Short-term impacts of sodium/glucose co-transporter 2 inhibitors in Japanese clinical practice: considerations for their appropriate use to avoid serious adverse events

Abstract

Sodium/glucose co-transporter 2 inhibitors (SGLT2i) represent a novel class of glucose-lowering agents that lower plasma glucose levels through pharmacological inhibition of glucose reuptake from the kidney, independent of insulin secretion and action. Clinical trials of SGLT2i demonstrated therapeutic benefits on glycemic control and bodyweight in individuals with type 2 diabetes, with few cases of serious adverse events (SAEs). However, a considerable number of SAEs were reported in patients receiving SGLT2i clinically in Japan during the first 3 months of their use. These included urogenital infections, hypoglycemia and dehydration. Unexpectedly, serious skin and subcutaneous disorders, mainly reported as generalized rash or skin eruption, were prominent in patients receiving SGLT2i, but with unknown mechanisms. There is also concern for potential SAEs associated with chronic SGLT2i administration, especially in the non-obese type 2 diabetes characterized by reduced insulin secretion often seen in East Asia. Chronic SAEs may include severe hypoglycemia due to depletion of hepatic glycogen storage, acceleration of diabetes-associated sarcopenia and ketosis/ketoacidosis. The current information on acute SAEs confirms the importance of caution in the appropriate use of SGLT2i. Furthermore, careful long-term observation of patients receiving SGLT2i is essential to avoid SAEs and for better clinical use of this drug class.

Keywords:

• dehydration
• hypoglycemia
• serious adverse events
• sodium/glucose co-transporter 2 inhibitors
• urogenital infections

Acknowledgments

The authors thank T Kurose, H Kuwata and T Mitani of Kansai Electric Power Hospital and K Sugawara and I Mori of Kobe University for discussion, and M Yamane of Kansai Electric Power Hospital for secretarial assistance.

Declaration of interest

D Yabe has received a Grant-in-Aid for Young Scientists (B) from Japan Society for Science Promotion and Grants for young researchers from Japan Association for Diabetes Education and Care. Y Seino has received grants from Japan Vascular Disease Research Foundation. D Yabe has received speaker fees from Eli Lilly, MSD, Sanofi, Novo Nordisk, Boehringer Ingelheim, Takeda and Taisho Pharmaceutical. Y Seino has received consulting and/or speaker fees from Eli Lilly, Sanofi, Novo Nordisk, GlaxoSmithKline, Taisho Pharmaceutical, Astellas Pharma, BD, Boehringer Ingelheim, Johnson & Johnson and Takeda. M Kaneko and R Nishikino are employees of the Japan Medical Data Center. M Iwasaki declares no conflict of interest. D Yabe and Y Seino take responsibility for the contents of the article. D Yabe and Y Seino collected and analyzed data, and wrote the manuscript. M Kaneko and R Nishikino contributed to data collection and discussion. M Iwasaki contributed to discussion on a hypothetical model on chronic use of sodium/glucose co-transporter 2 inhibitors.

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