Expert Opinion on Drug Safety

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ieds20

Euglycaemic diabetic ketoacidosis as a

complication of SGLT-2 inhibitors: epidemiology,
pathophysiology, and treatment

Erasmia Sampani , Pantelis Sarafidis & Aikaterini Papagianni

To cite this article: Erasmia Sampani , Pantelis Sarafidis & Aikaterini Papagianni
(2020): Euglycaemic diabetic ketoacidosis as a complication of SGLT-2 inhibitors:
epidemiology, pathophysiology, and treatment, Expert Opinion on Drug Safety, DOI:
10.1080/14740338.2020.1764532

To link to this article: https://doi.org/10.1080/14740338.2020.1764532

Published online: 10 Jun 2020.

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EXPERT OPINION ON DRUG SAFETY
https://doi.org/10.1080/14740338.2020.1764532

REVIEW

Euglycaemic diabetic ketoacidosis as a complication of SGLT-2 inhibitors:

epidemiology, pathophysiology, and treatment
Erasmia Sampani, Pantelis Sarafidis and Aikaterini Papagianni
Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece

ABSTRACT ARTICLE HISTORY

Introduction: Sodium-glucose co-transporters 2 (SGLT-2) inhibitors are a relatively novel class of oral Received 7 February 2020
medications for the treatment of Type 2 Diabetes Mellitus, which lower plasma glucose by inhibiting Accepted 30 April 2020
glucose reabsorption in the proximal renal tubule. Apart from their hypoglycemic action, recent data KEYWORDS
suggest these agents have additional major cardioprotective and nephroprotective properties. SGLT-2 inhibitors; Type 2
Areas covered: This review summarizes the existing data on epidemiology, pathophysiology, and Diabetes Mellitus; diabetic
treatment of euglycaemic ketoacidosis (euDKA) as a complication of SGLT-2 inhibitor use. ketoacidosis; euglycaemic
Expert opinion: Although SGLT-2 inhibitors have a relatively good adverse event profile, they have diabetic ketoacidosis;
been associated with the serious and potentially life-threatening metabolic complication of euDKA. adverse effects; metabolic
Data from major outcome trials suggest that the rate of DKA is quite low. However, the rate of DKA acidosis
could be generally underestimated in clinical trials due to the atypical presentation of ketoacidosis, and
even more so in real-life conditions. Management of this serious metabolic complication requires
a proper understanding of its pathophysiology as well as increased awareness and early recognition
of the potential risk factors involved. Following this, the institution of an array of simple supportive
measures, could safely restore normal acid–base balance in most patients.

1. Introduction 2. Sodium-glucose cotransporter-2 inhibitors: from

Diabetes Mellitus (DM) represents a major public health burden
and a prominent risk factor of cardiovascular morbidity and
mortality. The prevalence of DM is constantly rising, currently
affecting more than 400 million people worldwide, a number
expected to rise to more than 600 million in the next 20 years,
according to the International Diabetes Federation [1]. Diabetic
ketoacidosis (DKA) is a rare but serious metabolic complication of
DM. It usually occurs in patients with type 1 DM (T1DM); how-
ever, it has also been described in patients with type 2 DM
(T2DM) [2,3], usually under conditions of extreme physical stress
such as trauma, surgery, or infection. According to the American
Diabetes Association (ADA), the diagnostic criteria for DKA
include blood glucose levels >250 mg/dl (13.9 mmol/L), arterial
pH <7.3, anion gap >12mEq/L, HCO3− <15 mEq/L and the pre-
sence of ketones in blood and urine [4]. Recently a new class of
oral medications for T2DM, Sodium-Glucose Cotransporter-2
(SGLT-2) inhibitors, has been associated with rare events of
a serious and potentially life-threatening complication, which
involves ketoacidosis with only mild to moderate glucose eleva-
tion named euglycemic ketoacidosis (euDKA) [5]. After briefly
discussing current evidence on the effects of SGLT-2 inhibitors
on cardiovascular and renal outcomes that signifies a more
extended future use of these agents, this article performs an
overview of the epidemiology, pathophysiology, prevention,
and treatment of euDKA associated with SGLT-2 inhibitors
which possibly represents their most important adverse effect.
glucose-lowering to cardio- and nephroprotection
SGLT-2 inhibitors are novel therapeutic agents for treating
hyperglycemia in patients with Τ2DM. They can be used
alone or in combination with other oral antidiabetic drugs or
insulin. SGLT-2 inhibition has been first shown to offer hypo-
glycemic effects several decades ago, but the first tested agent
of this class, phlorizin, a naturally occurring glucoside
extracted from the root bark of apple trees, was never
approved due to its poor oral bioavailability [6]. During the
past decade novel SGLT-2 inhibitors have been developed;
among them, dapagliflozin, canagliflozin, empagliflozin, ipra-
gliflozin, luseogliflozin, tofogliflozin, and ertugliflozin, are cur-
rently marketed for the treatment of T2DM in various
countries worldwide [7]. It has to be noted that following
the publication of the DEPICT-1 trial [8], the European
Medicines Agency approved the use of dapagliflozin also for
patients with T1DM in March 2019 [9].
SGLT-2 is a high-capacity/low-affinity glucose transporter
located in the apical surface of renal proximal tubular cells of
the S1 segment at the kidneys. It is responsible for 90% of
renal glucose reabsorption [10]. The co-transportation of glu-
cose and sodium is active in a 1:1 ratio [11]. The remaining
10% of glucose is reabsorbed in the S2/S3 segment of prox-
imal tubules by SGLT-1 protein. In this way, the SGLTs family
proteins reabsorb almost all of the glucose that is freely
filtered at the glomeruli, up to a maximum of around

