International Journal of Medical Sciences

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20 April 2019

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Int J Med Sci 2018; 15(9):937-943. doi:10.7150/ijms.22224

Research Paper

Susceptibility to serious skin and subcutaneous tissue disorders and skin tissue distribution of sodium-dependent glucose co-transporter type 2 (SGLT2) inhibitors

Toshiyuki Sakaeda1✉, Shinji Kobuchi1, Ryosuke Yoshioka1, Mariko Haruna1, Noriko Takahata1, Yukako Ito1, Aki Sugano2, Kazuki Fukuzawa3, Toshiki Hayase3, Taro Hayakawa4, Hideo Nakayama4, Yutaka Takaoka2, Masahiro Tohkin3

1. Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan
2. Department of Medical Informatics and Bioinformatics, Kobe University Hospital, Kobe 650-0017, Japan
3. Department of Regulatory Science, Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya 467-8603, Japan
4. Department of Hospital Pharmacy, Otsu City Hospital, Otsu 520-0804, Japan


Objectives: In Japan, sodium-glucose co-transporter type 2 (SGLT2) inhibitors have been reported to be associated with serious skin and subcutaneous tissue disorders. A post-marketing surveillance (PMS) study suggested that the association was specific for ipragliflozin and, to a lesser extent for dapagliflozin. These studies were performed to confirm the association of 6 SGLT2 inhibitors with serious skin disorders in a clinical setting, to elucidate the role of melanin in serious skin disorders and to understand the underlying mechanisms.

Methods: The latest PMS records were retrieved from the Japanese Adverse Drug Event Report (JADER) database, and the associations were analyzed by data mining techniques. In silico 3-D docking simulation of SGLT2 inhibitors with melanin was performed using the MOE software. The skin tissue distribution of SGLT2 inhibitors was evaluated using albino rats after oral administration at clinical doses.

Results: The adjusted reporting odds ratio (95% confidential limit) was 1.667 (1.415, 1.963) for ipragliflozin, 0.514 (0.317, 0.835) for dapagliflozin, 0.149 (0.048, 0.465) for tofogliflozin, 0.624 (0.331, 1.177) for luseogliflozin, 0.590 (0.277, 1.257) for canagliflozin and 0.293 (0.073, 1.187) for empagliflozin, when drugs other than the SGLT2 inhibitors were referred, and the association was detected only for ipragliflozin in clinical use. In silico 3-D docking simulation suggested the influence of melanin in ipragliflozin-specific serious skin disorders. The skin tissue-to-plasma concentration ratio of ipragliflozin was 0.45 ± 0.20 (±SD) at 1 hr after administration and increased in a time-dependent manner to 5.82 ± 3.66 at 24 hr (p<0.05), but not in case of other SGLT2 inhibitors.

Conclusions: Serious skin disorders were suggested to be specific for ipragliflozin. Interaction with melanin might be implicated in ipragliflozin-specific serious skin disorders. Ipragliflozin was retained in the skin tissue, which suggested its interaction with the skin tissue in serious skin disorders.

Keywords: Sodium-glucose co-transporter type 2 (SGLT2), skin and subcutaneous tissue disorders, ipragliflozin, dapagliflozin

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
How to cite this article:
Sakaeda T, Kobuchi S, Yoshioka R, Haruna M, Takahata N, Ito Y, Sugano A, Fukuzawa K, Hayase T, Hayakawa T, Nakayama H, Takaoka Y, Tohkin M. Susceptibility to serious skin and subcutaneous tissue disorders and skin tissue distribution of sodium-dependent glucose co-transporter type 2 (SGLT2) inhibitors. Int J Med Sci 2018; 15(9):937-943. doi:10.7150/ijms.22224. Available from