Case Report: Prolonged Ketoacidosis in Sodium-Glucose Transport-2 Inhibitor (SGLT2i) User

Case Report

Austin Crit Care Case Rep. 2024; 9(1): 1052.

Case Report: Prolonged Ketoacidosis in Sodium-Glucose Transport-2 Inhibitor (SGLT2i) User

Imran Khan, Bsc Pharm, ACPR, BCPS, PharmD1*; Bernadett Kovacs, MD, FRCPC2; Daniel Bédard, MSc3; Christine Landry, BPharm, MSc, PharmD4; Caitlin Richler, ACPR, PharmD5; Pierre Thabet, B Pharm, ACPR6

1Hôpital Montfort, Clinical Pharmacist, Adjunct Professor, University of Ottawa School of Pharmaceutical Sciences, Institut du Savoir Montofrt, Canada

2Critical Care Medicine, Chief of Critical Care Medicine, Hôpital Montfort, University of Ottawa, Institut du Savoir Montfort, Canada

3Institut du Savoir Montfort, Canada

4Hôpital Montfort, Clinical Pharmacist, Director, Pharmacy Program and Accreditation, School of Pharmaceutical Sciences, University of Ottawa, Canada

5Hôpital Montfort, Clinical Pharmcist, Assistant Clinical Professor, University of Ottawa School of Pharmaceutical Sciences, Canada

6Hôpital Montfort, Department of Critical Care, Assistant Clinical Professor, University of Ottawa School of Pharmaceutical Sciences, Institut du Savoir Montfort, Canada

*Corresponding author: Imran Khan Bsc Pharm, ACPR, BCPS, PharmD, Hôpital Montfort, Clinical Pharmacist, Institut du Savoir Montofrt, Canada. Email: imrankhan@montfort.on.ca

Received: June 27, 2024 Accepted: July 05, 2024 Published: July 12, 2024

Abstract

Background: Sodium Glucose Transport-2 inhibitors (SGLT2i), initially approved for diabetes treatment, have demonstrated clinical benefits in heart failure and renal disease. Despite their increasing use, the potential for adverse drug events necessitates appropriate prescribing information. Notably, ketoacidosis is a significant complication associated with SGLT2i, leading to various complications, including renal, neurological, respiratory, and cardiac issues. Prolonged episodes of ketoacidosis are being increasingly common and this case report details a prolonged episode of diabetic ketoacidosis in a SGLT2i user.

Case Presentations: A 54-year-old male, admitted to the ICU for Diabetic Ketoacidosis (DKA), was using a SGLT2i at home. After three days of IV insulin treatment, his acidosis resolved. On day 4, transitioning to subcutaneous insulin led to a recurrence of acidosis. Monitoring continued, and by day 7, acidosis resolved again. The patient’s beta-hydroxybutyric acid remained detectable for the first 9 days. Prolonged ketoacidosis was attributed to SGLT2i use in the context of poor renal function.

Conclusions: This case underscores the risk of prolonged ketoacidosis associated with SGLT2i use, especially in patients with compromised renal function. The report contributes to the growing literature on extended durations of acidosis secondary to SGLT2i use, emphasizing the need for heightened awareness, careful monitoring, and tailored interventions to mitigate adverse outcomes.

Keywords: SGLT2 Inhibitors; Euglycemic DKA; Hyperglycemic DKA; Diabetic ketoacidosis duration; Metabolic profiles

Introduction

Sodium-Glucose co-Transporter 2 inhibitors (SGLT2i) are an innovative class of oral antihyperglycemic drugs that function by inhibiting renal glucose reabsorption, thus promoting glucosuria and reducing blood glucose levels. SGLT2i’s were initially approved for diabetes treatment, and have since demonstrated clinical benefits in heart failure and renal disease [1]. Despite their increasing use, the potential for adverse drug events necessitates appropriate prescribing education. DKA is a rare complication associated with SGLT2i use with reported incidence rates ranging from 0.6 to 2.2 events per 1,000 person-year in studies [2]. Several case reports have noted prolonged ketoacidosis related to SGLT2i use, with potential contributing factors including the slow dissociation rate from SGLT2 transporter, genetic polymorphisms, decreased renal function, and the lipophilicity of the drug [3]. Episodes of ketoacidosis are considered prolonged when the resolution extends beyond 24 hours [4]. This phenomenon is being increasingly common and may complicate a patient’s clinical course. While case reports and case series have previously documented prolonged episodes of ketoacidosis resulting from SGLT2i use, the prevalence of this occurrence remains largely uncertain [3,8,15]. This case report provides a detailed account of a prolonged episode of DKA in a patient using a SGLT2i.

Case Presentation

A 54-year-old male presented to the Emergency Department (ED) with general weakness, rapid atrial fibrillation and DKA. He had a 4-day history of feeling weak with severe nausea and vomiting over the last 48 hours prior to ED visit. He had very little to eat in the last 48 hours. He denied any chest pain, syncope, palpitations or dyspnea. He also did not have any cough, fever, expectorant, diarrhea, no signs and symptoms of bleeding. The patient had a history of type II diabetes, hypertension and dyslipidemia. His medical conditions were being managed with Empagliflozin 10 mg daily, Glyburide 5 mg twice daily, Metformin 1000 mg twice daily, Atorvastatin 20 mg daily, Ramipril 10 mg daily and Aspirin 81 mg daily. Regarding his diabetes history, the patient received a diagnosis of type 2 diabetes approximately five years prior his admission. Initially, he was prescribed Metformin, and over the first two years, the dosage was gradually increased to 2000 mg per day. In his third-year post-diagnosis, Glyburide was added to his treatment regimen as his hemoglobin A1C% (HbA1C%) remained above target at 7.4%. Despite these medications, over the next two years, his HbA1C level continuously increased to 11.2% two months before admission, prompting his family physician to introduce a third agent, the SGLT2i Empagliflozin. Upon admission, the patient was taking a combination of Metformin, Glyburide, and Empagliflozin. However, due to feeling unwell, experiencing nausea and vomiting in the 48 hours leading up to his admission, he had not taken any of his diabetes medications.