CONTACT Pantelis Sarafidis psarafidis11@yahoo.gr Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki,
Konstantinoupoleos 49, Thessaloniki GR54642, Greece
© 2020 Informa UK Limited, trading as Taylor & Francis Group
2 E. SAMPANI ET AL.
Article highlights
● SGLT2 inhibitors are a relatively novel class of oral medications for
the treatment of Type 2 Diabetes Mellitus. Apart from their hypogly-
cemic action, recent data suggest these agents possess cardioprotec-
tive and nephroprotective properties
● EuDKA is a rare but serious metabolic complication associated with
SGLT2 inhibitor therapy. Patients with euDKA often present with
serious high anion gap metabolic acidosis but only mild to moderate
glucose elevation [<250 mg/dl (13.9 mmol/L)].
● The rate of DKA in major trials was quite low, but there are sugges-
tions that the incidence of DKA in everyday practice could be under-
estimated due to its atypical presentation.
● Understanding of the pathophysiology of euDKA, employment of
simple preventive measures in high-risk patients, increased aware-
ness and prompt diagnosis of this complication is of major
importance.
● Early institution of simple therapeutic measures will safely restore
normal acid–base balance in most patients.
This box summarizes the key points contained in the article.
375 mg/min (2.08 mmoL/min) (glucose transport maximum)
[12]. In the setting of acute hyperglycemia, the increased
amount of filtered glucose leads to saturation of the SGLTs,
resulting in excretion of the excessive glucose. However, in
diabetic patients, the kidneys increase up to threefold the
expression of SGLT-2, which from an evolutionary perspective
can be seen as an adaptive response of the body to preserve
glucose, i.e. the precious fuel; thus, their glucose reabsorption
capacity is increase by at least by ~20%, compared to healthy
individuals [13]. The consequence of this adaptation is the
minimization of glucosuria which further enhances hypergly-
cemia, representing one of the multiple pathophysiological
mechanisms for glucose increase in T2DM2. SGLT-2 inhibitors
reach their target from the luminal side through glomerular
filtration and result in excretion of 50–60% of the filtered
glucose, instead of 90% because of a partial compensation
by an upregulation of SGLT-1 co-transporters [13].
Apart from reducing blood glucose levels, these agents also
have other beneficial cardiovascular and renal effects, for
example, weight loss and blood pressure (BP) lowering, possi-
bly due to glucosuria-induced calorie loss and natriuresis,
respectively, [14]. The daily urinary glucose loss that these
drugs induce ranges from 60 to 100 grams/day, which repre-
sents an important amount of daily carbohydrate intake in
men and a higher amount of carbohydrate intake in women.
This effect results in a weight loss of around 2–4 kg usually
within a period of 3–6 months [15]. Similarly, several clinical
trials evaluating BP as a primary or secondary outcome clearly
suggest that SGLT-2 inhibitors are associated with reductions
in SBP/DBP of 4–5/2–3 mmHg [7,16].
In addition to the aforementioned pleiotropic actions on
weight and BP, these drugs offer both cardioprotection and
nephroprotection. The apparent benefit of SGLT-2 inhibitors
on major cardiovascular events in patients with atherosclerotic
cardiovascular disease is well established, although the mode
of action of those drugs offering cardioprotection needs to be
further investigated. In the EMPA-REG OUTCOME trial, 7,020
patients with T2DM and established cardiovascular disease
were randomized to receive empagliflozin or placebo. Non-
fatal myocardial infarction and non-fatal stroke were not sig-
nificantly affected by empagliflozin; however, the effect of
empagliflozin on cardiovascular death and hospitalization for
heart failure was reduced by 38% and 35%, respectively, a fact
of major importance. In addition, all-cause mortality was
reduced by 32% [17]. Thus, in contrast to most cardioprotec-
tive agents, reduction in cardiovascular mortality with SGLT-2
inhibitors was not due to the reduction in atherothrombotic
events. The Canagliflozin Cardiovascular Assessment Study
(CANVAS) randomized 10,142 T2DM patients with either
established cardiovascular disease or multiple cardiovascular
risk factors to receive canagliflozin or placebo [18].
Canagliflozin was associated with a significant reduction in
the primary outcome, which was a composite of death from
cardiovascular causes, nonfatal myocardial infarction, or non-
fatal stroke (HR 0.86; 95%CI 0.75–0.97; P = 0.02 for superiority),
and a non-significant reduction in all-cause mortality (HR 0.87;
95%CI 0.74–1.01). The effect of SGLT-2 inhibitors on new-onset
heart failure was once again confirmed in the CANVAS trial as
the reduction in the rates of HHF (HR 0.67 in the CANVAS
Program and HR 0.65 in the EMPA-REG OUTCOME study) was
almost identical to that of the EMPAREG study.
In addition to the above, The Multicenter-Trial-to-Evaluate-the-
Effect-of-Dapagliflozin-on-the-Incidence-of-Cardiovascular-Events
-Thrombolysis-In-Myocardial-Infarction 58 (DECLARE-TIMI 58) trial
showed non-inferiority of dapagliflozin in the primary safety out-
come [a composite of major cardiovascular events (MACE) defined
as cardiovascular death, myocardial infarction, or ischemic stroke]
compared to placebo. Dapagliflozin was not superior to placebo in
the two primary efficacy outcomes, which was MACE and
a combination of cardiovascular death or hospitalization for
heart failure; however it showed superiority compared to placebo
with regards to hospitalization for heart failure (HR, 0.73, 95%CI,
0.61–0.88) [19]. In addition, in the recent DAPA-HF study that
randomized 4744 patients (with or without T2DM) with
New York Heart Association class II–IV heart failure and an ejection
fraction <40% to dapagliflozin 10 mg or placebo, dapagliflozin
significantly reduced the primary outcome of worsening heart
failure (hospitalization or an urgent visit resulting in intravenous
therapy for heart failure) or cardiovascular death (HR, 0.74; 95%CI
0.65–0.85) [20]. As a result of the above the premise that SGLT-2
inhibitors reduce cardiovascular events primarily through preven-
tion of heart failure was generally accepted. Based on the above
findings, the latest consensus report and its recent update by ADA
and the European Association of the Study of Diabetes (EASD)
[21,22] recommend that, when considering a hypoglycemic agent
additional to metformin in patients with atherosclerotic cardiovas-
cular disease, CKD or heart failure, SGLT-2 inhibitors should be the
drug of choice for glycemic control. Moreover, SGLT-2 inhibitors
should also be preferred in the absence of these comorbidities,
when weight reduction is important. An important notion is that
SGLT-2 inhibitors can be used down to specific levels of eGFR for
glycemic control and their prescription should fit the relevant
licensing information (recently >45 ml/min/1.73 m2 for empagli-
flozin and canagliflozin and >60 ml/min/1.73 m2 for dapagliflozin,
but subject to possible changes in the future) [23].

