Empagliflozin induced diabetes ketoacidosis: a review of literature

doi:10.21203/rs.3.rs-1505037/v1

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Empagliflozin induced diabetes ketoacidosis: a review of literature

https://doi.org/10.21203/rs.3.rs-1505037/v1

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Background

Sodium-Glucose Co-Transporter 2 inhibitors have been proven to have positive effects on blood glucose control and decrease major atherosclerosis cardiac and renal outcomes. Diabetic ketoacidosis and genitourinary infections are two major side effects of this class. Hyper-, normo- or hypoglycemic diabetic ketoacidosis has been reported with SGLT2is. In this study, we report two cases of empagliflozin-associated diabetic ketoacidosis (DKA).

Aim

in this narrative review we summarized cases of Sodium-Glucose Co-Transporter 2 inhibitors associated diabetes ketoacidosis. First, we described two cases of empagliflozin induced diabetes ketoacidosis.

Method

Databases including PubMed, Scopus, Cochrane library, and Google scholar were searched for eligible reports during February 2022.

Results

A review on etiology, signs, symptoms, laboratory data, and treatments for diabetic ketoacidosis associated sodium glucose transporter 2 inhibitors are provided here.

Conclusion

Early recognition, good past medical history taking, discontinuation before/during invasive procurers and acute illness, appropriate fluid and insulin replacement therapy are cornerstones of treatment.

Diabetic ketoacidosis

Sodium-Glucose Transporter 2 Inhibitors

Risk factors

Presentations

Management

The SGLT2is are responsible for 6.6% of all cases of the DKA
The SGLT2is associated DKA may be severe and life-threatening
The SGLT2is should be discontinued 24-72 hours before planed surgeries and in acute illness

Sodium glucose cotransporter 2 inhibitors (SGLT2is) are a group of medications that inhibit glucose reuptake in the S1 segment of proximal tubule and pancreatic alpha cells [1]. In the normal conditions, only 500 mg from 180 g daily filtered glucose is excreted in urine [2]. Sodium glucose cotransporter is responsible for 90% of glucose reabsorption in the kidney [2]. However, following the use of SGLT2is up to 50% (90g) of filtered glucose (180g) was excreted in urine per day [3]. SGLT2is lowers blood glucose, HgbA1c, blood pressure, sympathetic activities, inflammation, body weight, and plasma volume [4, 5]. Cardiovascular benefits of the SGLT2is were medicated through the preload reduction, natriuresis, sodium/hydrogen exchange inhibition, reducing cardiac necrosis or fibrosis, and lower inflammatory cytokines [6, 7]. These agents reduced the risk of cardiovascular, renal events, cerebrovascular events, heart failure exacerbation, and death [8]. They also reduced all causes of mortality, cardiovascular mortality, hospitalization, myocardial infarction, and renal events in patients with diabetes [9]. The recent ESC guidelines recommend SGLT2is along with angiotensin blockers, beta-blockers, and aldosterone antagonists for patients with heart failure with a decreased ejection fraction [10]. In addition, a recent meta-analysis suggested that empagliflozin can be the best option for patients with cardiovascular diseases in order to decrease renal and cardiac outcomes [11]. However, this group can increase the risk of diabetes ketoacidosis (DKA) genital infections [10]. The most recent UK guidelines for diagnosis and management of diabetes ketoacidosis defined the DKA as having diabetes mellitus or blood sugar (BS) > 11 mmol/l (198mg/dl), positive serum (> 3.0 mmol/L) or urine ketone (2 + or higher), and acidosis (either pH < 7.3 or bicarbonate < 15 mmol/l) [12].

Case 1

A 72-year-old diabetic patient who had been diagnosed with diabetes 20 years ago was brought to the emergency department with severe malaise and a decreased level of consciousness. Her blood sugar was partially controlled by glyburide (5 mg twice daily), metformin (500 mg twice daily), and empagliflozin (10 mg/day) combination regimen (fasting blood sugar < 110-180 mg/dl, HgA1c = 7.5%). The later was introduced 2 months before hospitalization by the patient without prescription (self-prescription). Three days before hospitalization, the patient experienced malaise, nausea, two episodes of vomiting, and one episode of diarrhea. She reported having a poor intake for three days. The malaise was deteriorated her disease and she was brought to the emergency department with decreased consciousness and severe malaise. During the initial examination, the patient was found paled. However, no polyuria, kussmaul sign, abdominal tenderness, fever, shivering, and hypotension was observed in the early examination in the emergency department. All the oral antihyperglycemic agents were discontinued and the patient was transferred to the Intensive Care Unit (ICU). Although, the initial vital signs were BP=110/70 mmHg, PR:100/min, RR:23 beats/min, O2 saturation: 98%, T:37.3 C., the patient developed hypotension and tachycardia (80/50 mmHg, HR 120 /min). So, she was transferred to the ICU. The initial significant lab data were as follows: blood sugar (BS) = 250 mg/dl, pH = 6.94, PCO₂: 18.5 mmHg, PO₂: 49 mmHg, O₂ saturation: 60.9%, serum HCO3- 3.4 mmol/L, and base excess -18 mmol/lit. The other lab data are presented in Table 1. The urine ketone body was positive (3+).

With diagnosis of the DKA, 1000 ml saline 0.9% and 50-ml sodium bicarbonate were initially infused over an hour in the emergency department and the patient was transferred to the ICU. Continuous insulin infusion (2-6 units/h), fluid (dextrose 5% and saline 0.9%), and sodium bicarbonate 50meq/lit at dose of 100-150 ml/hour were continued in the ICU. 20 hours of the vasopressor therapy with norepinephrine (4-10 mcg/min) was required. Intravenous bicarbonate was continued for 24 hours. The acidosis responded to the treatment slowly. Continuous infusion of fluid (saline 0.9% and dextrose 5%) and insulin after about 4 days was stopped after the patients reached pH = 7.4 and HCO3- = 18, and base excess = -12meq/l. However, after 12 hours, the pH and bicarbonate levels decreased to 7.3 and 12.5 mmol/l, respectively. Therefore, intravenous sodium chloride (0.9%) or half-saline with dextrose (5%) (to maintain blood glucose at 150-200 mg/dl) at a rate of 70-150 ml/hour (depending on the patient's blood sugar and fluid status) along with insulin at a dose of 2-5 unit/hour was continued for a total of 144 hours in order to correct the negative base excess and ketonuria. Acidosis slowly responded to the treatment (Fig 1 and 2). Finally, the patient was discharged with insulin (NPH 12 unit 6-AM, and 8 unit 6-PM) on the 7^th day of hospitalization with pH = 7.40, HCO3-= 19 mmol/l, negative urine and serum ketone, and normal base excess.

Case 2

A 65 years old female patient with a 10-year history of T2DM was brought to the emergency department with a decreased level of consciousness, tachycardia (125/min), and tachypnea (30/min). Her blood sugar was controlled by empagliflozin/linagliptin (25/5) and gliclazide. She had a history of laparoscopic cholecystectomy 5 days before the current presentation. Empagliflozin was discontinued 24 hours before the surgery and reintroduced again the day after surgery. The initial lab values included pH 7.11, bicarbonate 6.4 mmol/lit, ketone 3 +, base excess -26, PCO₂20 mmHg, and PaO2 40 mmHg. Continuous fluid infusion of 300 ml/hr (dextrose 5%/saline0.9%), and 1-4 unites insulin were initiated, which were continued for 52 hours, and piperacillin-tazobactam was initiated for her. The pH and base excess were normalized (pH 7.39, bicarbonate 15.6 mmol/lit, base excess -8, negative ketone). Blood culture results showed pseudomonas aeruginosa and susceptibility to piperacillin-tazobactam and meropenem. Piperacillin-tazobactam was continued for 10 days. The patient was discharged with insulin NPH 6 unites thrice daily and metformin. Empagliflozin was discontinued permanently.

