個案報告

Empagliflozin Related to Ketoacidosis and Early Neurological Deterioration in a Patient with Acute Ischemic Stroke

Empagliflozin Related to Ketoacidosis and Early

Neurological Deterioration in a Patient with
Acute Ischemic Stroke
Shin-Yi Lin1, 2, Chih-Fen Huang1, 2, Sung-Chun Tang3, Jiann-Shing Jeng3
1
Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan.
2
School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
3
Stroke Center and Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.

ABSTRACT
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are new class of anti-diabetic agents and display
benefits in cardiovascular protection. SGLT2i are recommended as part of a glucose-lowering regimen
among type 2 diabetic patients with established cardiovascular disease. Nevertheless, the side effect of
euglycemic diabetic ketoacidosis (euDKA) should not be overlooked, especially among patients with acute
illness or impaired oral intake. We present the case of a 66-year-old woman admitted for acute ischemic
stroke over the right pontine who had used empagliflozin 25 mg daily and metformin 850 mg twice daily
to treat hyperglycemia, and developed euDKA and early neurological deterioration after 3 days. From the
data of large-scale clinical trials, the benefit of empagliflozin in stroke is controversial, but their effects of
osmotic diuresis, lowered blood pressure, and hemoconcentration can be thwarted during an acute stroke.
Carefully evaluating the proper time to start therapy and closely monitoring the symptoms of euDKA is
important.

Keywords: ischemic stroke, sodium-glucose cotransporter-2 inhibitor, euglycemic diabetic ketoacidosis

empagliflozin, diabetes mellitus.

INTRODUCTION hypoglycemia and β cell overstimulation. Several

Sodium-glucose cotransporter-2 inhibitors
(SGLT2i), including empagliflozin, canagliflozin,
and dapagliflozin, are one of the latest class of
anti-diabetic agents. They inhibit the SGLT2
in the proximal renal tubule, prevent glucose
reabsorption, and further reduce serum glucose.
The mechanism of SGLT2i does not affect
insulin secretion, hence they lower the risk of
large-scale trials have proved the cardiovascular
benefits of SGLT2i among diabetic patients with
preexisting cardiovascular diseases. 1-4 Further,
meta-analysis showed SGLT2i significantly
reduced major adverse cardiovascular events (i.e.,
the composite of myocardial infarction, stroke or
cardiovascular death), hospitalization for heart
failure, and progression on kidney disease.5 In the
guidelines of the American Diabetes Association

Corresponding author: Dr. Sung-Chun Tang, Department of Neurology, National Taiwan University Hospital, No. 7, Chung-
Shan South Road, Taipei 100, Taiwan.
E-mail: tangneuro@gmail.com
DOI: 10.6318/FJS.202103_3(1).0005

