Euglycemic Ketoacidosis as a Complication of SGLT2

Inhibitor Therapy
Biff F. Palmer1 and Deborah J. Clegg2

Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are drugs designed to lower plasma glucose concentration by
inhibiting Na1-glucose–coupled transport in the proximal tubule. Clinical trials demonstrate these drugs have 1
Division of
favorable effects on cardiovascular outcomes to include slowing the progression of CKD. Although most patients Nephrology,
tolerate these drugs, a potential complication is development of ketoacidosis, often with a normal or only a Department of
Medicine, University of
minimally elevated plasma glucose concentration. Inhibition of sodium-glucose cotransporter-2 in the proximal
Texas Southwestern
tubule alters kidney ATP turnover so that filtered ketoacids are preferentially excreted as Na1 or K1 salts, leading Medical Center, Dallas,
to indirect loss of bicarbonate from the body and systemic acidosis under conditions of increased ketogenesis. Texas
2
Risk factors include reductions in insulin dose, increased insulin demand, metabolic stress, low carbohydrate Associate Dean for
intake, women, and latent autoimmune diabetes of adulthood. The lack of hyperglycemia and nonspecific Research, College of
Nursing and Health
symptoms of ketoacidosis can lead to delays in diagnosis. Treatment strategies and various precautions are Professionals, Drexel
discussed that can decrease the likelihood of this complication. University,
CJASN 16: 1284–1291, 2021. doi: https://doi.org/10.2215/CJN.17621120 Philadelphia,
Pennsylvania

Introduction inhibitors were used in combination with insulin in Correspondence: Dr.

Underappreciated is the role the kidney plays in ketoa-
cidosis defined as a primary decrease in plasma
bicarbonate concentration resulting from increased
ketoacids. Diabetic ketoacidosis (DKA) is a common
cause of this acid-base disturbance and is accompanied
by plasma glucose concentration .250 mg/dl, which is
a criterion for diagnosis. There are patients with diabe-
tes mellitus who develop ketoacidosis with less severe
hyperglycemia, often ,200 mg/dl. This form of ketoa-
cidosis is euglycemic ketoacidosis and is a recognized
complication of sodium-glucose cotransporter-2 inhibi-
tors (SGLT2is). There are new data about the benefits of
SGLT2i in individuals with kidney disorders; therefore,
here we remind the clinician of alterations in kidney
function induced by these drugs that increase the risk
of ketoacidosis. We highlight unique risk factors and
treatments of this disorder in individuals with kidney
disease.
Risk of Ketoacidosis with Sodium-Glucose
Cotransporter-2 Inhibitor
SGLT2is are drugs developed to reduce blood glu-
cose levels in patients with diabetes mellitus. Random-
ized controlled trials demonstrate risk reductions for
myocardial infarction, heart failure, kidney disease pro-
gression, and cardiovascular mortality, which likely
will increase their use (1–5). In 2015, the Food and
Drug Administration (FDA) issued a safety warning
on the risk of DKA (6). The frequency of ketoacidosis
in clinical trials was small in patients with type 2 diabe-
tes mellitus, but occurred in 4%–6% of patients when
Biff F. Palmer,
patients with type 1 diabetes mellitus (7–9). In the Kid- Department of Internal
ney Disease: Improving Global Outcomes 2020 clinical Medicine, University of
practice guideline for management of patients with dia- Texas Southwestern
betes and CKD, the risk of this disorder is described as Medical Center, 5323
Harry Hines Boulevard,
generally a rare event in patients with type 2 diabetes
Dallas, TX 75390.
mellitus (10). Reports examining postmarketing use Email: biff.palmer@
suggest that the frequency of this disorder is much utsouthwestern.edu
greater in real-world practice. An analysis of the FDA
Adverse Event Reporting System found a seven-fold
higher risk of acidosis in treated patients with type 2
diabetes mellitus when compared with dipeptidyl
peptidase-4 inhibitor therapy (11). This risk is approxi-
mately two- to four-fold greater than the numerical
imbalance reported in clinical trials of canagliflozin
and empagliflozin. Of those with ketoacidosis, euglyce-
mia was present in 71% of the patients. More recently, a
three-fold increase in the risk of DKA was found in a
population cohort study of over 350,000 adults with
type 2 diabetes mellitus compared with those treated
with dipeptidyl peptidase-4 inhibitor (12). Importantly,
fatality rates of this complication with SGLT2i therapy
are greater when compared with all patients with
DKA (13).
Increased Ketogenesis with Sodium-Glucose
Cotransporter-2 Inhibitor
SGLT2i lowers plasma glucose by pharmacologically
forcing excretion of glucose into the urine. The sodium-
glucose cotransporter-2 (SGLT2) is located in the early
(S1) proximal tubule and is responsible for reabsorption
of 80%–90% of filtered glucose (14). SGLT1 is located in