Ethics

Informed consent was obtained from the patients for publishing data.

We searched PubMed, Cochrane Library, Scopus databases, and google scholar on January 2022. The key words used were “empagliflozin” or “dapagliflozin” or “canagliflozin” or “Sodium glucose cotransporter 2 inhibitors” AND “diabetes ketoacidosis SGLT2 inhibitors”, “DKA AND SGLT2 inhibitors”. Two authors searched on these databases independently. Article references were also assessed for related studies. All eligible case reports (73 case reports and two case series) included in the present review. Data including signs, symptoms, tigers, lab data, and treatment modalities are summarized here.

Canagliflozin was the first Sodium-glucose cotransporter 2 inhibitor that has been approved by the FDA in march 2013 for glycemic control along with diet. Followed by empagliflozin in August 2014. Empagliflozin also lowers cardiovascular mortality, hospitalization, and renal outcomes in patients with heart failures [13, 14]. Subsequently, empagliflozin was approved for cardiovascular risk reduction in patients with Type 2 diabetes mellites (T2DM), treatment of patients with decreased ejection fraction, cardiovascular death, and hospitalization in patients with heart failure and low ejection fraction. These agents lower blood sugar through increasing urinary glucose elimination. The SGLT2is prescriptions have increased over recent years [15]. Although all available studies do not show an association between the SGLT2is and DKA versus other agents [16, 17]. However, the SGLT2is are responsible for 6.6% of all cases of the DKA [18]. The rate of the DKA in the SGLT2is is twice as dipeptidyl peptidase inhibitors in 180 days after initiation [19]. The overall incidence of the DKA associated with the SGLT2is was estimated as 0.1–0.43% by the studies [20, 21]. The incidence of the SGLT2is -induced DKA is 0.6 to 4.9 events per 1000 patient-years in recent studies [22–24]. In a meta-analysis on 59,747 patients, an odds ratio of 2.86 (1.39–5.86) versus placebo for the DKA was obtained [9]. A recent systematic review and meta-analysis found a hazard ratio of (HR 0.96–2.14) for the DKA with uncertainty [25]. In other words, these medications increase the risk of DKA by 2–3 times [23, 26, 27]. Similar findings were also obtained by another meta-analysis [27]. The FDA warned about the association between the diabetes ketoacidosis (DKA) and the SGLT2is [22]. The incidence of hyperglycemic, euglycemic (defined as BS < 250 mg/dl, arterial pH < 7.3, HCO3- < 18 meq/L, and anion gap > 10), and hypoglycemic DKA associated with SGLT2is were 0.34%, 0.26%, and 0.08%, respectively, in a recent cohort [21].

A recent multicenter study on 500 patients with DKA showed hazard ratios of 1.86, 2.52, and 3.58 for dapagliflozin, empagliflozin, and canagliflozin, respectively [26]. Euglycemic DKA may be more prevalent with canagliflozin, followed by empagliflozin and dapagliflozin [21]. Lower selectivity of canagliflozin for SGLT2/SGLT1 versus dapagliflozin and empagliflozin can be responsible for these differences [28]. DKA associated with the higher doses of sotagliflozin (400 mg vs. 200 mg) is greater and occurs in a shorter time [29]. Different mechanisms including lowering serum insulin levels, along with increased glucagon, counter regulators hormones, lipolysis, and ketone bodies serum concentration have been proposed for the SGLT2is induced DKA [30–32]. An increase in the circulatory concentration of ketone bodies through an increased tubular reabsorption occurs after 14 days of the SGLT2is [33, 34].

Vomiting, nausea, abdominal pain, tachycardia, malaise, tachypnea, tachypnea, altered mental status, dizziness, syncope, and diarrhea were among the most frequently reported signs in patients with the SGLT2is -induced DKA (Table 2). Severe acidosis and hypotension, shock, acute kidney injury, volume depletion are other life-threatening symptoms. In one of the largest case series, Meyer et al. found that 6 out of the 13 patient who developed DKA following SGLT2is used had reductions of missed insulin doses [35]. In 20 patients with DKA or diabetes ketosis, acute illness (70%), insulin dose reduction, alcoholism, low medication adherence, fasting, and low body weight were reported as the major risk factors for DKA following these agents [36]. The risk factors include the Latent Autoimmune Diabetes in Adults (LADA), discontinuing or lowering the dose of insulin, surgery, trauma, pregnancy, increased physical activity, decreased preoperative alcohol intake, starvation or low-calorie diets, fasting, acute coronary syndromes, heart failure, previous DKA, acute pancreatitis, and acute infections have been proposed as causes for the DKA associated with SGLT2is [37–48]. Nausea, vomiting, dehydration, severe exercise, omit insulin doses, viral and bacterial infections, COVID-19 infection, and acute illness can precipitate the DKA in SGLT2is s users [24, 35, 49–51]. Low carbohydrate (< 30-50g carbohydrate/day) and ketogenic diets can precipitate the DKA in patients based on the SGLT2is [45, 52–55]. Cardiothoracic surgery is considered as a risk factor for the SGLT2is associated DKA [56–60]. Prior DKA background, higher HA₁c (> 10%), baseline bicarbonate levels of < 18 meq/l, use of dementia medications, and digoxin use are other risk factors proposed in a recent cohort study [24].

