Canagliflozin (Invokana) is a selective sodium glucose cotransporter-2 (SGLT-2) inhibitor that was first introduced in 2013 for the treatment of type 2 diabetes mellitus (DM). Though not FDA approved yet, its use in type 1 DM has been justified by the fact that its mechanism of action is independent of insulin secretion or action. However, some serious side effects, including severe anion gap metabolic acidosis and euglycemic diabetic ketoacidosis (DKA), have been reported. Prompt identification of the causal association and initiation of appropriate therapy should be instituted for this life threatening condition.
More than 5 million patients are admitted annually to intensive care units (ICUs) in the United States. A number of life threatening medical conditions, including diabetic ketoacidosis, can be associated with metabolic acidosis. Metabolic acidosis may also arise from several drugs and toxins through a variety of mechanisms. Since approval of the first-in-class drug in 2013, data have emerged suggesting that Sodium Glucose Transporter-2 (SGLT-2) inhibitors, including canagliflozin, may lead to diabetic ketoacidosis [
A 54-year-old Middle-Eastern male with type 1 diabetes mellitus who had laparoscopic appendectomy for acute gangrenous appendicitis with localized peritonitis 2 days prior to his emergency department visit presented with vague chest discomfort, mild abdominal pain, generalized fatigue, and confusion for one day. He denies vomiting, fever, or diarrhea. He had poor appetite and stated not eating and drinking much. He was not paying attention to his carbohydrate count. He denies alcohol or nonprescription drug intake. The patient continued to take his home medication regimen which includes canagliflozin and glargine insulin 60 units at night time. He has been taking canagliflozin 300 mg daily for three years. On presentation, he had a blood glucose level of 142 mg/dL (normal 70–140), normal kidney function (eGFR 103), severe metabolic acidosis with PH of 7.058 (normal 7.35–7.45), anion gap of 37 (normal 8–16) and serum bicarb of 9 mg/dL (normal 22–28), normal lactate level, and
Sodium Glucose Transporter-2 (SGLT-2) inhibitors, including canagliflozin, dapagliflozin, and empagliflozin, are a newer class of antidiabetic medications that are US Food and Drug Administration (FDA) approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. They lower plasma glucose levels by reducing the renal threshold for glucose and increasing urinary glucose excretion. On March 29, 2013, FDA approved canagliflozin (Invokana, Janssen Pharmaceuticals, Inc.), a once-daily tablet indicated as an adjunct to diet and exercise, to improve glycemic control in adults with type 2 diabetes mellitus [
Results from the preclinical and clinical studies led canagliflozin to be the first-in-class SGLT-2 inhibitor approved in the United States and support canagliflozin as a safe and effective therapeutic option across a broad range of patients with type 2 diabetes mellitus [
Canagliflozin was generally well tolerated [
Factors identified in some reports as having potentially triggered the ketoacidosis included major illnesses, infections, trauma, reduced food and fluid intake, and reduced insulin dose [
Unlike in our case, a temporal association with SGLT-2 inhibitor initiation was noted in all cases. The median time to onset of symptoms following initiation of drug therapy was 2 weeks (range 1 to 175 days) [
Our case clearly illustrates the rare association of severe anion gap metabolic acidosis with ketoacidosis and normal glucose levels with SGLT-2 inhibitors. Even though these patients are euglycemic, they should be treated as if they have diabetic ketoacidosis. Prompt identification of the causal association and initiation of appropriate therapy should be instituted for this life threatening condition. This case also points out that SGLT-2 inhibitors should preferably be avoided in circumstances where poor oral intake is much anticipated.
Future research should be directed toward identifying which patients are at greatest risk for this side effect. A possible association of SGLT-2 inhibitors and high osmolar gap metabolic acidosis needs to be further investigated.
The corresponding author is the guarantor of submission.
The authors declare that they have no competing interests.
Alehegn Gelaye was responsible for conception and design, acquisition of data, analysis and interpretation of data, drafting the paper, critical revision of the paper, and final approval of the version to be published. Abdallah Haidar, Christina Kassab, Syed Kazmi, and Prabhat Sinha were responsible for conception and design, acquisition of data, analysis and interpretations of data, critical revision of the paper, and final approval of the version to be published.