The Case

A 67-year-old male with past medical history significant for coronary artery disease (CAD) status-post myocardial infarction and coronary artery bypass graft (CABG) surgery, obstructive sleep apnea (OSA) on continuous positive airway pressure (CPAP), obesity (body mass index, 30), hyperlipidemia, and well-controlled insulin-requiring type 2 diabetes (HgbA1c of 7.1%) presented to the hospital for elective implantation of a cardiac resynchronization and defibrillator device (CRT-D). He was discharged the following day. One day later, he returned to the hospital emergency department with severe nausea, vomiting, and abdominal pain, and he was found to have euglycemic diabetic ketoacidosis (eDKA), with a serum glucose of 278 mg/dL, pH of 7.0 (normal value: 7.35-7.45), serum bicarbonate of 8 mEq/L (normal value: 22-29 mmol/L), beta-hydroxybutyrate (BHB) of 11.8 mmol/L (normal value: 0.02 - 0.27mmol/L), and calculated serum osmolality of 305 mOsm/kg. All chemistry test results are shown in the table below (bold indicates abnormal values).

On further questioning, it was discovered that the patient had not been instructed to stop taking his empagliflozin, a sodium-glucose co-transporter protein 2 inhibitor (SGLT2i), three days before his elective cardiology procedure. He was told only to hold it on the day of the procedure, and to resume all medications after discharge; he carefully followed these instructions. The patient was admitted to the ICU and started on an insulin infusion with intravenous hydration, but his course was complicated by acute chest pain. He was moved to the Cardiac ICU with a non-ST elevation myocardial infarction (NSTEMI). Left heart catheterization revealed diffuse CAD and he was managed medically.

The Commentary

By Berit Bagley, RN, MSN, CDCES, BC-ADM, Charity L. Tan, MSN, ACNP-BC, CDCES, BC-ADM, and Deborah Plante, MD

A 67-year-old male with well-controlled type 2 diabetes mellitus underwent elective CRT-D implantation. His pre-procedure medication instructions were to stop all medications the night prior to the procedure. The procedure was apparently successful, and the patient was discharged the next day with instructions to resume all his prior medications, including empagliflozin. However, when he returned to the hospital one day later, he had a high anion gap metabolic acidosis. Euglycemic diabetic ketoacidosis (eDKA) was diagnosed, and he was transferred to the ICU for insulin infusion. However, his recovery was complicated by an NSTEMI requiring further medical management.

Euglycemic diabetic ketoacidosis (eDKA) is characterized by three clinical findings: mild hyperglycemia or euglycemia (blood glucose <250 mg/dL), high anion gap metabolic acidosis (pH <7.3, HCO3 <18 mEq/L), and ketonemia. Due to the lack of severe hyperglycemia, the diagnosis of eDKA is challenging and is often delayed or missed. eDKA is a state of carbohydrate deficiency with relative insulin deficiency and increased levels of counter-regulatory hormones, resulting in lipolysis, increased free fatty acids and ketoacidosis, but without severe hyperglycemia. It is estimated that 3% of admissions for DKA are consistent with eDKA.¹ Precipitating factors for eDKA include fasting, pregnancy, alcohol, surgery, and, more recently, the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i).^1,2 SGLT2i represent a class of medications that work on the renal system to enhance glucose excretion and block glucose reabsorption from the proximal tubule. This class of medications has been shown to improve glycemic control with a favorable cardiorenal profile, including decreased rates of major adverse cardiovascular events (MACE), fewer hospitalizations for heart failure, and delayed progression of kidney disease. As a result of these favorable outcomes, the use of SGLT2i is growing over time. ^2,3,4

Risk factors for eDKA with these medications include surgical stress, acute postoperative illness, and decreased carbohydrate intake. The human body can maintain normoglycemia through the breakdown of glycogen stores by the liver, which triggers the pancreas to produce insulin. SGLT2i decrease glucose levels through urinary excretion of excess glucose. With the decrease in plasma glucose levels, insulin secretion by the pancreas is reduced, which then leads to increase glucagon secretion, resulting in lipolysis, increased free fatty acids, and ketone production.^3,4