Additionally, the patient stated to be a non-smoker and reported no consumption of alcohol or illicit substances. However, the patient did report a slight increase in weight over the last year, and admitted to a poor baseline glucose control with levels ranging from 215 to 320 mg/dL (12 to 17 mmol/L). Of note, his kidney function was normal prior to admission with a creatinine of 1.04 mg/dL (92 umol/L).

In the emergency department, the patient had a temperature of 35.8°C, blood pressure of 112/53 mmHg, heart rate of 166 bpm, a respiratory rate of 22 bpm and a SpO2 of 100%. He received 15 mg of Diltiazem intravenously for suspected atrial fibrillation as patient presented with tachycardia with premature atrial complexes on his initial electrocardiogram. Importantly, his initial laboratory values showed a glucose of 800 mg/dL (44.4 mmol/L). His initial blood gas analysis revealed a pH of 7.00, bicarbonate level of 7 mmol/L, and an anion gap of 27 mmol/L. Additionally, his ketone (beta-hydroxybutyric acid) concentration was measured at 11.30 mmol/L. Based on these findings, he was diagnosed with DKA, characterized by a pH below 7.30, an elevated Anion Gap (AG) metabolic acidosis (AG >12 mmol/L and bicarbonate [HCO3] <24 mmol/L), and elevated ketone levels. To address his hyperglycemic presentation, 10 units of rapid insulin was administered subcutaneously. Following hospital protocol, intravenous fluids were initiated to manage the suspected DKA and the severe dehydration reported over the last few days. With an estimated fluid loss of 6 to 9 liters in typical DKA presentations, 50% of the total volume loss was administered upon admission. The patient was initially given 2 liters of normal saline, followed by Ringer's Lactate at a rate of 100 mL/hour for an additional 2 liters.

A septic work-up was completed and his laboratory values demonstrated an elevated white blood cell count of 19.8 x10^9/L, a creatinine of 2.32 mg/dL (205 mmol/L), an eGFR of 35 mL/min, and a corrected sodium of 147 mmol/L.

Investigations

Chest X ray on admission and day 2 of visit demonstrated cardio-mediastinal contours within normal limits and clear lungs. Both urine and blood cultures were negative on admission. Subsequent electrocardiograms on admission demonstrated atrial fibrillation. An echocardiogram on admission day 4 demonstrated a mildly dilated left ventricular size and a ventricular ejection fraction of 41%.

Treatment

In the emergency department, he was promptly initiated on Ceftriaxone for possible infection of which the source was unknown. In regards to his home medications, Empagliflozin, Glyburide, Metformin and Ramipril were not continued on admission given his dehydrated status. For his DKA, the patient was administered Insulin regular IV infusion at 10 units/hour and titrated as per glycemia based on institutional protocol. He was also administered dextrose 10% IV along with potassium-containing IV maintenance fluids and transferred to the Intensive Care Unit (ICU). The above regimen was administered for 24 hours and the following day (post-admission day 1) his blood gas was reevaluated; pH of 7.15, bicarbonate of 12.6 mmol/L and an anion gap of 26 mmol/L. His beta-hydroxybutyric acid was 11.3 mmol/L and his hemoglobin A1C result on admission was 13.7%. Given the small improvements in his metabolic profile, the decision was made to continue the DKA protocol with insulin regular IV infusion.

On admission day 4, the patient’s blood gas demonstrated a pH of 7.28, bicarbonate of 17.9 mmol/L and an anion gap of 17 mmol/L. The patient’s beta-hydroxybutyric acid was also reducing now at 5.35 mmol/L. Given the improvements in the patient’s clinical status and bloodwork, the decision was made to transition the patient to long-acting insulin Glargine along with sliding scale rapid acting insulin aspart. The following day, on admission day 5, the patient become more acidotic with a pH decreased to 7.24, bicarbonate decreased to 15.3 mmol/L and his anion gap increased to 21 mmol/L. Given the patient was otherwise clinically stable, he was maintained on the same insulin regimen. Furthermore, it is crucial to emphasize that no new medications initiated, and no additional electrolyte or metabolic abnormalities identified to account for the exacerbation of acidosis. On admission day 7, his anion gap was normalizing again at 10 mmol/L and his beta-hydroxybutyric acid was 1.90 mmol/L. His glucose levels remained persistently elevated and the decision was made to initiate ultra-long acting insulin Degludec instead of Glargine for a more stable and prolonged blood glucose lowering effect. On admission day 8, the patient’s anion gap increased slightly to 13 mmol/L with a rise in his beta-hydroxybutyric acid. Again, the patient was clinically stable and so no immediate changes were made to his insulin regimen. As of admission day 9, the patient still had detectable ketones in his blood with a beta-hydroxybutyric acid of 1.89 mmol/L (Table 1).

Citation:Khan I, Kovacs B, Bédard D, Landry C, Richler C, et al. Case Report: Prolonged Ketoacidosis in Sodium-Glucose Transport-2 Inhibitor (SGLT2i) User. Austin Crit Care Case Rep. 2024; 9(1): 1052.