Euglycemic Diabetic Ketoacidosis Associated with SGLT2 Inhibitors

Euglycemic diabetic ketoacidosis (EDKA) is characterised by the triad of metabolic acidosis with elevated anion gap, ketonaemia or ketonuria and near-normal blood glucose levels, typically below 200 mg/dL. The emergence of sodium–glucose cotransporter 2 (SGLT2) inhibitors has revived interest in this condition, as these agents predispose to ketosis through glucosuria, mild insulinopenia and a shift towards increased lipolysis and hepatic ketogenesis. Volume depletion, enhanced counter-regulatory hormone release and reduced insulin-to-glucagon ratio further contribute to ketone accumulation. Clinically, EDKA is a diagnostic challenge because normoglycaemia may mask the severity of acidosis, necessitating vigilance in at-risk scenarios such as acute illness, surgery, prolonged fasting and insulin dose reduction. Although rare, the global adoption of SGLT2 inhibitors for type 2 diabetes and cardiovascular risk reduction underscores the need for awareness, prompt recognition and tailored management to prevent morbidity.

Research from Nature Portfolio

Recent experimental work using rodent models has elucidated the mechanistic interplay between insulin deficiency and dehydration in precipitating EDKA. By administering an SGLT2 inhibitor under insulinopenic conditions, investigators demonstrated that volume depletion amplifies catecholamine and corticosterone levels, driving adipose lipolysis, hepatic acetyl-CoA accumulation and ketogenesis independent of hyperglucagonaemia. These findings suggest that prevention of EDKA may hinge on maintenance of euvolaemia and careful insulin titration during intercurrent stress. Complementing these mechanistic insights, a multicentre cohort study of type 2 diabetic patients on SGLT2 inhibitors revealed a EuDKA prevalence of approximately 0.4 percent, with certain analogues such as canagliflozin showing higher relative incidence. Infection emerged as the predominant trigger, while differential SGLT2 inhibitor effects on intensive care admission rates point to the need for analogue-specific risk stratification and prospective evaluation.

Euglycemic Diabetic Ketoacidosis Associated with SGLT2 Inhibitors publication trend

The graph below shows the total number of articles in euglycemic diabetic ketoacidosis associated with sglt2 inhibitors across all publications each year (not limited to Nature Index journals).

Technical terms

Sodium–glucose cotransporter 2 (SGLT2) inhibitors: Oral agents that block renal glucose reabsorption, promoting glucosuria and lowering blood glucose independently of insulin.

Euglycemic diabetic ketoacidosis (EDKA): A variant of diabetic ketoacidosis presenting with significant ketonaemia and acidosis but only mild or normal hyperglycaemia.

Lipolysis: The enzymatic breakdown of triglycerides in adipose tissue into free fatty acids, which serve as substrates for ketone body production.

Ketogenesis: Metabolic pathway in the liver converting acetyl-CoA derived from fatty acids into ketone bodies for peripheral energy use.

Anion gap metabolic acidosis: A measure of unmeasured plasma anions; an elevated gap indicates accumulation of organic acids, such as ketone bodies, in the bloodstream.

References

1. Dehydration and insulinopenia are necessary and sufficient for euglycemic ketoacidosis in SGLT2 inhibitor-treated rats. Nature Communications (2019).
2. SGLT-2 inhibitors associated euglycemic and hyperglycemic DKA in a multicentric cohort. Scientific Reports (2021).
3. Euglycemic Diabetic Ketoacidosis and Sodium-Glucose Cotransporter-2 Inhibitors: A Focused Review of Pathophysiology, Risk Factors, and Triggers. Cureus (2021).
4. Severe euglycemic diabetic ketoacidosis of multifactorial etiology in a type 2 diabetic patient treated with empagliflozin: case report and literature review. BMC Nephrology (2020).
5. Dapagliflozin-induced Late-onset Euglycemic Diabetic Ketoacidosis. Cureus (2019).