A case of SGLT2 inhibitor-induced euglycemic diabetic ketoacidosis

Sodium glucose cotransporter 2 inhibitors (SGLT2i) are a class of oral diabetes drugs that have shown improved cardiovascular and renal outcomes in patients with and without diabetes. Although rare, serious side effects including euglycemic diabetic ketoacidosis (EDKA) are of concern. We present an interesting case of SGLT2i-induced EDKA that occurred two years after the start of therapy.

A 57-year-old man presented to the emergency department for a week with generalized weakness, nausea, vomiting, and poor oral intake. His medical history was significant for diabetes mellitus (treated with empagliflozin and metformin). On presentation he was tachycardic and tachypneic. Physical examination revealed dry mucous membranes and a soft, nontender abdomen. Initial laboratory diagnostics were notable for leukocytosis, elevated blood urea nitrogen, elevated creatinine, low bicarbonate, mild hyperglycemia, and high anion gap metabolic acidosis (HAGMA). Lactic acid levels, liver function tests and troponin-I were within the normal range (Tab 1). The ECG showed no acute ischemic changes. He received 2 liters of normal saline and was admitted to treat HAGMA.

The patient denied having recently consumed ethanol or other toxic alcohols. He advocated adherence to all home medications. Acetaminophen, ethanol and salicylate levels were negative. Urinalysis revealed glucosuria and ketonuria (Table 1). Based on the clinical history, examination findings and laboratory diagnostics, the patient was diagnosed with EDKA and transferred to the intensive care unit for further treatment. He was started on a continuous infusion of regular insulin and his intravascular volume loss was corrected with a continuous infusion of dextrose 5% in Ringer’s lactate. After the anion gap normalized, he was switched to subcutaneous insulin and his clinical symptoms improved dramatically. He was discharged on basal and short-acting subcutaneous insulin with scheduled outpatient follow-up. Empagliflozin was discontinued at the time of discharge. At his follow-up visit, he was doing well with no worrisome symptoms.

SGLT2i are a newer class of antidiabetics recommended as second-line drugs for type 2 diabetes mellitus because they improve clearance and prevent reabsorption of filtered glucose molecules from the proximal renal tubules [1,2]. Recently, their use has increased significantly as many large studies have shown significant cardiovascular protective effects [1,3]. SGLT2i has also been included in current guidelines as a guideline-compliant drug therapy for patients with heart failure [4]. EDKA is the presence of ketonemia or ketonuria along with HAGMA with obtained blood glucose levels below 250 mg/dL [5-7]. Not all patients on SGLT2i develop EDKA [5]. In a large multicenter cohort study, the incidence of SGLT2i-induced EDKA was estimated at 0.25%. [5]. Usually, a trigger such as infection, pregnancy, fasting, or episodes of vomiting leads to a physiological state of relative insulopenia and increased starvation [7-8].

The elimination of glucose due to SGLT2i mimics a state of carbohydrate starvation and volume starvation. This leads to an increase in the glucagon/insulin ratio. In addition, SGLT2i directly stimulates the release of glucagon by acting on the alpha cell of the pancreas, thereby promoting hepatic ketogenesis and accelerating ketone formation (Figure 1). The balance between glucosuria and glucagon stimulation leads to the maintenance of a state of euglycemia [6,7]. The Adverse Reaction Probability Scale can be used to estimate the likelihood of a causal relationship between empagliflozin and EDKA. In the case of our patient, the total score was 7, suggesting that an adverse drug reaction is likely to be present [9].

The treatment of EDKA is essentially the same as that of DKA, except for the timing of administering the dextrose infusion [7-10]. For EDKA, immediate initiation of aggressive IV dextrose is advisable. Any SGLT2i should be held immediately. A favorable prognosis depends on early detection and screening with serum or urine ketones, even when serum glucose is normal [5-7]. Most patients with EDKA recover with prompt detection and treatment. Educating patients about early sign detection remains a cornerstone of early detection and response to SGLT2i-induced EDKA [7,10].

EDKA is a rare but serious side effect of SGLT2i that requires prompt recognition and early initiation of appropriate therapy. Physicians should have a high suspicion of EDKA in patients with euglycemia and HAGMA using SGLT2i. Most patients recover with timely detection and treatment, and patient education about detecting early signs remains a cornerstone of prompt treatment.