Current Diabetes Reports (2020) 20:25

https://doi.org/10.1007/s11892-020-01307-x

OTHER FORMS OF DIABETES AND ITS COMPLICATIONS (JJ NOLAN AND H THABIT, SECTION EDITORS)

Euglycemic Ketoacidosis
Benedetta Maria Bonora 1 & Angelo Avogaro 1 & Gian Paolo Fadini 1

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Purpose of Review Diabetic ketoacidosis is a life-threatening complication of diabetes characterized by hyperglycemia, acidosis,
and ketosis. Ketoacidosis may occur with blood glucose level < 200 mg/dl (improperly defined as euglycemic ketoacidosis,
euKA) and also in people without diabetes. The absence of marked hyperglycemia can delay diagnosis and treatment, resulting in
potential serious adverse outcomes.
Recent Findings Recently, with the wide clinical use of sodium glucose co-transporter 2 inhibitors (SGLT2i), euKA has come
back into the spotlight. Use of SGLT2i use can predispose to the development of ketoacidosis with relatively low or normal levels
of blood glucose. This condition, however, can occur, in the absence of diabetes, in settings such as pregnancy, restriction on
caloric intake, glycogen storage diseases or defective gluconeogenesis (alcohol abuse or chronic liver disease), and cocaine
abuse.
Summary euKA is a challenging diagnosis for most physicians who may be misled by the presence of normal glycemia or mild
hyperglycemia. In this article, we review pathophysiology, etiologies, clinical presentation and the management of euKA.

Keywords Euglycemic ketoacidosis . Ketoacidosis . Sodium-glucose cotransporter-2 inhibitors . Starvation . Pregnancy .

Alcohol

Introduction DKA suggest using a blood glucose (BG) threshold of

It is common sense that most cases of ketoacidosis oc-
cur in people with diabetes. Diabetic ketoacidosis
(DKA) is a potentially life-threatening acute complica-
tion of diabetes that is still an important cause of mor-
bidity and mortality among people with diabetes. DKA
may occurs both in people with type 1 (T1D) and rarely
type 2 diabetes (T2D) [1, 2]. DKA is a metabolic de-
compensation caused from an absolute or severe relative
insulin deficiency and an increased concentration of
counterregulatory hormones (glucagon, catecholamines,
cortisol, and growth hormone), resulting in a combina-
tion of hyperglycemia, ketosis, and metabolic acidosis.
The US and the UK guidelines for the management of
This article is part of the Topical Collection on Other Forms of Diabetes
and Its Complications
* Gian Paolo Fadini
gianpaolo.fadini@unipd.it
1 physician, as the relatively low or normal BG may delay the
Department of Medicine, University of Padova, Via Giustiniani 2,
35128 Padova, Italy
250 mg/dL and 200 mg/dL, respectively, to make the
diagnosis [1, 3].
Nevertheless, in 1973, Munro and colleagues reported that
among a series of 211 episodes of DKA in T1D, 37 had a BG
levels < 300 mg/dL and 16 episodes < 200 mg/dL [4]. They
referred this condition as “euglycemic ketoacidosis” (euKA).
In a subsequent case series of 722 episodes of DKA in
Birmingham, UK, 23 episodes of euKA were identified as
defined by Munro’s criteria, but only eight presented with a
BG < 200 mg/dL [5].
This euglycemic presentation has been described in set-
tings such as pregnancy in women with or without diabetes
[6], restriction on carbohydrate intake or starvation [7], in
people with glycogen storage diseases [8, 9] or defective glu-
coneogenesis (alcohol abuse or chronic liver disease) [10],
sepsis [11], pancreatitis [12], and cocaine abuse [13].
Recently, interest in euKA has been renewed as euKA has
been associated with sodium glucose co-transporter 2 inhibi-
tors (SGLT2i) [14].
It presents a diagnostic and management challenge for the
recognition, diagnosis, and treatment.
 25 Page 2 of 7 Curr Diab Rep (2020) 20:25

In this article, we briefly review pathogenesis, diagnosis,

causes, and treatment of euKA in people with and without
diabetes (Table 1).

