Clinical guidelines for SGLT2 inhibitors should distinguish between patients with and without diabetes prescribed the medication, considering the latter group has a “near-zero” risk of diabetic ketoacidosis, Australian endocrinologists say.

Writing in a perspective for the Medical Journal of Australia [link here], the Sydney doctors said the rare adverse event had led to guidelines that recommended withholding the medication in the presence of low carbohydrate diets or excessive alcohol intake, if fasting for a procedure, or if unwell with active infection.

The researchers pointed out that most guidelines did not differentiate between patients with and without diabetes, despite SGLT2 inhibitors becoming an established treatment for conditions other than diabetes such as heart failure with reduced or preserved ejection fraction and chronic kidney disease.

“SGLT2 inhibitor-induced diabetic ketoacidosis is postulated to be caused by increased glucagon relative to insulin, leading to lipolysis and excess free fatty acid production with increased hepatic ketogenesis. In diabetes, or pre-diabetes, there is a relative or absolute insulin deficiency, which contributes to this process. Individuals without diabetes secrete adequate insulin, which is protective and, as such, ketoacidosis is not generally described,” they said.

They cited large placebo-controlled trials of SGLT2is for heart failure, which found no reported cases of ketoacidosis in patients without diabetes. Although they said trial protocols had specified temporary discontinuation in clinical situations known to predispose ketoacidosis, which might have protected against events if followed.

They noted the EMPA-KIDNEY trial reported a single case of ketoacidosis in a patient without a diabetes diagnosis treated with empagliflozin, but there were no further details and no reported cases of SGLT2i-induced ketoacidosis outside of a clinical trial setting.

They suggested undiagnosed diabetes might explain such cases.

“As diabetes status appears important in stratifying risk of ketoacidosis with SGLT2 inhibitors, it must be noted that globally 14.7–58.8% of individuals with diabetes remain undiagnosed. Hence, it is likely that many individuals who commence treatment with SGLT2 inhibitors may have underlying undiagnosed diabetes or pre-diabetes,” wrote the authors from UNSW and St Vincent’s Hospital, Sydney.

“Vigilance in screening for diabetes before commencing SGLT2 inhibitors is important. With scarcity of data, the risk–benefit profile and potential costs of unnecessary testing is unknown.”

They said that pharmacovigilance will be critical to determining the real-world risk of ketoacidosis in patients without diabetes as SGLT2i are increasingly used.

“Theoretically, the risk of ketoacidosis in a patient without diabetes should be negligible. However, the risk can be minimised with increased awareness,” they said.

“Guidelines may need to be updated to differentiate between patients with and without diabetes to avoid unnecessary investigations and, potentially, deferment of surgery if the apparently negligible risk of ketoacidosis in clinical trials eventuates in clinical practice.”