1284 Copyright © 2021 by the American Society of Nephrology www.cjasn.org Vol 16 August, 2021
CJASN 16: 1284–1291, August, 2021
the more distal part of the proximal tubule (S2/S3) and is
responsible for the reabsorption of the remaining 10%–20%
of filtered glucose. Inhibition of these transporters reduces
the transport maximum for glucose reabsorption, leading
to glycosuria and reductions in plasma glucose concentra-
tions. Decreased plasma glucose concentration signals a fall
in insulin levels and causes plasma glucagon levels to
increase due to a paracrine effect induced by diminished
inhibition of insulin on glucagon release in the pancreas. In
addition, inhibition of SGLT2 on pancreatic a-cells triggers
release of glucagon. Glucagon further suppresses insulin
by promoting hepatic release of kisspeptin-1 that, in turn,
suppresses glucose-stimulated insulin secretion (15). The
reduction in plasma insulin and glucose levels decreases
carbohydrate oxidation and shifts metabolism toward
lipid oxidation fueled by increased circulating fatty acids
and lipolysis. Changes in fuel preference are detected by
measurable drops in the respiratory quotient following initi-
ation of SGLT2i therapy (16). By way of background, the
respiratory quotient is a dimensionless number used in
calculations of basal metabolic rate when estimated from
carbon dioxide production. Greater amounts of fatty acid
metabolism lower the quotient toward 0.7, whereas a shift
to carbohydrate metabolism raises the quotient to values
more than one.
SGLT2i causes daily glucose losses of 50–100 g corre-
sponding to 200–400 kcal/d, which represent up to half of
estimated carbohydrate intake in men and even higher
amounts in women (17). SGLT2i therapy leads to weight
loss in both rodents and humans in association with reduc-
tions in visceral and subcutaneous fat mass as measured by
dual-energy x-ray absorptiometry (18). In rodent models,
SGLT2is increase energy expenditure with activation and
recruitment of brown and beige adipocytes, respectively
(19). Caloric deficits due to glucose loss in the urine com-
bined with enhanced lipid oxidation and increases in energy
expenditure account for reductions in fat mass (19,20).
The combination of increased lipolysis and a reduced
insulin-glucagon ratio leads to increased hepatic production
of ketoacids. Increased production of acetyl-CoA from fatty
acid b-oxidation is preferentially directed toward ketoacid
production because glucagon stimulates and insulin inhibits
the rate-limiting enzyme for this pathway (hydroxylmethyl-
glutaryl-CoA). This pattern is similar to what occurs with
fasting, except changes following SGLT2i are more rapid.
In one study, fasting plasma ketone concentrations increased
four-fold over baseline in the first 2 weeks of therapy with
dapaglifozin (16). This shift to increased fat oxidation and
ketogenesis also occurs in SGLT2i-treated individuals with-
out diabetes mellitus, but to a lesser extent (21). Despite mea-
surable increases in plasma ketone levels in treated patients,
development of ketoacidosis is unusual. Those with the
greatest increase in b-hydroxybutyrate levels have lower
fasting and postmeal insulin levels and impaired b-cell
insulin sensitivity when compared with subjects in the lower
quartiles, suggesting the amount of endogenous insulin
secretion reserve may factor into the magnitude of ketogenic
response (22). As discussed below, factors leading to
either a brisk reduction in exogenous insulin dose or inade-
quate endogenous insulin secretion predispose to overt
ketoacidosis.
Euglycemic Ketoacidosis, Palmer and Clegg 1285
Sodium-Glucose Cotransporter-2 Inhibitor Effects on
Kidney Function Predisposing to Ketoacidosis
Although changes in insulin and glucagon levels are cen-
tral to increased production of ketoacids, SGLT2is further
increase the risk of overt ketoacidosis by altering ATP turn-
over in the proximal tubule (Figure 1). Na1-coupled glucose
reabsorption is an example of secondary active transport
where ATP hydrolysis fuels activity of the basolateral
Na1-K1-ATPase to maintain a low intracellular Na1 concen-
tration and secondarily provide a favorable inward gradient
for Na1-coupled glucose transport across the apical mem-
brane. This pathway normally reabsorbs approximately
4%–6% of total filtered Na1 (22,23). In patients with diabetes
mellitus, the threshold for glucose excretion is increased
from 150 to 250 mg/dl due to glucose-mediated hypertrophy
of the proximal tubule and increased expression of SGLT2
(24,25). It is estimated these changes lead to a doubling in
percentage of filtered Na1 reabsorbed by this segment and
a 50% increase in daily kidney ATP turnover (22,26).
The energy required to fuel Na1-K1-ATPase pump
activity to maintain a low intracellular Na1 concentration
decreases following pharmacologic inhibition of SGLT2. In
addition to decreasing Na1 entry into the cell coupled to glu-
cose, SGLT2is also decrease Na1 entry by inhibiting Na1-H1
antiporter (NHE3) activity. Studies in rodents show SGLT2
and NHE3 colocalize in the proximal tubule brush border
membrane (27). Inhibition of SGLT2 decreases activity of
NHE3, and the natriuretic effect of SGLT2i is diminished in
models where NHE3 is knocked down (28). The estimated
daily kidney ATP turnover decreases by approximately
50% in patients with diabetes mellitus treated with SGLT2i
(26). Because ATP is not stored, reduced consumption
will secondarily decrease pathways that normally generate
ATP (29). Because metabolism of glutamine to NH41 and
HCO32 in the proximal tubule results in an obligatory
production of ATP, ammoniagenesis decreases following
SGLT2i therapy. A similar reduction in ammoniagenesis
occurs when cellular ATP utilization is lowered by decreas-
ing the filtered Na1 or directly inhibiting Na1-K1-ATPase
pump activity in the proximal tubule, supporting the notion
that the rate of ATP utilization places an upper limit on
ammonia production in the kidney (30).
Inhibition of ammonia synthesis indirectly predisposes to
HCO32 loss from the body and development of metabolic
acidosis. The production of b-hydroxybutyric acid consumes
HCO32 and generates Na-b-hydroxybutyrate and H2CO3,
the latter of which quickly disassociates into CO2 (exhaled
by the lungs) and water. When b-hydroxybutyrate is
excreted in the urine coupled to NH41, there is no net change
in acid-base balance because production of NH41 from glu-
tamine generates HCO32. By contrast, urinary excretion of
b-hydroxybutyrate as either an Na1 or K1 salt is the equiv-
alent to losing HCO32 from the body and will generate
metabolic acidosis (31,32). The inhibitory effect on ammonia
synthesis by SGLT2i favors excretion of Na1- and/or K1-
coupled b-hydroxybutyrate in the urine.
SGLT2i also suppresses ammoniagenesis by causing a
shift toward greater fatty acid oxidation by the proximal
tubule. Under normal circumstances, this nephron segment
preferentially utilizes fatty acids as a fuel source to generate
ATP to meet the high metabolic demand of the tubule
because fatty acids provide more energy per gram as
1286 CJASN

Figure 1. | Alterations in ATP turnover predispose to systemic acidosis following sodium-glucose cotransporter-2 inhibitor (SGLT2i) admin-
istration. Decreased Na1 entry into the proximal tubular cell following inhibition of sodium-glucose cotransporter-2 decreases consumption
of ATP by the Na1-K1-ATPase pump. SGLT2i also restores fatty acid oxidation, which delivers more energy per gram than glucose. The com-
bined effect of reduced consumption along with increased generation of ATP decreases activity of other pathways that normally generate ATP to
include ammoniagenesis and uptake and oxidation of filtered ketone bodies. These changes predispose to urinary loss of filtered ketone bodies as
Na1 or K1 salts, causing indirect loss of bicarbonate from the body and development of metabolic acidosis under conditions of increased keto-
genesis. NaBOH, sodium b-hydroxybutyrate; NaHCO3, sodium bicarbonate; NH42, ammonium; NH4BOH, ammonium betahydroxybutyrate.

