Diabetic ketoacidosis (DKA) is most commonly reported in patients with type 1 diabetes, but it can also occur in patients with poorly controlled type 2 diabetes in the presence of stress and concomitant medical and surgical illnesses. Drugs that affect carbohydrate metabolism such as corticosteroids, sympathomimetics, and atypical antipsychotics might also precipitate the development of DKA. In recent years, an association between the use of sodium glucose co-transporter 2 (SGLT-2)-inhibitors and DKA has been reported in patients with type 1 and type 2 diabetes.
The US Food and Drug Administration (FDA) and European Medicines Agency have both issued warning statements listing DKA as a rare adverse reaction of SGLT-2-inhibitor treatment. In clinical trials of patients with type 1 diabetes treated with SGLT-2 inhibitors, about 10% of patients developed ketosis and 5-6% required hospitalization for DKA. In patients with type 2 diabetes, DKA is rare, reported in 0.1-0.8 per 1,000 patients. Most cases of DKA occur among patients with a concomitant precipitating cause, such as surgery, alcohol abuse, insulin pump malfunction, and poor adherence to medications. Awareness among healthcare professionals, as well as patient education, might facilitate early detection of DKA during SGLT-2 inhibitor treatment or even prevent development of this diabetes emergency.
Potential strategies include routine monitoring of blood and urine ketone bodies during acute illness, periods of starvation, and in the presence of hyperglycemia. Until more information is available, the use of SGLT-2 inhibitors should be avoided during severe illness, major surgical procedures, and when ketone bodies are detected despite increases in insulin dose. For patients taking an SGLT-2 inhibitor who present with symptoms suggestive of DKA, such as abdominal pain, nausea, vomiting, fatigue, and dyspnea, a diagnosis of DKA should be considered and an appropriate work-up carried out. Although a low bicarbonate and/or the presence of positive urinary ketones may be suggestive of DKA, these measures may be inaccurate.
Therefore, the American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) recommends direct measurement of blood ketones (beta-hydroxybutyrate) and arterial pH as necessary to confirm the diagnosis. Normal or modestly elevated blood glucose does not exclude the diagnosis of DKA during SGLT-2 inhibitor use. For management of DKA in patients taking SGLT-2 inhibitors, stop the drug immediately and proceed with traditional DKA treatment protocols. Note that although the drug is discontinued, SGLT-2 inhibitor-mediated increases in urinary glucose loss may persist for several days. To minimize the risk of DKA associated with SGLT-2 inhibitors, AACE/ACE recommends stopping the SGLT-2 inhibitor at least 24 hours prior to elective surgery, planned invasive procedures, or anticipated severe stressful physical activity such as running a marathon. Routine measurement of urine ketones is not recommended during use of SGLT-2 inhibitors because this measurement can be misleading. Instead, measurement of blood ketones is preferred for diagnosis of DKA in asymptomatic patients.