Pathogenesis and Precipitating Factors

The pathogenesis of DKA is well established (Fig. 1). Briefly,

DKA is the result of an absolute or relative deficiency of
insulin associated with an increase of counter-regulatory hor-
mones (glucagon, cortisol, catecholamine, and growth hor-
mone). These metabolic changes promote an increase in he-
patic gluconeogenesis, an accelerated glycogenolysis, an im-
pairment of glucose utilization by peripheral tissues—which
causes hyperglycemia—and lipolysis with increased free fatty
acids (FFAs) mobilization from adipose tissue. In the liver,
FFAs are catabolized into ketone bodies (β-hydroxybutyrate
Fig. 1 Pathogenesis of diabetic ketoacidosis
and acetoacetate) [15]. Ketone bodies are the main contribu-
tors to metabolic acidosis. Hyperglycemia leads to glycosuria
and osmotic diuresis resulting into severe dehydration, hypo- Generally, DKA and euKA are induced by one or more of
volemia and a reduction in glomerular filtration, thus imped- the following precipitating factors: severe infection, discontin-
ing further glucose excretion [15]. uation of or inadequate insulin therapy, insulin pump failure,
In euKA, insulin deficiency and insulin resistance are often low carbohydrate intake or prolonged fasting, alcohol con-
milder, thereby limiting the surge in BG levels [16]. sumption, intercurrent acute events (pancreatitis, myocardial
Therefore, glucose overproduction and underutilization are infarction, cerebrovascular accident), drugs that affect carbo-
lesser than in DKA. In SGLT2i-induced euKA renal glucose hydrate metabolism (e.g., corticosteroids), surgery, and other
clearance is increased, contributing to lower BG levels [17]. stressful physical and medical conditions [18•]. These