Table 2

SGLT2is severe DKA recent cases
Study	Sex/age	Symptoms / BS	Medications	Time after SGLT2i initiation	ABG finding		Treatment/ outcome
Sampani et al (74)	F, 51y	T2DM Trigger: hysterectomy After three days fasting Symptoms: weakness, tachypnea, anorexia, vomiting, and mild abdominal pain Glucose: 121 mg/dl	Metformin/vildagliptin, empagliflozin 25 mg o.d. and omeprazole	--	pH 7.05, HCO3 3 mmol/L, PCO2: 12 mmHg, AG: 16.9 mEq/L, lactate: 0.6 mmol/L,		Fluids (sodium bicarbonate, dextrose), insulin, Patient discharged on metformin/vildagliptin Empagliflozin was D/C
Dull et al (101)	F, 55 y	T2DM Initiated following a E. coli infection (unknown source). Epigastric pain, nausea, vomiting, chills, and diaphoresis Glucose 199 mg/dL	Alogliptin 25 mg once daily, aspirin, atorvastatin dapagliflozin/ metformin, levothyroxine, multivitamin, ondansetron	Unknown	PH 7.12, PCO2 < 18 mm Hg, HCO3 < 3.5 mmol/L, base excess 23.6 mmol/L		Ketoacidosis three days of intravenous fluid, insulin, and antimicrobial treatment
Dull et al (101)	M,62 y	T2DM Symptoms: Dysuria, urinary frequency, fever, chills, and myalgia Triggered: urinary tract infection Glucose 120 mg/dL	Aspirin, cholecalciferol, empagliflozin 25 mg once daily, metformin, multivitamin/day, pravastatin	11 months	PH 7.32, PCO2 30 mm Hg, HCO3 15.5 mmol/L, Base excess 9.3 mmol/L
Lau et al (59)	M, 54 y	T2DM Symptoms: Nausea, vomiting, tachycardia Triggered: cardiac surgery Glucose 102 mg/dl	NPH insulin (13–15 units), empagliflozin 25 mg daily (Empagliflozin withheld 48h before surgery)	--	pH 7.28, PCO2 40 mmHg, HCO3–18 mmol/L, base excess [BE] -8 mmol/l, lactate 1.1 mmol/l, glucose 12.0 mmol/l		Improved by insulin and fluid replacement (dextrose, sodium bicarbonate) Empagliflozin was discontinued
	M, 58 y	T2DM Symptoms: nausea, vomiting, tachycardia, Triggered: cardiac surgery Glucose 88 mg/dl	Metformin, gliclazide, and empagliflozin 25 mg daily (Withheld 28 hours prior to surgery)	--	pH 7.38, PCO2 38 mmHg, HCO3–22 mmolL-1, BE -2 mmolL-1, anion gap 6 mmolL-1, glucose 9.6 mmolL-1 serum beta-hydroxybutyrate level of 4.63 mmol/L		Improved by insulin and fluid replacement (dextrose 5%) Empagliflozin was discontinued
	M, 54 y	T2DM Symptoms: Nausea, vomiting, tachypnea, Triggered: cardiac surgery Glucose 127 mg/dl	Metformin, and empagliflozin 25 (Withheld 20 hours prior to surgery)	--	PH 7.33, Hco3 25 Pco2 32, BE 16, serum beta-hydroxybutyrate 0.98 mmol/l		Improved by insulin and fluid infusion
Latif et al (75)	F, 43 y	T2DM Symptoms: vomiting, cough, shortness of breath and generalized weakness Trigger: Ketogenic diet Glucose: 169 mg/dl	Empagliflozin 25mg/d, metformin 1000mg/bd	2 months	pH of 7.01, PO2 119mm Hg, CO2 5mm Hg, HCO3: 5 mmol/L		Fluid and insulin infusion
Puls et al (77) (Median data)	5 patients (3 were M) 57 y (43, 53, 57, 63, 73)	T2DM Symptoms: Nausea (60%), vomiting (60%) and fatigue (40%), one patient (20%) loss of consciousness Glucose 191 mg/dl (176, 190, 191, 192, 215)	Not specified (at least three oral agents)	20 months (17, 20, 21)	PH 7.01 (6.95, 7.01, 7.01, 7.10, 7.30) HCO3 = 8 (6, 7, 8, 9, 13) AG 27 (26, 27, 27, 28, 31), serum beta-hydroxybutyrate 9.9 mmol/L (9.2, 9.4, 9.9, 11.4, 12.3) urine ketones 150 mg/dL (150–150).		Fluid and Insulin treatment for median 23.82 hours
Meyer et al (35)	12 patients (9 female)	with euglycemic DKA 8/13 T2DM, 5 T1DM Trigger (some patients may have multiple risk factors): Surgery or preoperative (13/13), Acute coronary syndrome (2/13), Infections (4/13), Reduced oral intake (1/13) CABG (1/13) Missed insulin (5/13), Chemotherapy (1/13), cardiomyopathy, cardiogenic shock (1/13) Renal or kidney impairment (2/13) No risk (1/13) Blood glucose <250 mg/dl	13 patients with DKA (9/13) dapagliflozin (10 mg/d) and 4/13 empagliflozin (10 -25mg/d) Metformin 13/13, Sitagliptin or linagliptin 3/13, gliclazide 1/13, acarbose 1/13	< 1month (3/13), 1–3 months (2/13) > 3 months (6/13) Unknown (2/13)	PH 6.9 (2/13) 7 (1/13) 7.1 (2/13) 7.2 (1/13) 7.3 (2/13) unknow (5/13)	HCO3 2–4 (3/13) 5–9 (6/13) 10–14 (4/13)	Time to resolution 24–48 hours, Death (1/13)
Sethi et al (102)	F, A 55y	T2DM Symptoms: Low-grade fever, vomiting, and lethargy Triggered: lower respiratory infection Glucose 125-175mg/dL	Dapagliflozin 10 mg/d glimepiride 2 mg, and insulin glargine 18 units at bedtime	Not mentioned	pH 7.18, pCO2 14.3 mmHg, pO2 107 mmHg, HCO3 5.2 mmol/L		Insulin and hydration
Chou et al (76)	F, 61 y	T2DM Symptoms: weakness, nausea, vomiting, abdominal pain, Kussmaul breathing, sunken eyes, dry oral mucosa, reduced skin turgor Trigger: Reduced intake due to toothache, Glucose 180 mg/dl	Dapagliflozin 10 mg/day, metformin and glibenclamide	2 weeks	pH 6.986, CO2 20.9 mm Hg, HCO3− 7.0 mEq/L, anion gap 20 mEq/L		Dapagliflozin d/c Discharged after two days of insulin fluid replacement
Iqbal et al (103)	F,74y	T2DM Symptoms: Confusion and loss of consciousness, hypotension, bradycardia Trigger: influenza Glucose 187 mg/dL	Metformin, pioglitazone, amlodipine, atorvastatin, and ezetimibe, dapagliflozin	2 weeks	pH: 7.009, pCO2: 18.2 mmHg, HCO3: 5.1 mmol/L. Serum osmolarity 312 mOsm/kg, osmolar anion gap of 12 mOsm/kg.		Dapagliflozin d/c Fluid and insulin for 15 hours
Hussaini et al (63)	M, 49y	T2DM Craniotomy (right-sided middle cerebral artery stroke) Glucose 163 mg/dl	Sitagliptin/metformin, gliclazide, dapagliflozin 10 mg daily	5 years (DKA was occurred 72 hours after dapagliflozin D/C	Arterial pH 7.168, HCO3 12 mmol/l, Pco2 37, anion gap 20.7,		Intravenous fluids, dextrose, and insulin
Osafehinti et al (57)	M, 60y	T2DM, Asymptomatic Trigger: CABG Glucose 138mg/dl	Glimepiride, metformin, subcutaneous semaglutide, empagliflozin (10 mg orally daily)	1 year	pH 7.275, HCO3 15 mmol/L, anion gap of 25 mmol/L,		Insulin and infusion of 5% dextrose for 3 days norepinepHrine (for 24 hours)
Alabdaljabar et al (58)	M, 52y	T2DM Triger: CABG Asymptomatic Glucose 166 mg/dl	vildagliptin-metformin, empagliflozin (10 mg), pioglitazone, irbesartan-hydrochlorothiazide, atorvastatin (20 mg), aspirin (Empagliflozin was D/C 24 hours before surgery)	--	pH of 7.225, HCO3 − 14.60 mmol/L anion gap of 17.40 sodium 152 mg/dl urine ketone 3+ urine glucose 4+		IV fluids and insulin infusion (12 hours)
Steinmetz-Wood et al (54)	M, 47y	T2DM Symptoms: weakness, intermittent chest discomfort, and shortness of breath (first episode) Symptoms: tachypneic and tachycardic and had mild abdominal tenderness (Second episodes) Trigger: ketogenic diet/ low intake, and urinary tract infection Glucose 269 mg/dl glucose 269 mg/dl	Metformin and empagliflozin	--	pH 7.22 HCO3 13 mmol/L anion gap of 21, second episode: pH 6.94, HCO3 5 mmol/L, 3 + urinary ketones, beta-hydroxybutyrate level of 8.9 mmol/L,		Fluid and insulin, In the first episode ketogenic diet was considered responsible for DKA Empagliflozin D/C at the second presentation indefinitely
