Discussion
As shown in Figure 2 , ketoacidosis, various infection,
peripheral ischemia, renal impairment, inflammation including
osteomyelitis might more likely to occur among SGLT2i users, especially
canagliflozin. Our findings suggested that SGLT2i increased the risk of
these issues, or was less effective on them. SGLT2i treatment for
patients who suffered from ketoacidosis, cardiovascular issues, renal
problem and inflammation was therefore not recommended. Osteomyelitis
and cellulitis are AEs unique to canagliflozin. Since osteomyelitis is
considered to greatly increases the risk of a lower-extremity amputation
[17, 18], our findings indicated that exposure to canagliflozin
could notably increase the risk of developing osteomyelitis while other
A10 drugs could reduce such a risk. On the other hand, these events
could be monitored as warning prior to lower limb extreme amputation.
Most osteomyelitis-related cases were referred to canagliflozin,
indicated that there might be a strong correlation between SGLT2i
exposure, especially canagliflozin, and developing osteomyelitis
according to FAERS data. In this study, ROR and BCPNN method were
applied to investigate association between hypoglycemic drugs and
osteomyelitis. Signals with high value of ROR were detected for
canagliflozin-osteomyelitis pairs, as well as any drug group containing
canagliflozin. Since the value of ROR did not directly indicate the
significance of a signal, all positive signals were validated by BCPNN
method, strong signals were generated canagliflozin or any drug groups
containing canagliflozin associated with osteomyelitis, while weak
signal was generated for insulin (A10A-osteomyelitis pair), and no
signal was ever generated for other A10 drugs or drug groups excluding
canagliflozin as well as insulin. Therefore, these findings indicated
that association between canagliflozin treatment and osteomyelitis was
quite convincing. Weak signal generated by insulin-osteomyelitis pair,
might be explained by the insulin exposure as well as morbidity of
diabetes since insulin treatment indicating a proxy of disease severity
or disease advanced stage [26, 27], but the morbidity of diabetes
might neither be a sufficient condition nor necessary condition for a
patient with diabetes to develop osteomyelitis. Case number of targeted
drugs presented notable differences with or without filtering diabetes
as indication, and IC025 of canagliflozin-osteomyelitis
pairs with the filtering was lower than without it, which could lead to
the conclusion that casting out cases without a specific indication as
diabetes resulted in dwindling the intensity of BCPNN signal.
Among patients developed osteomyelitis, 73.50% of whom are male, while
the gross gender ratio for each category of drugs is relatively more
balanced (Table 1 ). Further disproportional analysis using
gender as filtering was applied and results suggested that there was
significant difference in the ROR of canagliflozin-osteomyelitis pairs
between two genders. Since the cleansing procedure according to
including/excluding criteria mention above had excluded all reports with
infection know as competing indication and reaction [29], the gender
ratio as well as differences of ROR and IC025 value
between male and females was possibly due to sex differences, negative
correlation might existed between glycosylated hemoglobin (HbA1c) and
serum testosterone levels [31]. As displayed by
insulin-osteomyelitis pair, only the dataset of male patients could
generate a valid ROR and a weak signal of BCPNN, these findings support
the hypothesis that male patient might more likely to develop
osteomyelitis. When exposure to SGT2i, and canagliflozin were the major
factor for causing disproportionality, dataset of male could generate
ROR value three times larger than female. When the signals were
validated by BCPNN method, both genders generated strong signals
(IC025 7.96 for male vs. IC025 6.69 for
female), which indicated that for reports of each gender, however their
difference in ROR, canagliflozin presented a strong correlation with
developing osteomyelitis.
A new approach so-called quarterly ROR (q-ROR) was introduced to
demonstrate the ROR developing pattern, and the series of q-ROR
generated by different drugs or drug groups was subjected to Chi-square
tests to determine their correlations statistically. Canagliflozin (wo),
canagliflozin, SGLT2i and A10 demonstrates no prevalence difference
although there might be gap in the scale of ROR value
(Supplement Table 2 & Figure 4 ) and supported the
speculation mentioned above that the disproportionality of
osteomyelitis-related reports was generated by canagliflozin. For
hypoglycemic drugs other than canagliflozin and drug groups excluding
SGLT2i, no positive signal was ever generated. These findings strongly
indicated that developing pattern of these drugs or drug groups were
synchronised by the presents canagliflozin.
