From the Guidelines
Yes, SGLT-2 inhibitors can lead to euglycemic diabetic ketoacidosis (DKA), a serious complication where ketoacidosis occurs despite relatively normal blood glucose levels. This condition is particularly dangerous because the absence of significant hyperglycemia may delay diagnosis and treatment. SGLT-2 inhibitors, including medications such as empagliflozin (Jardiance), canagliflozin (Invokana), dapagliflozin (Farxiga), and ertugliflozin (Steglatro), increase the risk of this complication by promoting glucosuria and reducing insulin levels while increasing glucagon, which shifts metabolism toward ketogenesis 1.
Risk Factors and Prevention
Risk factors for euglycemic DKA in patients taking SGLT-2 inhibitors include:
- Surgery
- Fasting
- Reduced carbohydrate intake
- Alcohol consumption
- Acute illness
- Insulin dose reduction
Patients taking these medications should be educated about this risk and advised to:
- Temporarily discontinue the medication during periods of acute illness, reduced oral intake, or before surgical procedures
- Monitor for symptoms of DKA (nausea, vomiting, abdominal pain, fatigue, and rapid breathing) even when blood glucose levels are not significantly elevated
- Seek immediate medical attention if these symptoms develop
Monitoring and Management
It is essential to monitor patients for signs and symptoms of euglycemic DKA, particularly those with a history of insulin deficiency or those taking insulin therapy 1. Patients should be advised to measure ketones in urine or blood if they have unexplained hyperglycemia or symptoms of ketosis and implement sick day rules and/or seek medical advice if urine or blood ketones are increased 1.
Key Considerations
- SGLT-2 inhibitors have been associated with an increased risk of genital mycotic infections, volume depletion, and hypovolemia 1
- Canagliflozin has been associated with an increased risk of lower limb amputation and fractures 1
- The risk of euglycemic DKA can be reduced by raising awareness and counseling patients on potential triggers and advising them to seek immediate medical attention if symptoms develop 1
From the FDA Drug Label
In patients with type 1 diabetes mellitus, dapagliflozin significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate... Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL).
In patients with type 1 diabetes mellitus, INVOKANA significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate... Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL).
Yes, SGLT-2 inhibitors can lead to euglycemic DKA. This is because the blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL) 2, 3, 2.
- Key points:
- SGLT-2 inhibitors increase the risk of diabetic ketoacidosis.
- Euglycemic DKA can occur with SGLT-2 inhibitors.
- Blood glucose levels may be below 250 mg/dL at presentation.
From the Research
SGLT-2 Inhibitors and Euglycemic DKA
- SGLT-2 inhibitors have been associated with the serious and potentially life-threatening metabolic complication of euglycemic diabetic ketoacidosis (euDKA) 4, 5, 6, 7, 8.
- The rate of DKA is quite low, but it could be generally underestimated in clinical trials due to the atypical presentation of ketoacidosis, and even more so in real-life conditions 4.
- Euglycemic DKA can occur in patients with type 2 diabetes mellitus who are taking SGLT-2 inhibitors, even with normal or mildly elevated serum glucose levels 5, 6, 7.
- The use of a ketogenic diet while taking an SGLT-2 inhibitor can increase the risk of developing euDKA 5.
- Surgical stress, acute postoperative illness, and decreased carbohydrate intake can also contribute to the development of ketosis in patients taking SGLT-2 inhibitors 7.
- Clinical considerations to ensure safe SGLT-2 inhibitor therapy include appropriate holding parameters, timely diagnosis of euDKA, and recognition that the pharmacologic effects of SGLT-2 inhibitor treatment may persist beyond several half-lives of elimination 7.
- Increased awareness of euDKA is essential for a timely diagnosis, and an early diagnosis and treatment can improve clinical outcomes 8.
Risk Factors and Mechanisms
- Multiple possible risk factors and mechanisms may contribute to the pathogenesis of ketoacidosis, including SGLT-2 inhibitor use and prescription by non-diabetologists 6.
- SGLT-2 inhibitor therapy can promote lipolysis and ketogenesis while maintaining euglycemia, especially during periods of carbohydrate deficiency, volume depletion, and upregulation of counter-regulatory stress hormones 7.
- The absence of hallmark hyperglycemia seen in diabetic ketoacidosis (DKA) can make diagnosis of euDKA challenging 8.
Diagnosis and Treatment
- A low threshold to screen for DKA is recommended if a patient presents with symptoms of DKA and is eating a carbohydrate-free diet while taking an SGLT-2 inhibitor 5.
- Monitoring anion gap and ketones can guide insulin and fluid management, and a slower transition to subcutaneous insulin can help prevent relapse 8.
- A treatment algorithm is proposed to guide clinicians in managing euDKA, including classification systems for the severity of euDKA and stages of euDKA based on anion gap and ketones 8.