compared with glucose. Studies in humans and rodent mod-
els of diabetes mellitus show metabolism in the kidney is
shifted toward utilization of glucose for anaerobic glycolysis
and away from oxidative phosphorylation of fatty acids
(33,34). Rather than being utilized as fuel, lipid accumulates
in the cell, where it has been linked to tubular injury through
lipotoxicity. Upregulation of hypoxia-inducible factor is etio-
logically linked to this change in fuel preference (35). Admin-
istration of dapagliflozin prevents stabilization of HIF and
attenuates the metabolic shift, suggesting that reabsorption
of excess glucose by the diabetic kidney is responsible for
the switch from fatty acid oxidation to glycolysis. The
increase in ATP production following restoration of fatty
acid oxidation in combination with reduced utilization
accounts for the decrease in ammoniagenesis that occurs
with SGLT2i (36).
The increase in fat oxidation following SGLT2i can further
exacerbate indirect loss of HCO32 from the body by impair-
ing uptake and oxidation of filtered b-hydroxybutyrate. The
kidney normally has a large capacity to reabsorb filtered
ketone bodies. With prolonged fasting, blood concentrations
and the filtered load of acetoacetate and b-hydroxybutyrate
progressively increase. At the same time, the absolute reab-
sorption rate of ketone bodies increases linearly with no evi-
dence of a tubular maximum (37,38). Reabsorption and sub-
sequent oxidation in the kidney regenerate consumed
HCO32, thereby lessening the degree of acidosis that would
otherwise occur if the ketone was excreted as an Na1 or K1
salt. The complete oxidation of ketones by the tubule also
generates ATP, adding to the pool derived from fatty acid
oxidation. This additional amount of ATP adds to the inhib-
itory effect on ammonia production. In starvation, the
decrease in ammonia availability does not adversely affect
acid-base balance because oxidation of the ketone body in
the proximal tubule regenerates an amount of HCO32 equal
to what was consumed in their production. This suppressive
effect on ammoniagenesis by way of ATP turnover is advan-
tageous during starvation because the requirement for gluta-
mine uptake by the kidney will be reduced, resulting in less
proteolysis and providing a protein-sparing effect. In this
regard, infusion of b-hydroxybutyrate has been shown to
reduce kidney NH41 production in dogs and humans with
chronic metabolic acidosis (39–41). Following SGLT2i, the
reduction in ATP utilization in combination with the large
quantity of ATP produced from fat oxidation will not only
suppress ammoniagenesis but also decrease uptake and oxi-
dation of ketone bodies. These changes cause increased uri-
nary excretion of b-hydroxybutyrate coupled to Na1 or
K1, predisposing to acidosis through the indirect loss
of HCO32 from the body (42,43). In a study of 66 patients
treated with empagliflozin, kidney b-hydroxybutyrate
excretion rose three-fold, and fractional excretion increased
by approximately 70% after 28 days of therapy (42).
Risk Factors for Development of Ketoacidosis
Changes in systemic metabolism and kidney ATP turn-
over following SGLT2i do not cause overt metabolic acidosis
in most treated patients. Rather, these changes create a tenu-
ous state whereby metabolic acidosis can quickly develop
CJASN 16: 1284–1291, August, 2021
following some precipitating factor that leads to accelerated
ketogenesis (Table 1). This situation occurs when insulin
deficiency becomes more pronounced, explaining reports
of ketoacidosis when SGLT2is are used off label in patients
with type 1 diabetes mellitus or when the insulin dose is
reduced by either patients or health care workers due to
reductions in plasma glucose levels.
Adjunctive therapy with SGLT2i to intensive insulin regi-
mens improves glycemic control in type 1 diabetes mellitus
but is associated with a dose-dependent increase in the abso-
lute risk of DKA (44–47). The higher risk is attributable to the
failure to recognize early manifestations of metabolic decom-
pensation secondary to a blunted rise in plasma glucose lev-
els due to increased urinary glucose excretion (48). Use of
SGLT2i in type 1 diabetes mellitus should be restricted to
specialists with the resources necessary to train, educate,
and support carefully selected patients.
A sudden restriction in carbohydrate availability will
increase lipolysis and lipid oxidation, explaining reports of
ketoacidosis under conditions of surgical stress, intercurrent
illness, or prolonged fasting (49). A weight loss strategy cen-
tered on carbohydrate restriction is a risk factor and should
be discouraged or implemented with close monitoring. The
glycosuric response of SGLT2i relative to the filtered glucose
load is independent of body size. This finding may explain
the higher risk of acidosis in lean individuals on a low-
carbohydrate diet because they are exposed to a higher def-
icit of carbohydrate when compared with obese subjects (50).
Use of SGLT2i in the setting of alcohol use or salicylate toxic-
ity is a risk factor because these conditions are characterized
by increased ketogenesis (32,51).
Sex-based differences in substrate metabolism may
explain the higher risk of ketoacidosis reported in women
(11,45,52). During fasting, women demonstrate a greater
increase in circulating nonesterified fatty acids and ketone
bodies and a greater fall in the rate of endogenous glucose
production and utilization when compared with men (53).
Women also demonstrate increased lipid and reduced carbo-
hydrate utilization as a fuel during exercise, whereas the
opposite is true in men (54). This proclivity to utilize lipids
as a fuel under conditions of metabolic stress is due to the
permissive effect of estrogen on lipolysis through enhance-
ment of hormone-sensitive lipase in adipocytes. In addition,
a sexually dimorphic response of autonomic nerve activity
may play a role (55). Circulating catecholamines and skeletal
muscle sympathetic nerve activity with exercise are lower in
women as compared with men. Despite the blunted
response, women demonstrate a greater degree of lipolysis
but lower rates of glucose production and utilization. Lipol-
ysis in women is solely mediated by b-adrenergic receptors,
whereas in men, there is also activation of a-adrenergic
receptors, which exert an inhibitory effect on lipolysis (56).
Given the divergent effects of a- and b-receptor activation,
stimulation of both receptors in men will blunt the degree
of lipolysis when compared with women, in whom only lipo-
lytic b-receptors are stimulated. The shift to greater fat oxida-
tion in women during metabolic stress increases the risk of
ketoacidosis with SGLT2i.
Patients with a longer duration of disease or the require-
ment for insulin have more impaired insulin secretory
reserve and are at higher risk. In addition to type 1 diabetes
mellitus, an analysis of canagliflozin trial data found DKA
Euglycemic Ketoacidosis, Palmer and Clegg 1287
events higher in patients with latent autoimmune diabetes
of adulthood or those testing positive for glutamic acid
decarboxylase 65-kD isoform antibodies (57). In one series
of SGLT2i-associated ketoacidosis, approximately one third
of patients had this form of the disease (49). These patients
have circulating islet cell antibodies and are diagnosed
with diabetes mellitus later in life. Upon presentation, insulin
may not be required due to the presence of residual b-cell
function, leading to misclassification as type 2 diabetes mel-
litus. Soon after diagnosis, there is a relatively rapid decline
in insulin release due to autoantibody-mediated injury.
SGLT2i can acutely accelerate this decline due to increased
release of glucagon, rendering the patient at risk for ketoaci-
dosis following a minimal metabolic stress.
Because urinary excretion of ketoacid salts coupled to NH41
is neutral with regard to acid-base balance, it will be important
to determine if people with diabetes and reduced GFR or those
on renin angiotensin system blockers are at increased risk for
ketoacidosis because these conditions can limit ammoniagen-
esis in the kidney. There may also be additional concerns in
individuals with type 4 renal tubular acidosis because hyper-
kalemia further suppresses ammoniagenesis.
Clinical Features and Treatment of Sodium-Glucose
Cotransporter-2 Inhibitor–Induced Ketoacidosis
A normal anion gap hyperchloremic metabolic acidosis is
present in the initial stages of ketoacidosis (31). Loss of Na1-
b-hydroxybutyrate in the urine secondarily causes kidney
retention of NaCl in an attempt to maintain extracellular
fluid volume near normal. Volume depletion or a reduction
in GFR will limit filtration of ketoacid salts, causing Na1-
b-hydroxybutyrate to accumulate in the plasma resulting
in an increased anion gap metabolic acidosis. At presenta-
tion, most patients exhibit some combination of increased
anion gap and a normal anion gap acidosis (58). Because
insulin deficiency induced by SGLT2i is less severe com-
pared with DKA, glucose overproduction and underutiliza-
tion are quantitatively less pronounced (Table 2). This effect,
combined with pharmacologic inhibition of glucose reab-
sorption in the kidney, likely accounts for why the plasma
glucose is only minimally elevated in patients with
SGLT2i-induced ketoacidosis. The lack of significant hyper-
glycemia despite development of ketoacidosis can delay
the diagnosis because plasma glucose is what is typically
monitored by the patients on a day-to-day basis. Most
patients present with abdominal pain, nausea, anorexia,
vomiting, or other nonspecific symptoms (49) (Table 3).
Given the benefits demonstrated in nondiabetic kidney
disease in the Dapagliflozin and Prevention of Adverse Out-
comes in Chronic Kidney Disease study, use of SGLT2i by
nephrologists is likely to increase. Little is known about
development of ketoacidosis in such individuals, but certain
risk factors may increase the risk of this complication. Insulin
resistance is a feature of uremia and increases in severity
with advancing stages of CKD (59). Concomitant use of
immunosuppressive drugs, particularly corticosteroids, can
worsen insulin resistance and predispose to ketoacidosis.
In nondiabetic rodents, euglycemic ketoacidosis developed
with SGLT2i when animals were stressed with volume
depletion (60). This observation suggests clinical conditions
1288 CJASN

