Article Text

Real-world risk of hypoglycemia-related hospitalization in Japanese patients with type 2 diabetes using SGLT2 inhibitors: a nationwide cohort study
  1. Takeshi Horii1,
  2. Yoichi Oikawa2,
  3. Narumi Kunisada1,
  4. Akira Shimada2,
  5. Koichiro Atsuda1
  1. 1Pharmacy Practice and Science I, Research and Education Center for Clinical Pharmacy, Kitasato University School of Pharmacy, Kanagawa, Japan
  2. 2Department of Endocrinology and Diabetes, School of Medicine, Saitama Medical University, Iruma-gun, Saitama, Japan
  1. Correspondence to Takeshi Horii; horiit{at}


Introduction Sodium-glucose cotransporter 2 (SGLT2) inhibitors are believed to lower glucose levels and inhibit cardiovascular events related to type 2 diabetes (T2D). To maximize their benefits, the risk of resultant hypoglycemia has to be minimized; however, the magnitude of this risk remains unclear. Here, we aimed to identify clinical factors linked to an increased risk of hypoglycemia among Japanese patients with T2D and treated with SGLT2 inhibitors.

Research design and methods This was a real-world retrospective cohort study conducted using the Japanese Medical Data Vision database. We identified patients with T2D and treated with SGLT2 inhibitors who were enrolled in the database from April 2014 to October 2019. Cox multivariate regression analyses were performed to determine demographical and clinical factors linked to SGLT2 inhibitor-associated hypoglycemia-related hospitalization.

Results Of 171 622 patients prescribed SGLT2 inhibitors, hypoglycemia-related hospitalization occurred in 216 (0.13%), with 0.60 incidences per 100 person-years. The risk of SGLT2 inhibitor-associated hypoglycemia was higher with each 10-year increase in age (HR 1.49; 95% CI 1.32 to 1.68) and high in patients with body mass index <25 kg/m2 (HR 1.98; 95% CI 1.50 to 2.61), insulin use (HR 3.26; 95% CI 2.43 to 4.38), and sulfonylurea use (HR 1.44; 95% CI 1.02 to 2.03). The risk was lower in women than in men (HR 0.73; 95% CI 0.54 to 0.98) and low in concomitant metformin users (HR 0.52; 95% CI 0.37 to 0.74).

Conclusions These findings may help minimize the risk of hypoglycemia-related hospitalization due to T2D treatment with SGLT2 inhibitors. We revealed that the risk of hypoglycemia may be higher when combining SGLT2 inhibitors with sulfonylureas and/or insulin. Furthermore, we discovered a high risk of hypoglycemia in older and non-obese patients. These findings may assist in maximizing the benefits of SGLT2 inhibitors for the treatment of T2D.

  • hypoglycemia
  • diabetes mellitus
  • type 2
  • hypoglycemic agents

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  • Contributors TH and NK designed the study and analyzed the data. TH wrote the manuscript in consultation with YO, KA and AS. YO, KA and AS reviewed the manuscript and contributed to the discussion. TH is the guarantor of this work and, as such, had full access to all the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests AS has received lecture fees from Astellas Pharma, Eli Lilly Japan, Novo Nordisk Pharma, and Sanofi.

  • Patient consent for publication Not required.

  • Ethics approval This study was conducted in accordance with ethical guidelines for medical and health research involving human subjects. The ethics board of Kitasato University approved the study (control number: B19-285) and provided permission to review patient records and use the corresponding data. Because all patient data are anonymized for personal data, informed consent was not required for publication.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplemental information. Additional data are available on reasonable request.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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