Wang et al (30)	40y, F	T2DM Symptoms (associated): slurred speech, MRI showed acute left anterior cerebral infarct Trigger: cerebral revascularization postoperatively,	Atorvastatin, levothyroxine, metformin, pioglitazone, and empagliflozin.	--	pH of 7.01, PCO2 11 mm Hg, anion gap 27, HCO3 not mentioned		Patients treated for one day (iv fluid and insulin), pHenylepHrine, and fludrocortisone. Patient died due to acute stroke
Yasuma et al (104)	F, 43y	T2DM Trigger: insulin D/C Symptoms: fatigue and vomiting Glucose 184 mg/dl	Switched from insulin to metformin 500 mg/d, empagliflozin 10 mg/d, and vildagliptin 100 mg/d.	4 days	pH, 7.18; pCO2, 18 mmHg; HCO3, 6.6 mEq/L; base excess, -19.3 mmol/L; A-gap, 27.6 mmol/L		Fluid and insulin for two days,
Lindsay et al (44)	M, 51y	T2DM, Trigger: gangrene Fournier glucose level of 212 mg/dL	Empagliflozin 25 mg daily, metformin 1000 mg twice daily, lisinopril 10 mg daily, atorvastatin 20 mg daily and aspirin 81 mg daily	--	pH 7.12, anion gap 31), low bicarbonate level (6 mmol/L), elevated creatinine (1.64 mg/dL)		All oral medications d/c 24 h before presentation, DKA resolved after fluid, insulin and few hours vasopressor therapy
Kasbawala et al (46)	F, 37y	T2DM Symptoms: Dysuria, pain Trigger: gangrene Fournier Glucose 402 mg/dL	Canagliflozin, Cetirizine, Citalopram, Levothyroxine, levothyroxine, pantoprazole, pravastatin, Sitagliptin-metformin, trazodone, valacyclovir	1 month	b-hydroxybutyrate of 2.49 mmol/L. pH of 7.23 PCO2 34 mmHg.		Insulin infusion with aggressive fluid resuscitation canagliflozin was D/C
Hernandez-Quiles et al (105)	M, 52y	T2DM Symptoms: altered mental status and breathlessness at presentation. Nausea, vomiting and abdominal pain for 7 days Glucose 300mg/dl	changed from glibenclamide and vildagliptin to metformin plus empagliflozin	1 month	pH 6,9 HCO3 13.3 mEq/l Anion Gap 23.1		Fluids, insulin, potassium and bicarbonate
Mistry et al (62)	F, 47y	T2DM Trigger: low-carbohydrate diet for 2 months Symptoms: acute-onset left-arm numbness and chest pain and a few months history of polyuria and polydipsia Glucose 187 mg/dL,	Metformin, empagliflozin 25 mg daily, and linagliptin.	only one dose of empagliflozin,	pH 7.24. HCO3 11 mmol/L, anion gap 22 mmol/L, β-hydroxybutyrate 6.78 mmol/L,		Insulin drip and fluid (9 lit) for 5 days prior to resolving her acidosis. Empagliflozin was d/c
Mistry et al (62)	M, 34y	T2DM Triger: ketogenic diet Symptoms: chest pain and shortness of breath, Glucose 251 mg/dL	canagliflozin 100 mg daily, and subcutaneous dulaglutide 0.5 mL every 7 days	2 months previously	venous blood gas pH of 7.27, bicarbonate level of 12 mmol/L, anion gap level of 24 mmol/L, β-hydroxybutyrate level of 5 mmol/L
Kelmenson et al (64)	F, 50y	T2DM Symptoms: 4 days of nausea, vomiting, abdominal pain, and decreased oral intake Triger: decreased food intake Glucose of 68 mg/dL,	Canagliflozin 300 mg daily, metformin and sitagliptin.	6 days	pH of 7.1, bicarbonate 6 mmol/L, anion gap of 21, β-hydroxybutyrate of 90 mg/dL, arterial pCO2 of 12 mm Hg, and arterial. Urinalysis contained glucose > 500 mg/dL and ketones 80 mg/dL		Improved after fluid/ insulin therapy Significant glucosuria resolved after 9 days, canagliflozin was D/C
Bobrowski et al (87)	F, 81y	T2DM Symptoms: acute respiratory distress with a respiratory rate of 40 breaths per minute and Kussmaul breathing. Triger: dehydration? Glucose: 198 mg/dl	Canagliflozin, metformin, and perindopril, ASA, Rosuvastatin, Amlodipine, metoprolol, Quetiapine, bisacodyl, multivitamin, cranberry,	--	pH of 7.08 (reference range: 7.35–7.45), partial pressure of carbon dioxide of 17 mmHg (reference range: 40–52 mmHg), and a serum bicarbonate of < 8 mmol/L (reference range: 23–29 mmol/L).		Dextrose/saline, insulin therapy,
Yehya et al (89)	F, 57y	T2DM Triger: breast abscess (right breast tenderness and fever), Glucose 469 mg/dl at first course of therapy, < 150 mg/dl at the second course (definite diagnosis of empagliflozin related DKA)	Metformin, pioglitazone, empagliflozin 25 mg	3 weeks	Bicarbonate 5 mEq/L, elevated anion gap of 29 mEq/L, glucosuria 3+, 7 hours after treatment d/c: 7 hours later 7 mEq/L, anion gap increased to 22 mEq/L, and BHOB increased to 6.45 mmol/L		Early fluid and insulin therapy improved ABG, however, 28 hours fluid (saline/dextrose) and insulin therapy
Adachi et al (106)	F, 27y	T2DM Symptoms: dizziness, and then upper abdominal pain, thirst and malaise, and polyuria (> 5l/day) Triger: low carbohydrate diet Glucose: 240 mg/dL	Gliclazide, metformin, sitagliptin, and canagliflozin (300 mg/day)	3 months	pH 6.906, pCO216.6 mmHg, pO2128.2 (mmHg), Bicarbonate (mmol/L) 6.6, Base excess(mmol/L) -28.5		Improved after 4 days of fluid therapy,
Aggarwal et al (107)	M, 53y	T2DM Trigger: laparoscopic appendectomy? Symptoms: generalized abdominal pain, non-exertional shortness of breath, and fever. Fever, tachycardia, tachypnea, low oxygen saturation. Glucose 126 mg/dL	Metformin and canagliflozin,	--	pH 7.21, Bicarbonate 17 mEq/L, blood urea nitrogen (BUN) 11 mg/dL, and creatinine 0.9 mg/dL, anion gap of 20.8 mEq/L, glucosuria (urine glucose > 1500 mg/dL) and ketonuria		Canagliflozin was d/c, insulin drip with 10% dextrose for two days,
Fieger et al(108)	F, 42y	T2DM, Symptoms: nausea and vomiting, tachypnea, tachycardia, Trigger: very low carbohydrate ketogenic diet, insulin d/c Blood glucose was 152 mg/dL	Insulin and glyburide, sitagliptin-metformin. Insulin and glyburide d/c and canagliflozin was started two weeks before presentations.	Two weeks	pH of 7.11 and a pCO2 of 16 mm Hg, Urinalysis ketones of 80 mg/dL, glucosuria at > 500 mg/dL PCO2 7 mmol/L, anion gap of 19 mmol/L		four days of fluid and insulin treatment. discharged on 30 units of glargine insulin daily, sitagliptin-metformin 50 mg/1,000 mg twice a da
Kapila et al (109)	F, 51y	T2DM Symptoms: generalized abdominal pain, shortness of breath, and fever. Trigger: ketogenic diet for two weeks and sleeve surgery Blood glucose 150 to 180 mg/dL	insulin aspart, insulin glargine, metformin, and canagliflozin	--	pH of 7.21, bicarbonate 8 mEq/L, Pco2 60 mmHg, anion gap of 37 mEq/L.		Three days of fluid (dextrose 5%) and insulin therapy, canagliflozin D/c
Matli et al (110)	M, 48y	T2DM symptoms: generalized weakness for a few days, nausea, loss of appetite, lightheadedness, polydipsia, and polynocturia. Trigger: low carbohydrate diet	insulin glargine daily with pre-prandial aspart insulin, metformin with glipizide (500 mg + 5 mg) daily, and dapagliflozin (10 mg once daily	6 months	PH:7.1, PO2:127, PCO2:18, Anion Gap:20 mmol/dL, Bicarbonate:12 mmol/L		Insulin and fluid for 15 hours
Shah et al (111)	M, 66y	T2DM Trigger: traumatic brain injury BS: 236 mg/dl	empagliflozin (10 mg OD), metformin), (regular insulin thrice a day and degludec once a day	--	Anion gap: 20.4,
	M, 74y	T2DM Triger: CABG) surgery Glucose 216 mg/dl	empagliflozin 25 mg + linagliptin 5 mg once daily	--	Anion gap 22.0,
	F, 71y	T2DM Trigger: bowel obstruction surgery Glucose 186 mg/dl	empagliflozin 12.5 mg once daily	--	Anion gap 16, ketone 2.8,