The use of SGLT2is in patients with diabetes, cardiovascular, and renal disease has increased dramatically in the past few years. However, these medications can have adverse events, including genitourinary infections and eDKA.^4,5 eDKA with SGLT2i may occur among patients with either type 1 or type 2 diabetes. The incidence of eDKA during clinical trials has been reported to be as low as 0.24 to 0.76 per 1000 patient-years with canagliflozin and 0.2 to 0.6 per 1000 patient-years with empagliflozin. However, analysis of the FDA Adverse Event Reporting System (FAERS) by Blau and colleagues suggested that the risk of eDKA in patients with type 2 diabetes taking SGLT2is may be increased as much as seven-fold, compared with patients taking dipeptidyl peptidase IV (DPP IV) inhibitors (e.g., sitagliptin, saxagliptin).⁵ The risk of eDKA is higher among patients with insulin deficiency, and thus, higher in the setting of type 1 diabetes than type 2 diabetes. Rates vary but are reported to be as high as 12% among patients with type 1 diabetes; therefore, these agents are not recommended for use in this patient population.⁶ Additional risk factors for eDKA with SGLT2i use include recent surgery, acute medical illness, poor fluid and food intake, and relative insulin deficiency.^7,8

Approach to Improving Safety & Patient Safety Target

Studies have shown that patients with diabetes mellitus on any SGLT2i have an increased risk of developing eDKA; therefore, healthcare professionals need to be vigilant in educational and preventive measures.⁹ American Diabetes Association Standards of Care recommend that most SGLT2is (e.g., canagliflozin, dapagliflozin, and empagliflozin) be stopped three days before scheduled surgery and ertugliflozin stopped up to four days before surgery. The half-life of SGLT2i ranges from 11 to 17 hours, so even after holding the medication, the pharmacological effects of glucosuria and ketonemia may be present for several days.^8,9,10 The risk for SGLT2i-related eDKA is notably higher among patients with emergent procedures.¹¹ Providers should educate patients about clinical scenarios that justify pausing the use of SGLT2i, such as decreased oral intake or volume depletion. In the inpatient setting, SGLT2i should be paused with anticipated procedures, acute illness, or decreased oral intake. Lau and colleagues recommended resuming SGLT2i only once adequate oral intake can be maintained post-operatively.^5,12,13

Systems Optimization

A health system approach to safely manage medication transitions in the periprocedural period involves a comprehensive and coordinated effort to ensure that patients receive the most appropriate and safe medication regimens.¹⁴ This approach involves multiple stakeholders, including prescribers, nurses, pharmacists, informaticists and patients working together to minimize risks and optimize patient outcomes. Components of this approach include:

1. Preoperative Assessment:

• Conduct a thorough preoperative assessment to gather information about the patient's medical history, current medications, allergies, and any previous adverse reactions to medications (or withdrawal of medications).
• Assess the patient's risk factors, including comorbidities and conditions that may affect medication choices and dosages in the perioperative period.

2. Medication Reconciliation:

• Obtain a detailed and accurate list of the patient's current medications, dosages, and times of administration, including prescription drugs, over-the-counter medications, supplements, and herbal remedies.
• Review the medication list to identify drugs that need to be discontinued, adjusted, or temporarily stopped before surgery to reduce the risk of complications.
• Leverage best practice alerts to automatically trigger for high-risk medications that need to be discontinued under certain situations.

3. Evidence-based Guidelines:

• Develop and follow evidence-based guidelines for medication management prior to surgery. These guidelines should consider the patient's medical history, the type of surgery being performed, and the planned type of anesthesia.

4. Information Systems:

• Utilize electronic medication algorithms and pharmacy information systems to track medication recommendations and changes throughout the process. One example of such a system, tailored to support preoperative management of patients with diabetes, is shown here.
• EHR systems can “push” appropriately timed information and reminders (or cautions) to patients, such as a reminder to stop medications three days prior to a procedure or if unable to eat or drink.

5. Preoperative Education:

• Educate patients about medication changes and the importance of adherence to these recommendations. Using teach-back methods and written or online resources, ensure that patients understand why specific medications need to be adjusted or discontinued, and the potential risks associated with not doing so.

6. Postoperative Medication Management:

• Ensure that appropriate medications are resumed or continued postoperatively as needed.

7. Continuous Quality Improvement:

• Regularly evaluate and audit the medication management process to identify areas for improvement and ensure patient safety, including soliciting feedback from patients about the clarity of medication management instructions.

With specific reference to this case, clinicians and patients should be made aware of the risks of developing eDKA associated with SGLT2i use, especially in patients who are not eating or drinking normally, or undergoing a procedure that requires them to fast.^8,15 Furthermore, the patient should only resume the SGLT2i once they are able to eat and drink normally.⁶ For emergent or unplanned procedures, which preclude pausing SGLT2i in advance, increased monitoring, fluid replacement, and vigilance for eDKA is necessary.