Table 1 Causes, pathogenesis, and management of euKA

Causes Type of subjects Pathogenesis Treatment

SGLT2i Diabetic people Glycosuria ➔ reduction of blood glucose levels ➔ reduction in Stop SGLT2i, fluid replacement,
insulin production or self-reduction of insulin dose in insulin infusion and intravenous
insulin-treated patients + increase in glucagon concentrations ➔ glucose solution
Lipolysis and ketone production
Direct stimulation of alpha cells?
Strict diet/starvationPeople without Deficit carbohydrate ➔ shift to lipolysis Intravenous infusion of glucose
diabetes Depletion glycogen stores maintain BG level relatively low solution
Trigger in people Insulin only if diabetic patients
with diabetes
Pregnancy People with diabetes Nausea and vomiting Fluid replacement, insulin infusion
(T1D, T2D, Insulin resistance and intravenous glucose solution
GDM), usually Accelerated starvation Only intravenous glucose solution if
People without Respiratory alkalosis woman without diabetes
diabetes (rarely) Physiological hemodilution maintain BG level relatively low
Alcohol People without Oxidation ethanol ➔ ketones Intravenous glucose and large
diabetes Restriction on caloric intake amounts of intravenous saline
Trigger in people Depleted hepatic glycogen stores
with diabetes Impaired gluconeogenesis
Glycogen storage People with or Impaired glycogen storage Intravenous glucose solution, fluid
disease and chronic without diabetes Impaired gluconeogenesis replacement (insulin infusion)
liver disease
Cocaine abuse People with and Poor caloric intake Intravenous glucose solution, fluid
without diabetes Hypoglycemic effects of cocaine replacement, insulin infusion
Inherited metabolic People with or Defects of gluconeogenesis or glycogen metabolism Fluid replacement and intravenous
disease without diabetes glucose solution (insulin
infusion)
Curr Diab Rep (2020) 20:25
precipitating factors are responsible for inducing significant
increase in counter-regulatory hormones production.
Clinical Presentation and Diagnosis
Individuals with DKA and euKA typically present with the
following clinical features: nausea, vomiting, diffuse abdom-
inal pain, polyuria, polydipsia, weight loss, dehydration,
weakness, fatigue, tachycardia, tachypnoea, and Kussmaul
breathing. Mental status can vary from full alertness to pro-
found lethargy or coma [1].
DKA is classically defined by the presence of the triad
hyperglycemia (≥ 250 mg/dL), metabolic acidosis with elevat-
ed anion gap (arterial pH < 7.3 and serum bicarbonate <
15 mEq/L, anion gap > 10–12 mEq/L) and elevated concen-
trations of ketone bodies. euKA is characterized by lower (<
200 mg/dL) BG levels; therefore, it is improperly defined as
euglycemic because it also includes episode with BG above
the normal range. The severity of DKA is classified as mild,
moderate, or severe based on the severity of metabolic acido-
sis (blood pH, bicarbonate, and anion gap) and the presence of
altered mental status [18].
Causes of euKA
SGLT2i
SGLT2i constitute the latest developed class of glucose-
lowering medications approved for the treatment of people
with T2D. Recently, the clinical indication for SGLT2i
dapagliflozin was extended to people with T1D with BMI ≥
27 kg/m2 [19] but only in Europe. To date, SGLT2i approval
for T1D has been turned down by the US Food and Drug
Administration (FDA), because available data on the
SGLT2i as an adjunct to insulin for the treatment of people
with T1D suggested that the overall benefits did not outweigh
the risks for potentially fatal DKA [20].
SGLT2i block sodium-dependent glucose transporter-2
(SGLT2) located in the early proximal renal tubule, which is
responsible for reabsorption of most (80–90%) of the glucose
filtered by the glomerulus. The resulting increase in urinary
glucose excretion lowers plasma glucose concentrations [17].
In 2015, the US FDA and the European Medicines Agency,
based on the report of few cases, released a warning that
SGLT2i may cause DKA in both T1D and T2D people [21,
22]. The number of reports is steadily increasing and several
case reports of SGLT2i-associated DKA, as well as analysis of
the FDA Adverse Event Reporting System have been pub-
lished in medical literature [14, 23]. The clinical trial programs
for the 3 most commonly used SGLT2i (canagliflozin,
dapagliflozin, and empagliflozin) reported numeratively small
Page 3 of 7 25
numbers of DKA, with an incidence of less than 1 per 1000
patient- or person-years [14]. However, the scenario might be
different in real life clinical practice, where conditions are far
from the “ideal” setting of randomized controlled trials
(RCTs). In RCTs, patients are homogeneous, highly selected
and with close follow-up. A cohort study, using four large
insurance claims US databases, reported an almost twofold
increased DKA risk in new users of SGLT2i compared to
non-SGLT2i users [24]. Similarly, recent evidences derived from
large claims database of commercially insured people in the USA,
suggests that the rate of DKA within 180 days after the initiation
of an SGLT2i was about twice the rate after the initiation of a
DPP4 inhibitor (4.9 events per 1000 person-years vs. 2.2 events
