Sodium-glucose cotransporter-2 inhibitor-associated euglycemic diabetic ketoacidosis in COVID-19-infected patients: A systematic review of case reports

Table 1 Data summarized from included studies

Ref.	Study Origin	Number of patients	Sex	Age	Type of DM	Previous co-morbidities	SGLT2 inhibitors used before	COVID-19 symptoms onset	Eu-DKA diagnosis	Method of COVID-19 diagnosis	Autonomic symptoms	ABG count	Serum Analysis	Urinalysis	Eu-DKA management	COVID-19 Management	Outcome	Treatment intervention after resolution
Dass et al[14]	United States	1	Female	59	T2DM	COVID-19, Community acquired pneumonia	Empagliflozin, sitagliptin	9 d before eu-DKA onset	ABG analysis, serum analysis, urine analysis	Not reported	Tachypnea and tachycardia	pH: 6.94; PaCO2: 13; PaO2: 99; HCO3: 3	Lactate: 0.9; glucose: 154; confirmed bicarb: < 10; serum osmolality: 346; anion gap: 30	3+ glucose and 2+ ketones; negative UDS and normal salicylate levels	insulin drip and IV fluid	Not reported	Discharged after complete recovery	Sitagliptin and metformin continued; empagliflozin discontinued; started with 20 units of insulin glargine
Vitale et al[15]	United Kingdom	5	3 males, 2 females	52-79	T2DM	Covid-19, Hypertension	Empagliflozin, Canagliflozin	3-8 d before eu-DKA onset	ABG analysis, serum analysis	RT-PCR	Tachypnea, dyspnea, nausea, anorexia, abdominal pain	pH: 7.09-7.31; PaCO2: 19-43; HCO3: 5-20	Lactate: 1.1-2.4; glucose: 146-286; anion gap: 20-40	Not analyzed	IV insulin, intubation	Not reported	1 male died; rest of the patients recovered	Not reported
Batista et al[16]	Brazil	1	Male	56	T2DM	COVID-19	Empagliflozin	5 d before eu-DKA onset	ABG analysis, serum analysis, urine analysis	RT-PCR	Tachypnea, tachycardia	pH: 7.28; pCO2: 19 mmHg; HCO3: 8.9; base excess: 15.7	Sodium: 132; potassium: 5.6; chloride: 99; glucose: 118; hemoglobin A1c (HbA1c) 7.2%	ketones	Glucose, insulin, and KCl	Oxygen therapy, Azithromycin 500 mg	Discharged after complete recovery	Not reported
Philippe et al[17]	Belgium	1	Male	60	T1DM	COVID-19, hypothyroidism, obstructive sleep apnea	Empagliflozin	2 d before eu-DKA onset	ABG analysis, serum analysis, urine analysis	RT-PCR	Polypnea, myalgia, diarrhea. And fever	pH: 7.48; pO2: 17, pCO2: 27; HCO3: 19; anion gap: 17	Lactate: 1.4; glucose: 234; HbA1c: 7.4	3+ ketones	IV fluids, IV insulin	Oxygen therapy, invasive mechanical ventilation	Discharged after complete recovery	Empagliflozin was discontinued and subcutaneous glargine was started
Morrison et al[18]	United States	1	Male	40	T2DM	COVID-19	Empagliflozin	3 d before eu-DKA onset	ABG analysis, serum analysis, urine analysis	RT-PCR	Tachypnea, tachycardia, diaphoretic	pH: 7.06; pCO2: 37; pO2: 31; HCO3: 10.0; lactate: 2.3	Sodium level: 133; carbon dioxide: 11; glucose:177; anion gap: 25; HbA1c: 10.6%	Glucose (> 1000 mg/dL) and ketones (> 80 mg/dL)	IV fluids, IV insulin	No intervention due to mild symptoms	Discharged after complete recovery	Subcutaneous glargine started
Fang et al[19]	United States	1	Male	52	T2DM	COVID-19, hypertension, hyperlipidemia	Empagliflozin	2 d before eu-DKA onset	ABG analysis, serum analysis, urine analysis	RT-PCR	Hypoxia, dyspnea. Fever, anorexia	pH: 7.30; pCO2: 37	glucose:113; anion gap: 18	Glucose (> 500 mg/dL) and ketones (> 80 mg/dL)	IV fluids, IV insulin	Intubation, oxygen therapy	Discharged after complete recovery	Not reported
Yii ESS et al[28]	Malaysia	1	Male	37	T2DM	COVID-19	Empagliflozin	3 d before eu-DKA onset	ABG analysis, serum analysis, urine analysis	Not reported	Dyspnea, Tachypnea, Stable heart rate	pH: 6.87; pCO2: 17; pO2: 37; HCO3: 3.1; lactate: 1.7	Glucose: 11.9; urea 11.4; sodium 136; potassium 4.5; chloride 106; creatinine 105	Ketone: 3.0	18 h of renal replacement therapy, noradrenaline infusion	Intubation, ICU	Discharged after complete recovery	Not reported
Oriot et al[29]	Belgium	1	Male	52	T1DM	COVID-19, hypothyroidism, obstructive sleep apnea syndrome	Empagliflozin	2 d before	ABG analysis, serum analysis	RT-PCR	Polypnea, myalgia, diarrhea, and fever	pH: 7.48; pCO2: 27; pO2: 47; HCO3: 19; lactate: 1.4; anion gap: 17	HbA1c: 7.4	Ketone: 3+	IC fluids, IV insulin	Not reported	Discharged after complete recovery	Empagliflozin was discontinued

Reporting units: Glucose (mg/dL), ketones (mg/dL), PaCO2 and PaO2 (mmHg), HCO3 (mEq/L), Lactate (mmol/L), Chloride measuring unit (mEq/L), Osmolarity (mOsm/Kg), CO2 (mEq/L), Ketone: mmol/L.

ABG: Arterial blood gases; COVID-19: Coronavirus disease 2019; ICU: Intensive care unit; RT-PCR: Real-time polymerase chain reaction; HB: Hemoglobin; DM: Diabetes mellitus; Eu-DKA: Diabetic ketoacidosis with glucose.