In pharmacovigilance study, disproportionality emerges when a specific
adverse event is associated with a given drug [32-34]. In this
study, we tried this approach called q-ROR to utilize the FAERS data
quarterly, and mimicked accumulation of reports to the database in real
world. Starting from a setting date, slice of data was added to dataset
in chronologically order on quarterly basis and a ROR value from the
setting date up to that quarter was calculated. A serial of RORs was
generated for any given interested drug (drug group)-AE pair. Finally,
value of q-ROR achieved equilibrium approached its theoretically true
value. For those lately approved drugs with limited reports but analogs
of which had been long approved, the q-ROR curve might be used to
predict its association with interested AE according to their precursors
or as a drug group, such as ertugliflozin, luseogliflozin, remogliflozin
and other new SGLT2i fail to generate any positive signal. The q-ROR
value of the insulin-osteomyelitis is always above the recognition
threshold and fluctuate consistently around 1.5 and positive signal
could be identified since Q1 of 2005, while series of q-ROR referring to
any drug group excluding canagliflozin and insulin went beneath the
thread hold of 1, since 2005. Coupled with the dramatic increasing
reports of canagliflozin related osteomyelitis in FAERS (25 cases in
2017 vs. 1,402 cases in 2018) (Table 1 ), the q-ROR pattern of
canagliflozin bounds from 3.24 in Q4 of 2017 to 79.54 in Q4 of 2018
(Supplement Table 2 ).This finding indicated that, q-ROR could
be used to monitor drug-induced ADRs unknown to premarketing trials as
pharmacovigilance, when a dramatic rise in ROR value was spotted for
given drug-AE pairs, and needed to be further vilified by BCPNN method.
Diabetes was a competing risk factor of developing osteomyelitis, which
occurs in approximately 10-20% of patients with diabetes-related foot
ulcers [17], and osteomyelitis of the lower extremity is a commonly
encountered problem in patients with diabetes [35]. In this study,
such a data pack in FAERS was equivalent to considering all hypoglycemic
drugs as a drug group and filtering with diabetes as indication which
generated a signal considered to be caused by both the treatment and the
morbidity. And this data pack was also examined by quarterly ROR method
(q-ROR).
Chi2
test was induced to comparing q-ROR value prior to and since
canagliflozin was approved in Q1 of 2013, and a p value of 0.00924
< 0.05 indicated that ROR developing pattern experienced a
significant change, which probably due to the exposure to SGLT2i,
especially canagliflozin, since before the approval of SGLT2i, ROR
serial of drug-event pair generated no positive signal and the
indication was confined as diabetes mellitus.
Although previous publication suggested that osteomyelitis of the lower
extremity is a commonly encountered problem in patients with diabetes
[35] and occurred in approximately 10-20% of patients with
diabetes-related foot ulcers [17]. According to our findings, q-ROR
series of drug groups excluding canagliflozin and insulin generates no
positive signal (Supplement Table 2 & Figure 4 ).
q-ROR serial of insulin presented all its value of q-ROR ranging 1.71 ±
0.44, with median as 1.57, as well as ranging 1.53 ± 0.25, with median
as 1.45, since Q2 of 2013, when canagliflozin was approved as the first
of SGLT2i, which indicated that the morbidity of diabetes mellitus, even
at a proxy of disease severity or disease advanced stage [26, 27]
might not be consider as a significant interfering factor for
drug-associated osteomyelitis based on FAERS, otherwise all drug groups
filtering diabetes as indication should consequently generate ROR
signals above 1. And therefore, it strengthened the results of Chi2 test
between q-ROR series, that was, canagliflozin exposure might be the
predominant cause of developing osteomyelitis for patients with or
without filtering diabetes as indication, based on FAERS database. On
the contrary, other widely used SGLT2i, such as dapagliflozin and
empagliflozin might not associated with developing osteomyelitis, and
for those lately approval SGLT2i which had not accumulated enough ADR
reports for disproportional analysis yet, predictions could be made base
on the q-ROR pattern as pharmacovigilance.
There are certain limitations might undermine this study. Spontaneous
reporting systems including FEARS were exposed to the biases inherent to
pharmacovigilance studies. To the best of our knowledge, in 2018, Chang,
H.Y., et al. [11] had mentioned about risk of osteomyelitis when
discussing about the association between SGLT2i treatment and lower
extremity amputation among patients with T2D, and osteomyelitis of the
lower extremity is a commonly encountered problem in patients with
diabetes [35] and occurs in approximately 10-20% of patients with
diabetes-related foot ulcers [17]. These publications coincidently
match with a gush of osteomyelitis related ADR reports and a surge in
ROR for canagliflozin-osteomyelitis pair.