per 1000 person-years; HR 2.2 95% CI 1.4–3.6) [25]. However,
in another cohort study, using a Korean Health Insurance data-
base, SGLT2i treatment did not increase the risk of DKA com-
pared with DPP-4 inhibitor treatment (HR 0.96 95% CI 0.58–
1.57) [26]. To date, the exact rate at which this specific adverse
event occurs during SGLT2i therapy is difficult to establish.
As expected, the risk of ketoacidosis is much greater in
people with T1D. SGLT2i phase 3 trials involving patients
with T1D have documented a significant increase in the risk
for DKA in patients treated with SGLT2i, which appears to be
dose dependent. In DEPICT-1 (Dapagliflozin Evaluation in
Patients With Inadequately Controlled Type 1 Diabetes), at
52 weeks of follow-up, more patients in the dapagliflozin
groups had events adjudicated as DKA, at 4.0%, 3.4%, and
1.9% in the dapagliflozin 5 mg, 10 mg, and placebo groups,
corresponding to incidence rate of 4.8, 3.7, and 2.2 per 100
patients-years, respectively [27]. In the EASE (Empagliflozin
as Adjunctive to inSulin thErapy) program, the rate of DKA in
patients on empagliflozin 2.5 mg was similar to placebo (0.8%
and 1.2%, respectively), while the rate was higher in the
empagliflozin 10- and 25-mg groups compared with placebo
(4.3%, 3.3%, and 1.2%, respectively) corresponding to inci-
dence rate of 5.9, 5.1, and 1.8 per 100 patients-years [28]. A
similar trend was observed in the trials of sotagliflozin and
canagliflozin [29, 30].
The proposed mechanism driving of SGLT2i-induced
ketoacidosis is primarily related to a reduction in insulin concen-
trations and an increase in glucagon concentrations. The low plas-
ma glucose levels caused by glycosuria during SGLT2i therapy
stimulates glucagon secretion and suppression of insulin produc-
tion leading to an increase in the glucagon:insulin ratio and
resulting in increased lipolysis, delivery of free fatty acids to the
liver, where they are oxidized. Lipid oxidation generates acetyl-
CoA that is converted in ketone bodies when glycolysis interme-
diates are unavailable due to reduced intracellular glucose oxida-
tion. These metabolic changes overall promote ketogenesis [31].
In addition, some studies have suggested that SGLT2 is also
expressed by human pancreatic alpha cells [32] and that
SGLT2i may exert a direct stimulatory effect on alpha cells [33,
34], although this finding is controversial and has not been
 25 Page 4 of 7
consistently replicated in all studies [35, 36, 37•]. Recently,
Capozzi et al. demonstrated, in diabetic mice, that SGLT2i-
induced ketosis is not affected by interruption of glucagon signal-
ing by a glucagon receptor blocking antibody. Thus, the ketogenic
effects of SGLT2i probably occurs independently from glucagon
[38].
SGLT2i-associated DKA episodes sometimes presented
with relatively low or normal glucose levels because of gly-
cosuria. Although the average glucose concentrations ob-
served during SGLT2i-induced DKA tended to be lower than
in classical DKA, most cases of SGLT2i-induced DKA had
elevated BG levels. In a review of 105 cases of SGLT2i-
induced DKA mean BG at admission was 294 ± 188 mg/dL
and in 37 patients (35.2%) DKA was euglycemic, with an
admission BG of less than 200 mg/dL [14].
Precipitating factors of SGLT2i-induced DKA include: ex-
cessive reduction of insulin doses (> 50%) or insulin omis-
sion, especially if combined with a low-carbohydrate diet,
alcohol intake, acute event (e.g., myocardial infarction), infec-
tion or fever, trauma, surgery and all counter-regulatory states,
insulin pump failure or malfunction. Some reports describe
the occurrence of DKA in people with presumed T2D who
subsequently proved to be affected by autoimmune diabetes.
Nonetheless a minority of cases (22%) was not associated
with any clear precipitating factor [14]. Duration of SGLT2i
treatment before DKA onset was extremely variable (0.3–
420 days) [14].
Low Caloric Intake or Starvation
Restriction on carbohydrate/caloric intake or prolonged
fasting with the maintenance of insulin therapy can be a pre-
cipitating factor of DKA. Starvation or strict restriction of
carbohydrate intake is a cause of euKA also in individuals
without diabetes [39, 40]. In fact, reduced dietary carbohy-
drate leads to the use of alternative energy sources, FFA and
ketones generated by lipolysis. It has been observed that dur-
ing fasting, lipolysis and FFA production are accelerated [41],
insulin is less effective at suppressing lipolysis, and ketogen-
esis occurs which leads to euKA [42]. In addition, prolonged
fasting may result in a nearly total depletion of glycogen stores
and contribute to the euglycemic state [43]. Owen et al. de-
scribed a case of a 24-year-old male without medical history
who, due to nausea and vomiting, fasted for 3 days. He pre-
sented at the emergency department with tachypnoea, sinus
tachycardia, metabolic acidosis with high anion gap, low bi-
carbonate, substantial ketonuria and increased blood level of
β-hydroxybutyrate. His pH started to normalize immediately
with intravenous infusion of dextrose [40]. However, starva-
tion or carbohydrate intake restriction can precipitate euKA
more commonly in diabetic than in non-diabetic people and
