Hidden risk of euglycemic diabetic ketoacidosis with sodium-glucose cotransporter 2 (SGLT2) inhibitors in emergency general surgery in the United States: a case report
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Understanding empagliflozin use during the perioperative period is crucial for improving outcomes, given the increasing use of sodium-glucose cotransporter 2 (SGLT2) inhibitors and the growing population of surgical patients with diabetes. A 62-year-old woman with poorly controlled type 2 diabetes (hemoglobin A1c, 11.9%), obesity, coronary artery disease, and prior euglycemic diabetic ketoacidosis (euDKA) was taking empagliflozin and insulin when she presented with acute cholecystitis. Initial evaluation demonstrated tachypnea and mild metabolic acidosis with near-normal glucose levels. While kept nothing by mouth and resuscitated with normal saline and sliding-scale insulin, she developed severe high–anion-gap metabolic acidosis (pH, 7.1) with marked ketosis and mild hyperglycemia within 6 hours, consistent with euDKA, requiring intensive care. Treatment with intravenous insulin, dextrose-containing fluids, and bicarbonate resolved the anion gap by hospital day 3, permitting an uncomplicated laparoscopic cholecystectomy. On postoperative day 1, euDKA recurred (pH, 7.2; glucose, 76 mg/dL) and responded to the same protocol with endocrinology-guided insulin adjustment. In urgent surgical settings, clinicians should discontinue SGLT2 inhibitors immediately, initiate early glucose-containing fluids and insulin therapy, and monitor ketones and acid-base status—even in the setting of normal glucose—to prevent delayed diagnosis. Increased awareness may assist providers who manage such patients and may reduce complications and morbidity in the acute care setting.
Empagliflozin (Jardiance) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has gained widespread use for the management of diabetes mellitus (DM) because it lowers blood glucose levels and provides additional cardiovascular and renal protective benefits [1]. However, its mechanism of action raises concerns regarding the risk of euglycemic diabetic ketoacidosis (euDKA), particularly in surgical patients who are in fasting states in preparation for surgery [2].
Several case reports and small observational studies have documented euDKA in patients taking SGLT2 inhibitors during periods of prolonged fasting, including those undergoing both elective and emergent surgery [2,3]. A review of the literature identified 15 reported cases of perioperative euDKA associated with SGLT2 inhibitors, most of which occurred in elective cardiothoracic procedures. These findings have led to recommendations to discontinue SGLT2 inhibitors at least 3 days before elective surgery to reduce the risk of euDKA during the perioperative period.
Despite these guidelines, comprehensive data regarding the prevalence and management of euDKA in emergency surgical settings remain limited. To date, only two cases have been reported in the context of emergency general surgery: Fournier gangrene and acute appendicitis [4,5]. In the Fournier gangrene case, euDKA developed intraoperatively after induction, whereas the appendicitis case involved postoperative euDKA that mimicked peritonitis and delayed diagnosis [4,5]. These reports, together with our case, suggest that euDKA may occur during any phase of surgery. Furthermore, there are currently no standardized protocols for managing patients on SGLT2 inhibitors who require urgent or emergent operations, and existing guidance is largely based on expert opinion rather than robust clinical evidence [3,6].
This case report describes the development of euDKA in a patient with poorly controlled type 2 DM who presented with acute cholecystitis while taking an SGLT2 inhibitor during a perioperative fasting state. The case highlights how the physiologic stress of severe infection and surgery may precipitate euDKA in predisposed patients. We aim to increase awareness of this complication, encourage early recognition and intervention, and contribute to the limited but growing literature on the perioperative management of patients receiving SGLT2 inhibitors in emergency general surgery.
CASE PRESENTATION
Ethics statement
Written informed consent for publication of the research details and clinical images was obtained from the patient. All identifying information has been removed or modified to protect patient confidentiality.
Patient information
A 62-year-old woman with multiple comorbidities, including type 2 DM (hemoglobin A1c, 11.9%) treated with empagliflozin (Jardiance) and insulin, obesity (body mass index, 34 kg/m2), hypertension, prior euDKA associated with empagliflozin in 2021, and coronary artery disease status after multiple coronary artery bypass grafts—presented with 1 day of worsening epigastric pain, anorexia, nausea, vomiting, and chills. She was diagnosed with acute cholecystitis with cholelithiasis requiring urgent surgery. Her last dose of empagliflozin was taken the day before presentation.
Clinical and diagnostic findings
On examination, the patient was hemodynamically stable except for tachypnea (respiratory rate, 26 breaths per minute) and a positive Murphy sign. Laboratory evaluation demonstrated mild metabolic acidosis with low bicarbonate (HCO3–) of 15 mmol/L, an anion gap of 12 mmol/L, an osmolar gap of 16 mOsm/kg, hyponatremia to 133 mmol/L, and serum glucose of 123 mg/dL. Abdominal ultrasonography was consistent with acute cholecystitis.
