Recommendations on SGLT2 Inhibitors and DKA

Despite recent reports of cases of diabetic ketoacidosis (DKA) in patients treated with sodium glucose cotransporter 2 (SGLT2) inhibitors, patients with type 2 diabetes mellitus (T2DM) should continue to use these drugs, according to a new scientific and clinical review announced by the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE).

This spring, the US Food and Drug Administration issued a warning about DKA associated with the use of SGLT2 inhibitors based on 20 cases reported to the agency's adverse-event reporting system. More than 100 cases of DKA were also linked to the drugs worldwide.

Over a two-day conference in late October, experts from Europe and the United States reviewed the available data and concluded that “the prevalence of DKA is infrequent and the risk-benefit ratio overwhelmingly favors continued use of SGLT2 inhibitors with no changes in current recommendations.”

The expert panel reached the following conclusions:

• Among T2DM patients, it is unclear whether DKA occurs at a higher frequency than it did before the advent of SGLT2 inhibitors. Patients with type 1 diabetes have a higher risk of DKA than those with T2DM, and their risk of developing DKA while taking SGLT2 inhibitors may be further elevated, but further study is needed. 

• The majority of DKA occurs in people with diabetes who are insulin deficient, such as long-standing T2DM, latent autoimmune diabetes in adults, and type 1 diabetes.

• Almost all cases of SGLT2 inhibitor–associated DKA occurred in patients challenged with metabolically stressful events, such as surgery, extensive exercise, myocardial infarction, severe infections, stroke, and other stressful medical conditions.

• Clinicians should consider a diagnosis of DKA for patients taking an SGLT2 inhibitor who present with symptoms such as abdominal pain, nausea, vomiting, fatigue, and dyspnea. The AACE/ACE recommends direct measurements of beta hydroxybutyrate and arterial pH, which are necessary to confirm the diagnosis. Normal or modestly elevated blood glucose does not exclude the diagnosis of DKA during SGLT2 inhibitor use.

• To manage DKA in patients taking SGLT2 inhibitors, stop the drug immediately and proceed with traditional DKA treatment protocols.

• To minimize the risk of DKA associated with SGLT2 inhibitors, consider stopping the SGLT2 inhibitor at least 24 hours prior to elective surgery, planned invasive procedures, or anticipated severe stressful physical activity, such as running a marathon. Patients taking SGLT2 inhibitors should avoid excess alcohol intake and very-low-carbohydrate/ketogenic diets.

• SGLT2 inhibitors are not approved for use in type 1 diabetes. However, AACE/ACE encourages continuation of ongoing studies because initial results have shown a promising impact on glycemic regulation.

The experts noted that “diagnosis of DKA is often missed or delayed due to atypical presentation involving lower-than-anticipated glucose levels or other misleading laboratory values. This presentation has been seen with SGLT2 inhibitors, but was also observed before the introduction of these agents.”

Reference: AACE/ACE scientific and clinical review: association of SGLT2 inhibitors and DKA. October 24-25, 2015.