usually represents a precipitating factor of typical DKA.
Curr Diab Rep (2020) 20:25
Pregnancy
DKA in pregnancy is a serious complication for the mother
and fetus and is associated with high mortality rates. DKA in
pregnancy can occur in T1D, T2D, and in people with gesta-
tional diabetes (GDM) [44]. The exact rate at which this ad-
verse event occurs during pregnancy is difficult to establish,
probably ranging between 0.5 and 10% of all diabetic gesta-
tions, with 90% of these cases being women with GDM [45].
Pregnancy is a ketosis-prone status due to intrinsic physi-
ological changes [6]. Especially in second and third trimester
of pregnancy, a state of insulin resistance, accelerated starva-
tion, and respiratory alkalosis develops. In addition, nausea
and vomiting are common in pregnancy. Maternal and placen-
tal counter-regulatory hormones (progesterone, estrogen, cor-
tisol, prolactin, human placental lactogen) and TNF-alpha
play a key role in the decline in insulin sensitivity and com-
pensatory increase in maternal insulin production to maintain
normal glucose metabolism. The decreased insulin sensitivity
is considered a physiological mechanism to deliver glucose to
the fetus and the placenta, where it is used as a source of
energy. This tends to reduce maternal BG concentrations
[46]. On the other hand, maternal metabolism is diverted to
the use of FFA as primary fuel. Lipolysis makes pregnant
women more susceptible to ketosis. In addition, to compen-
sate for respiratory alkalosis, an increased renal excretion of
bicarbonate takes place, favoring metabolic acidosis [45].
The physiological hemodilution during pregnancy like-
ly contributes to the maintenance of relatively low or nor-
mal BG levels in women with diabetes [6]. In fact, DKA
in pregnant woman tends to occur at lower BG levels than
in non-pregnant women with diabetes. Several cases of
euKA with BG < 200 in pregnancy were reported in the
literature. In almost all cases, the episode of euKA oc-
curred in the third trimester (32–37 week of gestation).
The average age of this cohort was 30-years and average
BG level 110 mg/dl. Cases were equally distributed
among T1D, T2D and GDM [47].
Fortunately, with improved prenatal counseling, under-
standing and management, the incidence of euKA/DKA in
pregnancy and its mortality have declined significantly over
recent years [44].
Precipitating factors and clinical presentation of diabetic
ketoacidosis in pregnancy is similar to that of non-pregnant
diabetic people, except they tend to develop more rapidly.
Treatment includes fluid replacement, insulin infusion, and
intravenous glucose solution [48].
Adverse outcomes for the fetus include malformations, in-
trauterine death, pre-term labor, hypoxia, distress, cardiac ar-
rhythmias, hyperbilirubinemia, hypoglycemia, and neurologic
complications. Maternal complications include preeclampsia,
eclampsia, acute kidney injury, adult respiratory distress syn-
drome, coma, and death [44, 47].
Curr Diab Rep (2020) 20:25
In addition, two cases of euKA have been reported to be a
consequence of starvation in pregnant women without diabe-
tes or GDM. Both patients were treated with intravenous dex-
trose [49, 50]. Thus, it is important to keep in mind that euKA
can also occurs in pregnant women without diabetes and that
early diagnosis and treatment can reduce the risk of adverse
outcomes for both the mother and the fetus.
Alcoholic Ketoacidosis
Alcoholic ketoacidosis (AKA) is a subtype of euKA that oc-
curs in individuals without diabetes [10]. In 1940, Dillon and
colleagues described a series of nine individuals without dia-
betes, with a history of chronic alcohol consumption, that
experienced ketoacidosis [51]. Further case series were sub-
sequently reported. AKA is similar in presentation to euKA
although often with normal or low glucose values and no
glycosuria [52]. The acidosis is attributable to the accumula-
tion of lactate and ketone bodies. The absence of hyperglyce-
mia is the result of prolonged restriction on caloric intake,
depleted hepatic glycogen stores, and impaired gluconeogen-
esis (caused by ethanol that raises the NADH/NAD ratio).
Ketones are derived by the oxidation of ethanol into acetalde-
hyde, which is, in turn, converted into acetate and then into
acetoacetate [53].
Patients typically present with classic DKA symptoms
which improve rapidly with intravenous glucose and large
volumes of intravenous saline, usually without insulin.
Occasionally, intravenous bicarbonate may be needed to cor-
rect the metabolic disturbance [10].
Other Causes of euKA
Other causes of euKA that have been reported in literature can
occur in both people with and without diabetes. Prater and
Chaiban described a case of euKA in a non-diabetic individ-
uals during an acute admission with pancreatitis [12].
euKA in an individual without diabetes and without history
of starvation/low-carbohydrate diet or alcohol abuse has been
described in a 76-year-old woman with septic shock due to
acute obstructive cholangitis [11]. The pathogenesis of the so
called “septic ketoacidosis” is not completely understood.
People with sepsis have increased level of counter-
regulatory hormones and insulin resistance mediated by