Lee et al (86)	F, 76y	T2DM Trigger: urinary tract infection. Symptoms: confusion, lethargy, stupor, nausea, vomiting, and abdominal pain. BS: 218mg/dl	Metformin, dapagliflozin (10 mg/day), ezetimibe/rosuvastatin calcium, clopidogrel, nicorandil, imipramine, tolterodine, and tamsulosin After three days metformin and dapagliflozin were reinitiated.	---	pH 6.90, pco2 12, hco3 3, AG 37		Dapagliflozin was D/c, intravenous fluid and insulin, Patients discharged with insulin lispro and metformin in the 8 days after DKA.
Sharma et al (112)	F, 56y	Type 2DM Trigger: pyelonephritis Glucose 377 mg/dl	Canagliflozin (300mg daily) Lisinopril Simvastatin Levemir 50 units QHS Metformin	2–3 weeks	pH 7.39, Pco2 31.6, Hco3 16, AG 19		Fluid and insulin, Canagliflozin D/c,
Sharma et al (112)	F, 57y	T2DM Symptoms: nausea and abdominal pain for 2 days and confusion Glucose 235	Canagliflozin (300mg daily) Amlodipine Atorvastatin Lisinopril Metoprolol Metformin Pioglitazone	2 weeks	PH 7.18 Pco2 16.2 Hco3 9 AG 24		Insulin and fluid
	F, 46y	T2DM Symptoms: Trigger: nausea and diarrhea for two days Glucose 203	Canagliflozin (300 mg daily) Pioglitazone Metformin Atorvastatin	5 days	PH 7.04 Pco2 20 Hco3 8 AG 23		Fluid and insulin Canagliflozin D/C, insulin detemir was add to medications
	F, 63y	T2DM Symptoms: generalized weakness, abdominal pain, nausea, vomiting and diarrhea for four days Trigger: poor compliance to medications (insulin and metformin), bacteremia Glucose 400 mg/dl	Dulaglutide Metformin Empagliflozin (10mg daily)	Unknown	PH 7.24 Pco2 20 Hco3 9 AG 22		Insulin and fluid
Badwal et al (113)	M, 25y	T2DM Trigger: acute pancreatitis, Symptoms: tachypnea and tachycardia BS: 120mg/dl and 200mg/dl	Type II diabetes on metformin, sitagliptin, and dapagliflozin All were continued until diagnosis of DKA	---	PH 7.14 Pco2 20 Hco3 5 AG 32		Fluid and insulin Dapagliflozin, pioglitazone and sitagliptin was D/C,
Morrison et al (50)	M, 40y	T2DM Symptoms: non-bloody, non-bilious vomiting, and poor oral intake, diaphoretic Trigger: COVID-19, poor intake, glucose 177 mg/dL	empagliflozin 25mg/ daily, semaglutide, metformin, atorvastatin, modafinil	---	pH of 7.06, PCo2 37 mm Hg, PaO₂ 31 mm Hg, bicarbonate 10.0 mEq/L, lactate 2.3 mmol/L.		Fluid and insulin for 3 days, discharged after 4 days on glargine
Brown et al (114)	M, 53y	T2DM symptoms: nausea, vomiting, anorexia, and generalized abdominal pain. trigger: poor intake glucose 162 mg/dL	Metformin, dapagliflozin, omeprazole, perindopril, atorvastatin, and amitriptyline	--	PH 7.24, Anion gap of 30, and lactate of 4.5 mmol/L		Insulin and fluid
Allison et al (115)	M, 47y	T2DM Symptoms: generalized weakness Trigger: Glucose 216 mg/dL	teriflunomide for the treatment of MS, subcutaneous regular insulin taken with meals, metformin, and empagliflozin	---	bicarbonate 10 mmol/L, anion gap was 24. Urine ketones 4 + and 3 + glucose.		Fluid and insulin
Goto et al (73)	Female, 52y	T2DM symptoms: tachypnea, vomiting, and decreased blood pressure Trigger: low intake due to dental pain glucose: 178 mg/dL	empagliflozin 10 mg sitagliptin), ezetimibe 10 rosuvastatin, clopidogrel 75	--	pH, 6.84; HCO3– level, 2.1 mEq/L; base excess, − 20.0 mmol/L; anion gap, 31.9 mmol/L; and lactate level, 2.4 mmol/L		Empagliflozin D/C, fluid, bicarbonate, insulin, vasopressor
Goto et al (73)	F, 76-y	Type 2 diabetes mellitus Trigger: gastrojejunal bypass surgery Symptoms: cardiac arrest due to acidemia, Glucose: 140 mg/dL	canagliflozin 100 mg daily and metformin, cilnidipine, fenofibrate	---	pH, 7.25; HCO3– level, − 17.3 mEq/L; base excess, − 9.1; anion gap, 16.2 mmol/L; and lactate level, 0.8 mmol/L		Fluid and insulin treatment,
Fukuda et al (72)	F, 71y	T2DM Symptoms: malaise, nausea and abdominal pain Trigger: reduced oral intake for two weeks Glucose: 259 mg/dL.	canagliflozin, metformin, and saxagliptin	1 month	pH, 6.860; CO2, 8 mmHg, HCO3, − 1.0 mEq/L; base excess: − 31.3 mmol/L
Chai et al (116)	F, 55y	T2DM Symptoms: nausea, vomiting, abdominal pain, and polyuria over 24 hours, Glucose 366 mg/dl	Canagliflozin 300 mg	--	PH 7.09 Hco3 8.8 Pco2 29 Anion gap:32		Canagliflozin was D/C, insulin and fluid was initiated. Patient discharged on metformin and glipizide
Chai et al (116)	M, 54 y	T1DM Symptoms: abdominal pain, nausea, vomiting, and abdominal pain Glucose327 mg/dL	insulin (humalog 25/35 AM/PM), albiglutide 50 mg, and canagliflozin 300 mg PO daily	---	PH 7.15 Hco3 10 Pco2 29 Anion gap:27		Fluid and insulin
Lucero et al (117)	F, 50y	T2DM Symptoms: diarrhea and vomiting Glucose 165 mg/dl	Dapagliflozin 10 mg/day, and NPH insulin at 40 and 60 IU.	--	PH 7.13 Hco3 2 BE -23.7 AG 32		Fluid and insulin
Sloan et al (88)	M, 63y	T2DM Symptoms: vomiting, diarrhea, anorexia and right upper quadrant abdominal pain glucose: 239 mmol/L	Metformin, aspirin, simvastatin and twice daily pre-mixed insulin. canagliflozin	7 months	blood glucose was 13.3mmol/L and 3-hydroxybutyrate 5.2mmol/L. Venous blood glucose was determined; pH: 7.15 and bicarbonate: 8mmol/L		All medications were D/C, Fluid and insulin after improvement in glucose, pH, bicarbonate and 3-hydroxybutyrate subcutaneous insulin was initiated on day 3. However, ketonemia aggravated and additional two days (total 5 days) was required to biochemical improvement.
Earle et al (55)	F, 31y	T2DM Symptoms: slurring of her speech, nausea, radiating pain of legs, and constipation Trigger: very low carbohydrate diet, insulin discontinuation Glucose139	Canagliflozin	--	pH 7.056 HCO3 8.0 mEq/L, Anion Gap 29 blood ketones 80 mg/dL		Fluid and insulin
Elshimy et al (118)	F, 28y	T2DM Symptoms: abdominal pain Tachypnea, tachycardia, Trigger: - Glucose 252 mg/dl (55 mg/dl following one liter fluid replacement)	Dapagliflozin and metformin.	2 months	PH 7.18. HCO3 9 mmol/dl,		Dextrose 50%, dextrose containing fluids, insulin She was discharged on insulin
Mendelsohn et al (119)	M, 39y	T2DM Symptoms: retrosternal pain, Trigger: fasting, pericarditis Serum glucose of 158 mg/dL	Metformin and empagliflozin	--	pH of 7.22 HCO3 8.3 mmol/L anion gap of 22 mEq/L		Intravenous fluid and insulin, empagliflozin was D/C
Yii et al (60)	M,37y	T2DM Symptoms: lethargic and shortness of breath Trigger: COVID-19 Glucose 10.9 mmol	empagliflozin 25 mg daily and subcutaneous liraglutide	--	pH 6.87, pCO2 17 mmHg, pO2 37 mmHg, HCO3 − 3.1 mmol/L, lactate 1.7 mmol/L)		Fluid and insulin, norepinepHrine to maintain mean arterial pressure > 65 mmHg, continuous veno-venous hemodiafiltration. Patient discharged from ICU 3 days
Kitahara et al (69)	M, 59y	T2DM Symptoms: acidosis within 2 hours after initiation of surgery Trigger: thoracic surgery (empagliflozin was D/C 28 h before surgery) Glucose 162 mg/dL	Empagliflozin,	18 months	pH 7.12, pCO2 53.6 mmHg, HCO3 − 16.7 mmol/L, urine ketone and glucose + 3/+4		Insulin, dextrose 5% for 24 hours, discharged on insulin
Nappi et al (68)	F, 67 F	T2DM Symptoms: abdominal pain and impaired level conscious, tachypnea, tachycardia, hypotension, acute kidney injury, dehydration. Trigger: low calory regimen, infection Glucose 299mg/dl	Empagliflozin 25 mg/day, metformin, NSAIDS,	1 month	PH 6.91 Hco3 1.8 AG 31 Lactate 1.3 Pco2 9 Pao2 138		Insulin, fluid, bicarbonate, renal replacement therapy, Patient discharged on insulin