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 Empagliflozin Related to Ketoacidosis and Early Neurological Deterioration in a Patient with Acute Ischemic Stroke
released in 2021, an SGLT2i is recommended as
part of glucose-lowering regimen among type 2
daibetic patients with established atherosclerotic
cardiovascular disease, defined as coronary heart
disease, cerebrovascular disease or peripheral
arterial disease of atherosclerotic origins or kidney
6
disease.
The reduction in serum glucose levels
due to SGLT2i therapy forces cells to shift the
metabolism to enhanced fatty acid oxidation and
lipolysis, which further increases the production of
ketone bodies. Ketone bodies are a more efficient
energy source for the myocardium compared to
adenosine triphosphate, which is the proposed
mechanism behinds the cardiovascular benefits of
the SGLT2i. However, the increased production
of ketone bodies causes the notoriously adverse
effect of diabetic ketoacidosis (DKA), especially in
patients undergoing major surgery.7-9 In 2015, the
Food and Drug Administration released a warning
for SGLT2i related to ketoacidosis and suggested
that SGLT2i should be temporarily stopped 3 to 4
days before an operation.10 We present the case of a
patient admitted for an acute ischemic stroke who
had used empagliflozin to treat hyperglycemia and
later developed ketoacidosis and early neurological
deterioration.
CASE REPORT
A 66-year-old female who had hypertension
and type 2 diabetes presented to the emergency
department due to a sudden onset of left-side limb
weakness, slurred speech, and left-side facial
dropping. Before admission, she did not take
any regular medications. Upon hospital arrival,
her blood pressure was 201/75 mmHg and the
National Institute of Health Stroke Scale (NIHSS)
scored 5 points. After excluding an intracerebral
hemorrhage by head computed tomography (CT),
0.9 milligrams per kilogram (mg/kg) alteplase
(rtPA) was administered. The CT angiography and
perfusion imaging right after the bolus injection
of rtPA showed multifocal stenosis of the basilar
artery and intracranial vertebral arteries (Figure
1A) and impaired perfusion over bilateral posterior
circulation. After rtPA therapy, the NIHSS
was stationary at 5 points. The brain magnetic
resonance imaging (MRI) on day (D) 2 showed a
recent right pontine infarction, and the NIHSS was
6 points. The blood pressure after rtPA therapy was
maintained below 180/105 mmHg with intermittent
nicardipine infusion, ranging from 138/59 to
175/63 mmHg.
The patient’s random glucose level at
emergency department was 300 milligrams per
deciliter (mg/dL) and the glycated hemoglobin
(HbA1C) was 9.8%. Despite a regular insulin
(RI) sliding scale that was implemented right
after admission, the glycemic control was still
sub-optimal, as depicted in Figure 2. Therefore,
850 milligrams (mg) of metformin twice daily
and 25 mg of empagliflozin daily were added on
top of the RI sliding scale from D3 after stroke.
Feeding through a nasogastric tube was also
started on D3, but her digestion was poor. During
D3 to D5, she had repeated vomiting. Therefore,
food was prohibited (nothing by mouth, NPO) on
D5. In addition, her consciousness level became
drowsy and her responses were slow. A gradual
deterioration in muscle power of the left limbs was
also noted. The NHISS on D3 was 6 points, but it
deteriorated to 7 points at D4 evening. The blood
pressure did not change a lot, with systolic pressure
ranging from 147 to 180 mmHg. Non-contrast
brain CT was arranged on D4, which showed no
new lesion. Hydration with hydroxyethylstarch
was administered, and the NIHSS reduced to 5
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 Empagliflozin Related to Ketoacidosis and Early Neurological Deterioration in a Patient with Acute Ischemic Stroke

Fig. 1. The CT angiography on D1 showed multifocal stenosis of the basilar artery and intracranial vertebral
arteries (A, arrow). A brain MRI on D2 showed a recent right pontine infarction (B, arrow). A
follow-up brain MRI on D10 showed multiple infarcts in the bilateral pons (C, arrow) and posterior
cerebral artery territory (D, arrow).

points on D5. In addition, an infection associated 1B).

with consciousness disturbance was suspected,
hence ampicillin/sulbactam was added on the
same day. Nevertheless, the drowsy consciousness
persisted. On D6, the muscle power of the left
limbs further deteriorated. She could barely move
her left upper limb, and the NIHSS increased to 28
points at noon. In addition, reduced blood pressure
was also noted, with systolic pressure around 120
mmHg. Emergent brain CT angiography disclosed
no large artery occlusion, but there was still multi-
focal stenosis in the vertebrobasilar arteries (Fig.
A laboratory check on D6 showed profound
metabolic acidosis [pH = 7.04; bicarbonate (HCO3−)
= 4.6 millimolars per liter (mM/L); partial pressure
of carbon dioxide (PCO2) = 17.5 millimeters of
mercury (mmHg) and partial pressure of oxygen
(PO 2 ) = 153.1 mmHg, base excess −26] and
positive blood ketones (6.7 mmol/L). The serum
glucose did not elevate initially (194 mg/dL).
Acute kidney injury and electrolyte imbalance
were also noted, but the lactate level was within
normal range. Her blood pressure further dropped

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Empagliflozin Related to Ketoacidosis and Early Neurological Deterioration in a Patient with Acute Ischemic Stroke

Fig. 2. The laboratory test and medication use.

