SGLT2 Inhibitor-Linked Diabetic Ketoacidosis Is Rare, but Severe

Miriam E Tucker

February 21, 2018

Many cases of sodium-glucose cotransporter-2 (SGLT2) inhibitor-associated diabetic ketoacidosis (DKA) are preventable, new research suggests. 

But physicians and patients are missing the signs and symptoms of this rare side effect — or not even aware of the link — and as a result, any cases are severe and one was fatal, according to this latest audit of Australian databases, published online February 13 in Diabetes Care by Emily J Meyer, MBBS, of the Royal Adelaide Hospital and University of Adelaide, Australia, and colleagues.

As DKA was initially missed by both patients and physicians, likely due in part to relative euglycemia, this led to delayed treatment, say the researchers.

However, "identifiable precipitants were often present, suggesting the potential for risk mitigation," Meyer and colleagues write.

Stop SGLT2 Inhibitors for Acute Illness, Surgery

The US Food and Drug Administration (FDA) first warned about the risk for DKA with SGLT2 inhibitors, a relatively new class of oral agents for type 2 diabetes, in 2015, and the European Medicines Agency followed suit in 2016.  

The phenomenon has also been reported several times in the literature, including in the New England Journal of Medicine in 2017.

The advice has been, and the Australian authors agree, that SGLT2 inhibitors should be temporarily stopped during acute illness or surgery.

The possibility of DKA should be considered in any patient taking one of the agents who presents with malaise, nausea, and/or vomiting, they add. The drug should be stopped and, if caught early, the patient given hydration, carbohydrates, and insulin to prevent progression to DKA.

Also, Meyers and colleagues suggest excluding a diagnosis of autoimmune diabetes (type 1 or latent autoimmune diabetes of adulthood) prior to restarting the SGLT2 inhibitor.

In Most Cases, DKA Was Preventable or Predictable

In this latest analysis, the first part consisted of a South Australia audit of 13 cases of SGLT2 inhibitor-associated DKA between December 2015 and April 2017 for which medical records were available. Eight were adults with type 2 diabetes — half of whom were taking insulin — and five had type 1 diabetes. Two of the latter were only identified retrospectively via autoantibody testing after the DKA presentation.

Dapagliflozin (Farxiga, Xigduo XR, AstraZeneca) was implicated in nine of the cases, and empagliflozin (Jardiance, Lilly/Boehringer Ingelheim) in four.  

Nine of the patients required intensive/high-dependency care, and all required intravenous insulin and dextrose. The one death was because of Takotsubo cardiomyopathy.

Treating physicians had missed the DKA diagnosis in two patients, while in six patients the physicians were unaware of the link between SGLT2 inhibitors and DKA. 

In addition to the two cases with undiagnosed type 1 diabetes, other precipitating events included missed insulin doses in five, infection in five, surgery in three, and reduced carbohydrate intake (because of fasting for surgery, low-carbohydrate diet, or anorexia) in five.

Based on a total of 85 851 dapagliflozin and empagliflozin prescriptions written in South Australia from December 2015 to March 2017, the 13 cases work out to an event rate of SGLT2 inhibitor-associated DKA episodes of 1.8 cases per 1000 patient-years.

That rate is higher than most previous reports, but should be viewed cautiously because of uncertainty about case detection, Meyers and colleagues caution.

The authors then performed a second analysis of 82 unique adverse event reports of SGLT2 inhibitor-associated ketoacidosis from the Therapeutic Goods Administration (TGA, the Australian equivalent of the FDA) from the time the drugs came on the market through April 2017.

The 82 cases presumably would have included the aforementioned 13, although that can't be confirmed, the authors note. 

Diabetes status was not reported in 47 of the 82 reports. Two occurred with off-label use of the SGLT2 inhibitor for weight loss or insulin resistance, both precipitated by a gastrointestinal illness. The drugs were discontinued in most cases, but in at least two they were restarted.

Average duration of SGLT2 inhibitor use prior to DKA was 11.6 weeks, but ranged from 1 day to 76 weeks.

The DKA was usually serious, requiring intensive care in 18 cases and classified as life-threatening in 16 cases, with a mean pH of 7.06, bicarbonate 7.35 mmol/L, ketones 6.2 mmol/L, and anion gap 23.7 mmol/L.

Precipitating factors were similar to those seen in the smaller group, including undergoing surgery in 13 cases, acute coronary events in three cases, and low carbohydrate intake in one case.

Mean glucose was 14.1 mmol/L (253.8 mg/dL), ranging from 4.8 mmol/L (86.4 mg/dL) to 35 mmol/L (630 mg/dL), and four patients had glucose ≤ 8.0 mmol/L (144 mg/dL).

"The TGA reports are unlikely to have captured all cases of SGLT2 inhibitor-associated DKA as adverse drug events are generally underreported," Meyers and colleagues conclude.

The authors have reported no relevant financial relationships.

Diabetes Care. Published online February 13, 2018. Article

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