Table 1. Risk factors for sodium-glucose cotransporter-2 inhibitor–associated ketoacidosis

Risk Factor Mechanism Precautions to Reduce Risk

Reduction in insulin dose
Lowering of plasma glucose concentration
following SGLT2i may prompt lowering of
insulin dose by patient or prescriber
Decreased insulin effect stimulates lipolysis and
increases glucagon-insulin ratio, predisposing
to ketogenesis in liver
Avoid .20% reductions in insulin dose;
implement frequent pre- and post-
prandial glucose monitoring following
changes in insulin dose
Frequent monitoring of urine ketones
following insulin dose adjustments

Off-label use in type 1 diabetes Increased risk with pump therapy due to
mellitus operational failures causing sudden decrease
in insulin dose; lower risk with subcutaneous
regimens utilizing longer-acting formulations
compared with rapid-acting analogs in pump
regimens
Reduce insulin up to 20% following first
dose of SGLT2i, then up titrate to
original baseline or maintain stable
insulin regimen for first 7 treatment d,
and adjust thereafter according to
glucose levels.a Assess ketones to
detect early DKA in event of
nonspecific symptoms regardless of
glucose levels; adhere to optimized
sick-day protocols

Restriction in dietary carbohydrate
availability as seen with the use
of ketogenic diets
Glycosuric effect of SGLT2i combined with Avoid very low–carbohydrate diets
decreased dietary carbohydrate intake leads
to decreased insulin levels
Increased lipolysis due to reductions in
carbohydrate intake leads to an increased
glucagon-insulin ratio, which predisposes to
ketogenesis

Surgical stress, trauma,
intercurrent illness such as
gastroenteritis where there is an
inability to eat or drink
Lean body habitus
Decreased food intake leads to reduced insulin
levels, thereby increasing likelihood of
ketogenesis
Nonspecific symptoms, such as malaise and
nausea, along with mild or absent glycemia
may cause patient to decrease insulin dose,
thus increasing risk of ketosis
Increased levels of counter-regulatory hormones
(catecholamines and cortisol) accelerate
lipolysis and increase insulin demand
Carbohydrate deficit is greater in lean versus
obese individuals because the degree of
glycosuria relative to filtered load is
independent of body size following SGLT2i
Discontinue SGLT2i 3 d prior to elective
surgery
Discontinue SGLT2i with acute illness
Educate patient to monitor for ketonuria,
in addition to glucose, and contact
provider with any symptoms or
detectable ketonuria
Supplemental doses of rapid-acting
insulin, along with fluids and
ingestion of carbohydrates
Educate lean/muscle-bound patients as
to their increased risk and symptoms