In parallel to cardioprotection, accumulated evidence clearly
suggests that SGLT-2 inhibitors are prominent nephroprotective
agents. A recent meta-analysis of clinical trials showed that SGLT-2
inhibitors reduced albuminuria levels by an average of 25% in
comparison to placebo or other active antihyperglycemic agents.
This reduction was greater in patients with baseline microalbumi-
nuria or macroalbuminuria (35–40%) compared to those with
normoalbuminuria [24]. Likewise, in a meta-analysis of the three
aforementioned randomized, placebo-controlled, cardiovascular
outcome trials in patients with T2DM (EMPAREG-OUTCOME,
CANVAS and DECLARE-TIMI), SGLT-2 inhibitors were associated
with a reduction of worsening of renal function (doubling of the
serum creatinine level, accompanied by an eGFR of ≤45 ml
per minute per 1.73 m2), end-stage renal disease (ESRD) or renal
death by 45% (HR 0.55, 95% CI 0.48–0.64). The observed benefit
was similar in patients with and without atherosclerotic cardiovas-
cular disease [25]. Of note, the effect of empagliflozin, canagliflozin,
and dapagliflozin on renal outcomes in these trials was almost
identical, clearly suggesting a class-effect of SGLT-2 inhibitors.
Moreover, the recent CREDENCE study, the first SGLT-2 inhibitor
study with a combined renal end-point as a primary outcome,
randomized 4401 patients with T2DM, chronic kidney disease
(CKD), and albuminuria (ratio of albumin [mg] to creatinine [g],
>300 to 5000) who were already treated with renin-angiotensin-
system (RAS)-blockers in canagliflozin and placebo. This study was
prematurely terminated after a planned interim analysis on the
recommendation of the data and safety monitoring committee
due to the clear benefit of canagliflozin versus placebo. The relative
risk of the renal-specific composite of end-stage kidney disease,
a doubling of the serum creatinine level, or death from renal causes
was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81;
P < 0.001), and the relative risk of ERSD was lower by 32% (HR
0.68, 95% CI 0.54–0.86 P = 0.002) [26]. Finally, it was recently
announced that the Study-to-Evaluate-the-Effect-of-Dapagliflozin-
on-Renal-Outcomes-and-Cardiovascular-Mortality-in-Patients-
With-Chronic-Kidney-Disease (DAPA-CKD), a randomized trial eval-
uating the effect of dapagliflozin to prevent the progression of
CKD or cardiovascular/renal death in patients with eGFR ≥25 and
≤75 mL/min/1.73 m2, and UACR ≥200 and ≤5000 mg/g, was
prematurely terminated due to benefit [27]; its results are awaited
in a few months.
The mechanisms that enable the SGLT-2 inhibitor to offer
nephroprotection are under investigation. Following an ele-
gant human study in young hyperfiltrating patients with
T1DM that showed empagliflozin to reduce GFR together
with effective renal plasma flow and to increase renal vascular
resistance [28], it was suggested that SGLT-2 inhibitors could
modulate the afferent arteriole tone through interference with
the tubuloglomerular feedback mechanism [23]. In particular,
the inhibition of renal glucose and sodium reabsorption in the
proximal renal tubules is expected to increase the distal avail-
ability of sodium-chloride. The macula densa functions by
sensing the increased sodium-chloride availability and
through this restores the tubuloglomerular feedback resulting
in a reversal of the vasodilation of the afferent arteriole; this
decreases glomerular hyperfiltration, intraglomerular pressure,
and albumin excretion [23,28]. However, a recent randomized
trial examining the effects of dapagliflozin on renal
EXPERT OPINION ON DRUG SAFETY 3
microcirculation in 44 patients with T2DM, did not confirm
the above findings [29]. In particular, dapagliflozin also
reduced GFR but did not increase renal vascular resistance,
suggesting that the reduction in intraglomerular pressure with
SGLT-2 inhibitors is not due to vasoconstriction of the afferent
but to vasodilation of the efferent arteriole. Thus, the mechan-
istic details of the SGLT-2 inhibitor action on kidney vascula-
ture possibly need to be further investigated by larger studies.
3. Euglucemic diabetic ketoacidosis associated with
SGLT-2 inhibitors
According to ADA, typical DKA is defined as a combination of
hyperglycemia, high anion gap metabolic acidosis, and ele-
vated ketone bodies in plasma or urine. In both the ADA
proposed diagnostic criteria and the Joint British Diabetes
Societies guideline document for the management of DKA
the proposed level of blood glucose for the diagnosis of
DKA is over 250 mg/dl (13.9 mmol/L) and over 200 mg/dl
(11.1 mmol/L), respectively [4,30]. Thus, a blood sugar level
of 200 mg/dl (11.1 mmol/L) could be set as an upper limit for
euDKA, as was first described by Munro et al. in 1973 [31].
These authors reported on a series of 211 episodes of diabetic
metabolic decompensation, from which 37 had severe ketoa-
cidosis defined by blood glucose levels of <300 mg/dl
(16.6 mmol/L) and plasma bicarbonate of <10 mEq/l. Of
those patients, 16 had blood glucose <200 mg/dl
(11.1 mmol/L), congruent with the aforementioned definition
of euDKA [31]. In a United Kingdom cohort study (reporting
before the widespread use of SGLT-2 inhibitors) with T1DM
patients, the incidence of euDKA was 3% of all DKA cases [32].
Among the factors associated with euDKA are pregnancy,
insulin use prior to hospital admission for DKA, decreased
caloric intake, heavy alcohol use, cocaine abuse, chronic liver
disease pancreatitis, and sepsis [32,33].
3.1. Epidemiology
After the introduction of SGLT-2 inhibitors, there was an
increased concern about some rare but serious events of
euDKA in patients under this medication. The first cases of
euDKA with SGLT-2 inhibitors were reported in patients with
T2DM, but there were also rare reports of serious DKA in
patients with T1DM, where the drug was used off-label at
the time [33]. As a result of those reports, the U.S. Food and
Drug Administration issued a safety announcement reporting
that 20 cases of DKA associated with the use of SGLT-2 inhi-
bitor had been reported from March 2013 (which is the date of
approval of the first drug in this class) through 6 June 2014 [5].
It was also reported that ‘glucose levels were only mildly
elevated at less than 200 mg/dL (11.1 mmol/L) in some
reports’ [5]. Α further review of the FDA Adverse Event
Reporting System database identified 73 cases of ketoacidosis
in patients with T1DM or T2DM treated with SGLT-2 inhibitors