She was admitted to the medical floor, kept nothing by mouth, resuscitated with normal saline, placed on sliding-scale insulin, and started on parenteral antibiotics while awaiting surgical intervention. Six hours later, she developed euDKA, likely precipitated by infection in the setting of ongoing SGLT2 inhibitor effect, and was transferred to the intensive care unit (ICU). Arterial blood gas and laboratory testing demonstrated severe high–anion-gap metabolic acidosis with pH of 7.1, pCO2 of 25.6 mmHg, HCO3– of 8.8 mmol/L, an anion gap of 17 mmol/L, β-hydroxybutyrate of 6.9 mmol/L, mild hyperglycemia of 107 mg/dL, and leukocytosis of 14,000 cells/µL. Serum lactate was normal at 0.6 mmol/L.
Therapeutic intervention
The patient was treated with a continuous intravenous insulin infusion along with D5LR (5% dextrose in lactated Ringer’s solution) and sodium bicarbonate. After resolution of euDKA on hospital day 3, she underwent an uncomplicated laparoscopic cholecystectomy.
Follow-up and outcomes
However, the patient was readmitted to the ICU on postoperative day 1 (hospital day 4) for recurrent euDKA, likely triggered by surgical stress. Laboratory evaluation revealed an anion gap of 15 mmol/L, β-hydroxybutyrate of 5.5 mmol/L, serum glucose of 76 mg/dL, and a venous blood gas pH of 7.2. The patient was managed similarly to the initial ICU admission, with the addition of an endocrinology consultation during which her home insulin regimen was adjusted. After closure of the anion gap on ICU day 2 (hospital day 5), she was transferred to the medical floor and transitioned back to her home insulin regimen with a low-carbohydrate diet. She was subsequently discharged on hospital day 7 with normalized glucose levels and stable laboratory parameters.
DISCUSSION
This case report describes both preoperative and postoperative euDKA precipitated by acute cholecystitis and ongoing SGLT2 inhibitor use. Although uncommon, euDKA is a potentially life-threatening condition defined by metabolic acidosis (pH <7.3 or serum bicarbonate <18 mmol/L) with ketosis and blood glucose levels of <200 mg/dL [5]. Its atypical presentation, characterized by minimal or absent hyperglycemia, makes diagnosis particularly challenging in emergency and acute perioperative settings [3,6,7]. In addition to diabetes, other recognized risk factors include SGLT2 inhibitor use, prolonged fasting, surgery, and infection [8,9], all of which were present in this patient. Notably, fasting-induced carbohydrate deficiency, glucagon release, and glycogen depletion promote lipolysis and ketogenesis [9]. SGLT2 inhibitors increase urinary glucose excretion and reduce circulating insulin levels, thereby lowering the insulin to glucagon ratio and shifting metabolism toward enhanced lipolysis and hepatic ketoacid production [10]. These mechanisms collectively contribute to metabolic acidosis. Moreover, initial resuscitation with normal saline rather than a dextrose-containing fluid may have intensified ketogenesis, contributing to the first episode of euDKA and delaying surgical intervention. Postoperatively, persistent surgical stress compounded by residual empagliflozin effects likely precipitated recurrence of euDKA, prolonging recovery and necessitating ICU readmission.
SGLT2 inhibitors have been approved by the US Food and Drug Administration (FDA) for use as antidiabetic agents [8,11]. They have a rapid onset of action, peaking 1 to 2 hours after administration, and a relatively long half-life of 10.6 to 16.6 hours [12,13]. Empagliflozin specifically reaches peak plasma concentration at approximately 1.5 hours and has a half-life of 12.5 hours [8,12]. Given this pharmacokinetic profile, current recommendations advise discontinuing SGLT2 inhibitors at least 72 hours before surgery to reduce the risk of postoperative ketoacidosis [2,8,12]. However, this preventive strategy is primarily feasible in planned surgical settings. Implementation of preoperative cessation protocols has been associated with a lower incidence of euDKA in elective procedures, as drug metabolism and clearance occur before exposure to surgical stress and fasting. In contrast, in urgent or emergent surgical settings, the cessation window is often absent or abbreviated. Consequently, patients may remain susceptible to residual pharmacologic effects that promote ketogenesis and impair glucose utilization, contributing to euDKA even after drug discontinuation.
Recent systematic reviews have reported an increasing incidence of euDKA, particularly in the context of surgery and prolonged fasting [9]. In a recent retrospective cohort study by Tallarico et al. [10], postoperative euDKA occurred in 29.7% of SGLT2 inhibitor users and in 46.2% of those undergoing emergency surgery. Patients with comorbidities such as type 2 DM, obesity, heart failure, or recent infection appear to be at increased baseline risk [13]. Multiple case reports and retrospective analyses suggest that approximately 60% to 70% of reported euDKA cases occur in patients with DM [14]. Obesity may further increase risk by promoting insulin resistance, thereby enhancing lipolysis and ketogenesis during physiologic stress, fasting, or infection [6]. In patients with both obesity and DM, as in this case, early symptoms of ketosis may be blunted, potentially delaying diagnosis and treatment [15].