Alcohol use disorder and salicylate
toxicity
Alcohol withdrawal and salicylate toxicity Discontinue SGLT2i
are both associated with increased lipolysis Be aware of patients with chronic
and decreased insulin-glucagon ratio, thereby salicylate toxicity
increasing risk of ketogenesis, conditions
made worse following SGLT2i

Women Women preferentially oxidize fatty acids and
exhibit greater increase in ketogenesis with
metabolic stress
Estrogen enhances hormone-sensitive lipase in
adipocytes
Patient education that increased risk is
confined to premenopausal women or
postmenopausal women taking
hormonal replacement therapy to
include estrogens

LADA LADA is phenotypically similar to type 2 Increased awareness of disorder

diabetes mellitus, but insulin dependency
develops rapidly (5–6 yr) due to immune-
mediated b-cell injury
Unrecognized rapid loss of b-cell secretory
reserve combined with metabolic stress
increases risk in the setting of SGLT2i
Prevalence is about 10% among patients
diagnosed with type 2 diabetes
mellitus with islet antibodies
Presence of impaired b-cell function at
diagnosis warrants early insulin
therapy

Long-standing type 2 diabetes Longer duration of disease increases likelihood Patient education and more frequent
mellitus of marked b-cell insufficiency monitoring when SGLT2i is given to
Imposition of metabolic stress readily unmasks patients with long duration of disease
limited insulin secretory reserve

SGLT2i, sodium-glucose cotransporter-2 inhibitor; DKA, diabetic ketoacidosis; LADA, latent autoimmune diabetes in adults.
a
Strategies utilized to decrease risk of ketoacidosis in clinical trials of type 1 diabetes mellitus (44,45).
CJASN 16: 1284–1291, August, 2021 Euglycemic Ketoacidosis, Palmer and Clegg 1289

Table 2. Selected clinical and laboratory findings distinguishing ketoacidosis due to sodium-glucose cotransporter-2 inhibitor from typ-
ical diabetic ketoacidosis

Factor
Endogenous glucose production
Insulin release
Insulin resistance
Tissue glucose disposal
Kidney glucose clearance
Plasma glucose levels
Extracellular fluid volume
Presenting symptoms
Sodium-Glucose Cotransporter-2
Diabetic Ketoacidosis
Inhibitor–Induced Diabetic Ketoacidosis
" ""
# ##
" ""
# ##
"" "
Normal or increased, often ,250 mg/dla Typically 350–800 mg/dl
# ##
More nonspecific to include malaise, Polyuria and polydipsia due to osmotic
nausea, anorexia, abdominal pain diuresis, nausea, vomiting, shortness
of breath

a
Because the plasma glucose is either normal or only modestly increased in most patients, transcellular shift in water and K1 is
minimal, making disturbances in plasma Na1 and K1 concentration less severe when compared with typical diabetic ketoacidosis
(mechanisms are reviewed in ref. 31).

predisposing to insulin resistance, such as activation of
sympathetic nerve activity or increased circulating glucocor-
ticoids, may be sufficient to cause this complication in
susceptible individuals without known diabetes mellitus.
The risk of SGLT2i-induced ketoacidosis can be minimized
by close monitoring and making appropriate adjustments in
medications upon changing clinical conditions. For example,
major surgery or trauma is a common precipitating risk fac-
tor. These conditions lead to stress-induced increases in cir-
culating catecholamines and cortisol, which, in combination,
can reduce insulin sensitivity. The glycosuric effect of
SGLT2i may prevent significant increases in plasma glucose
concentration, masking the true requirement for insulin and
increasing the risk of ketoacidosis. Current recommenda-
tions suggest SGLT2i should be discontinued at least 3
days prior to an elective surgical or invasive procedure
(61). Insulin can be used as a bridge for glycemic control dur-
ing this period. Although this time period provides approx-
imately five t1/2 of elimination, it should be noted that phar-
macologic effects of the drugs, such as glycosuria and
ketonemia, can be detected up to 10 days after discontinua-
tion (62). Patient reports have described the onset of DKA
up to 14 days after drug discontinuation (63). Patients should
be educated about possible symptoms of ketoacidosis and, if
present, instructed to contact their physician even if glucose
monitoring does not indicate hyperglycemia (Table 3). When
SGLT2is are prescribed to patients treated with insulin, the
dose of insulin may need to be reduced to avoid hypoglyce-
mia. Such a change requires close monitoring as the reduc-
tion in inulin dose increases the risk for ketoacidosis.
There are no specific guidelines for treatment of SGLT2i-
induced ketoacidosis; however, the treatment approach is
like that of typical DKA (31). In addition to drug discontinu-
ation, restoration of extracellular fluid volume with normal
saline should be the initial approach. The degree of volume
depletion may be less severe because hyperglycemia is less
pronounced, minimizing the severity of osmotic diuresis.
Early intravenous insulin is required to facilitate utilization
of glucose and diminish ketogenesis. In typical DKA, a 5%
dextrose solution is recommended after the plasma glucose
falls to 250 mg/dl. This solution along with insulin may be
appropriate earlier in the treatment of SGLT2i-induced ketoa-
cidosis because the plasma glucose concentration may only
be minimally increased. In the absence of life-threatening

Table 3. Recommendations to patients when prescribed sodium-glucose cotransporter-2 inhibitor

Recommendations
Maintain appropriate fluid intake
Ensure adequate carbohydrate intake and avoid low-carbohydrate diets
Avoid skipping insulin doses and skipping meals
In situations of acute illness, vomiting, diarrhea, or inability to eat or drink
Discontinue SGLT2i
Contact provider even if blood glucose levels are not elevated
Continue to monitor glucose levels and monitor for presence of urinary ketones
If on insulin therapy, contact provider for dose adjustments; do not stop insulin
Ketoacidosis symptoms are nonspecific (malaise, nausea, anorexia, vomiting) and can occur despite normal or minimally
elevated blood glucose level
If ketonuria detected, patient may be advised to administer dose of rapid-acting insulin and consume 30 g carbohydrate
Restart SGLT2i when eating and drinking normally, usually after 24–48 h as directed by medical provider