Take Home Points

• SSTOP (Stop SGLT2 inhibitors Three days bef-O-re Procedures!!!)
• Educate clinical staff to recognize the signs and symptoms of eDKA.
• Screen early for urine or serum ketones in patients with unplanned procedures or high risk for eDKA.
• Standardize and optimize medication adjustment recommendations before and after procedures and operations so they can be implemented by any staff member.
• Utilize information systems to “push” reminders (or cautions) to patients regarding appropriate times to stop or hold certain medications.

Berit Bagley, RN, MSN, CDCES, BC-ADM
Advanced Practice Nurse Specialist
Patient Care Services
UC Davis Health
bmbagley@ucdavis.edu

Charity L. Tan, MSN, ACNP-BC, CDCES, BC-ADM
Inpatient Glycemic Team Nurse Practitioner
Patient Care Services
UC Davis Health
cltan@ucdavis.edu

Deborah Plante, MD
Director Inpatient Glycemic Team
Professor 
Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism
UC Davis Health
dkplante@ucdavis.edu

References

1. Jenkins D, Close CF, Krentz AJ, et al. Euglycaemic diabetic ketoacidosis: does it exist?.Acta Diabetol. 1993;30(4):251-253. [Free full text]
2. Plewa MC, Bryant M, King-Thiele R. Euglycemic Diabetic Ketoacidosis. In:StatPearls. Treasure Island (FL): StatPearls Publishing; January 29, 2023. [Free full text]
3. Patel K, Nair A. A literature review of the therapeutic perspectives of sodium-glucose cotransporter-2 (SGLT2) inhibitor-induced euglycemic diabetic ketoacidosis.Cureus. 2022;14(9):e29652. [Free full text]
4. Juneja D, Nasa P, Jain R, et al. Sodium-glucose cotransporter-2 inhibitors induced euglycemic diabetic ketoacidosis: a meta summary of case reports.World J Diabetes. 2023;14(8):1314-1322. [Free full text]
5. Blau JE, Tella SH, Taylor SI, Rother KI. Ketoacidosis associated with SGLT2 inhibitor treatment: Analysis of FAERS data.Diabetes Metab Res Rev. 2017;33(8):10.1002/dmrr.2924. [Free full text]
6. Barski L, Eshkoli T, Brandstaetter E, et al. Euglycemic diabetic ketoacidosis.Eur J Intern Med. 2019;63:9-14. [Available at]
7. Mehta PB, Robinson A, Burkhardt D, et al. Inpatient perioperative euglycemic diabetic ketoacidosis due to sodium-glucose cotransporter-2 inhibitors - lessons from a case series and strategies to decrease incidence.Endocr Pract. 2022;28(9):884-888. [Free full text]
8. Drug Safety Communication. FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. Silver Spring, MD: US Food and Drug Administration. Accessed November 29, 2023. [Free full text]
9. Pujara S, Ioachimescu A. Prolonged ketosis in a patient with euglycemic diabetic ketoacidosis secondary to dapagliflozin. J Investig Med High Impact Case Rep. 2017;5(2):2324709617710040. [Free full text]
10. American Diabetes Association. 15. Diabetes Care in the Hospital:Standards of Medical Care in Diabetes-2021.Diabetes Care. 2021;44(Suppl 1):S211-S220. [Free full text]
11. Penna LEM, Rivera MO, Rosado Burgos A, et al. ODP244 SGLT2 inhibitor-induced euglycemic DKA and its challenges. J Endocr Soc. 2022;6(Supplement_1):A333-A334. [Free full text]
12. Lau A, Bruce S, Wang E, et al. Perioperative implications of sodium-glucose cotransporter-2 inhibitors: a case series of euglycemic diabetic ketoacidosis in three patients after cardiac surgery. Can J Anaesth. 2018;65(2):188-193. [Free full text]
13. Khalifa M, Aftab H, Kantorovich V. Euglycemic DKA in patients on SGLT2 inhibitor and potentially ketotic state. J Endocr Soc. 2021;5(Suppl 1):A382–383. [Free full text]
14. Abdelmasih R, Abdelmaseih R, Rifai F, et al. SGLT2 inhibitor induced euglycemic DKA (EDKA) with proximal renal tubular acidosis (RTA) as a rare fatal complication in a non-insulin dependent diabetic patient: a challenging dilemma. J Endocr Soc. 2021;5(Supplement_1):A400-A401. [Available at]
15. Burkhardt D, Mehta P, Robinson A, et al. ODP212 inpatient euglycemic DKA due to SGLT2 inhibitors – lessons from a case series and strategies to decrease incidence. J Endocr Soc. 2022;6(Supplement_1):A320-A321. [Free full text]