Euglycemic Diabetic Ketoacidosis and Sodium-Glucose Cotransporter-2 Inhibitors: A Focused Review of Pathophysiology, Risk Factors, and Triggers

Abstract

Diabetic ketoacidosis (DKA) is an acute and significant life-threatening complication of diabetes. The association of sodium-glucose cotransporter-2 inhibitors (SGLT2i) with euglycemic diabetic ketoacidosis (EDKA) has been well reported. This literature review was conducted to understand the mechanism of EDKA and identify the potential risk factors and precipitants for patients taking SGLT2i. After reviewing the published literature between 2010 and 2020, 32 articles are included in the final review. The underlying mechanism is mainly enhanced lipolysis and ketone body reabsorption. SGLT2i also stimulates pancreatic alpha cells and inhibits beta cells, causing an imbalance in glucagon/insulin levels, further contributing to lipolysis and ketogenesis. Most patients were diagnosed with blood glucose less than 200 mg/dL, blood pH <7.3, increased anion gap, increased blood, or urine ketones. Perioperative fasting, pancreatic etiology, low carbohydrate or ketogenic diet, obesity, and malignancy are identified precipitants in this review. As normoglycemia can conceal the underlying acidosis, physicians should be cognizant of the EDKA diagnosis and initiate prompt treatment. Patient education on risk factors and triggers is recommended to avoid future events.

Keywords: canagliflozin; diabetes; diabetic ketoacidosis; edka; empagliflozin; euglycemic diabetic ketoacidosis; risk factors; sodium; sodium-glucose cotransporter 2 inhibitor.

Figure 1. Flow chart explaining the process of the literature review.

Figure 2. Pathophysiology and mechanism of SGLT2i causing EDKA.

SGLT2 = sodium-glucose cotransporter-2, Na⁺ = sodium; EDKA = euglycemic diabetic ketoacidosis

Figure 3. Precipitating factors, symptoms, and diagnostic criteria for SGLT2i-associated EDKA.

SGLT2i = sodium-glucose cotransporter-2 inhibitors; EDKA = euglycemic diabetic ketoacidosis