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American Journal of  
Chemistry and Pharmacy (AJCP)

Empagliflozin-Induced Acute Pancreatitis and Euglycemic Diabetic 
Ketoacidosis in Type 2 Diabetes Mellitus

Yasser Sadawey1*, Hesham Metwally2

Volume 1 Issue 2, Year 2022
ISSN: 2834-0116 (Online)

DOI: https://doi.org/10.54536/ajcp.v1i2.747
https://journals.e-palli.com/home/index.php/ajcp

Article Information ABSTRACT

Received: October 11, 2022

Accepted: October 19, 2022

Published: October 23, 2022

Acute pancreatitis and euglycemic DKA, EDKA, are uncommon but potentially fatal com-
plications in diabetic patients on sodium-glucose cotransporter 2 inhibitors (SGLT2). This 
case report presents the exceptional occurrence of  a 49-year-old; male patient diagnosed 
with empagliflozin-induced EDKA coupled with T2DM as a precursor to acute pancreatitis. 
Euglycemic DKA may be produced after administering just one dose of  SGLT2. On dis-
charge, empagliflozin was managed to stop. Since the initial administration of  SGLT2, this 
diagnosis should be considered a potential consequence. Appropriate medical treatment is 
made possible by diagnosing and treating this life-threatening condition promptly.Keywords

Diabetic Ketoacidosis, Euglycemic 
DKA, Sodium-Glucose 
Cotransporter-2, Empagliflozin, 
Type 2 Diabetes Mellitus, 
Pancreatitis.

1 Department of  Medicine, Mediclinic ME, Al Jowhara Hospital, AL Ain, UAE
2 Department of  Radiology, Mediclinic ME, Al Jowhara Hospital, AL Ain, UAE
* Corresponding author’s e-mail: Dr.yassersadawey@gmail.com

INTRODUCTION
The clinical trifecta of  metabolic acidosis, hyperglycemia, 
and elevated ketone bodies in the urine and blood is 
known as diabetic ketoacidosis (DKA). Euglycemic DKA 
(EDKA) is the precursor to a particular group of  people 
whose blood glucose levels are between normal ranges 
(Nyenwe & Kitabchi, 2016). At the presentation time, 
37 out of  211 DKA patients had normal blood sugar 
levels (300 mg/dL) and a plasma bicarbonate level of  10 
mmol/L. Munro et al. (1973) were the first to document 
this phenomenon. Normoglycemia was interpreted as 
less than 250 mg/dL. Thus, when serum glucose levels 
are below 250 mg/dL, EDKA is described as a trifecta 
that includes high anion gap metabolic acidosis with 
positive urine and serum ketones (Kitabchi et al., 2009). 
One of  the most recent classes of  oral drugs for the 
treatment of  T2DM has been legalized, and it is called 
sodium-glucose cotransporter-2 (SGLT-2) inhibitors. 
They may be administered to these patients alone or with 
other medications. They prevent glucose reabsorption 
in the proximal renal tubule, which lowers blood sugar 
levels (Sarafidis et al., 2019). The US Food and Drug 
Administration (FDA) officially warned patients using 
these medications in 2015 that they are at an elevated 
risk of  developing DKA with unusually mild to moderate 
glucose spike, or EDKA (Do, n.d.). Therefore, the 
present case report explores the rare presentation of  
empagliflozin-induced euglycemic DKA, (EDKA) and 
acute pancreatitis in a patient with T2DM just 6 days after 
empagliflozin introduction. 

Abbreviations
DKA=Diabetic ketoacidosis, EDKA=euglycemic DKA, 
SGLT-2=Sodium-glucose cotransporter-2, FDA= 

Food and Drug Administration, VBG=Venous Blood 
Gas, CVA=Cerebral Vascular Accident, HDU=High 
Dependency Unit, CT= Computed Tomography

METHODOLOGY    
Case Presentation
A presentation from a 49-year-old man nonsmoker 
with a 5-year medical history and worsening type 2 
diabetes mellitus due to poor compliance was made to 
the Mediclinic Al Jowhara Hospital in the United Arab 
Emirates. Additionally, he had three days’ history of  
upper abdominal pain, nausea, and vomiting. He denies 
fever, loose motion, melena, cough, or headache. Six 
days before the presentation, he suffered from CVA with 
residual right-sided weakness. During his admittance, he 
was initiated on Aspirin, clopidogrel, Atorvastatin 40mg, 
Lisinopril 5mg, Linagliptin/Metformin 5mg/1000mg 
once, and Empagliflozin 25mg. 
The initial observational analysis revealed that he was 
tachypneic but otherwise vitally normal. Other vital 
signs include his RBG as 11.1 mmol/L, dry mucous 
membranes, but normal capillary refill time. Additionally, 
on clinical assessment, there was right lower limb’s minor 
motor impairment, intact sensory functions, normal 
reflexes, and normal cranial and cerebellar functions were 
notable. His venous blood gases (VBG) represented pH 
7.121, HCO3 9.6 mmol/L, pCO2 25.4 mmHg, Lactate 
2.1 mmol/L, Na 128 mmol/L, Cl 101 mmol/L, and K 5.2 
mmol/L and urine showed ketone +3 suggestive of  high 
Anion gap (17.4), severe metabolic ketoacidosis and his 
HbA1C was 8.1%. The patient’s lipase and amylase were 
elevated at 440 U/L and 354 U/L, respectively, compatible 
with acute pancreatitis (Table 1). ECG assessment was 
reported normal, as well as chest X-ray and Abdominal 

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Figure 1: Axial and coronal CT images in venous phase showing minimal peripancreatic fat stranding around the 
head and body as early features of  pancreatitis. No peripancreatic fluid.

