Diabetic Ketoacidosis Risk in Patients Taking SGLT2 Inhibitors

Incidence and Relative Risk

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
The relative risk in randomized controlled trials is 2.46 (95% CI 1.16–5.21) compared to placebo or active comparator 1, 2
The relative risk in observational studies is 1.74 (95% CI 1.07–2.83) 1, 2

Patients with latent autoimmune diabetes in adults (LADA) misdiagnosed as type 2 diabetes, or those with pancreatic insufficiency, face elevated risk of DKA 3, 2
Type 1 diabetes patients, approximately 5-10% of adult-onset diabetes, carry substantially increased DKA risk 3, 4
Pregnant individuals with pregestational diabetes face risk of euglycemic DKA 1

Insulin dose reduction or omission (>20% reduction should be avoided) is a critical precipitating factor for DKA 3, 4
Reduced caloric intake, such as very-low-carbohydrate diets, prolonged fasting, or poor oral intake during illness, can precipitate DKA 1, 2
Volume depletion and dehydration can also precipitate DKA 5, 2
Excessive alcohol consumption is a precipitating factor for DKA 1, 2
Acute illness or infection can precipitate DKA 5, 2

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 3
Perioperative management: Discontinue SGLT2 inhibitors at least 3 days before elective surgery or procedures requiring fasting 2, 4
Insulin management: Avoid substantial initial insulin dose reductions (>20%) when initiating SGLT2 inhibitors 3, 4
Sick day rules: Temporarily discontinue SGLT2 inhibitors during acute illness, dehydration, or prolonged fasting 5, 2
Complex insulin regimens: Initiate SGLT2 inhibitors in collaboration with diabetes care providers for patients on complex insulin regimens or with labile glucose control 3, 4
Patient education: Counsel on monitoring for ketones (urine or blood) during high-risk situations 2

The American Diabetes Association notes that SGLT2 inhibitors, such as empagliflozin, dapagliflozin, and canagliflozin, are the leading cause of euglycemic DKA in contemporary practice, allowing ketoacidosis to develop while maintaining relatively normal blood glucose levels 6, 7, 8
Corticosteroids can increase insulin resistance and counter-regulatory hormones, precipitating DKA 6, 7, 8
Atypical antipsychotics are associated with metabolic derangements that can lead to DKA 6, 7, 8

The American College of Clinical Endocrinologists recognizes that recent insulin use prior to presentation is a classic cause of euglycemic DKA, as insulin administration lowers glucose while ketoacidosis persists, although no specific citation is provided in this context, insulin omission due to psychological problems and financial constraints is recognized as a cause of DKA in patients with established diabetes 9

Myocardial infarction can precipitate euglycemic DKA when combined with other factors, such as SGLT2 inhibitor use 6, 7

Acute physiologic stress (infection, especially urinary‑tract infection, myocardial infarction, major surgery, and volume depletion) can trigger euglycemic DKA in patients with diabetes. The American Diabetes Association (Diabetes Care) highlights these stressors as common precipitants. 10, 11, 12

Obtain a complete blood count with differential when euglycemic DKA is suspected. This laboratory test aids in identifying infection or hematologic abnormalities that may influence management. (American Diabetes Association, Diabetes Care) 11
Perform an electrocardiogram as part of the initial assessment of suspected euglycemic DKA. ECG helps detect electrolyte‑related cardiac effects and underlying cardiac pathology. (American Diabetes Association, Diabetes Care) 11

Patients receiving SGLT2‑inhibitor therapy should be instructed to stop the medication and seek immediate medical attention if they develop symptoms suggestive of ketoacidosis (e.g., nausea, vomiting, abdominal pain, weakness). This recommendation is based on evidence from the Annals of Internal Medicine. 13