from March 2013 to May 2015. In many of those cases ketoa-
cidosis was not immediately recognized because of only mild
glucose elevation, below the expected for typical DKA (eugly-
caemic ketoacidosis) [3].
4 E. SAMPANI ET AL.
In contrast to the above, data from major randomized
controlled trials suggested that the incidence of DKA with
the use of SGLT-2 inhibitors with T2DM was low (Table 1). Of
note, in the majority of cases, clinical trials recorded events of
DKA and not specifically euDKA. In the EMPA-REG OUTCOME
trial, the frequency of reported events of DKA was less than
0.1% [17]. A meta-analysis from randomized controlled trials at
that time showed that SGLT-2 inhibitors were not significantly
associated with an increased risk of DKA when compared to
placebo or dipeptidyl peptidase 4 (DPP-4) inhibitors [34]. An
analysis of all serious adverse events of DKA including 17,596
patients from randomized studies of canagliflozin [35] showed
an incidence rate of 0.763 per 1,000 patient-years for those
treated with the high dose of canagliflozin (300 mg/day),
consistent with observational data in the general population
with T2DM [2]. Similarly, in the CANVAS trial [18] a small
number of DKA was observed with canagliflozin and placebo
(0.6 vs. 0.3 per 1000 patient-years, HR: 2.33, 95% CI 0.76
to 7.17).
As the rates of DKA, in early randomized controlled trials,
were determined from coding data from the Medical
Dictionary for Regulatory Activities, it was pointed out that
the true incidence of DKA might be higher than that reported,
and it was recommended the events to be adjudicated and
reported as DKA by each trial safety committee [36,37].
Following this, the incidence of DKA in more recent major
trials was reported, showing that events were rare but more
frequent with dapagliflozin than placebo in DECLARE-TIMI
(0.3% vs 0.1%, HR:2.18, 95%CI 1.10–4.30, P = 0.02) [19], and
in DAPA-HF (0.1 vs 0 per 100 patient-years) [20], as well as with
canagliflozin in CREDENCE, (2.2 vs 0.2 per 1000 patient-years,
HR:10.8, 95%CI 1.39–83.65) [26], respectively. Based on
a review of the available data on the prevalence of SGLT-2–
associated DKA, the American Association of Clinical
Endocrinologists (AACE) and the American College of
Endocrinology (ACE), suggested in a position statement that
DKA occurs infrequently and there was no need for changes in
current recommendations [38]. However, they noted that
euDKA diagnosis could be missed or that the diagnosis
could be delayed, due to atypical presentation involving
lower than anticipated glucose levels or other misleading
laboratory values.
Of great importance are the real-world data of the rate of
DKA with SGLT-2 inhibitors compared to other antidiabetic
agents. A cohort study from Sweden and Denmark compared
17,213 new users of SGLT-2 inhibitors with an equal number of
new users of glucagon-like peptide 1 (GLP1) receptor agonists.
In this study, SGLT-2 inhibitor use, was associated with
a twofold increased risk of DKA [39]. A recent retrospective
cohort study that used a large database of commercially
Table 1. Occurrence of DKA in major outcome studies of SGLT-2 inhibitors.
Study Main comparison Incidence in SGLT-2 inhibitor groups
EMPAREG-OUTCOME empagliflozin vs placebo
CANVAS canagliflozin vs placebo
DECLARE-TIMI dapagliflozin vs placebo
CREDENCE Canagliflozin vs placebo
DAPA HF Dapagliflozin vs placebo
insured patients in the United States identified 50,220 patients
who started an SGLT-2 inhibitor and 90,132 who started
a DPP-4 inhibitor. The unadjusted rate of DKA within
180 days after SGLT-2 inhibitor initiation was about twice the
rate of that after initiation of a DPP-4 inhibitor (4.9 vs. 2.3 per
1000 patient-years, HR: 2.1, 95%CI 1.5 to 2.9). After propensity-
score matching to adjust for differences in individual charac-
teristics, the HR was almost similar, i.e. 2.2 (95% CI, 1.4 to 3.6)
[40]. In an analysis of the FDA Adverse Event Reporting System
(FAERS) the reports of acidosis in patients treated with SGLT-2
inhibitor were compared to those treated with the two most
commonly used DPP-4 inhibitors, sitagliptin, and saxagliptin.
In T2DM patients the use of SGLT-2 inhibitors was associated
with ~7-fold increase in developing acidosis and euDKA
accounted for 71% of these cases [41]. Based on the above
data from observational studies and clinical trials, the overall
risk for developing DKA in patients with DM2 treated with
SGLT-2 inhibitors is about 2 to 2.2-times higher than with
placebo or other antidiabetic drugs. The absolute incidence
is relatively low, but again cannot be determined with cer-
tainty, as it is reported from 0.3 to 5 events per 1000 patient-
years in different studies, a fact possibly associated with differ-
ences of the populations under study.
3.2. Pathophysiology
The SGLTs are a member of the SLC5 (sodium/glucose cotran-
sporters) of active glucose transporters family, which includes
12 member proteins and related human genes [42]. In the S1
segment of proximal tubules, ketoacids are reabsorbed via
another member of this family, the Sodium-coupled
MonoCarboxylate Transporter-2 (SMCT-2) which shows some
symmetry to SGLT-2 [11] and its function might be altered by
SGLT-2 inhibition. Moreover, co-expressed with SMCT-2 is the
urate anion transporter 1 (URAT-1) which reabsorbs filtered
urate in exchange with ketones or lactate; thus ketones or
lactate can recycle, in that way, across the apical membrane
(Figure 1) [43]. The reabsorption of ketones along with lactate
via SMCT-2 depends on the sodium gradient between the
lumen and the proximal tubule cells. By inhibiting sodium
reabsorption, SGLT-2 inhibition may increase the sodium
available to SMCTs in the lumen and an early animal study
showed phlorizin to enhance ketones reabsorption [44]. On
the other hand, pharmacologic inhibition of SGLT-2 activity
may decrease energy expended by the basolateral Na+/K+
ATPase [23] which mainly promotes the sodium gradient
across the apical membrane. Phlorizin was shown to produce
a marked inhibition of the apical Na+/H+ antiporter ΝΗΕ3 [45]
reducing even more the proximal sodium flux. In parallel, in
T2DM patients, empagliflozin increased lactate excretion
Incidence in placebo groups P-value
0.1% <0.1% P = NS
0.6 per 1000 patients-yr 0.3 per 1000 patients-yr P = 0.14
0.3% 0.1% P = 0.02
2.2 per 1000 patients-yr 0.2 per 1000 patients-yr P = NS
0.1 per 100 patients-yr 0 per 100 patients-yr P = NS
 EXPERT OPINION ON DRUG SAFETY 5

