vol. 27: 1141–1151
Recently, antidiabetic agents have been evaluated as vascular protective agents. Newly identified antidiabetic agents such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors have been studied for their efficacy and safety for cardiovascular events (CVE)1), and our previous basic experiments revealed some of their mechanisms2, 3). Among antidiabetic agents, sodium-glucose cotransporter 2 (SGLT2) inhibitor is the most attractive drug and the focus of attention because of its CVE-reducing effects in large-scale clinical trials. In fact, the SGLT2 inhibitor canagliflozin has demonstrated CVE-reducing effects in the CANVAS program4).
In the present study5), Rahadian et al. investigated a mechanism by which canagliflozin attenuates atherosclerosis and CVE mainly using diabetic and atherogenic mouse model. Atheroma formation in the aortic arch was significantly decreased by orally administered canagliflozin. Canagliflozin inhibited gene expressions of contributing factors for vascular inflammation and advanced glycation end products (AGE)-receptor for AGE system, decreased serum AGE and oxidative stress marker levels, and subsequently improved vascular relaxation. Blood glucose and total cholesterol but not body weight and blood pressure were significantly decreased by canagliflozin. Further in vitro experiments using endothelial cells demonstrated that methylglyoxal (MGO), an AGE, decreased vascular relaxation signals and increased vascular inflammation signals. The summarized mechanism is provided in Fig. 1.
Fig. 1.
The mechanism by which SGLT2 inhibitor demonstrates vascular protective effect
Such a study, which elucidates the detailed mechanism of clinical investigation using basic science, is very important in the “bench-to-bedside” aspect. The present study confirmed one aspect of vascular protective mechanism by canagliflozin. Regarding the present data, I had two discussion points. First, this vascular protective effect might be a class effect of SGLT2 inhibitor or specific drug effect of canagliflozin. In fact, the same group performed similar experiments and observed similar effects using another type of SGLT2 inhibitor, empagliflozin6). In addition, other groups have also reported vascular protective effects of other SGLT2 inhibitors, luseogliflozin7) and dapagliflozin8). These experimental data and clinical trials1) suggested that SGLT2 inhibitor may show vascular protective effects as a class effect. Second, this vascular protective effect is dependent or independent of the glucose lowering effect. In the present study5), the authors discussed that this effect might be dependent on glucose lowering and clearance of glucose toxicity. However, canagliflozin decreased inflammatory gene expressions induced by MGO as shown in Fig. 5A, but this was not statistically significant. This suggested the possibility of direct vascular protective effect of canagliflozin in endothelial cells. In addition, we previously reported that SGLT2 inhibitor directly attenuated vascular smooth muscle cell proliferation in in vitro experiments9). The direct vascular protective effects of SGLT2 inhibitor beyond blood glucose control should be investigated further in future studies. Furthermore, the serum insulin level was increased by canagliflozin in the present study (Table 2, 3)5). According to the glucose lowering mechanism of SGLT2 inhibitor, insulin secretion could be decreased, as reported in a clinical study10). SGLT2 inhibitor may be able to improve insulin secretion in an STZ (streptozotocin)-induced diabetic model, and this point should be investigated in detail.
New antidiabetic agents make diabetes care more exciting. In the 21st century breakthroughs in diabetology, we should focus on not only the glucose lowering effect but also pleiotropic effects to improve the quality of life and lifespan of patients with diabetes mellitus. Antidiabetic agents should be able to evolve from being just glucose lowering agents to being the best partner of patients to improve the quality of life.
Conflict of Interest
Takashi Nomiyama has received lecture fees from Ono Pharmaceutical Co. Ltd, Sumitomo Dainippon Pharma Co.Ltd and MSD K. K.
References
- 1). Acharya T, Deedwania P. Cardiovascular outcome trials of the newer anti-diabetic medications. Prog Cardiovasc Dis, 2019; 62: 342-348 [DOI] [PubMed] [Google Scholar]
- 2). Takahashi H, Nomiyama T, Terawaki Y, Kawanami T, Hamaguchi Y, Tanaka T, Tanabe M, Bruemmer D, Yanase T. Glucagon-like peptide-1 receptor agonist exendin- 4 attenuates neuron- derived orphan receptor 1 expression in vascular smooth muscle cells. J Atheroscler Thromb, 2019; 26: 183-197 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3). Terawaki Y, Nomiyama T, Kawanami T, Hamaguchi Y, Takahashi H, Tanaka T, Murase K, Nagaishi R, Tanabe M, Yanase T. Dipeptidyl peptidase-4 inhibitor linagliptin attenuates neointima formation after vascular injury. Cardiovasc Diabetol, 2014; 13: 154. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4). Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. New Engl J Med, 2017; 377: 644-657 [DOI] [PubMed] [Google Scholar]
- 5). Rahadian A, Fukuda D, Salim HM, Yagi S, Kusunose K, Soeki T, Sata M. Canagliflozin prevents diabetes-induced vascular dysfunction in apo E-deficient mice. J Atheroscler Thromb, 2020; 27: 1141-1151 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6). Ganbaatar B, Fukuda D, Shinohara M, Yagi S, Kusunose K, Yamada H, Soeki T, Hirata KI, Sata M. Empagliflozin ameliorates endothelial dysfunction and suppresses atherogenesis in diabetic apolipoprotein E-deficient mice. Eur J Pharmacol, 2020; 875: 173040. [DOI] [PubMed] [Google Scholar]
- 7). Nakatsu Y, Kokubo H, Bumdelger B, Yoshizumi M, Yamamotoya T, Matsunaga Y, Ueda K, Inoue Y, Inoue MK, Fujishiro M, Kushiyama A, Ono H, Sakoda H, Asano T. The SGLT2 inhibitor luseogliflozin rapidly normalizes aortic mRNAlevels of inflammation-related but not lipid-metabolism-related genes and suppresses atherosclerosis in diabetic apoE KO mice. Int J Mol Sci, 2017; 18 pii: E1704. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8). Leng W, Ouyang X, Lei X, Wu M, Chen L, Wu Q, Deng W, Liang The SGLT-2 inhibitor dapagliflozin has therapeutic effect on atherosclerosis in diabetic apoE-/-mice. Mediators Inflamm, 2016; 2016: 6305735. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9). Takahashi H, Nomiyama T, Terawaki Y, Horikawa T, Kawanami T, Hamaguchi Y, Tanaka T, Motonaga R, Fukuda T, Tanabe M, Yanase T. Combined treatment with DPP-4 inhibitor linagliptin and SGLT2 inhibitor empagliflozin attenuates neointima formation after vascular injury in diabetic mice. Biochem Biophys Rep, 2019; 18: 100640. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10). Nomiyama T, Shimono D, Horikawa T, Fujimura Y, Ohsako T, Terawaki Y, Fukuda T, Motonaga R, Tanabe M, Yanase T. Efficacy and safety of sodium–glucose cotransporter 2 inhibitor ipragliflozin on glycemic control and cardiovascular parameters in Japanese patients with type 2 diabetes mellitus; Fukuoka Study of Ipragliflozin (FUSION). Endocr J, 65: 859-867 [DOI] [PubMed] [Google Scholar]