Recommendations to patients when prescribed sodium-glucose cotransporter-2 inhibitor (SGLT2i) are especially important for lean
women who are premenopausal or postmenopausal on hormone replacement therapy.
1290 CJASN
acidosis or a pH,7.1, alkali therapy is generally not required
because insulin administration slows the rate of ketoacid pro-
duction, and oxidation of ketoanions regenerates HCO32.
The presence of a predominately normal gap acidosis indi-
cates that only a small amount of organic anions is available
for regeneration of HCO32, and the indirect loss of HCO32
from the body has been considerable. Regeneration of
HCO32 and establishment of normal acid-base balance can
take up to 72 hours or even longer in the presence of CKD
in this setting. Alkali therapy may be useful to shorten the
total duration of acidemia in such patients.
In summary, use of SGLT2i is likely to increase dramatically
given the evidence that these drugs confer cardiovascular
benefit. These drugs alter ATP turnover in the kidney, predis-
posing to euglycemic ketoacidosis under conditions of accel-
erated ketogenesis. Clinicians should be familiar with risk fac-
tors so the likelihood of this disorder can be minimized.
Disclosures
All authors have nothing to disclose.
Funding
None.
References
1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S,
Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC,
Inzucchi SE; EMPA-REG OUTCOME Investigators: Empagliflozin,
cardiovascular outcomes, and mortality in type 2 diabetes.
N Engl J Med 373: 2117–2128, 2015
2. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod
MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS,
B
elohl €hm M, Chiang CE, Chopra VK, de Boer RA,
avek J, Bo
Desai AS, Diez M, Drozdz J, Dukat A, Ge J, Howlett JG, Katova
T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O’Meara
E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held
C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjo €strand
M, Langkilde AM; DAPA-HF Trial Committees and Investigators:
Dapagliflozin in patients with heart failure and reduced ejection
fraction. N Engl J Med 381: 1995–2008, 2019
3. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P,
Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura
K, Schnee J, Zeller C, Cotton D, Bocchi E, Bo€hm M, Choi DJ,
Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gon-
zalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B,
Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M,
Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F;
EMPEROR-Reduced Trial Investigators: Cardiovascular and renal
outcomes with empagliflozin in heart failure. N Engl J Med 383:
1413–1424, 2020
4. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL,
Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon
CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pol-
lock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G,
Brenner BM, Mahaffey KW; CREDENCE Trial Investigators:
Canagliflozin and renal outcomes in type 2 diabetes and
nephropathy. N Engl J Med 380: 2295–2306, 2019
5. Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM,
Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Ross-
ing P, Sjo€stro
€m CD, Toto RD, Langkilde AM, Wheeler DC;
DAPA-CKD Trial Committees and Investigators: Dapagliflozin in
patients with chronic kidney disease. N Engl J Med 383: 1436–
1446, 2020
6. US Food and Drug Administration: Drug Safety Communication:
FDA warns that SGLT2 inhibitors for diabetes may result in a
serious condition of too much acid in the blood, 2015. Available
at: www.fda.gov/downloads/Drugs/DrugSafety/UCM446954.
pdf. Accessed June 22, 2015
7. Bonora BM, Avogaro A, Fadini GP: Sodium-glucose co-trans-
porter-2 inhibitors and diabetic ketoacidosis: An updated review
of the literature. Diabetes Obes Metab 20: 25–33, 2018
8. Peters AL, Henry RR, Thakkar P, Tong C, Alba M: Diabetic
ketoacidosis with canagliflozin, a sodium-glucose cotransporter
2 inhibitor, in patients with type 1 diabetes. Diabetes Care 39:
532–538, 2016
9. Dandona P, Mathieu C, Phillip M, Hansen L, Tscho €pe D, Thoren
F, Xu J, Langkilde AM; DEPICT-1 Investigators: Efficacy and
safety of dapagliflozin in patients with inadequately controlled
type 1 diabetes: The DEPICT-1 52-week study. Diabetes Care 41:
2552–2559, 2018
10. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes
Work Group: KDIGO 2020 clinical practice guideline for dia-
betes management in chronic kidney disease (CKD). Available
at: https://kdigo.org/guidelines/diabetes-ckd/
11. Blau JE, Tella SH, Taylor SI, Rother KI: Ketoacidosis associated
with SGLT2 inhibitor treatment: Analysis of FAERS data. Diabe-
tes Metab Res Rev 33: e2924, 2017
12. Douros A, Lix LM, Fralick M, Dell’Aniello S, Shah BR, Ronksley
PE, Tremblay E, Hu N, Alessi-Severini S, Fisher A, Bugden SC,
Ernst P, Filion KB: Sodium-glucose cotransporter-2 inhibitors and
the risk for diabetic ketoacidosis: A multicenter cohort study.
Ann Intern Med 173: 417–425, 2020
13. Diaz-Ramos A, Eilbert W, Marquez D: Euglycemic diabetic
ketoacidosis associated with sodium-glucose cotransporter-2
inhibitor use: A case report and review of the literature. Int J
Emerg Med 12: 27, 2019
14. Ghezzi C, Loo DDF, Wright EM: Physiology of renal glucose