Figure 1. Handling of the ketoacids in the proximal tubule. Under normal conditions, glucose and Na+ are transported through (Sodium-glucose Transporter-2)
SGLT-2 proteins in the S1 segment. Ketoacids are reabsorbed through the Sodium-coupled MonoCarboxylate Transporter-2 (SMCT-2) which shows some symmetry
to SGLT-2. In the apical membrane, co-expressed with SMCT-2 is the urate anion transporter 1 (URAT-1) which reabsorbs filtered urate in exchange with ketones or
lactate. The reabsorption of ketones along with lactate via SMCT-2 is dependent on the sodium gradient between the lumen and the proximal tubule cells.
Ketoacids exit the tubular cell via the SMCT1 transporter in the basal membrane. SGLT-2 inhibition could possibly increase ketoacid reabsorption through: (i) direct
action on the SMCT-2 transporter; (ii) increase Na+ availability to SMCT-2 receptors; (iii) decrease energy expended by the basolateral Na+/K+ ATPase, which can
increase the sodium gradient across the apical membrane. NHE3, sodium-hydrogen exchanger 3; βΗΒ, β-hydroxybutyrate.

contributing to lower plasma lactate levels [46]. The increased
clearance rates of lactate could reduce its availability in tub-
ular cells and affect renal gluconeogenesis as well as URAT-1
mediated urate reabsorption. In confirmation of the above,
increased urinary urate excretion has been observed with
SGLT-2 inhibitors but more studies are needed to better
understand the effect of SGLT-2 inhibition on SMCT-2 and
URAT-1 function [11].
The central factor controlling metabolic pathways involved
in ketoacidosis is the relative lack of insulin; in such cases, low
levels of insulin are combined with high levels of glucagon,
cortisol, and adrenaline. A decline in circulating levels of insu-
lin leads to a decreased antilipolytic activity of insulin and,
thus, stimulation of free fatty acid, as in the case of insulin
resistance [47]. In this metabolic setting, free fatty acids are
released from adipocytes and delivered to the liver where they
are directed toward the ketogenic pathway [48]. In addition to
the above, the decrease in circulating insulin levels promotes
the production of ketone bodies through activation of carni-
tine palmitoyltransferase–I (CPT-I). By stimulating the activity
of acetyl-CoA carboxylase, insulin increases the production of
malonyl-CoA, a potent inhibitor of (CPT-I). CPT-I is an enzyme
known to promote the transport of fatty acids into the mito-
chondria; this will increase the rate of b-oxidation and there-
fore the production of ketoacids [49]. SGLT-2 inhibitors are the
only anti-diabetic drugs to increase glucose excretion and
thus, their use prevents high glucose levels in T2DM patients.
Therefore, in most of these cases, apart from the expected
euglycemia, plasma insulin, and insulin to glucagon ratio
remain low [10].
SGLT-2 receptors are expressed in glucagon-secreting alpha
cells of the pancreatic islets and one study with SGLT-2 inhi-
bitor dapagliflozin was shown to trigger glucagon secretion in
human islets [50]. However, in a recent animal study [51]
dapagliflozin did not affect pancreatic islets but rather pro-
moted glucagon secretion through a central mechanism, as
SGLTs are also found in the brain, while alpha cell glucagon
release was propelled by catecholamines. Another recent
study in isolated mouse, rat and human pancreatic islets,
confirmed these findings by showing no direct effect of
SGLT-2 inhibition on glucagon secretion [52]. Thus, SGLT-2
inhibition may increase glucagon levels through multiple
mechanisms, as previously suggested [53]. In the later study,
insulinopenia along with dehydration was identified as a two-
hit model to provoke euglycemic ketoacidosis secondary to
SGLT-2 inhibitor treatment. In such settings, volume depletion
is associated with an increase in both plasma cortisol and
catecholamine levels and, although it is considered temporal
at the initiation of treatment, it could reappear in case there is
no free access to water and solutes.
Ketone bodies are removed by oxidation in the brain,
heart, and the kidneys. A limit in this oxidation is set by the
rate of performing biologic work which, with regards to the
kidneys, is mainly consisted of proximal sodium reabsorption.
Ferranini et al. reported that in T2DM patients, fasting
β-hydroxybutyrate (β-HB) levels were doubled after
6 E. SAMPANI ET AL.
empagliflozin administration [54]. The observed rise in β-HB
was suggested to result not due to reduced renal clearance
but due to overproduction of β-HB, as both the clearance
rate and fractional excretion of β-HB increased [46]. In that
study, it was pointed out that SGLT-2 inhibition induces
a degree of glucosuria which is relative to the filtered glucose
load and independent of body size. As the degree of gluco-
suria is independent of body size, lean individuals would be
possibly exposed to a greater carbohydrate deficit than
obese ones. Lean patients with T2DM on SGLT-2 inhibitors
treatment that are on a low carbohydrate diet could be
dependent on fat use for energy production and thus, are
exposed to a higher risk for hyperketonemia and DKA [55]. It
has also been speculated that the SGLT-2 inhibitors induced
rise in ketone bodies is involved in the cardioprotective
effects reported with these agents. As β-HB is freely taken
up by the heart and oxidized in preference to fatty acids, an
increased ketone bodies concentration would switch sub-
strate oxidation rates from fatty acids and would improve