Dorcely et al (120)	M, 61y	T2DM Symptoms: nausea and right-sided chest pain Trigger: ketogenic diet glucose 84 mg/dl	Empagliflozin 10 mg daily, metformin liraglutide, rosuvastatin, ezetimibe, omeprazole	3 years	PH --- anion gap 17 bicarbonate 17 beta hydroxybutyric acid 4.1		Fluid (3 lit) and insulin, empagliflozin was d/c Improved after 24 hours
Polina et al (121)	F, 45y	T1DM Symptoms: weakness, nausea, and emesis, chills, fatigue, and polyuria the day prior to presentation, non-bloody emesis Trigger: Glucose: 224 mg/dl	Canagliflozin, and insulin pump	--	pH of 7.199 AG 32, beta-hydroxybutyrate 5.89. PaCO2 20		Fluid and insulin
Yeo et al (47)	F, 23y	T2DM Symptoms: severe abdominal pain Trigger: pancreatic, clostridium infection Glucose 148mg/dl	Metformin and dapagliflozin (10 mg, once a day) as oral hypoglycemic	2 years	H, 7.029; HCO3- 1.8 mmol/L; serum ketone, 2+; Urine ketone, 2+		continuous renal replacement therapy, dapagliflozin was D/C discharged on metformin and insulin
Bitar et al (81)	F, 64y	T2DM Symptoms: headaches and breathlessness, tachycardia, tachypnea, hypotension Trigger: Glucose: 90 mg/dl	GlucopHage/da-pagliflozin, aspirin, and atorvastatin	4 weeks	PH 6.6 HCO3, mmol/L5 Lactate, mmol/L1.2 Anion gap38 β-hydroxybutyrate, mmol9		Intravenous fluid, insulin (up to 10 units/hour), and dextrose, and bicarbonate Insulin was continued for 48 hours Discharged on glargine basal insulin, insulin aspart, before meals, and GlucopHage
Bitar et al (81)	M, 56y	T1DM Symptoms: dizziness, tachycardia,	Insulin aspart before each meal, insulin degludec (ultralong-acting basal insulin), and liraglutide semaglutide	2 months	PH 6.9 HCO3, mmol/L8.8 Lactate, mmol/L1.4 β-hydroxybutyrate, mmol6.9 urine ketones +++++		intravenous dextrose fluid with normal saline and insulin infusion in two different intravenous lines, with a bolus of Na2HCO3 to keep the pH above 7
Gajjar et al (122)	F, 28y	T2DM Symptoms: one-week history of polyuria, polydipsia, poor appetite, and vomiting. Trigger: poor intake for 3 days Glucose: 111 mg/dl	Metformin, glipizide, dapagliflozin, atorvastatin gemfibrozil, dapagliflozin	6 months	venous pH 7.27 Bicarbonate 18 mmol/l, anion gap 20, Beta- hydroxybutyrate 5.29 mmol/L		Fluid and insulin discharged on of insulin glargine at night, insulin lispro, and metformin.
Vitale et al (24)	M, 79y	T2DM Symptoms: shortness of breath, nausea/vomiting, and abdominal pain Trigger: COVID-19, cholecystitis,Vomiting Glucose: 276mg/dl	Empagliflozin (10 mg daily), metformin (500 mg twice daily), and lisinopril (2.5 mg daily).	--	pH 7.16 (venous) AG 40, beta-hydroxybutyrate 11.2 PaCO2 22 HCO3 5 Lactate 2.4		Discharged to rehabilitation facility
	M, 52y	T2DM Symptoms: fever, cough, and 8 days of dyspnea trigger: COVID-19, anorexia glucose 146	Empagliflozin (25 mg daily), glipizide, metformin XR, and irbesartan	--	pH 7.30 (venous) AG 23, beta-hydroxybutyrate 4.9 PaCO2 39 HCO3 15 Lactate 2.1		Died
	M, 69y	T2DM Symptoms: cough, shortness of breath, and anorexia for 3 days Trigger: COVID-19, anorexia Glucose 166	Empagliflozin (10 mg daily), metformin, and enalapril.	---	pH 7.31 (venous) AG 20, beta-hydroxybutyrate 3 PaCO2 43 HCO3 20 Lactate 1.1		Discharged to rehabilitation facility
	F, 53y	T2DM Symptoms: fever and anorexia for 1 week Trigger: COVID-19, anorexia Glucose: 151 mg/dL	Empagliflozin (10 mg daily), insulin glargine, exenatide, metformin, and glimepiride	--	pH 7.27 (venous) AG 30, beta-hydroxybutyrate 5.9 PaCO2 19 HCO3 5 Lactate 1.5		Discharged home
	F, 70y	T2DM Symptoms: COVID-19 diagnosis with a pulseless foot from arterial thrombosis Trigger: COVID-19, ischemic foot, anorexia Trigger: covid-19 Glucose 166	canagliflozin (300 mg daily), dulaglutide, sitagliptin-metformin, and losartan and hydrochlorothiazide	--	pH 7.09 (venous) AG 20, beta-hydroxybutyrate 5.3 P_aCO2 40 HCO3 10 mmol/lit Lactate 1.5		Discharged to rehabilitation facility
Calçada et al (61)	M, 70y	T2DM Symptoms: epigastric pain and vomiting for 3 days, tachycardia (116/min), fever (38C) Trigger: pancreatitis Glucose: 188 mg/dL	Dipeptidyl peptidase-4 inhibitor, biguanide and sulfonylurea, empagliflozin	1 days	pH 7.28; pCO2 22 mmHg; HCO3 − 10.3 mEq/L; lactate 2.0 mmol/L; AG 26 mmol/L Ketone 6.6 mmol/L		Saline0.9%, dextrose 5%, insulin
Yeoh et al (123)	M, 61y	T2DM Symptoms: - Trigger: vertebral fracture Glucose: 149 mg/dl	Metformin, Empagliflozin 10 mg at night Aspirin, Bisoprolol, Atorvastatin, Fish oil capsules, Calcium supplement	3 months	pH 7.12, HCO3 8.3 meq/l anion gap 18.7 mmol/L, base excess − 19.4 mmol/L urine ketones (2+), serum ketones 6 mmol/l		sodium bicarbonate 8.4% 200 mL of over 1 hour, saline 0.9% 2 L/day and Hartmann’s solution 1 L/day patient ABG was normalized after 44hours
Dyatlova et al (92)	F, 23 y	T2DM Symptoms: shortness of breath, dry cough, chills, malaise, diaphoresis, tachycardia and tachypnea Trigger: COVID-19 Blood glucose: 181 mg/dl	Not mentioned. Oral hypoglycemic agents including Empagliflozin (poorly controlled T2DM)	--	pH of 7.02, PCO2 16.7, PO2 67, and HCO3 4. Urinalysis was positive for glucose, protein, and ketones		Oral hypoglycemic agents were discontinued, sliding scale insulin didn’t improve HCO3. Sodium bicarbonate, saline, insulin infusion.
Ozer et al (124)	F, 42 y	T2DM Symptoms: nausea, vomiting and dyspnea, tachypnea, tachycardia Trigger: COVID-19 Glucose: 196 mg/dl,	Metformin, and empagliflozin (10 mg/day)	--	pH7.08, Hco3 8.9 mmol/L, anion gap 20 mEq/L, and urine ketones 2+		Isotonic fluids, dextrose 5%, and insulin infusion Oral agents were D/C, Acidosis resolved after 12 hours
Smyth et al (90)	M, 54	T2DM Symptoms:	Metformin and dapagliflozin Dapagliflozin was hold 24 before CABG	2 months	pH 7.2 Hco3 6.7mmol/lit Base excess − 7.7 mmol/l) Serum ketone 4.9 mmol/l Urine ketone 3+		Dextrose/ insulin infusion for 90 hours
Mackintosh et al (125)	F, 68Y	T2DM Symptoms: lethargic with confusion and worsening expressive aphasia, Trigger: craniotomy Glucose 140–160 mg/dl	empagliflozin 10 mg once daily	--	pH of 7.2. Hco3 9 mmol/L, AG 21, Blood serum b-hydroxybutyrate, positive urine ketones, urine glucose > 1000 mg/dL		Fluid and insulin for 2 days Neurologic symptoms were improved
Chaudhry et al (48)	M,41y	T2DM Symptoms: right-sided chest discomfort, nausea, and two episodes of nonbilious and non-bloody vomiting Trigger: acute pancreatitis	metformin, empagliflozin 12.5 mg PO BID, and semaglutide 1 mg	--	pH of 7.21, pCO2 16 mmHg, pO2 107 mmHg, HCO3 6.4 mmol/L Second ABG pH of 7.17, AG 26 pCO2 17 mmHg, pO2 68 mmHg, HCO3 6.2 mol/lit		Fluid, bicarbonate, and insulin infusion Discharged on metformin 500 mg twice daily and glimepiride 5mg/day
Smith et al (126)	F, 51 y	T2DM Symptoms: lethargy and tachycardia, Trigger: sleeve surgery glucose 160 mg/dL	canagliflozin-metformin insulin, metoprolol	--	pH of 7.21 HCO3- of 3 mmol/L AG 37 mmol/L		Ringer lactate, bicarbonate, insulin infusion Patient was discharged on insulin