handling via SGLT1, SGLT2 and GLUT2. Diabetologia 61: 2087–
2097, 2018
15. Song WJ, Mondal P, Wolfe A, Alonso LC, Stamateris R, Ong BW,
Lim OC, Yang KS, Radovick S, Novaira HJ, Farber EA, Farber CR,
Turner SD, Hussain MA: Glucagon regulates hepatic kisspeptin
to impair insulin secretion. Cell Metab 19: 667–681, 2014
16. Daniele G, Xiong J, Solis-Herrera C, Merovci A, Eldor R, Tripathy
D, DeFronzo RA, Norton L, Abdul-Ghani M: Dapagliflozin
enhances fat oxidation and ketone production in patients with
type 2 diabetes. Diabetes Care 39: 2036–2041, 2016
17. Rosenstock J, Ferrannini E: Euglycemic diabetic ketoacidosis: A
predictable, detectable, and preventable safety concern with
SGLT2 inhibitors. Diabetes Care 38: 1638–1642, 2015
€ Kullberg J, Johansson L, Wilding J,
18. Bolinder J, Ljunggren O,
Langkilde AM, Sugg J, Parikh S: Effects of dapagliflozin on body
weight, total fat mass, and regional adipose tissue distribution in
patients with type 2 diabetes mellitus with inadequate glycemic
control on metformin. J Clin Endocrinol Metab 97: 1020–1031,
2012
19. Xu L, Nagata N, Nagashimada M, Zhuge F, Ni Y, Chen G,
Mayoux E, Kaneko S, Ota T: SGLT2 inhibition by empagliflozin
promotes fat utilization and browning and attenuates inflam-
mation and insulin resistance by polarizing M2 macrophages in
diet-induced obese mice. EBioMedicine 20: 137–149, 2017
20. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T,
Broedl UC, Woerle HJ: Metabolic response to sodium-glucose
cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest
124: 499–508, 2014
21. Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto
R, Mari A, Pieber TR, Muscelli E: Shift to fatty substrate utilization
in response to sodium-glucose cotransporter 2 inhibition in
subjects without diabetes and patients with type 2 diabetes.
Diabetes 65: 1190–1195, 2016
22. Brady JA, Hallow KM: Model-based evaluation of proximal
sodium reabsorption through SGLT2 in health and diabetes and
the effect of inhibition with canagliflozin. J Clin Pharmacol 58:
377–385, 2018
23. Thomas MC, Cherney DZI: The actions of SGLT2 inhibitors on
metabolism, renal function and blood pressure. Diabetologia 61:
2098–2107, 2018
24. Wang XX, Levi J, Luo Y, Myakala K, Herman-Edelstein M, Qiu L,
Wang D, Peng Y, Grenz A, Lucia S, Dobrinskikh E, D’Agati VD,
Koepsell H, Kopp JB, Rosenberg AZ, Levi M: SGLT2 protein
expression is increased in human diabetic nephropathy: SGLT2
protein inhibition decreases renal lipid accumulation,
CJASN 16: 1284–1291, August, 2021
inflammation, and the development of nephropathy in diabetic
mice. J Biol Chem 292: 5335–5348, 2017
25. Mather A, Pollock C: Glucose handling by the kidney. Kidney Int
Suppl 120: S1–S6, 2011
26. Ferrannini E: Sodium-glucose co-transporters and their inhibi-
tion: Clinical physiology. Cell Metab 26: 27–38, 2017
27. Pessoa TD, Campos LC, Carraro-Lacroix L, Girardi AC, Malnic
G: Functional role of glucose metabolism, osmotic stress, and
sodium-glucose cotransporter isoform-mediated transport on
Na1/H1 exchanger isoform 3 activity in the renal proximal
tubule. J Am Soc Nephrol 25: 2028–2039, 2014
28. Onishi A, Fu Y, Patel R, Darshi M, Crespo-Masip M, Huang W,
Song P, Freeman B, Kim YC, Soleimani M, Sharma K, Thomson
SC, Vallon V: A role for tubular Na1/H1 exchanger NHE3 in the
natriuretic effect of the SGLT2 inhibitor empagliflozin. Am J
Physiol Renal Physiol 319: F712–F728, 2020
29. Halperin ML, Cheema-Dhadli S: Renal and hepatic aspects of
ketoacidosis: A quantitative analysis based on energy turnover.
Diabetes Metab Rev 5: 321–336, 1989
30. Halperin ML, Vinay P, Gougoux A, Pichette C, Jungas RL: Reg-
ulation of the maximum rate of renal ammoniagenesis in the
acidotic dog. Am J Physiol 248: F607–F615, 1985
31. Palmer BF, Clegg DJ: Electrolyte and acid-base disturbances in
patients with diabetes mellitus [published correction appears in
N Engl J Med 381: 1598, 2019 10.1056/NEJMx190026]. N Engl J
Med 373: 548–559, 2015
32. Palmer BF, Clegg DJ: Electrolyte disturbances in patients with
chronic alcohol-use disorder. N Engl J Med 377: 1368–1377,
2017
33. Jang HS, Noh MR, Kim J, Padanilam BJ: Defective mitochondrial
fatty acid oxidation and lipotoxicity in kidney diseases. Front
Med (Lausanne) 7: 65, 2020
34. Kang HM, Ahn SH, Choi P, Ko YA, Han SH, Chinga F, Park AS,
Tao J, Sharma K, Pullman J, Bottinger EP, Goldberg IJ, Susztak K:
Defective fatty acid oxidation in renal tubular epithelial cells has
a key role in kidney fibrosis development. Nat Med 21: 37–46,
2015
35. Cai T, Ke Q, Fang Y, Wen P, Chen H, Yuan Q, Luo J, Zhang Y,
Sun Q, Lv Y, Zen K, Jiang L, Zhou Y, Yang J: Sodium-glucose
cotransporter 2 inhibition suppresses HIF-1a-mediated meta-
bolic switch from lipid oxidation to glycolysis in kidney tubule
cells of diabetic mice. Cell Death Dis 11: 390, 2020
36. Vinay P, Lemieux G, Cartier P, Ahmad M: Effect of fatty acids on
renal ammoniagenesis in in vivo and in vitro studies. Am J Physiol
231: 880–887, 1976
37. Sapir DG, Owen OE: Renal conservation of ketone bodies during
starvation. Metabolism 24: 23–33, 1975
38. Owen OE, Caprio S, Reichard GA Jr, Mozzoli MA, Boden G,
Owen RS: Ketosis of starvation: A revisit and new perspectives.
Clin Endocrinol Metab 12: 359–379, 1983
39. Desir G, Bratusch-Marrain P, DeFronzo RA: Effect of hyperke-