the transduction of oxygen consumption into work efficiency
at the mitochondrial level; this would result in improvement
of cardiac contractility [56]. Overall, despite the fact the
increase in ketone body formation can be beneficial for
cardiac function an asymptomatic rise in ketone bodies may
predispose to the development of DKA and there are no safe
ketone levels regarding the threshold for the induction of
SGLT-2 inhibitors induced DKA.
In the initial stages of DKA, as glomerular ketoacids filtra-
tion increases, some ketoacids are excreted in urine as sodium
and potassium salts. From an acid-base perspective, excreted
ketoacids are equivalent to bicarbonates. Therefore, this loss
represents an indirect NaHCO3 loss resulting in hyperchlore-
mic metabolic acidosis, which is usually revealed during the
recovery phase. In time, allowing for the induction of key
enzymes in the renal ammoniagenesis process, ketoacids are
excreted along with ΝΗ4+ partially restoring the bicarbonate
buffer system [57]. However, previous studies pointed out that
ammoniagenesis is not sufficient for an optimal renal response
to the ketoacids load. Ammoniagenesis implies glutamine
oxidation and proximal tubular cells preferentially use ketones
and free fatty acids, if available, for their energy needs to
reabsorb sodium [58]. SGLT-2 inhibitors reduce the transcellu-
lar sodium flux in the proximal tubule and less biologic work
would suppress the metabolic pathways leading to oxidation,
in particular ammoniagenesis. Thus, in that case, ammonia-
genesis is a less competent pathway to respond to the ketoa-
cids load [59].
Patients with DKA often present with hypovolemia, due to
osmotic diuresis and reduced glomerular filtration rate (GFR).
In this case, not only renal response to acidosis is blunted but
the rate of removal of ketoacids is diminished as well, leading
to marked ketonemia and the classic high anion gap ketoaci-
dosis. The ratio of anion gap raise to HCO3− drop
(ΔAG/ΔHCO3−) has been proposed as a tool to detect mixed
acid-base disturbances, including mixed metabolic acidosis
with both hyperchloremic and high anion gap components.
In DKA the mean ΔAG/ΔHCO3− ratio is close to 1.0 but values
can range from 0 to 2 [60]. Values of the ratio less than 0.8
indicate a hyperchloremic component on top of a high anion
gap acidosis and are usually encountered in DKA patients with
preserved renal function and a noticeable amount of indirect
NaHCO3 loss. In a systemic review of 34 euDKA cases asso-
ciated with SGLT-2 inhibitors [61], the mean ΔAG/ΔHCO3− was
0.66. However, this review also included cases in T1DM
patients and there was no report of renal function. In case
reports restricting to T2DM patients with preserved renal func-
tion, the ΔAG/ΔHCO3− ratio values as low as 0.36 have been
reported [62]. Thus, euDKA patients seem to have a lower
mean ΔAG/ΔHCO3− compared to classic DKA as they present
less hypovolemic and with better preserved GFR. Overall,
cases of severe metabolic acidosis, in this setting, indicate
a defect in renal response regarding ammoniagenesis.
3.3. Prevention and treatment
As SGLT-2 inhibitors associated DKA may present with atypical
features such as normal or moderately increased blood glu-
cose levels, a high level of awareness would ensure early
recognition and diagnosis [63]. Increased awareness of this
atypical presentation is necessary not only among diabetolo-
gists, but also among other health professionals, for example,
emergency room physicians and nurses that are more likely to
encounter this disorder in the emergency setting. The
European Medicines Agency (EMA) has made recommenda-
tions to minimize the risk of diabetic ketoacidosis [64].
According to these recommendations, patients at high risk
include those with a low reserve of insulin-secreting cells,
patients on conditions that restrict food intake or can lead to
hypovolemia, as well as patients with a sudden reduction in
insulin dose or increased requirements for insulin due to ill-
ness, surgery or alcohol abuse (Table 2). As mentioned above,
in a systemic review regarding euDKA due to SGLT-2 inhibitors
there were also T1DM patients included [61] and off-label use
of these therapeutic agents in T1DM patients is a well-
recognized risk factor for DKA [38]. In the analysis of DKA
from randomized studies of canagliflozin [35], half of those
being diagnosed with a DKA-related event was reported to
either have autoimmune diabetes (latent autoimmune dia-
betes of adulthood [LADA] or T1DM) or to have tested positive
for GAD65 antibodies. Patients who have a longer duration of
diabetes and receive insulin therapy are considered to have
a low reserve of insulin-secreting cells. Evidence from clinical
studies support that lean patients with T2DM on SGLT-2 inhi-
bitors treatment and a low carbohydrate diet are at a higher
risk for euDKA [46,55].
In addition, the European Medicines Agency recommended
to temporarily stop SGLT-2 inhibitor treatment in patients
Table 2. Types of patients at high risk for euDKA with SGLT-2 inhibitors.
• Patients with a low reserve of insulin-secreting cells
• Patients at restricted food intake
• Patients at risk of hypovolemia
• Patients with a sudden reduction in insulin dose
• Patients at increased requirements for insulin due to illness, surgery or
alcohol abuse
• Patients with type 1 DM receiving the drugs off-label
• Patients with a hidden diagnosis of latent autoimmune diabetes of
adulthood (LADA) or positive for GAD65 antibodies.

