June 14, 2016

AACE/ACE Position Statement on SGLT2 Inhibitors

In spite of the FDA warning a year ago, the American association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) has taken a strong position in opposition to the FDA warning.

This position paper represents the official position of the AACE and ACE and is meant to provide guidance. It is not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.

The FDA warning in May 2015 that SGLT-2 inhibitors may lead to ketoacidosis, generated considerable attention. Now, AACE/ACE have issued a joint position statement concluding that the incidence of diabetic ketoacidosis in patients with type 2 diabetes taking an SGLT-2 inhibitor is no greater than the low levels occurring in the general diabetes population. While this is true, the cases are not considered similar to what develops in those with type 1 diabetes. The AACE/ACE concluded that the risk of DKA when using inhibitors is infrequent and the risk-benefit ratio favors continued use.

In an interview with Endocrine Today, study co-author Zachary T. Bloomgarden, MD, MACE, stated that “There is no definite evidence that these agents are associated with DKA in type 2 diabetes, and some reports have actually described patients with ketosis, or even just ketonuria, which likely are not clinically significant. The DKA cases that have been reported generally involve patients with type 1 diabetes, although reports in atypical diabetes (such as that with pancreatic disease) and in patients with longstanding type 2 diabetes who require multiple-dose insulin treatment similar to that used in type 1 diabetes suggests that a necessary mediator of DKA is marked insulin deficiency.”

The consensus group reviewed over 82 DKA cases from the literature, including those involving SGLT-2 inhibition and those cases occurring before SGLT-2 inhibitor therapy was available. In patients taking an SGLT-2 inhibitor, DKA occurred most often in insulin-deficient individuals, including those with longstanding type 2 diabetes, type 1 diabetes or latent autoimmune diabetes in adults. SGLT-2 inhibitors are not FDA approved for patients with type 1 diabetes, and 7 out of 9 patients in the American case series that prompted the FDA safety warning had type 1 diabetes, the authors wrote.

Nonetheless, the authors urge further study of SGLT-2 inhibitors in type 1 diabetes because initial studies have shown promise in glycemic regulation for patients with type 1. For future T1D trials, lower SGLT-2 inhibitor doses should be considered and insulin doses should not routinely be reduced when SGLT-2 inhibitors are begun, but adjusted based on the individual response.

Further, the position statement notes that almost all cases of SGLT-2 inhibitor-associated DKA occurred in patients challenged with metabolically stressful events, which acted as precipitants of DKA, such as surgery, extensive exercise, myocardial infarction, stroke, severe infections, prolonged fasting, and other stressful physical and medical conditions.

The statement recommends that SGLT-2 inhibitors be stopped at least 24 hours before planned stressful events, such as surgery, or very intensive exercise, such as running a marathon. Patients prescribed SGLT-2 inhibitor therapy should also avoid excess alcohol intake and very low carbohydrate diets, both of which are potentially ketogenic, the researchers wrote.

Once diagnosis of DKA is suspected, the SGLT-2 inhibitor should be stopped immediately and a DKA protocol initiated, including fluids, insulin and other standard interventions.

DKA diagnosis may be missed or delayed due to atypical presentation involving lower-than-anticipated glucose levels or other misleading laboratory values. This presentation has been seen with SGLT-2 inhibitors, but has also been observed for decades before the introduction of these agents. Gaps in understanding call for more studies of the mechanisms behind the metabolic effect of SGLT-2 inhibitors as well as more healthcare professional education focused on the proper diagnosis and treatment of DKA.

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