Diabetic ketoacidosis induced by SGLT2 inhibitors in acute ischemic stroke: a report of two cases

Jin-Heon Jeong

doi:10.18700/jnc.240039

Abstract

Background

Diabetic ketoacidosis (DKA) is a common hyperglycemic emergency characterized by hyperglycemia, metabolic acidosis, and ketonemia. DKA is a rare but serious complication of sodium-glucose cotransporter-2 (SGLT2) inhibitors that requires careful monitoring.

Case Report

We present two cases of acute ischemic stroke in patients who developed DKA during the administration of SGLT2 inhibitors. Case 1 was a 70-year-old woman with a right middle cerebral artery (MCA) infarction who developed severe metabolic acidosis and ketonemia on hospital day 5, which resolved after insulin and fluid therapy. Case 2 was a 52-year-old woman with a right MCA infarction and carotid stenosis who developed DKA on hospital day 3. Despite initial resolution, DKA recurred after SGLT2 inhibitor re-administration and permanent discontinuation was necessary.

Conclusion

These cases highlight the risk of DKA in the acute phase of ischemic stroke in patients treated with SGLT2 inhibitors.

Key Words: Diabetic ketoacidosis; Ischemic stroke; Diabetes; SGLT2 inhibitor

INTRODUCTION

Diabetic ketoacidosis (DKA) is a common hyperglycemic emergency in patients with diabetes mellitus and is characterized by hyperglycemia, metabolic acidosis, and ketonemia [1]. It arises from insulin deficiency and hyperglycemia and is often triggered by stressors such as acute medical illness, dehydration, intense physical activity, surgery, or alcohol intake [1-3]. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are widely used to manage diabetes and improve cardiovascular and renal outcomes, which may benefit patients with stroke. However, DKA can be a severe adverse event caused by the administration of SGLT2 inhibitors in patients with diabetes and requires careful monitoring. This report presents two cases of DKA associated with SGLT2 inhibitors in patients with acute ischemic stroke.

CASE REPORTS

Case 1

A 70-year-old woman presented with left-sided hemiparesis. Brain computed tomography (CT) angiography and magnetic resonance imaging (MRI) confirmed a right middle cerebral artery (MCA) infarction with a right proximal MCA occlusion. The patient underwent intra-arterial thrombolysis and was admitted to the stroke unit. The patient had a two-year history of diabetes mellitus managed with metformin 1,000 mg twice daily (BID), gliclazide 90 mg once daily (QD), and empagliflozin 25 mg QD, all of which were discontinued upon admission to the hospital. The fluid balance of the patient was managed using a target input and output (I/O) balance of 0 to +500 mL.

On day 2, the patient developed a fever and was started on piperacillin/tazobactam for suspected pneumonia. On day 5, the patient developed dyspnea and altered consciousness, which necessitated intubation and mechanical ventilation. Arterial blood gas analysis (ABGA) revealed severe metabolic acidosis with a pH of 6.936, pCO₂ levels of 27.6 mm Hg, and bicarbonate levels of 5.7 mEq/L. Furthermore, the anion gap was elevated to 23.3 mEq/L. Although lactate levels were normal, serum ketone levels were markedly elevated (11.06 mmol/L), and the blood glucose level was 291 mg/dL, which was consistent with DKA. Insulin therapy and intravenous fluids were initiated, leading to the normalization of ketone levels to 0.79 mmol/L within 3 days. The DKA resolved, and her diabetes management was shifted to a multiple-daily insulin injection regimen. The patient was subsequently transferred to a rehabilitation facility in stable condition.

Case 2

A 52-year-old woman presented with left-sided hemiparesis and dysarthria. Brain CT angiography and MRI identified a right MCA infarction with a right proximal internal carotid artery stenosis. The patient was then admitted to the stroke unit. The patient had a seven-year history of diabetes mellitus managed with metformin 1,000 mg BID, glimepiride 2 mg QD, and empagliflozin 25 mg QD. Metformin was discontinued upon admission to the hospital. The fluid balance of the patient was managed using a target I/O balance of 0 to +500 mL.

