Why are SGLT2 inhibitors associated with euglycemic diabetic ketoacidosis?

• A. They promote ketogenesis and reduce insulin levels while glucose may be normal or only mildly elevated, especially with illness or dehydration.
• B. They increase insulin production leading to hyperglycemia.
• C. They prevent DKA entirely.
• D. They only cause DKA with severe hyperglycemia.

Answer: (A)

SGLT2 inhibitors lower blood glucose by promoting glucosuria, which reduces the insulin level relative to glucagon. This shift in the insulin-to-glucagon ratio stimulates lipolysis and hepatic ketogenesis. When a patient is ill, dehydrated, or not eating, counterregulatory hormones rise and ketone production increases further. Because glucose is being lost in the urine, blood glucose can stay normal or only mildly elevated even as ketones build up, leading to ketoacidosis with euglycemia. So you can have diabetic ketoacidosis without high glucose levels, which is why these drugs are associated with euglycemic DKA.

This isn’t due to increased insulin production or hyperglycemia, and they do not prevent DKA; they can even precipitate DKA in the right (or rather wrong) circumstances.