Table 3. Preventive and therapeutic measures for euDKA associated with SGLT-2
inhibitor use.
Prevention
• Withdraw SGLT2-inhibitor in patients scheduled to undergo major surgical
procedures at least 3 days before surgery
• Withdraw SGLT2-inhibitor in patients hospitalized due to serious illness
• Use insulin instead of SGLT-2 inhibitors in the presence of other
predisposing risk factors for DKA
Treatment
• Stop SGLT-2 inhibitor immediately and do not re-start unless another cause
for the ketoacidosis is identified and resolved
• Ensure volume restoration with the isotonic fluid of NaCl 0.9%
• Ensure potassium levels are above 3.3 mEq/L before insulin administration
• Start insulin administration with continuous intravenous infusion; change to
intensive subcutaneous regime when acid–base balance is restored
• Consider additional glucose infusion at the initiation of therapy
• Bicarbonate could be administrated at a higher than the aforementioned pH
level (<6.9)
• Ensure proper ventilation is achieved while infusing bicarbonate in order to
avoid intracellular acidosis
• In case of bicarbonate use, consider administration of calcium intravenously
to prevent fall in Ca2+
scheduled to undergo major surgical procedures or hospita-
lized due to serious illness (Table 3). For elective major surgical
procedures, it is required to withhold SGLT-2 inhibitors at least
3 days prior surgery [65] as their effect can persist for a few
days after discontinuation of the drug [66]. A similar strategy
to administer insulin instead of SGLT-2 inhibitors could pre-
vent DKA in the presence of other predisposing risk factors for
DKA. If diabetic ketoacidosis is suspected or confirmed, SGLT2
inhibitor should be immediately withdrawn and not be re-
started unless another cause for the ketoacidosis is identified
and resolved [64].
Guidelines for the treatment of euDKA are not available.
Relevant recommendations for the treatment of DKA suggest
volume restoration with isotonic fluid (NaCl 0.9%) [4],
although NaCl infusion could deteriorate metabolic acidosis.
Insulin therapy is essential for the treatment of DKA because it
allows cells to use glucose as a fuel and therefore diminishes
ketogenesis [4,67]. Intravenous insulin administration is pre-
ferred during the initial stages of DKA. Insulin therapy should
start only after ensuring serum potassium levels are above
3.3mEq/L and volume loss is restored with isotonic NaCl
0.9%. Frequent electrolyte and biochemical monitoring should
be performed during DKA therapy. The ADA recommends an
initial bolus dose of regular insulin 0.1 IU/Kg followed by
continuous insulin infusion or starting directly with continuous
infusion. At typical DKA, NaCl 0.9% is replaced with Dextrose
5% solution when blood glucose levels fall below 200 mg/dl
(11.1 mmol/L). This rule may not apply in euDKA, as euDKA
may present with only moderately increased blood glucose
levels and Dextrose 5% infusion along with insulin may be
appropriate early during treatment, in parallel to isotonic NaCl
0.9%. Once acid–base balance is restored, intravenous insulin
is switched to subcutaneous insulin in an intensive regimen,
such as fast acting insulin 0.5–0.8 IU/kg 3 times daily in com-
bination with a long-acting analogue during the night [4,67].
With regards to base therapy, in adults diagnosed with
classic DKA with an initial pH less than 7.0 no significant
difference in time to resolution of acidosis as well as time to
hospital discharge was observed between patients who
EXPERT OPINION ON DRUG SAFETY 7
received intravenous bicarbonate compared to those who
did not [68]. For this reason, according to the ADA guidelines,
bicarbonate infusion should only be considered in cases of
life-threatening acidosis with a blood pH level of 6.9 or less,
revisiting the previous cutoff level of 7.0 [4].
Patients with preserved renal function and a considerable
amount of indirect NaHCO3 loss may have a striking hyper-
chloremic component of metabolic acidosis characterized by
slightly increased or even near normal anion gap and
a particularly low ratio value for ΔAG/ΔHCO3−. In that case,
bicarbonate could be administrated at a higher than the
aforementioned pH level, as there are fewer organic anions
of the offending ketoacids to be rapidly metabolized and
generate equivalent quantities of new bicarbonate [69].
Sodium bicarbonate should be administered as an isosmotic
solution and infused at a slow rate, ~0.1 mEq/kg per min. Base
requirements are calculated using a bicarbonate space of 50%
body weight (kg) and targeting a desired serum [HCO3−] of
10 mmol/L [70]. An isosmotic solution of sodium bicarbonate
could also be used for volume expansion as an alternative to
NaCl 0.9%, along with KCl as indicated. In parallel to volume
expansion, proper ventilation should be maintained while
infusing bicarbonate in order to alleviate the detrimental
effects on intracellular acidosis. It has been previously
reported that even in the non-anion gap metabolic acidosis,
the bicarbonate administration can lead to an increase in the
generation of CO2, as suggested by the need to increase
ventilation by 40% to maintain a stable pCO2 [71]. In case of
bicarbonate use, one should consider the administration of
calcium intravenously to prevent fall in Ca2+ after treatment
with base [70].
4. Conclusions
SGLT-2 inhibitors are a promising class of oral medications for
the treatment of T2DM. Their use is expected to rise over the
following years due to their favorable profile in conditions
such as proteinuric CKD and heart failure. They generally
seem to have an acceptable adverse effect profile; a possible
exception, is the rare occurrence of euDKA, which is a serious
side-effect, often with a multifactorial etiology. Increased
awareness and recognition of the pathophysiology and
involved risk factors is warranted to safely restore normal
acid–base balance. Overall, physicians need to familiarize
themselves with euDKA and its treatment in order to readily
manage this serious complication for the benefit of our
patients.
5. Expert opinion
SGLT-2 inhibitors represent one of the latest classes of oral
