Understanding SGLT2 Inhibitors' Diabetic Ketoacidosis Risk

This article was collaboratively written with Shannon Anthony, PharmD Candidate.

In May 2015, the FDA issued a warning about the risk of developing diabetic ketoacidosis while using SGLT2 inhibitors. That December, the FDA updated the drugs’ labels to include warnings about developing ketoacidosis even with near-normal blood glucose levels.¹

SGLT2 inhibitors lower blood glucose levels by decreasing renal glucose reabsorption, which increases urinary glucose excretion.² Three drugs in this class are currently available in the United States: canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance).¹

These medications are approved for managing type 2 diabetes, although they’re increasingly used off-label to treat type 1 diabetes (T1D), and trials are currently being conducted to evaluate their efficacy for this potential indication.³

Diabetic ketoacidosis (DKA) develops most frequently in T1D patients secondary to omission or decreased dosage of insulin, acute illness, or a recent surgical procedure.⁴ The typical clinical presentation includes hyperglycemia (>250mg/dL), anion-gap acidosis, and elevated plasma and urine ketones.³

Early diagnosis and management of ketoacidosis is vital. The cornerstone DKA treatment is fluid replacement, insulin therapy, and correction of electrolyte imbalances.⁴

In the DKA cases reported with SGLT2 inhibitors, patients had an atypical presentation of DKA resulting in delayed diagnosis and treatment. Patients presented euglycemic or with only slightly elevated blood glucose levels.^1,3,5

An analysis of 9 patients who experienced an episode of DKA while on an SGLT2 inhibitor showed their range of blood glucose levels upon presentation was 96 to 224 mg/dL.³ Based on that, insulin administration was unchanged or decreased and DKA treatment was delayed due to misdiagnosis.³

The results from case reports identified multiple risk factors that may predispose ketoacidosis. Patients who have recently had their insulin dosage decreased, acute febrile illness, recent surgery, alcohol intake, or pancreatic disorders are at higher risk.^1,3

When insulin-dependent patients are initiated on an SGLT2 inhibitor, the insulin dose should be decreased to avoid the risk of hypoglycemia. However, the decreased insulin dose may not be sufficient to suppress ketogenesis and therefore can increase the patient’s risk for developing DKA.⁶ Temporary discontinuation of SGLT2 inhibitor use in settings known to increase ketoacidosis risk, like a planned surgical procedure, should be considered.⁷

The FDA conducted a review of its adverse event reporting system between March and May 2015 and found 73 reported cases of DKA in patients treated with SGLT2 inhibitors. However, the number of cases is most likely underestimated due to misdiagnosis and underreporting.

Physician and patient awareness of DKA risk when using SGLT2 inhibitors is important to quickly and accurately identify and treat the condition. Patients should be counseled that if they experience symptoms like nausea, vomiting, shortness of breath, abdominal pain, or confusion, they should seek medical attention immediately.¹ Increased patient and physician awareness of ketoacidosis risk while using SGLT2 inhibitors will lead to improved outcomes for patients in the emergent setting of DKA.

References

1. FDA. FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. www.fda.gov/Drugs/DrugSafety/ucm446845.htm. Accessed June 17, 2016.

2. Scheen AJ. Pharmacodynamics, efficacy, and safety of the sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75(1):33-59.

3. Peters AL, et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38(9):1687-1693.

4. Gosmanov AR, et al. Management of adult diabetic ketoacidosis. Diabetes Metab Syndr Obes. 2014;7:255-264.

5. Kitabchi AE, et al. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-1343.

6. Taylor SI, et al. SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015;100:2849-2852.

7. Fala L. Invokamet: first fixed-dose combination with an SGLT2 inhibitor approved for the treatment of patients with type 2 diabetes. Am Health Drug Benefits. 2015;8:70-74.