On day 2, the left-sided weakness of the patient worsened, and hemispatial neglect developed. The follow-up brain MRI revealed progression to a right MCA total infarction. Mannitol was administered for brain swelling, and piperacillin/tazobactam was initiated for suspected pneumonia. All diabetes medications were withheld, and the patient was placed on nothing-by-mouth status. On day 3, the patient developed dyspnea with a respiratory rate of 30 breaths per minute. ABGA revealed metabolic acidosis with a pH of 7.221, pCO₂ levels of 10.1 mm Hg, and bicarbonate levels of 4.1 mEq/L. Moreover, the anion gap was elevated at 21.9 mEq/L. Although lactate levels were normal, serum ketone levels were elevated (7.53 mmol/L), and the blood glucose level was 318 mg/dL, which was indicative of DKA.

Insulin therapy and intravenous fluids were initiated, and intubation with mechanical ventilation was performed because of anticipated respiratory failure. Ketone levels normalized (0.25 mmol/L) within 3 days, and insulin therapy was discontinued. However, after empagliflozin was resumed along with glimepiride, ketone levels increased again the next day despite clinical stability. The recurrent DKA was attributed to empagliflozin, which was subsequently discontinued. After adjusting medication, the patient experienced no further episodes of ketoacidosis and was transferred to a rehabilitation facility in stable condition.

DISCUSSION

These cases illustrate that DKA can occur in patients with acute ischemic stroke treated with SGLT2 inhibitors. Although DKA is typically associated with type 1 diabetes, it can also develop in patients with type 2 diabetes, particularly during acute illness [1,2]. In case 1, SGLT2 inhibitor-related adverse effects were not initially considered, and ketoacidosis was first attributed to contrast agent use in a patient taking metformin. In case 2, DKA initially improved but recurred after re-administration of the SGLT2 inhibitor despite no other changes in the condition of the patient (Fig. 1). The fluctuations in the ketone levels were observed with ketonemia resolving after treatment and rising again upon re-administration of SGLT2 inhibitors, implicating them as the primary cause of DKA. Similarly, the re-evaluation of case 1 implicated the same medication. Both cases highlight the risk for DKA development during the acute phase of ischemic stroke in patients treated with SGLT2 inhibitors. Additional factors, such as the concurrent use of other diabetes medications and contrast imaging for stroke evaluation, may have contributed to their metabolic disturbances.

DKA is diagnosed based on the presence of hyperglycemia, anion gap metabolic acidosis, and ketonemia, with metabolic acidosis being the hallmark feature [1-3]. It results from insulin deficiency, leading to unopposed lipolysis and free fatty acid oxidation, which produce excessive ketone bodies and cause anion gap metabolic acidosis. DKA is typically triggered by factors such as insulin dose reduction, severe illness, dehydration, or alcohol consumption.

SGLT2 inhibitor-associated DKA occurs in approximately 0.2% of treated patients [4]. Identified risk factors include a history of DKA, baseline hemoglobin A1c level, creatinine level, bicarbonate level, and concomitant use of dementia medications [4,5]. While DKA generally develops after the prolonged use of SGLT2 inhibitors, rare cases have been reported shortly after initiation [6]. SGLT2 inhibitor-related DKA often presents as euglycemic DKA with relatively low glucose levels [3,5]. In the present cases, the glucose levels were lower than those typically observed in classic DKA, further implicating SGLT2 inhibitors as a contributing factors.

The association between DKA and stroke in adults is uncommon, though some evidence suggests DKA may increase the stroke risk [7,8]. Proposed mechanisms include systemic inflammation, cerebral hypoperfusion, and heightened coagulopathy [7,9]. Thrombotic risk during DKA is elevated due to coagulation factors, platelet activation, blood volume, and vascular reactivity abnormalities. Although acute vascular events in patients with diabetes may trigger DKA, data regarding the incidence of DKA in patient with acute ischemic stroke remain limited [10].

DKA is a serious and potentially life-threatening complication that can occur during the acute phase of ischemic stroke in patients treated with SGLT2 inhibitors. This report presents the first documented cases showing a strong association between the use of SGLT2 inhibitors and DKA development in the patient with acute ischemic stroke. In cases of sudden clinical deterioration accompanied by metabolic acidosis, ketone level assessment is critical for timely diagnosis and management.