counter-regulatory hormones and pro-inflammatory cytokine
through mechanisms involving hypothetically insulin receptor
and post-receptor signaling. These metabolic changes can in-
duce ketogenesis even in people without diabetes mellitus
[54]. Finally, septic shock induces kidney dysfunction that
may reduce ketone excretion [11].
Segebrecht et al. reported 2 cases of euKA in diabetic in-
dividuals after abdominal surgery apparently not due to
prolonged fasting [55].
Page 5 of 7 25
In individuals with cocaine abuse, poor caloric intake and
hypoglycemic effects of cocaine are potential causes of
euglycemia observed during ketoacidosis [13]. Ingestion of
drugs such as salicylate, methanol, ethylene glycol, and par-
aldehyde can also cause metabolic acidosis with euglycemia,
accompanied by increased levels of ketone bodies [56, 57].
Measurement of these drugs and intoxicants may be helpful
for differential diagnosis.
Ketoacidosis is also a feature of several inherited metabolic
disease seen mostly in childhood. When due to defects of
gluconeogenesis or glycogen metabolism (e.g., glycogen stor-
age disease), and maple syrup urine disease, ketogenesis is
accompanied by euglycemia or even hypoglycemia [58].
Mitigating euKA
Prevention of ketosis and progression to ketoacidosis is ideal-
ly the first target to mitigate euKA. People with diabetes or
with other conditions that predispose to euKA, as well as
physicians, should be instructed about precipitating factors
and how to avoid them. They should be able to recognize
promptly signs and symptoms of ketoacidosis and be advised
that ketoacidosis can occur at any glycemic level. Individuals
with diabetes using interstitial glucose sensors may be misled
by glucose readings within or close to target range, thereby
failing to recognize incipient euKA.
People with diabetes should be educated on how to adjust
their insulin dosage during illness. Self- measurement of cap-
illary blood ketones in those using devices licensed for this
use should be recommended during illness or with signs and
symptoms consistent with ketosis (malaise, nausea, and
vomiting).
To minimize the risk of DKA/euKA associated with
SGLT2i, international societies released a position statement
that recommend: (i) stopping SGLT2i at least 24 h prior to
elective surgery, planned invasive procedures, or anticipated
severe stressful physical activity; (ii) stopping immediately for
emergency surgery or any extreme stress event or any situa-
tion that might precipitate DKA including acute illness; (iii)
avoid stopping insulin or decreasing the dose excessively;
and(iv) avoid excess alcohol intake and very-low-carbohy-
drate/ketogenic diets [59•].
Careful management of DM in pregnant women, particu-
larly in the last trimester, is very important to prevent the
occurrence DKA/euKA.
Management of euKA
The treatment of euKA in diabetic individuals is similar to that
of hyperglycemic DKA. Guidelines for the management of
DKA recommend rapid fluid replacement, followed by
 25 Page 6 of 7
continuous intravenous insulin infusion, correction of electro-
lyte imbalances and dextrose-containing solutions when BG
levels are below 250 mg/dL. The treatment should continue
until resolution of ketoacidosis (normalization of acidosis and
ketone bodies). Bicarbonate therapy can be necessary for se-
vere acidosis [1]. In case of euKA in non-diabetic individuals,
insulin infusion is not necessary, whereas fluid replacement,
correction of electrolyte imbalances and intravenous glucose
solution are sufficient for the resolution of acidosis [60].
Conclusions
Ketoacidosis is a rare but serious medical emergency that
requires immediate hospital care. EuKA is a diagnostic chal-
lenge due to the absence of marked hyperglycemia, which can
result in delayed recognition and treatment leading to poten-
tially serious complications and death. With the introduction
of SGLT2i for the management of diabetic subjects, the inci-
dent of euKA has increased, but is still rare. People with dia-
betes or with conditions that predispose to euKA, as well as
healthcare professionals looking after them, should be educat-
ed about precipitating factors, signs and symptoms of
ketoacidosis and be advised that ketoacidosis can occur at
any glycemic levels.
References
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
1. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic
crises in adult patients with diabetes. Diabetes Care. 2009
Jul 1;32(7):1335–43.
2. Wang ZH, Kihl-Selstam E, Eriksson JW. Ketoacidosis occurs in
both type 1 and type 2 diabetes— a population-based study from
northern Sweden. Diabet Med. 2008 Jul 1;25(7):867–70.
3. Joint British Diabetes Societies Inpatient Care Group The
Management of Diabetic Ketoacidosis in Adults. 2013. https://
abcd.care/joint-british-diabetes-societies-jbds-inpatient-care-group
4. Munro JF, Campbell IW, McCuish AC, Duncan LJP. Euglycaemic
diabetic ketoacidosis. Br Med J. 1973 Jun 9;2(5866):578–80.
5. Jenkins D, Close CF, Krentz AJ, Nattrass M, Wright AD.
Euglycaemic diabetic ketoacidosis : does it exist? Acta Diabetol.
1993;30(4):251–3.
6. Guo R-X, Yang L-Z, Li L-X, Zhao X-P. Diabetic ketoacidosis in