medications for the treatment of T2DM. They can be used
alone or in combination with other drugs in these patients.
Those drugs have a novel mechanism of action, i.e. reduction
of plasma glucose concentration through inhibition of glucose
reabsorption in the proximal renal tubule. Apart from their
glucose-lowering effect with a low risk of hypoglycemia when
given as monotherapy or added to metformin, those agents
8 E. SAMPANI ET AL.
have gained great interest, due to their favorable cardiopro-
tective and nephroprotective profile [7,23,72]. Moreover, the
safety profile of those drugs has been well established [73].
The most frequent adverse event reported in major outcome
clinical trials and observational studies was genital mycotic
infections. A borderline increase in urinary tract infections
was also noted in some, but not all studies, with the current
consensus being that SGLT-2 inhibitors do not increase the
risk of urinary tract infections [74,75]. In the CANVAS study [18]
an increase in the risk of lower limp amputations was noted,
but this was not apparent in the CREDENCE study [26] or other
trials with SGLT-2 inhibitors [73]. Euglycaemic ketoacidosis was
a rare but serious adverse event of these agents, originally
described in case reports and resulting in an increased con-
cern about the safety profile of those drugs [5].
Although the frequency of the reported events of DKA in
the first large outcome trials was extremely low [17,18], it was
suggested that the overall frequency of DKA may have been
underestimated due to the atypical presentation of those
cases often presenting with ketoacidosis but only mild to
moderate glucose elevation. In major outcome trials with
SGLT-2 inhibitors in patients with T2DM (EMPA-REG,
CANVAS), the incidence of DKA was rare, ranging between
0.1% and 0.6%, and it was not different between the active
and placebo groups [17,18]. However, in a recently published
retrospective cohort study, the incidence of diabetic ketoaci-
dosis in patients treated with SGLT-2 inhibitors was at least
double compared to controls [40]. It has to be noted, however,
that given the limited amount of data available to date, it is
difficult to judge precisely whether the reported cases of DKA
were directly due to SGLT-2 inhibitors or were induced inde-
pendently of these drugs and, SGLT-2 inhibitors simply
reduced blood glucose levels during the events.
As previously mentioned, the mechanism of euDKA differs
from that of typical DKA. The main difference with typical DKA
is that in euDKA, plasma glucose levels remain low (usually
below 250 mg/dl or 13.9 mmol/L) despite the presence of
ketoacidosis. The pathophysiologic mechanism that leads to
this serious metabolic disorder has been previously described.
Accumulation of ketoacids in DKA, typically results in high
anion gap metabolic acidosis. In addition, hyperchloremic
metabolic acidosis complicating diabetic ketoacidosis during
the recovery phase has been well documented; however, its
contribution at the presentation of euglycemic DKA has been
only recently recognized. Different pathophysiologic mechan-
isms have been proposed for the presence of ketoacidosis
including increased production as well as decreased excretion
of ketoacid load. It is important to note, that in addition to
increased ketoacid concentration in the tubule, which repre-
sents an indirect NaHCO3 loss resulting in hyperchloremic
metabolic acidosis, in cases of SGLT-2, a defect in ammonia-
genesis could further deteriorate acidosis. This defect can be
attributed to reduced transcellular sodium flux in the proximal
tubule, which results in decrease energy expenditure and
suppression of biologic work and the metabolic pathways
leading to ammoniagenesis.
It is obvious that not all patients are at the same risk of
developing euDKA and physicians should be aware of the
pathophysiologic mechanism and potential risk factors involved
in this serious metabolic complication. Patients at high risk
include individuals with T1DM that receive the drug off-label
[38], patients mistakenly diagnosed with T2DM while having
LADA, patients who are scheduled to undergo major surgery
or hospitalized for major illness, lean patients on a low carbohy-
drate diet or patients who have decreased or discontinued
insulin [64,65]. In the same regard, prevention of euDKA can
be achieved by simple measures, including withdraw of SGLT-2
inhibitor at least 72 hours prior to major surgery and insulin
administration in cases of patients at high risk for ketoacidosis.
Finally, with regards to treatment, knowledge of the patho-
physiologic mechanisms involved, increase awareness of the
atypical presentation of the disorder (especially among emer-
gency unit staff), early recognition of its presence, and prompt
institution of simple measures are warranted. These measures
include those applied in any case of DKA (volume restoration
with isotonic fluid of NaCl 0.9%, ensuring that serum K is
>3.3 mmol/l before insulin administration), as well as mea-
sures that could be beneficial due to the presence of euDKA
(glucose administration in parallel with insulin and sodium
bicarbonate infusion, targeting a desired serum [HCO3−] of
10 mmol/L) [67,69]. Such a treatment approach would enable
the successful restoration of acid–base balance in most cases.
Funding
This paper was not funded.
Author contributions
ES and PA conceived the idea of the paper and drafted the manuscript. AP
critically revised the manuscript for intellectual content.
Declaration of interest
PA Sarafidis has received research support for an Investigator-Initiated
Study from Astra Zeneca and is an advisor/speaker to Astra Zeneca and
Boehringer Ingelheim. E Sampani and A Papagianni have no relevant
affiliations or financial involvement with any organization or entity with
a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript. This includes employment, consul-
tancies, honoraria, stock ownership or options, expert testimony, grants or
patents received or pending, or royalties
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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