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

Abstract

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.

Case Report: Fixed Drug Eruption Caused by Dapagliflozin

“…In a previous study on Japanese population, six SGLT-2 inhibitors have been evaluated for possible skin reactions wherein serious generalized rashes, eruptions, urticaria, erythema, and eczema and subcutaneous tissue disorders with ipragliflozin alone were observed. Ipragliflozin is stored in the skin tissue, and interacts with melanin; therefore skin reactions might be related to the disturbed skin tissue homeostasis (9). Such reactions, however, were not observed with dapagliflozin in the present study.…”

Safety and tolerability of empagliflozin in East Asian patients with type 2 diabetes: Pooled analysis of phase I–III clinical trials

“…The vast majority of skin reactions were mild, but not severe or serious. In addition, serious skin disorders defined from 77 skin‐related AEs were not associated with EMPA in the Japanese Adverse Drug Event Report database provided by the Pharmaceuticals and Medical Devices Agency (PMDA). However, allergic skin reactions; that is, skin rash, are considered a side‐effect for EMPA, as per prescribing information.…”

Psoriasis and Cardiovascular Risk: A Comprehensive Review

“…As with other drug groups, there is evidence that associates thiazolidinediones (especially with pioglitazone) with a lower incidence of psoriasis and, in those subjects with established [111,112]. Previously, the sodium glucose cotransporter-2 (SGLT-2) inhibitors have been reported to be associated with serious skin and subcutaneous tissue disorders [113]. However, recent research suggests that such findings would be specific for ipragliflozin and not with other drugs of the same group.…”

“…Previously, the sodium glucose cotransporter-2 (SGLT-2) inhibitors have been reported to be associated with serious skin and subcutaneous tissue disorders [ 113 ]. However, recent research suggests that such findings would be specific for ipragliflozin and not with other drugs of the same group.…”