pregnancy tends to occur at lower blood glucose levels: case–con-
trol study and a case report of euglycemic diabetic ketoacidosis in
pregnancy. J Obstet Gynaecol Res. 2008 Jun 1;34(3):324–30.
7. Joseph F, Anderson L, Goenka N, Vora J. Starvation-induced true
diabetic euglycemic ketoacidosis in severe depression. J Gen Intern
Med. 2008;24(1):129.
Curr Diab Rep (2020) 20:25
8. Stoimenis D, Spyridonidou C, Theofanidou S, Petridis N,
Papaioannou N, Iasonidou C, et al. Euglycemic ketoacidosis in
spinal muscular atrophy. Case Rep Pediatr. 2019;2019:2862916.
9. Lee SH, Park JH, Hong M-K, Hyeon S, Kim MY, Lee SE, et al.
True euglycemic diabetic ketoacidosis in a person with type 2 dia-
betes and Duchenne muscular dystrophy. Diabetes Res Clin Pract.
2011;92(1):e7–8.
10. McGuire LC, Cruickshank AM, Munro PT. Alcoholic ketoacidosis.
Emerg Med J. 2006 Jun;23(6):417–20.
11. Nakamura K, Inokuchi R, Doi K, Fukuda T, Tokunaga K, Nakajima
S, et al. Septic ketoacidosis. Intern Med. 2014;53(10):1071–3.
12. Prater J, Chaiban JT. Euglycemic diabetic ketoacidosis with acute
pancreatitis in a patient not known to have diabetes. AACE Clin
Case Rep. 2014;1(2):e88–91.
13. Abu-Abed Abdin A, Hamza M, Khan MS, Ahmed A. Euglycemic
diabetic ketoacidosis in a patient with cocaine intoxication. Case
Rep Crit Care. 2016;2016:4275651.
14. Bonora BM, Avogaro A, Fadini GP. Sodium-glucose co-
transporter-2 inhibitors and diabetic ketoacidosis: an updated re-
view of the literature. Diabetes Obes Metab. 2018;20(1):25–33.
15. Kitabchi AE, Wall BM. Diabetic ketoacidosis. Med Clin North Am.
1995;79(1):9–37.
16. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a
predictable, detectable, and preventable safety concern with
SGLT2 inhibitors. Diabetes Care. 2015 Sep 1;38(9):1638–42.
17. Bakris GL, Fonseca VA, Sharma K, Wright EM. Renal sodium–
glucose transport: role in diabetes mellitus and potential clinical
implications. Kidney Int. 2009;75(12):1272–7.
18.• Nyenwe EA, Kitabchi AE. The evolution of diabetic ketoacidosis:
An update of its etiology, pathogenesis and management.
Metabolism. 2016;65(4):507–21. Detailed and updated review
on etiology, pathogenesis and management of ketoacidosis.
19. Tahrani AA, Barnett AH, Bailey CJ. SGLT inhibitors in manage-
ment of diabetes. Lancet Diabetes Endocrinol. 2013;1(2):140–51.
20. Nathan DM. Adjunctive treatments for type 1 diabetes. N Engl J
Med. 2017 Sep 13;377(24):2390–1.
21. U.S. Food and Drug Administration. Drug Safety Communication.
FDA warns that SGLT2 inhibitors for diabetes may result in a seri-
ous condition of too much acid in the blood. 2015. https://www.fda.
gov/media/92185/download
22. European Medicines Agency. Review of diabetes medicines called
SGLT2 inhibitors started Risk of diabetic ketoacidosis to be exam-
ined. 2015;44(June):1–2. https://www.ema.europa.eu/en/documents/
referral/sglt2-inhibitors-article-20-procedure-review-started_en.pdf
23. Fadini GP, Bonora BM, Avogaro A. SGLT2 inhibitors and diabetic
ketoacidosis: data from the FDA Adverse Event Reporting System.
Diabetologia. 2017;60(8):1385–9.
24. Wang L, Voss EA, Weaver J, Hester L, Yuan Z, DeFalco F, et al.
Diabetic ketoacidosis in patients with type 2 diabetes treated with
sodium glucose co-transporter 2 inhibitors versus other
antihyperglycemic agents: An observational study of four US ad-
ministrative claims databases. Pharmacoepidemiol Drug Saf.
2019;28(12):1620–8.
25. Fralick M, Schneeweiss S, Patorno E. Risk of diabetic ketoacidosis
after initiation of an SGLT2 inhibitor. N Engl J Med. 2017
Jun 7;376(23):2300–2.
26. Kim Y-G, Jeon JY, Han SJ, Kim DJ, Lee K-W, Kim HJ. Sodium-
glucose co-transporter-2 inhibitors and the risk of ketoacidosis in
patients with type 2 diabetes mellitus: a nationwide population-
based cohort study. Diabetes Obes Metab. 2018 Aug 1;20(8):1852–8.
27. Dandona P, Mathieu C, Phillip M, Hansen L, Tschöpe D, Thorén F,
et al. Efficacy and safety of Dapagliflozin in patients with inade-
quately controlled type 1 diabetes: the DEPICT-1 52-week study.
Diabetes Care. 2018 Dec 1;41(12):2552–9.
28. Rosenstock J, Marquard J, Laffel LM, Neubacher D, Kaspers S,
Cherney DZ, et al. Empagliflozin as adjunctive to insulin therapy in
Curr Diab Rep (2020) 20:25
type 1 diabetes: the EASE trials. Diabetes Care. 2018 Dec 1;41(12):
2560–9.
29. Sands AT, Zambrowicz BP, Rosenstock J, Lapuerta P, Bode BW,
Garg SK, et al. Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, as
adjunct therapy to insulin in type 1 diabetes. Diabetes Care. 2015
Jul 1;38(7):1181–8.
30. Henry RR, Thakkar P, Tong C, Polidori D, Alba M. Efficacy and
safety of canagliflozin, a sodium–glucose cotransporter 2 inhibitor,
as add-on to insulin in patients with type 1 diabetes. Diabetes Care.
2015 Dec 1;38(12):2258–65.
31. Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto
R, et al. Shift to fatty substrate utilization in response to sodium–
glucose cotransporter 2 inhibition in subjects without diabetes and
patients with type 2 diabetes. Diabetes. 2016 May 1;65(5):1190–5.
32. Chen J, Williams S, Ho S, Loraine H, Hagan D, Whaley JM, et al.
Quantitative PCR tissue expression profiling of the human SGLT2
gene and related family members. Diabetes Ther. 2010;1(2):57–92.
33. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T,
