In conclusion, based on FAERS data, diabetes is a predominant risk for lower extremity amputation, and most antidiabetic drugs demonstrated curative affects on this prognosis, while SGLT2i was less effective on this issue. Ketoacidosis, infections, peripheral ischemia, renal impairment, inflammation might more likely to occur among SGLT2i users, especially canagliflozin. Osteomyelitis and cellulitis are AEs unique to canagliflozin, and therefore intensively discussed. ROR, IC025 as well as q-ROR tendency of canagliflozin-osteomyelitis pair were significantly different from those generated by insulin-osteomyelitis pair, and there was no positive signal for hypoglycemic drugs other than canagliflozin and insulin. Our findings strongly indicated that canagliflozin treatment increasing the risk of developing osteomyelitis from the very early stage, prior to the advanced stage when insulin was prescribed. It is worth investigating whether SGLT2i can result in developing osteomyelitis also in patients without diabetes, and association between osteomyelitis and the lately approved SGLT2i, whenever there are enough reports. Further studies are needed to characterize a better understanding the association between SGLT2i treatment and risk of osteomyelitis.
Acknowledgements: We would like to thank the pharmacist Shu-Shan Wu of University of Nebraska Medical Center College of Pharmacy, Omaha, USA for preparing the raw data from FAERS database, and all the co-workers of Pharmacy Department, Huashan Hospital, Fudan University, Shanghai, China for their supporting which enables this effort.
Conflict of interest: The authors have stated explicitly that there are no conflicts of interest in connection with this article.
Author contribution: Xiao-Yan Qiu and Ming-Kang Zhong designed the study; Ming-Ming Yan, Hui Zhao conducted the study; Zi-Ran Li and Qian Zhang contributed to the formation of figures and Jun-Wei Chow contributed to improve the analytical method. Ming-Ming Yan and Hui Zhao contributed equally to the manuscript. Xiao-Yan Qiu and Ming-Kang Zhong are co-corresponding authors. Xiao-Yan Qiu is the lead contact author.
Funding: This study was sponsored by 2020 Shanghai ”Rising Stars of Medical Talent” Youth Development Program-Clinical Pharmacist Program (SHWSRS (2021) 099).