Introduction

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are a class of oral hypoglycemic agents that spell their glucose lowering effect by lowering the renal threshold for glucose reabsorption in the proximal renal tubule, causing glycosuria, increasing renal excretion of glucose. In patients with type 2 diabetes (T2D), SGLT2i are effective in controlling glycaemia, blood pressure, and body weight [1]. Since approval of canagliflozin in 2013, these drugs have been reported to demonstrate protective effect on renal and cardiovascular disease (CVD) [2-4], such as preventing hospitalization for heart failure (HF) in patients with T2D with or without a prior history of HF or cardiovascular disease at baseline [5], or significantly improving outcomes for patients with HF and reduced ejection fraction , 42–50% of whom had T2D [6].
However, in 2017, the US Food and Drug Administration (FDA) issued a Drug Safety Communication regarding a boxed warning about foot and leg amputations with the use of canagliflozin, and removed it in 2020 reconsidering its additional benefits [7, 8]. The amputation risk with canagliflozin remains and is still described in the Warnings and Precautions section of the prescribing information. Health care professionals and patients should continue to recognize the importance of preventative foot care and monitor for new pain, tenderness, sores, ulcers, and infections in the legs and feet. Risk factors that may predispose patients to the need for amputation should be considered when choosing antidiabetic medicines [8]. This warning was based on the evidence from two clinical trials. The Canagliflozin Cardiovascular Assessment Study (CANVAS) program used data from two trials and showed that there was a statistically significantly higher risk of amputation with canagliflozin than with placebo (6.3 vs. 3.4 participants with amputations per 1,000 patient-years) [9, 10]. A retrospective cohort study has raised concerns in relation to increased risk of lower extremities amputation with canagliflozin and it remains unclear whether and to what extent this side effect could also occur with other SGLT2i, in which risk of osteomyelitis was also mentioned about [11].
To the best of our knowledge there is no assessment of association between hypoglycemic drugs and AEs, which might be precursors to lower extremity amputation, especially osteomyelitis, based on real world data. Osteomyelitis is an inflammatory bone disease that is caused by an infecting microorganism and leads to progressive bone destruction and loss [12, 13], which complicates approximately 10−20% of foot ulcers in individuals with diabetes attending specialist clinics [14], although a frequency of as high as 68% has been reported in one study [15, 16]. This complication greatly increases the risk of a lower-extremity amputation [17, 18]. Although, both the CANVAS and Canagliflozin Cardiovascular Assessment Study–Renal (CANVAS-R) suggested an increased risk for lower limb amputations, they underestimated the importance of osteomyelitis, since its treatment might greatly reduce the risk of amputation. In this study, based on the US Food and Drug Administration Adverse Event Reporting System (FAERS), we investigated the association between treatment of hypoglycemic drugs and adverse events (AEs) referred, as well as association between diabetes and AEs. Drug-AEs which could generated stronger signals than the pair of the same AEs and diabetes, especially osteonecrosis-related AEs, could be used as warning for prognosis of lower extremity amputation.