et al. Metabolic response to sodium-glucose cotransporter 2 inhibi-
tion in type 2 diabetic patients. J Clin Invest. 2014;124(2):499–508.
34. Bonner C, Kerr-Conte J, Gmyr V, Queniat G, Moerman E,
Thévenet J, et al. Inhibition of the glucose transporter SGLT2 with
dapagliflozin in pancreatic alpha cells triggers glucagon secretion.
Nat Med. 2015 Apr 20;21:512–7.
35. Solini A, Sebastiani G, Nigi L, Santini E, Rossi C, Dotta F.
Dapagliflozin modulates glucagon secretion in an SGLT2-
independent manner in murine alpha cells. Diabetes Metab.
2017;43(6):512–20.
36. Kuhre RE, Ghiasi SM, Adriaenssens AE, Wewer Albrechtsen NJ,
Andersen DB, Aivazidis A, et al. No direct effect of SGLT2 activity
on glucagon secretion. Diabetologia. 2019;62(6):1011–23.
37.• Wang M, Yu X, Lee Y, McCorkle SK, Chen S, Li J, et al.
Dapagliflozin suppresses glucagon signaling in rodent models of
diabetes. Proc Natl Acad Sci. 2017;114(25):6611–6. Recently
published paper on the ketogenic effects of SGLT2i that chal-
lenges the dogma that glucagon is a primary factor in the reg-
ulation of ketone production.
38. Capozzi ME, Coch RW, Koech J, Astapova II, Wait JB, Encisco
SE, et al. The Limited role of glucagon for ketogenesis during
fasting or in response to SGLT2 inhibition. Diabetes. 2020;69(5):
882–92.
39. Larroumet A, Camoin M, Foussard N, Alexandre L, Mesli S,
Redonnet I, et al. Euglycemic ketoacidosis induced by therapeutic
fasting in a non-diabetic patient. Nutrition. 2020;72:110668.
40. Owen D, Little S, Leach R, Wyncoll D. A patient with an unusual
aetiology of a severe ketoacidosis. Intensive Care Med. 2008;34(5):
971–2.
41. Wolfe RR, Peters EJ, Klein S, Holland OB, Rosenblatt J, Gary H.
Effect of short-term fasting on lipolytic responsiveness in normal
and obese human subjects. Am J Physiol Metab. 1987;252(2):
E189–96.
42. Jensen MD, Haymond MW, Gerich JE, Cryer PE, Miles JM.
Lipolysis during fasting. Decreased suppression by insulin and in-
creased stimulation by epinephrine. J Clin Invest. 1987 Jan;79(1):
207–13.
43. Burge MR, Hardy KJ, Schade DS. Short-term fasting is a mecha-
nism for the development of euglycemic ketoacidosis during pe-
riods of insulin deficiency. J Clin Endocrinol Metab. 1993
May 1;76(5):1192–8.
Page 7 of 7 25
44. Sibai BM, Viteri OA. Diabetic ketoacidosis in pregnancy. Obstet
Gynecol. 2014;123(1):167–78.
45. Parker JA, Conway DL. Diabetic ketoacidosis in pregnancy. Obstet
Gynecol Clin N Am. 2007;34(3):533–43.
46. Ryan EA, Enns L. Role of gestational hormones in the induction of
insulin resistance. J Clin Endocrinol Metab. 1988 Aug 1;67(2):
341–7.
47. Jaber JF, Standley M, Reddy R. Euglycemic diabetic ketoacidosis
in pregnancy: a case report and review of current literature. In:
Waxman KS, editor. Case Reports Crit Care, vol. 2019; 2019. p.
8769714.
48. Kamalakannan D, Baskar V, Barton DM, Abdu TAM. Diabetic
ketoacidosis in pregnancy. Postgrad Med J. 2003 Aug;79(934):
454–7.
49. Burbos N, Shiner AM, Morris E. Severe metabolic acidosis as a
consequence of acute starvation in pregnancy. Arch Gynecol
Obstet. 2008;279(3):399.
50. Patel A, Felstead D, Doraiswami M, Stocks GM, Waheed U. Acute
starvation in pregnancy: a cause of severe metabolic acidosis. Int J
Obstet Anesth. 2011;20(3):253–6.
51. Dillon E, Dyer W, Smelo L. Ketone acidosis of non-diabetic adults.
Med Clin North Am. 1940;24:1813–22.
52. Umpierrez GE, DiGirolamo M, Tuvlin JA, Isaacs SD, Bhoola SM,
Kokko JP. Differences in metabolic and hormonal milieu in
diabetic- and alcohol-induced ketoacidosis. J Crit Care.
2000;15(2):52–9.
53. Lefèvre A, Adler H, Lieber CS. Effect of ethanol on ketone metab-
olism. J Clin Invest. 1970 Oct;49(10):1775–82.
54. Chambrier C, Laville M, Rhzioual Berrada K, Odeon M,
Boulètreau P, Beylot M. Insulin sensitivity of glucose and fat me-
tabolism in severe sepsis. Clin Sci. 2000;99:321–8.
55. Segebrecht R, Moncure M, Bennett A, Geehan D, Van Way IIICW,
Weide L. Ketoacidosis in euglycemic patients with type 2 diabetes
after abdominal surgery. J Parenter Enter Nutr. 2019;43(7):937–40.
56. Arena FP, Dugowson C, Saudek CD. Salicylate-induced hypogly-
cemia and ketoacidosis in a nondiabetic adult. Arch Intern Med.
1978 Jul 1;138(7):1153–4.
57. Kraut JA, Kurtz I. Toxic alcohol ingestions: clinical features, diag-
nosis, and management. Clin J Am Soc Nephrol. 2008 Jan 1;3(1):
208–25.
58. Alfadhel M, Babiker A. Inborn errors of metabolism associated
with hyperglycaemic ketoacidosis and diabetes mellitus: narrative
review. Sudan J Paediatr. 2018;18(1):10–23.
59.• Handelsman Y, Henry RR, Bloomgarden ZT, Dagogo-Jack S,
DeFronzo RA, Einhorn D, et al. American Association of
Clinical Endocrinologists and American College of Endocrinolgy
position statement on the association of SGLT-2 inhibitors and
diabetic ketoacidosis. Endocr Pract. 2016;22(6):753–62. Detailed
and comprehensive position statement specifically dedicated to
the association of SGLT2i and Diabetic Ketoacidosis and for
management of DKA in patients taking SGLT2i.
60. Le Neveu F, Hywel B, Harvey JN. Euglycaemic ketoacidosis in
patients with and without diabetes. Pract Diabetes. 2013;30(4):
167–71.
Publisher’s Note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.