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.