Prevention of euDKA depends on early recognition of risk factors and timely intervention. Several centers (e.g., University of Texas, Michigan Medicine, University of Pennsylvania) and professional societies (e.g., the European Association for Cardiothoracic Surgery) have developed similar guidance for managing SGLT2 inhibitor–associated euDKA. The American Diabetes Association recommends withholding SGLT2 inhibitors at least 3 days before scheduled surgery [16]. However, in hospitalized or acutely ill patients, particularly those with reduced oral intake, emesis, or concurrent infection, a high index of suspicion for euDKA is warranted, even in the absence of marked hyperglycemia [15]. Laboratory evaluation should include a basic metabolic panel, urine ketones, and blood gas analysis to assess for ketosis and acidosis. Prophylactic administration of D5NS (5% dextrose in normal saline) or D10 (10% dextrose) may be considered, in addition to fluid resuscitation, to prevent catabolic ketosis [17]. Early initiation of intravenous insulin infusion rather than reliance on subcutaneous sliding-scale insulin may reduce the likelihood of euDKA development [5]. Once euDKA is identified, treatment parallels that of conventional diabetic ketoacidosis [15]. In the postoperative period, early resumption of adequate nutrition may help stabilize glucose levels and suppress ketone production [18].
Given the increasing use of SGLT2 inhibitors among patients with diabetes undergoing surgery, clinicians should maintain a high index of suspicion for euDKA, particularly in emergency general surgery settings. Patients with diabetes are already predisposed to ketoacidosis due to the physiologic stress of fasting and surgery, and SGLT2 inhibitors may further increase this risk. To reduce the likelihood of euDKA and prevent a complicated surgical course, SGLT2 inhibitors should be discontinued immediately upon presentation. Patients should receive glucose-containing fluids along with sliding-scale insulin or intravenous insulin infusion as clinically indicated [9]. Glucose levels should be monitored every 1 to 2 hours until acidosis resolves, and serum chemistries should be reassessed every 4 to 6 hours when metabolic derangement is suspected. If euDKA develops, prompt correction of the anion gap and metabolic acidosis with insulin and dextrose-containing fluids is essential. Early recognition and proactive management may reduce morbidity in this vulnerable patient population.
ARTICLE INFORMATION
Author contributions
Conceptualization: LR, BT; Investigation: LR, JY, CS; Methodology: LR, CS; Supervision: BT; Writing–original draft: LR, CS; Writing–review & editing: all authors. All authors read and approved the final manuscript.
Conflicts of interest
The authors have no conflicts of interest to declare.
Funding
The authors received no financial support for this study.
Data availability
Data sharing is not applicable as no new data were created or analyzed in this study.
REFERENCES
1. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014;129:587–97.
4. Lindsay PJ, Gibson LE, Bittner EA, Berg S, Chang MG. Sodium-glucose cotransporter-2 (SGLT2) inhibitor-induced euglycemic diabetic ketoacidosis complicating the perioperative management of a patient with type 2 diabetes mellitus (T2DM) and Fournier's gangrene: a case report. Int J Surg Case Rep 2020;77:463–6.
5. Kietaibl AT, Fasching P, Glaser K, Petter-Puchner AH. New diabetic medication sodium-glucose cotransporter-2 inhibitors can induce euglycemic ketoacidosis and mimic surgical diseases: a case report and review of literature. Front Surg 2022;9:828649.
7. Seki H, Kuratani N, Shiga T, et al. Multicentre prospective observational study of sodium-glucose cotransporter-2 inhibitor-associated postoperative ketoacidosis: the SAPKA study protocol. BMJ Open 2021;11:e049592.
8. Heise T, Seewaldt-Becker E, Macha S, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab 2013;15:613–21.
11. van der Aart-van der Beek AB, de Boer RA, Heerspink HJ. Kidney and heart failure outcomes associated with SGLT2 inhibitor use. Nat Rev Nephrol 2022;18:294–306.
12. Johnson KR, Kuhn JE, Daouadi M. Euglycemic diabetic ketoacidosis after robotic-assisted RYGB in a patient taking an SLGT-2 inhibitor: a re-examination of guidelines. ACS Case Rev Surg 2023;4:41–4.
13. Garay PS, Zuniga G, Lichtenberg R. A case of euglycemic diabetic ketoacidosis triggered by a ketogenic diet in a patient with type 2 diabetes using a sodium-glucose cotransporter 2 inhibitor. Clin Diabetes 2020;38:204–7.
15. Handelsman Y, Henry RR, Bloomgarden ZT, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis. Endocr Pract 2016;22:753–62.
16. American Diabetes Association Professional Practice Committee. 16. Diabetes care in the hospital: standards of care in diabetes: 2025. Diabetes Care 2025;48(Supplement_1):S321–34.
18. Choi JC, Jang YN, Lee JH, et al. Fasting is not always good: perioperative fasting leads to pronounced ketone body production in patients treated with SGLT2 inhibitors: a case report. Korean J Fam Med 2025;46:204–9.
Hidden risk of euglycemic diabetic ketoacidosis with sodium-glucose cotransporter 2 (SGLT2) inhibitors in emergency general surgery in the United States: a case report
Hidden risk of euglycemic diabetic ketoacidosis with sodium-glucose cotransporter 2 (SGLT2) inhibitors in emergency general surgery in the United States: a case report
E-SUBMISSION