In the present case, self-prescribing empagliflozin as well as decreased intake due to nausea and vomiting were major risk factors of the DKA [38]. Although they are likely to occur at any time, even after a single dose [18, 61], most cases occur within the first six months after SGLT2is initiation [35, 36, 62–64]. However, a recent systematic review and meta-analysis showed that the mean age > 60-year-old and longer duration of therapy (> 52weeks) are the major risk factors for the SGLT2is-induced DKA in patients with type 2 diabetes [65]. A systematic review on 47 patients (42 of whom were euglycemic) with perioperative SGLT2is-associated DKA found that most cases occur within the first few hours to 6 weeks after surgery [66]. Bariatric, abdominal, gynecologic, and cardiac surgery were the major operations associated with DKA [66].

some research claimed that female gender is more susceptible to the euglycemic DKA [36]. However, it was not shown in all studies [26]. It seems that male or female susceptibility to the SGLT2is induced DKA is related to other precipitating risk factors rather than gender. However, further studies are needed to confirm that.

The normal or moderate hyperglycemia (< 300 mg/dl) should not preclude ketone and blood gas assessment body measurement. The urine ketone body can be negative due to its tubular reabsorption or positivity [67, 68]. Therefore, blood ketone is more sensitive for detection of the DKA. Early clinical and biochemical (e.g., serum or capillary ketone bodies venous blood gas) monitoring for susceptible patients can be helpful [69].

About 70% of DKA episodes that are associated with SGLT2is are euglycemic (BS < 250mg/dl) [18, 31]. However, mild hyperglycemia and hypoglycemic DKA are possible [44, 64]. Therefore, the absence of hyperglycemia does not rule out the DKA [64, 70]. Euglycemia and hypoglycemia can be due to increased urinary glucose elimination. Cases of the SGLT2is-induced DKA can be severe in nature.

One of the largest case series on euglycemic DKA was reported by Meyer’s et al. study conducted on 13 (including 9 female) patients, 8 of whom had type 2 diabetes and the remaining 5 patients had LADA [35]. Dapagliflozin (9/13) and empagliflozin (4/13) with mean duration of 11.6 weeks were used along with the SGLT2is [35].