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 Empagliflozin Related to Ketoacidosis and Early Neurological Deterioration in a Patient with Acute Ischemic Stroke
to 86/54 mmHg in the afternoon. Empagliflozin-
related euglycemic diabetic ketoacidosis (euDKA)
was considered. Therefore, oral antihyperglycemic
agents were discontinued and norepinephrine
pump was initiated for shock. An intravenous RI
infusion and hydration with a glucose solution
were administered for euDKA treatment, therefore
elevated blood sugar was noted. Other supportive
care included electrolyte supplements to correct
an imbalance. Atrial fibrillation with a rapid
ventricular rate occurred almost at the same time
that euDKA was diagnosed. On the night of D6,
pulseless ventricular tachycardia developed. After
directed cardioversion, prophylactic endotracheal
intubation was performed with mechanical
ventilator support. The patient stabilized gradually
after treatment. The NIHSS recovered to 23+X
(with endotracheal tube), and the systolic pressure
returned to 130 to 150 mmHg. Norepinephrine
pump was discontinued soon on D7.
Regarding the antithrombotic agents after
ischemic stroke, aspirin was started on D2 but
was changed to enoxaparin from D5 due to the
concern of an early neurological deterioration and
cardiac embolism. A follow-up brain MRI on D10
showed multiple infarcts in the bilateral pons and
posterior cerebral artery territory (Figure 1C, 1D).
The NIHSS kept reducing to 19+X points, with
stationary blood pressure ranging from 140 to 170
mmHg for systolic pressure and 60 to 80 mmHg
for diastolic pressure. Enoxaparin was shifted to
apixaban for stroke prevention. After passing the
respiratory training, the endotracheal tube was
removed on D15. The patient was transferred to
the ordinary ward on D17. Figure 2 depicted the
change of serum glucose, laboratory tests and
antihyperglycemic therapy during the course.
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DISCUSSION
We presented a case of initiating empagliflozin
for diabetes treatment during NPO status after
acute ischemic stroke, and suffered from euDKA
and early neurological deterioration. The diagnosis
for euDKA was difficult, and several differential
diagnoses to cause metabolic acidosis should be
considered, such as metformin associated lactic
acidosis, acute kidney injury and sepsis. 11 The
existence of mixed lactic acidosis can be excluded
by normal lactate level. But the contribution for
acute kidney injury and sepsis were unable to be
determined. Taking into the specific pattern of non-
obviously elevated glucose level, acute illness
with poor oral intake, and history of empagliflozin
therapy, we believe SGLT2i associated euDKA was
an important precipitating factor for the occurrence
of metabolic acidosis.10, 12
As mentioned before, the beneficial effects of
SGLT2i in reducing major adverse cardiovascular
events makes it a promising selection among
patients with atherosclerotic cardiovascular
disease.1-3, 13 Nevertheless, the “stroke paradox”
w i t h S G LT 2 i h a s b e e n r e p o r t e d . 1 4 I n T h e
Empagliflozin Cardiovascular Outcome Event Trial
in Type 2 Diabetes Mellitus Patients–Removing
Excess Glucose (EMPA-REG OUTCOME)
study, a non-significant increase in stroke risk
was observed, with 3.5% in empagliflozin group
compared to 3.0% in placebo group, the hazard
ratio was 1.18 (0.89-1.56).3 Similar result was
reported in meta-analysis: SGLT2i significantly
increased non-fetal stroke risk, with a relative risk
of 1.30 (1.00-1.68) comparing to placebo.15 The
mechanism behind SGLT2i to increase stroke was
not clear. Currently, there was no clear evidence
to link bodyweight lowering and blood pressure
reduction with elevated stroke risk. One possible
 Empagliflozin Related to Ketoacidosis and Early Neurological Deterioration in a Patient with Acute Ischemic Stroke
explanation maybe the hemoconcentration caused
16
by SGLT2i via osmotic diuresis. In the EMPA-
REG study, empagliflozin group had increased
hematocrit, from 43.8 to 45.9% during 26-week of
treatment, as compared to reduced hematocrit in
placebo group (43.4 to 42.9%).3 The association
between hematocrit elevation and increased
risk of stroke has been reported in previous
investigations.17 For our patient, the hematocrit
did not increase obviously before the occurrence
of euDKA. To the contrast, due to aggressive
hydration, the hematocrit reduced after euDKA.
Nevertheless, from her blood urea nitrogen to
serum creatinine ratio, and the bodyweight change,
dehydrated status may exist after admission, which
may be one of the contributing factors for early
neurological deterioration.
The common adverse effects of SGLT2i
includes genitourinary infection, dehydration, and
8,
ketoacidosis, which should not be overlooked.
10
The SGLT2i-associated ketoacidosis is usually
euglycemic, defined as diabetic ketoacidosis
without a prominent elevation in glucose. In
most cases, the glucose level does not exceed
250 mg/dL. The most common presentations for
SGLT2i-associated euDKA are nausea, vomiting,
and abdominal pain. Other less frequent clinical
findings include altered mental state, tachycardia
or tachypnea, diarrhea, and general malaise.
Laboratory findings include positive urine ketones,
serum ketones, acidemia, and a positive anion gap.
To confirm euDKA, serum ketones (rather than
8,
urine ketones) and blood gas should be checked.
10
From our case, the clinical signs and symptoms,
and laboratory data were quite complied with the
typical presentation of euDKA. The glucose level
elevated mildly to around 200 mg/dL, with positive
blood ketones, gastrointestinal symptoms, and
altered mental status. The management of SGLT2i
associated euDKA is mainly supportive, includes
promptly discontinuation of SGLT2i, correction
of fluid status and electrolyte imbalance, insulin
therapy, and treatment of metabolic acidosis with
bicarbonates.16
The etiology behind SGLT2i-associated
euDKA is not only related to the increased
production of ketone bodies but also reduced
excretion. 8 SGLT2i reduce serum glucose by
around 20 mg/dL, which leads to a decrease
in insulin production by the β cells and further
stimulate α cells to increase glucagon production.
Glucagon stimulates hepatic ketoacidosis and
increases the production of ketone bodies. SGLT2i
also reduce the renal clearance of ketone bodies.7, 8
Precipitating factors for euDKA include poor oral
intake, major surgery, and stressful situations.12
Fasting status also increases the production of
ketone bodies. Acute illness increases insulin
requirement. However, the reduced serum glucose
level due to SGLT2i therapy masks the true need
for insulin requirement in stressful conditions. The
risk for euDKA increases.7, 8 For our present case,
empagliflozin was used during an acute stroke and
NPO status, both of which were risk factors for
developing euDKA.
The occurrence of early neurological
deterioration for this case could not be fully
attributed to empagliflozin treatment, because
the patient’s posterior circulation vasculature
was quite poor. For our present case, adequate
hydration and permissive hypertension to
maintain cerebral perfusion pressure were crucial,
especially during acute stroke stage.18 Treatment
with empagliflozin caused osmotic diuresis by
increasing urine glucose levels and putting the
patient at risk of dehydration.7, 9 Most importantly,
the euDKA was not promptly diagnosed despite
some typical presentations such as vomiting and
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 Empagliflozin Related to Ketoacidosis and Early Neurological Deterioration in a Patient with Acute Ischemic Stroke
general malaise, mainly due to non-prominent
hyperglycemia. The arrhythmia that occurred
during euDKA development may be related to
electrolyte imbalance and acidemia. Whether the
atrial fibrillation was long standing or transient
due to complications of euDKA could not be
concluded.
In conclusion, physicians should carefully
evaluate the proper time to start SGLT2i. The
SGLT2i may be avoided in patients who are in
an acute stage of stroke, especially those with
8, 10
impaired oral intake or enteral feeding.
patients start receiving the drug, physicians
should be aware of euDKA and patients should
be monitored for it. Once euDKA develops,
promptly interrupting SGLT2i therapy and starting
management are important.
ACKNOWLEDGMENTS
We acknowledge the support from Department
of Pharmacy, National Taiwan University Hospital
(NTUH) and Stroke Center and Department of
Neurology, NTUH for the support of this case
report. We also acknowledge BOLDFACEeditors
for the language editing.
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SGLT2 inhibitor. N Engl J Med 2017;376(23):
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 Empagliflozin Related to Ketoacidosis and Early Neurological Deterioration in a Patient with Acute Ischemic Stroke

