What is the association between Farxiga (dapagliflozin) and acidosis?

From the Guidelines

Farxiga (dapagliflozin) can cause a rare but serious condition called euglycemic diabetic ketoacidosis (eDKA), which is a form of metabolic acidosis, and patients should be aware of the symptoms and take precautions to minimize risk, as recommended by the most recent guidelines 1.

Key Points

• The risk of acidosis is higher during periods of acute illness, reduced food or fluid intake, reduced insulin doses, or after surgical procedures.
• To minimize risk, patients should temporarily stop taking Farxiga during these high-risk situations and ensure adequate hydration.
• Farxiga works by causing the kidneys to excrete glucose in urine, which can lead to an imbalance in insulin-to-glucagon ratio, triggering ketone production even when blood glucose levels are not significantly elevated.
• Regular monitoring of ketone levels during illness may be recommended for high-risk patients, and patients should seek immediate medical attention if symptoms of acidosis occur.

Recommendations

• Patients taking Farxiga should be educated on the symptoms of acidosis, which include nausea, vomiting, abdominal pain, fatigue, rapid breathing, fruity-smelling breath, and confusion.
• A sick day protocol should be implemented, which includes temporarily withholding SGLT2i, keeping drinking and eating (if possible), checking blood glucose and blood ketone levels more often, and seeking medical help early 1.
• Periprocedural/perioperative care should include informing patients about the risk of diabetic ketoacidosis, withholding SGLT2i the day of day-stay procedures, and limiting fasting to the minimum required 1.

Evidence

• The 2022 clinical practice guideline for diabetes management in chronic kidney disease recommends that SGLT2 inhibitors, including Farxiga, be used with caution and that patients be educated on the risk of diabetic ketoacidosis 1.
• The guideline also recommends that patients with high-risk features, such as insulin deficiency, be closely monitored for signs and symptoms of diabetic ketoacidosis 1.
• Other studies have also reported the risk of diabetic ketoacidosis associated with SGLT2 inhibitors, including a study published in 2020 that recommended stopping the drugs during illness and following sick day rules 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 DAPAGLIFLOZIN TABLETS can cause ketoacidosis that can be life-threatening and may lead to death. Ketoacidosis is a serious condition which needs to be treated in a hospital. People with type 1 diabetes have a high risk of getting ketoacidosis. People with type 2 diabetes or pancreas problems also have an increased risk of getting ketoacidosis Ketoacidosis can also happen in people who: are sick, cannot eat or drink as usual, skip meals, are on a diet high in fat and low in carbohydrates (ketogenic diet), take less than the usual amount of insulin or miss insulin doses, drink too much alcohol, have a loss of too much fluid from the body (volume depletion), or who have surgery

Association between Farxiga (dapagliflozin) and acidosis:

• Dapagliflozin increases the risk of diabetic ketoacidosis and other forms of ketoacidosis, particularly in patients with type 1 diabetes mellitus.
• The risk of ketoacidosis is also increased in patients with type 2 diabetes mellitus and those with pancreatic disorders.
• Ketoacidosis can be life-threatening and may lead to death, requiring immediate medical attention.
• Patients should be educated on the signs and symptoms of ketoacidosis and instructed to discontinue dapagliflozin and seek medical attention immediately if they occur 2 2 2.

From the Research

Association between Farxiga (dapagliflozin) and Acidosis

• Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has been associated with euglycemic diabetic ketoacidosis (eDKA), a serious and potentially life-threatening complication of diabetes mellitus 3, 4, 5, 6, 7.
• Euglycemic diabetic ketoacidosis is characterized by severe metabolic acidosis with an elevated anion gap, elevated ketones in blood and urine, and normal or mildly elevated blood glucose levels 3, 4, 5, 6, 7.
• The exact mechanism of dapagliflozin-induced eDKA is unknown, but various precipitating factors such as infection, dehydration, and recent surgery have been linked to its development 6.
• Dapagliflozin-induced eDKA can be challenging to diagnose in the emergency department due to the absence of marked hyperglycemia, and a high index of suspicion is required to prompt investigation with ketone studies and blood gas analyses 3, 7.
• Treatment of dapagliflozin-induced eDKA typically involves intravenous rehydration therapy with insulin infusion, and in some cases, continuous renal replacement therapy may be necessary 4, 5.
• Discontinuation of dapagliflozin is recommended in patients who develop eDKA, and patients should be educated about this rare but potentially morbid complication before commencing medication 6.