tonemia on renal ammonia excretion in man. Metabolism 35:
736–743, 1986
40. Sherwin RS, Hendler RG, Felig P: Effect of ketone infusions on
amino acid and nitrogen metabolism in man. J Clin Invest 55:
1382–1390, 1975
41. Lemieux G, Pichette C, Vinay P, Gougoux A: Cellular mecha-
nisms of the antiammoniagenic effect of ketone bodies in the
dog. Am J Physiol 239: F420–F426, 1980
42. Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Barsotti E, Clerico
A, Muscelli E: Renal handling of ketones in response to sodium-
glucose cotransporter 2 inhibition in patients with type 2 dia-
betes. Diabetes Care 40: 771–776, 2017
43. Yokono M, Takasu T, Hayashizaki Y, Mitsuoka K, Kihara R,
Muramatsu Y, Miyoshi S, Tahara A, Kurosaki E, Li Q, Tomiyama
H, Sasamata M, Shibasaki M, Uchiyama Y: SGLT2 selective
inhibitor ipragliflozin reduces body fat mass by increasing fatty
acid oxidation in high-fat diet-induced obese rats. Eur J Phar-
macol 727: 66–74, 2014
44. Mathieu C, Dandona P, Gillard P, Senior P, Hasslacher C, Araki
E, Lind M, Bain SC, Jabbour S, Arya N, Hansen L, Thoren F,
Langkilde AM; DEPICT-2 Investigators: Efficacy and safety of
dapagliflozin in patients with inadequately controlled type 1
diabetes (the DEPICT-2 study): 24-week results from a random-
ized controlled trial. Diabetes Care 41: 1938–1946, 2018
Euglycemic Ketoacidosis, Palmer and Clegg 1291
45. Rosenstock J, Marquard J, Laffel LM, Neubacher D, Kaspers S,
Cherney DZ, Zinman B, Skyler JS, George J, Soleymanlou N,
Perkins BA: Empagliflozin as adjunctive to insulin therapy in type
1 diabetes: The EASE trials. Diabetes Care 41: 2560–2569, 2018
46. Garg SK, Henry RR, Banks P, Buse JB, Davies MJ, Fulcher GR,
Pozzilli P, Gesty-Palmer D, Lapuerta P, Simo  R, Danne T,
McGuire DK, Kushner JA, Peters A, Strumph P: Effects of sota-
gliflozin added to insulin in patients with type 1 diabetes. N Engl
J Med 377: 2337–2348, 2017
47. Wolfsdorf JI, Ratner RE: SGLT inhibitors for type 1 diabetes:
Proceed with extreme caution. Diabetes Care 42: 991–993,
2019
48. Patel NS, Van Name MA, Cengiz E, Carria LR, Weinzimer SA,
Tamborlane WV, Sherr JL: Altered patterns of early metabolic
decompensation in type 1 diabetes during treatment with a
SGLT2 inhibitor: An insulin pump suspension study. Diabetes
Technol Ther 19: 618–622, 2017
49. Burke KR, Schumacher CA, Harpe SE: SGLT2 inhibitors: A sys-
tematic review of diabetic ketoacidosis and related risk factors in
the primary literature. Pharmacotherapy 37: 187–194, 2017
50. Herring RA, Shojaee-Moradie F, Garesse R, Stevenage M, Jack-
son N, Fielding BA, Mendis A, Johnsen S, Umpleby AM, Davies
M, Russell-Jones DL: Metabolic effects of an SGLT2 inhibitor
(Dapagliflozin) during a period of acute insulin withdrawal and
development of ketoacidosis in people with type 1 diabetes.
Diabetes Care 43: 2128–2136, 2020
51. Palmer BF, Clegg DJ: Salicylate toxicity. N Engl J Med 382: 2544–
2555, 2020
52. Fadini GP, Bonora BM, Avogaro A: SGLT2 inhibitors and dia-
betic ketoacidosis: Data from the FDA adverse event reporting
system. Diabetologia 60: 1385–1389, 2017
53. Marinou K, Adiels M, Hodson L, Frayn KN, Karpe F, Fielding BA:
Young women partition fatty acids towards ketone body pro-
duction rather than VLDL-TAG synthesis, compared with young
men. Br J Nutr 105: 857–865, 2011
54. Hedrington MS, Davis SN: Sexual dimorphism in glucose and
lipid metabolism during fasting, hypoglycemia, and exercise.
Front Endocrinol (Lausanne) 6: 61, 2015
55. Davis SN, Galassetti P, Wasserman DH, Tate D: Effects of gender
on neuroendocrine and metabolic counterregulatory responses
to exercise in normal man. J Clin Endocrinol Metab 85: 224–230,
2000
56. Palmer BF, Clegg DJ: The sexual dimorphism of obesity. Mol Cell
Endocrinol 402: 113–119, 2015
57. Erondu N, Desai M, Ways K, Meininger G: Diabetic ketoacidosis
and related events in the canagliflozin type 2 diabetes clinical
program. Diabetes Care 38: 1680–1686, 2015
58. Sampani E, Sarafidis P, Papagianni A: Euglycaemic diabetic
ketoacidosis as a complication of SGLT-2 inhibitors: Epidemi-
ology, pathophysiology, and treatment. Expert Opin Drug Saf 19:
673–682, 2020
59. Kobayashi S, Maesato K, Moriya H, Ohtake T, Ikeda T: Insulin
resistance in patients with chronic kidney disease. Am J Kidney
Dis 45: 275–280, 2005
60. Perry RJ, Rabin-Court A, Song JD, Cardone RL, Wang Y, Kibbey
RG, Shulman GI: Dehydration and insulinopenia are necessary
and sufficient for euglycemic ketoacidosis in SGLT2 inhibitor-
treated rats. Nat Commun 10: 548, 2019
61. US Food and Drug Administration: FDA approves label changes
to SGLT2 inhibitors regarding temporary discontinuation of
medication before scheduled surgery. Available at: https://www.
fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-
sglt2-inhibitors-diabetes-include-warnings-about-too-much-
acid-blood-and-serious. Accessed March 23, 2020
62. Yehya A, Sadhu A: Sodium-glucose cotransporter 2 inhibitor-
associated prolonged euglycemic diabetic ketoacidosis in type 2
diabetes: A case report and literature review. Clin Diabetes 38:
112–116, 2020
63. Iqbal I, Hamid M, Khan MAA, Kainat A, Tariq S: Dapagliflozin-
induced late-onset euglycemic diabetic ketoacidosis. Cureus 11:
e6089, 2019
Published online ahead of print. Publication date available at
www.cjasn.org.