Ultrasound. Abdomen CT showed mild enlargement of  
pancreatic head with subtle peri-pancreatic fat stranding, 
a picture of  mild pancreatitis.
The patient was admitted to HDU for management of  
EDKA, Linagliptin/Metformin, empagliflozin were held, 
and intravenous fluids and insulin infusion were initiated 
with repeated VBG every 2 hours. His pH normalized, 
ketonuria improved, and the Anion gap closed. He made 
a good recovery with normalizing pancreatic enzymes 

and improved symptoms. Once he could tolerate normal 
oral intake, he shifted to Sitagliptin/Metformin 100/1000 
mg and gliclazide 120 mg. After dietary consultation and 
education, he was discharged. Upon follow-up visits, he 
was clinically stable, tolerating his medications with good 
glycemic control, and his HbA1C became 6.2%. Using 
the Naranjo algorithm of  adverse drug reactions, we 
concluded that empagliflozin was the most likely culprit 
for his pancreatitis.

Table 1: Initial and follow up laboratory values
Parameters Initial Day1 Day 2 On Discharge
Venous pH (7.36–7.44) 7.121 7.224 7.36 7.439
Serum bicarbonate (21–28 mmol/L) 9.6 11.6 19.2 25.7
pCO2 (35-45mmHg) 25.4 22.5 33 39.9
Serum lactate (0.5–1.4 mmol/L) 2.1 1.7 1.6 1.7
Serum sodium (135–145 mEq/L) 128 132 134 134
Chloride (98–107 mmol/L) 101 108 103 99
Serum potassium (3.5–5.0 mmol/L) 5.2 5.7 4.1 3.8
Anion gap (8–16 mmol/L) 17.4 12.4 11.8 9.3
Urine ketone (negative) +++ ++ + - ve
HbA1C (%) 8.1 
Lipase (0-160U/L) 440 U/L 117 110
Amylase (23–85 U/L) 354U/L 123 78

DISCUSSION
DKA occurs in 1.34/million T2D patients annually 
(Jensen et al., 2017). In contrast, it is unknown how 
often euglycemic DKA will occur. The uncommon 
occurrence of  euglycemic DKA may cause a deferment 
in care and prognosis, which might have significant or 
fatal consequences(Calçada et al., 2021). A recent family 
of  anti-diabetic medications known as SGLT2 inhibitors 
(empagliflozin, canagliflozin, and dapagliflozin) increases 
the likelihood of  euglycemic DKA discrete to the 
length of  treatment (Peters et al., 2015; Somagutta et 
al., 2021; Taylor et al., 2015). However, the prevalence 
of  EDKA increased after the introduction of  sodium-

glucose transporter 2 (SGLT2) inhibitors in some rare 
cases. Although there have been few reports of  DKA in 
SGLT2i investigations, the precise numbers of  EDKA 
events have not been evaluated (Wibawa et al., 2021). The 
results of  another trial,“the EMPA-REG OUTCOME 
(Empagliflozin Cardiovascular Outcome Event Trial 
in Type 2 Diabetes Mellitus Patients-Removing Excess 
Glucose)” study, revealed that DKA occurs less frequently 
than 0.1% of  the duration (Rosenstock, 2015; Sampani et 
al., 2020). Rates of  DKA-related occurrences among type 
2 diabetic patients on SGLT2 inhibitors ranged from 0.16 
to 0.76 events per 1000 patient years (Goldenberg et al., 
2016).SGLT2 inhibitors raise the risk of  DKA in T2D 

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patients by seven times (Blau et al., 2017). According to 
other studies, SGLT2i improves beta cells in the pancreas, 
increasing lipolysis and raising the concentration of  
ketone bodies (da Silva et al., 2018). They have also been 
indicated to activate the pancreatic alpha cells, triggering 
glucagon production and inducing an imbalance in 
insulin and glucagon level (Candelario & Wykretowicz, 
2016; Pfützner et al., 2017).
The patient, in this case, presented with acute pancreatitis 
while taking prescribed empagliflozin, and there was no 
known cause of  pancreatitis, such as gallstones or alcohol 
consumption. The development of  pancreatitis with 
regular exposure to the medication and the symptom 
treatment response after withdrawal make empagliflozin 
a plausible cause of  pancreatitis. The molecular basis of  
pancreatitis caused by empagliflozin is unidentified. It is 
an unusual reaction similar to previous cases of  drug-
induced pancreatitis because of  the immunologic or 
cytotoxicity effects the drug or its metabolites have on 
the body. 

CONCLUSION
The FDA’s warning is supported by multiple pieces 
of  literature that detail many physiologically tenable 
possibilities for negative consequences of  SGLT2 
(empagliflozin) inhibitor. The preponderance of  the 
data supports the causative involvement of  SGLT2 
inhibitors in the pathogenesis of  acute pancreatitis and 
EDKA. Therefore, SGLT-2 inhibitor initiation should be 
avoided in acute conditions. Since normoglycemia might 
mask the presence of  acidosis, medical professionals 
should be aware of  this diagnosis and immediately begin 
therapy. Given the nature of  the disease, EDKA should 
be retained in the differential even if  it is rare. Patients 
should be informed about negative consequences and 
stimuli to prevent recurrences.

Acknowledgement
The authors are grateful to the Mediclinic Al Jowhara 
Hospital for their consistent support throughout the 
research.

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