第二型鈉－葡萄糖轉運蛋白抑制劑相關的酮酸中毒
和早期神經功能惡化：急性缺血中風單一個案報告

林欣儀 1, 2、黃幟芬 1, 2、湯頌君 3、鄭建興 3

1
台大醫院藥劑部、 2台灣大學醫學院藥學系、 3台大醫院神經部暨腦中風中心

摘　要
第二型鈉－葡萄糖轉運蛋白(sodium-glucose cotransporter-2〔SGLT2〕)抑制劑已證實能夠改善
心血管疾病相關預後，因此是糖尿病合併心血管疾病患者的建議用藥之一。然而，在急性疾病或進
食不佳的病人，使用SGLT2抑制劑可能導致正常血糖之酮酸中毒症。本文探討一位66歲女性病人因
急性中風入院，在加護病房照護期間選用SGLT2抑制劑作為血糖控制藥物，卻誘發正常血糖之酮酸
中毒症以及早期神經功能惡化的案例。事實上，SGLT2抑制劑並不能顯著降低中風的發生，但其藥
理機轉導致的滲透壓性利尿與降低血壓等作用可能在中風急性期造成症狀的惡化。因此在急性中風
病人應審慎評估開始使用SGLT2抑制劑的時機，並密切監測正常血糖之酮酸中毒症相關症狀。

關鍵詞：缺血中風、第二型鈉－葡萄糖轉運蛋白抑制劑、糖尿病酮酸中毒

通訊作者：湯頌君醫師　台大醫院神經部暨腦中風中心
E-mail: tangneuro@gmail.com

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