Clinical Edge

Summaries of Must-Read Clinical Literature, Guidelines, and FDA Actions

Diabetic Ketoacidosis and Adverse Events

Dangers for type 2 patients with canagliflozin

Serious adverse events of diabetic ketoacidosis (DKA) and related events occurred at low frequency among 17,596 patients from randomized studies treated with canagliflozin. Most patients with DKA and related events had blood glucose >300 mg/dL at presentation of DKA, were on insulin, and had DKA-precipitating factors, including some with type 1 diabetes.

• Serious adverse events were reported in 12 patients (0.07%), including 4 (0.07%), 6 (0.11%), and 2 (0.03%) treated with canagliflozin 100 and 300 mg and controls, respectively.

• Incidence rates were 0.522, 0.763, and 0.238 per 1,000 patient-years.

• Incidence was consistent with limited existing observational data in the general population with type 2 diabetes.

Citation: Erondu N, Desai M, Ways K, Meininger G. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care. [Published online ahead of print July 22, 2015]. doi: 10.2337/dc15-1251.

Commentary: In May 2015, the FDA announced a potential association between SGLT-2 inhibitors and high anion gap metabolic acidosis accompanied by elevation in urine or serum ketones.1 It emphasized that the reported cases were not associated with the high glucose levels usually seen in diabetic ketoacidosis and that clinicians should think of ketoacidosis in patients presenting with symptoms consistent with ketoacidosis, including tachypnea or hyperventilation, anorexia, abdominal pain, nausea, vomiting, lethargy, and mental status changes even when tested blood glucose levels were not in the range usually seen with ketoacidosis. The frequency of this presentation is not clear. The study reviewed above of more than 17,000 patients suggests that this condition is relatively rare, with an incidence in the study group similar to the usual diabetic population. Nonetheless, this new entity of diabetic ketoacidosis with relatively non-elevated glucose levels is important for clinicians to be aware of in appropriate patients on SGLT-2 inhibitors. —Neil Skolnik, MD

1. FDA website. FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. Update May 15, 2015. Accessed August 7, 2015.