What is the relationship between Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors and non-acidotic diabetic ketoacidosis (DKA)?

From the Guidelines

SGLT2 inhibitors can cause nonacidotic diabetic ketoacidosis (DKA), a serious condition that requires prompt medical attention, and patients should be educated about the risk and instructed to temporarily stop their SGLT2 inhibitor and seek medical attention if they develop concerning symptoms during illness. The risk of DKA with SGLT2 inhibitors is estimated to be 0.6-4.9 events per 1,000 patient-years in people with type 2 diabetes 1. Risk factors for DKA in individuals with type 2 diabetes treated with SGLT2 inhibitors include very-low-carbohydrate diets, prolonged fasting, dehydration, excessive alcohol intake, and other common precipitating factors 1.

Some key points to consider when using SGLT2 inhibitors include:

• Discontinuing SGLT2 inhibitors 3-4 days before planned procedures or surgeries to prevent euDKA 1
• Monitoring patients closely during acute illness to prevent euDKA 1
• Educating patients about the risk of euDKA and instructing them to seek medical attention if they develop concerning symptoms during illness 1
• Checking for metabolic acidosis, elevated ketones, and anion gap if euDKA is suspected 1
• Treating euDKA with standard DKA protocols, including IV fluids, insulin, and electrolyte management, though higher insulin doses may be needed 1

It is essential to note that the risk of DKA with SGLT2 inhibitors can be mitigated by raising awareness and counseling patients on the potential triggers, advising them to seek immediate medical attention if symptoms develop 1. Additionally, the use of SGLT inhibitors (whether for glycemic management or another indication) increases the susceptibility to diabetic ketoacidosis, particularly when other risk factors or situations occur 1.

Overall, the benefits of SGLT2 inhibitors in reducing the risk of heart failure and improving cardiovascular outcomes must be carefully weighed against the potential risk of DKA, and patients should be closely monitored and educated about the risk of euDKA 1.

From the FDA Drug Label

INDICATIONS AND USAGE JARDIANCE is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated: as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus, to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease. (1) Limitations of Use: Not for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis (1) The use of SGLT2 inhibitors like empagliflozin is associated with an increased risk of diabetic ketoacidosis (DKA), although the label does not specifically address nonacidotic DKA.

• The label explicitly states that empagliflozin is not for the treatment of diabetic ketoacidosis.
• Given the information provided, it is unclear if the SGLT2 inhibitor increases the risk of nonacidotic DKA specifically.
• A conservative clinical decision would be to exercise caution when using SGLT2 inhibitors in patients at risk for DKA, including nonacidotic DKA, due to the potential increased risk 2.

From the Research

SGLT2 Inhibitors and Nonacidotic DKA

• SGLT2 inhibitors are a new class of anti-diabetic medications that have been associated with an increased risk of diabetic ketoacidosis (DKA), including nonacidotic or euglycemic DKA 3, 4.
• The FDA has released a warning about the risk of DKA with SGLT2 inhibitors, highlighting the importance of monitoring patients for signs and symptoms of DKA 3.
• Studies have shown that SGLT2 inhibitors can increase the risk of metabolic acidosis, including lactic acidosis and euglycemic DKA, particularly when used in combination with metformin 4.
• The mechanism of action of SGLT2 inhibitors, which involves inhibiting the reabsorption of glucose in the kidneys, can lead to an increase in urinary glucose excretion and a reduction in blood glucose levels, but may also increase the risk of DKA 5, 6.
• Clinical trials have demonstrated the efficacy and safety of SGLT2 inhibitors, including canagliflozin, in improving glycemic control and reducing the risk of cardiovascular events in patients with type 2 diabetes, but have also highlighted the need for careful monitoring for adverse events such as DKA 7.

Key Findings

• SGLT2 inhibitors are associated with an increased risk of nonacidotic DKA, particularly when used in combination with metformin 4.
• The mechanism of action of SGLT2 inhibitors increases the risk of metabolic acidosis, including lactic acidosis and euglycemic DKA 4, 6.
• Clinical trials have demonstrated the efficacy and safety of SGLT2 inhibitors in improving glycemic control and reducing the risk of cardiovascular events in patients with type 2 diabetes 5, 7.

Adverse Events

• SGLT2 inhibitors are associated with an increased risk of adverse events such as genital and urinary tract infections, increased urination, and DKA 3, 4, 7.
• The risk of DKA with SGLT2 inhibitors highlights the importance of careful monitoring and patient education to recognize the signs and symptoms of DKA 3, 4.