What is the incidence of diabetic ketoacidosis (DKA) in patients taking Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors?

Incidence of DKA in Patients Taking SGLT2 Inhibitors

The incidence of diabetic ketoacidosis in patients with type 2 diabetes taking SGLT2 inhibitors is uncommon, occurring at a rate of 0.6–4.9 events per 1,000 patient-years, with meta-analyses showing a relative risk of approximately 2.46 compared to placebo in randomized controlled trials. 1, 2

Overall Incidence Rates

The risk of DKA with SGLT2 inhibitors varies significantly by clinical context:

• Type 2 diabetes (general use): 0.6–4.9 events per 1,000 patient-years 1, 2
• Relative risk in randomized controlled trials: 2.46 (95% CI 1.16–5.21) compared to placebo or active comparator 1, 2
• Relative risk in observational studies: 1.74 (95% CI 1.07–2.83) 1, 2
• Perioperative setting: Higher risk at 1.02 per 1,000 patients versus 0.69 per 1,000 in non-SGLT2 inhibitor users 2, 3
• Emergency surgery: 1.1% incidence versus 0.17% in elective surgery 2, 3

Key Clinical Characteristics

Euglycemic presentation is the hallmark concern, as approximately 10% of DKA cases present with plasma glucose <200 mg/dL (11.1 mmol/L), which delays recognition and treatment. 1 Case series data show average blood glucose on presentation of 265.6 ± 140.7 mg/dL, substantially lower than typical DKA. 4

The FDA drug label for empagliflozin (representative of the SGLT2 inhibitor class) explicitly warns that ketoacidosis may be present even with blood glucose levels less than 250 mg/dL, and that fatal cases have been reported. 5

High-Risk Populations and Precipitating Factors

Specific patient groups face elevated risk:

• Insulin-deficient states: Patients with latent autoimmune diabetes in adults (LADA) misdiagnosed as type 2 diabetes, or those with pancreatic insufficiency 1, 2, 6
• Type 1 diabetes: Approximately 5-10% of adult-onset diabetes is late-onset type 1, carrying substantially increased DKA risk 1, 3
• Surgical patients: Particularly those undergoing major procedures requiring prolonged fasting 2, 3, 4
• Pregnancy: Pregnant individuals with pregestational diabetes face risk of euglycemic DKA 1

Critical precipitating factors include:

• Insulin dose reduction or omission (>20% reduction should be avoided) 1, 3, 6
• Reduced caloric intake: Very-low-carbohydrate diets, prolonged fasting, or poor oral intake during illness 1, 2, 6
• Volume depletion and dehydration 1, 2, 6
• Excessive alcohol consumption 1, 2, 6
• Acute illness or infection 1, 2, 6

Prevention Strategies

The American College of Cardiology recommends patients be informed about euglycemic DKA risk and advised to seek immediate care for symptoms including nausea, vomiting, abdominal pain, or generalized weakness. 1

Specific preventive measures:

• Perioperative management: Discontinue SGLT2 inhibitors at least 3 days before elective surgery or procedures requiring fasting 2, 3
• Insulin management: Avoid substantial initial insulin dose reductions (>20%) when initiating SGLT2 inhibitors 1, 3
• Sick day rules: Temporarily discontinue SGLT2 inhibitors during acute illness, dehydration, or prolonged fasting 1, 2
• Complex insulin regimens: Initiate SGLT2 inhibitors in collaboration with diabetes care providers for patients on complex insulin regimens or with labile glucose control 1, 3
• Patient education: Counsel on monitoring for ketones (urine or blood) during high-risk situations 2, 6

Clinical Context and Reassurance

While the relative risk appears elevated in meta-analyses, the absolute incidence remains low when SGLT2 inhibitors are properly prescribed. 7 A 2017 meta-analysis of 72 randomized trials found no significant signal of increased ketoacidosis risk (OR 1.14,95% CI 0.45-2.88, p=0.78), and sensitivity analyses suggested potentially reduced incidence. 7 However, this contrasts with real-world observational data and FDA warnings, highlighting that proper patient selection and education are paramount. 5

The majority of case reports (67.53%) involve female patients with type 2 diabetes, with gastrointestinal symptoms being the most common presentation (58%). 8 Surgery was identified as the most common precipitating factor in systematic reviews. 4, 8