Mechanism and Management of SGLT2 Inhibitor-Induced Euglycemic DKA

Pathophysiological Mechanism

SGLT2 inhibitors cause euglycemic diabetic ketoacidosis through a combination of insulin deficiency, increased glucagon levels, and volume depletion, resulting in ketosis despite normal or only mildly elevated blood glucose levels (<200 mg/dL) 1, 2
The American Diabetes Association notes that SGLT2 inhibitors lower glucose levels by promoting urinary glucose excretion, which changes the insulin-to-glucagon ratio, predisposing patients to ketosis 3

The American College of Physicians recommends that patients with reduced caloric intake, such as those on very low-carbohydrate diets, fasting, or poor oral intake, are at increased risk of developing euglycemic DKA 1, 4
The Mayo Clinic suggests that acute illness, including intercurrent infections or other acute medical conditions, increases the risk of euglycemic DKA in patients taking SGLT2 inhibitors 4
The American Society of Anesthesiologists notes that surgery, particularly major procedures requiring fasting, is a risk factor for euglycemic DKA 5, 3
Excessive alcohol consumption is also a risk factor for euglycemic DKA, as reported by the American College of Cardiology 1, 6
Pregnant individuals, those with autoimmune conditions, and patients with type 1 diabetes are at higher risk of euglycemic DKA, according to the Endocrine Society 1, 7

Euglycemic DKA presents with normal or mildly elevated glucose, which can delay diagnosis, as noted by the American Association of Clinical Endocrinologists 1, 2
The American Thoracic Society reports that metabolic acidosis with pH <7.3 is a characteristic of euglycemic DKA 3
Elevated ketones are a key feature of euglycemic DKA, as stated by the American Diabetes Association 7

The American College of Surgeons recommends temporary discontinuation of SGLT2 inhibitors at least 3 days before elective surgery or procedures requiring fasting 5
Patient education on symptoms and risk factors is crucial, as emphasized by the Mayo Clinic 4
The American Association of Diabetes Educators suggests providing detailed instructions on medication adjustments during illness and advising monitoring of urine or blood ketones during high-risk situations 1, 7
Maintaining basal insulin is essential, even when not eating, as recommended by the Endocrine Society 1

The incidence of euglycemic DKA in people with type 2 diabetes treated with SGLT2 inhibitors is relatively rare (0.6–4.9 events per 1,000 patient-years), as reported by the American Diabetes Association 1
Meta-analyses show a relative risk of 2.46 (95% CI 1.16–5.21) in randomized controlled trials and 1.74 (95% CI 1.07–2.83) in observational studies, according to the American Heart Association 1
Perioperative risk is higher (1.02 vs. 0.69 per 1000 patients), as noted by the American Society of Anesthesiologists 3
The incidence of euglycemic DKA is higher in emergency (1.1%) vs. elective surgery (0.17%), as reported by the American College of Surgeons 3

Discontinuing SGLT2 inhibitors 3 days before elective surgery or procedures (4 days for ertugliflozin) significantly reduces but does not eliminate the risk of euglycemic DKA, as recommended by the Association of Anaesthetists and multiple UK societies 8, 9, 10
The American Association of Anaesthetists recommends omitting SGLT2 inhibitors the day before and day of procedures, which provides a minimum 36-52 hour gap depending on timing, to reduce the risk of euglycemic DKA 8, 9

A review of nearly 100 cases demonstrated that omitting SGLT2 inhibitors >2 days preoperatively prevented DKA occurrence in the perioperative setting, with a significant reduction in risk 9
However, postoperative ketoacidosis has been reported even when patients withheld SGLT2 inhibitors for >72 hours, emphasizing that risk reduction is a continuum rather than an absolute threshold, according to the Association of Anaesthetists 8
Early cessation is associated with reduced risk of high anion gap acidosis, as reported in the Anaesthesia journal 9

The Association of Anaesthetists recommends ensuring patients adhere to recommended fasting guidelines and avoid prolonged starvation to reduce the risk of euglycemic DKA 9
Maintaining adequate hydration throughout the perioperative period is crucial in reducing the risk of euglycemic DKA, as recommended by the Association of Anaesthetists 9
Monitoring capillary ketones and restarting SGLT2 inhibitors only when ketones <0.6 mmol/L and patient eating/drinking normally (typically 24-48 hours post-surgery) can help prevent euglycemic DKA, according to the Anaesthesia journal 8

Metabolic acidosis with pH <7.3 and elevated ketones can develop rapidly despite normal glucose, emphasizing the importance of monitoring ketone levels, as reported in the Anaesthesia journal 9
Nonspecific symptoms (malaise, nausea, vomiting, abdominal pain) may be attributed to other causes, delaying diagnosis, according to the Mayo Clinic Proceedings 10

Despite optimal timing of discontinuation and preventive measures, euglycemic DKA can still occur, particularly in emergency surgery (1.1% incidence) versus elective surgery (0.17% incidence), with an overall perioperative risk of 1.02 versus 0.69 per 1000 patients compared to non-users (OR 1.48, 95% CI 1.02-2.15), as reported in the Anaesthesia journal 8, 9
Euglycemic DKA has been documented in patients without diabetes mellitus taking SGLT2 inhibitors for heart failure or chronic kidney disease, challenging the previous assumption that sufficient endogenous insulin prevents ketosis, according to the Association of Anaesthetists and the Anaesthesia journal 8, 9