Euglycemic diabetic ketoacidosis associated with SGLT-2 inhibitors. Diagnostic and therapeutic challenge

Abstract

Euglycemic diabetic ketoacidosis (EDKA) associated with sodium-glucose cotransporter-2 (SGLT-2) inhibitors is a rare but potentially life-threatening condition, characterized by high anion gap metabolic acidosis, ketonemia or ketonuria, and normal or only mildly elevated blood glucose levels (<200 mg/dL)¹. This atypical biochemical profile may delay diagnosis and increase the risk of complications.

SGLT-2 inhibitors, widely used in the management of type 2 diabetes and, more recently, in heart failure and chronic kidney disease, promote urinary glucose excretion, thereby lowering glycemia and inducing a catabolic state that favors ketogenesis. Several pathophysiological mechanisms have been proposed to explain the development of EDKA. First, SGLT-2 receptors have been identified in pancreatic alpha cells; dapagliflozin has been shown to increase glucagon secretion at the pancreatic level. Second, animal studies have demonstrated that SGLT-2 inhibitors increase renal tubular reabsorption of ketone bodies. Lastly, these agents enhance fatty acid oxidation and ketone body production in patients with type 2 diabetes. These and other mechanisms under investigation support the notion that SGLT-2 inhibitors predispose to EDKA².

Precipitating factors include infections, surgery, fasting, insulin dose reduction, or dehydration. In this context, the absence of marked hyperglycemia may lead to underestimation of metabolic risk and delay of medical intervention.

Given these characteristics, the 2024 ADA/EASD/JBDS/AACE/DTS Consensus Statement updated the diagnostic criteria for diabetic ketoacidosis (DKA): beyond the classical hyperglycemia threshold (>250 mg/dL), a cutoff ≥200 mg/dL is now accepted, or even a prior diagnosis of diabetes regardless of blood glucose level. A high index of suspicion is warranted in patients receiving SGLT-2 inhibitors who present with nonspecific symptoms such as nausea, vomiting, abdominal pain, tachypnea, or altered mental status—even in the absence of hyperglycemia. Measurement of blood ketones (preferably beta-hydroxybutyrate) and venous blood gases should be part of the initial evaluation³.

Treatment of EDKA involves immediate discontinuation of the SGLT-2 inhibitor, fluid replacement, continuous insulin infusion with supplemental glucose to suppress ketogenesis, and correction of electrolyte imbalances. Patient and provider education on risk factors and warning signs is critical for prevention⁴.

In summary, SGLT-2 inhibitor-associated EDKA is a challenging clinical entity due to its silent presentation, requiring clinical awareness and early recognition to prevent adverse outcomes.