Several cases of DKA with life-threatening acidosis have been reported [71–73]. Soni et al. reported 8 patients with euglycemic DKA following empagliflozin initiation. 5 patients had bicarbonate levels of < 10 mmol/l and 3 had PH < 7.1 [71]. In addition, Goto et al. reported one patient with severe life-threatening DKA who received empagliflozin before elective coronary artery bypass grafting surgery [73]. Tachypnea, vomiting, hypotension, and severe acidosis (pH = 6.84; HCO3-level = 2.1 mEq/L; base excess = -20 mmol/L; anion gap = 31.9 mmol/L; and lactate level = 2.4 mmol/L) were the main clinical and metabolic factors in the patient. Metabolic acidosis was improved after two days of insulin and glucose/saline infusion [73]. Sampani et al. reported one patient with the DKA who developed severe metabolic acidosis (pH = 7.05; HCO3- = 3 mmol/l) following hysterectomy surgery [74]. Latif et al. reported one case of empagliflozin-associated DKA with malaise, nausea, vomiting, cough, shortness and severe acidosis (pH = 7.01, HCO3- = 5 meq/l) [75]. Chou et al. reported one patient with tachycardia, tachypnea, kaussmal signs, dry mucus, sunken eyes, and metabolic acidosis (pH = 6.986; CO2 = 20.9mm Hg; HCO3- = 7.0 mEq/L; and anion gap = 20mEq/L) [76]. In addition, Puls et al. described 5 cases (60% male) of severe euglycemic DKA with mean pH = 7.01, HCO3- 8 = meq/l, anion gap = 27 mEq/L, after averagely 20 months of the SGLT2is therapy [77]. Euglycemic DKA with respiratory alkalosis were likely to occur [78]. Death have been reported in the SGLT2is -associated DKA [30, 35].

No universal guideline is available for the treatment of the SGLT2is s-associated DKA in T2DM. Discontinuation of the SGLT2is, fluid replacement, and insulin therapy are the mainstays of treatment (Table 2) and (Fig. 3). Continuation of the SGLT2is s after the first episode of DKA can be a risk factor for subsequent attacks [54]. Therefore, reintroduction of SGLT2is is not recommended after the first occurrence of DKA. Unfortunately, our patients did not eat well for 2–3 days before admission, which could influence acidosis. Similar to our cases, Karakaya et al. reported one patient with severe DKA associated with canagliflozin (pH = 6.9; CO₂ = 16.6 mmHg; HCO3- = 9.2 mmol/L; anion gap = 20.7 mEq/L; and blood ketones level = 8.0mmol/L), who was successfully treated following rehydration, insulin, bicarbonate, and potassium replacement [79]. Recently, Yeo et al. reported a case of dapagliflozin-associated DKA with PH = 7.04 and HCO3- = 1.8 meq/l in a patient with pseudo-membrane colitis, which became complicated by septic shock and acute kidney injury [47]. The patient was effectively treated with continuous renal replacement therapy [47]. Although the infusion of sodium bicarbonate for patients with PH < 7 and/or renal replacement was successful [47, 80, 81]. However, it was not effective in all the patients with euglycemic DKA [42]. Intravenous infusion of sodium bicarbonate can paradoxically exacerbate acidosis and reduce serum potassium levels; therefore, it is only recommended for patients with pH < 6.9 [82]. In addition, empagliflozin use can either increase or decrease serum potassium level [83]. Prophylactic hydration and insulin infusion can prevent euglycemic diabetic ketoacidosis associated with sodium-glucose cotransporter 2 inhibitors in high-risk patients [84, 85]. Lee and Ahn reported DKA in a patient with loss of consciousness, pyelonephritis and acute kidney injury receiving metformin, dapagliflozin, clopidogrel, nicorandil, imipramine, tolterodine, and tamsulosin. The initial lab data included pH = 6.904, Pco₂ = 12.0 mmHg, HCO3- = 3.1 mmol/L, BS = 150–200 mg/dl, sodium = 162 meg/l, and potassium = 2.5 meq/l [86]. The patient improved in the 7th day after discontinuation of dapagliflozin and hydration [86]. Similar cases with prolonged acidosis or glucosuria were also reported by other studies [52, 64, 76, 87]. Bobrowski et al. studied cases with prolonged metabolic recovery and showed that some cases can recover 10 (4–12) days after initial presentations [87]. Furthermore, it seems that the time for recovery from the DKA based on the SGLT2is, insulin infusion, the amount required fluid, and duration of hospitalization is longer than the time for recovery from the DKA based on other causes [64, 68, 80, 88]. Early discontinuation of fluid and insulin treatment can be associated with return of the symptoms [88–90]. Consequently, precise medications history and monitoring of patients for at least five half-lives and longer after SGLT2is discontinuation are recommended [87]. The renal clearance of empagliflozin is significantly higher than that of dapagliflozin and canagliflozin [91]. Therefore, a decreased renal function results in an increase in empagliflozin concentration [91]. Patients’ blood pressure monitoring due to osmotic diuresis and electrolyte abnormalities (e.g., hypokalemia and hypernatremia) is necessary [68]. Short-term vasopressor therapy may be required for some patients, in particular for those with high anion-gap metabolic acidosis [44, 57]. Treatment with intravenous insulin, fluids (e.g., saline 0.9% or half-saline, with or without dextrose 5%), vasopressors, bicarbonate, and renal replacement therapy should be individualized. The most recent UK guidelines on management of DKA recommend stopping of the SGLT2is and replacement of fluid with dextrose 10% along with insulin (0.05–0.1 unit/kg) for euglycemic DKA [12]. Sliding scale insulin treatment can lead to an increase in the severity of acidosis [92]. Goldenberg et al. proposed the STOP DKA protocol for patients with type 1 diabetes mellites [93]. The Stop SGLT2is when patient is symptomatic for the DKA, Test for ketone body and blood sugar every 2–4 hours, Oral intake (250–500 cc fluid every 2 hours and up to 60 g carbohydrate ever 2–4 hours), and Protocol instruction (insulin and carbohydrate use) are recommended [93]. An international panel of experts recommends St (STOP SGLT2is), Insulin, Carbohydrate intake, and Hydration with suitable fluids for lower risk of DKA in type 1 diabetic patients [94].

Although most of the presented case reports followed such approach. However, this protocol has not been validated in patients with type 2 diabetes.

In the present literature review, we summarized available cases of the SGLT2is-induced DKA. Case reports can be of value about presentation, complications, risk factors, and management plans of the SGLT2is-induced DKA. However, the self-medication practice is relatively high in diabetic patients [95]. In the meta-analysis of the EMPEROR-Reduced and DAPA-HF trials, no case of the the DKA was seen in the patients with non-diabetic heart failure [96]. The SGLT2is should be discontinued in the case of acute illnesses at least 24 (24–72) hours before elective surgery, and for patients with the DKA [44, 97]. In terms of the SGLT2is users, during acute illness episodes, patients should check blood ketone, and patients with positive ketone should be instructed to receive bolus insulin injection, adequate fluid intake, carbohydrate ingestion (at least 30 gram/day), and check serum ketone concentration every four hours [82, 98]. Patients should seek emergency department if ketosis not resolved of the DKA symptoms appears [98]. Although, no case of the DKA was observed in the patients with acute heart failure in the EMPULSE trial [99]. As prescribing of the SGLT2is increases [100], clinicians should be aware of the DKA in patients with diabetes with polyuria, abdominal pain, nausea/vomiting, and confusion.

Ethical statement:

This study approved by ethics committee of Kermanshah University of Medical Sciences, Kermanshah, Iran.

This material is the authors' own original work, which has not been previously published elsewhere.

The patient gave their informed consent prior to their inclusion in the study

The paper is not currently being considered for publication elsewhere.

All sources used are properly disclosed (correct citation). Literally copying of text must be indicated as such by using quotation marks and giving proper reference.

All authors have been personally and actively involved in substantial work leading to the paper, and will take public responsibility for its content.

Conflict of interest statement:

The authors declare that they have no conflict of interests.

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Empagliflozin induced diabetes ketoacidosis: a review of literature

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