Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor Associated Euglycemic Diabetic Ketoacidosis

Thanks to LeslieAnn S. Kao, MD (General Surgery PGY-4) for suggesting this topic.

Somagutta MR, et al. Euglycemic Diabetic Ketoacidosis and Sodium-Glucose Cotransporter-2 Inhibitors: A Focused Review of Pathophysiology, Risk Factors, and Triggers. Cureus. 2021 Mar 3;13(3):e13665.

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.

Figure 2. Pathophysiology and mechanism of SGLT2i causing EDKA.
SGLT2 = sodium-glucose cotransporter-2, Na+ = sodium; EDKA = euglycemic diabetic ketoacidosis

Plewa MC, Bryant M, King-Thiele R. Euglycemic Diabetic Ketoacidosis. 2021 Feb 3. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–.

Euglycemic DKA (EDKA) is a clinical syndrome occurring both in type 1 (T1D) or type 2 (T2D) diabetes mellitus characterized by euglycemia (blood glucose less than 250 mg/dL) in the presence of severe metabolic acidosis (arterial pH less than 7.3 and serum bicarbonate less than 18 mEq/L) and ketonemia. DKA is one of the most severe and life-threatening complications of diabetes mellitus and can be seen in a variety of conditions. The incidence of EDKA, however, has grown with the introduction of sodium-glucose transporter 2 (SGLT2) inhibitors. It also presents a diagnostic challenge for physicians due to the variety of etiologies and normal blood glucose levels, often resulting in delayed diagnosis.

Bardia A, Wai M, Fontes ML. Sodium-glucose cotransporter-2 inhibitors: an overview and perioperative implications. Curr Opin Anaesthesiol. 2019 Feb;32(1):80-85.

Full-text for Emory users.

“Currently, there are no consensus guidelines for management of SGLT-2 inhibitors in the perioperative period. In the absence of formal guidelines, management of patients on SGLT-2 inhibitors should be undertaken on a case-by-case basis in a multidisciplinary fashion. Generally, it is recommended that these drugs be stopped at least 24-48 h prior to surgery [24,32]. Patients who undergo a bowel preparation prior to surgery or are on dietary modifications, may need a longer period off SGLT-2 inhibitors. Conditions that predispose to DKA, such as prolonged fasting, dehydration, low carbohydrate meals should be avoided in the perioperative period for diabetic patients regardless of antiglycemic therapy. Further, abrupt decrease in insulin doses is discouraged as low levels of insulin may also precipitate DKA.

Reintroduction of SGLT-2 inhibitors should be done cautiously, ideally in consultation with the patients’ diabetes management team. Our recommendation is that SGLT-2 inhibitors be reinitiated once patients are able to tolerate a full diet and are no longer experiencing postoperative nausea and vomiting. Also, it may be prudent to ensure adequate renal function prior to their resumption. Moreover, strict vigilance of blood glucose and appropriate dose adjustment of insulin is recommended once SGLT-2 inhibitors are reintroduced.” Bardia, et al., p. 84.)

Table 2. Precipitating Factors for DKA (Including Euglycemic DKA) Associated With SGLT2 Inhibitor Therapy in Patients. (DynaMed)

risk levelprecipitating factor
Moderate/highUse of illicit drugs
Reduced or inconsistent carbohydrate intake
Reduced basal insulin by > 10%-20%
Insulin pump or infusion site failure
Excessive alcohol use
Acute illness of any sort (viral or bacterial)
Volume depletion/dehydration
Low/moderateVigorous or prolonged exercise
Reduced prandial insulin dose by > 10%-20%
Travel with disruption in usual schedule/insulin regimen
Insulin pump use
Minimal/lowFemale sex
Low BMI (< 25 kg/m2)
Inconsistent caloric intake
Moderate alcohol use (if levels of ketones increase from baseline)
Abbreviations: BMI, body mass index; DKA, diabetic ketoacidosis; SGLT2, sodium-glucose cotransporter 2. From: Danne T, et al. International Consensus on Risk Management of Diabetic Ketoacidosis in Patients With Type 1 Diabetes Treated With Sodium-Glucose Cotransporter (SGLT) Inhibitors. Diabetes Care. 2019 Jun;42(6):1147-1154.


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