A case series detailing the association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and a serious side effect of euglycemic diabetic ketoacidosis (DKA) in nine patients, seven of whom had type 1 diabetes and two type 2 diabetes, has been published online June 15 in Diabetes Care, by Anne L Peters, MD, of the University of Southern California, Los Angeles, and colleagues.

The report provides more details about this potentially life-threatening side effect, which is particularly concerning because in this instance, the DKA is euglycemic, so those affected have near-normal glucose and few symptoms.

The new information comes on the heels of a review into the risk of euglycemic DKA associated with SGLT2-inhibitor use launched by the European Medicines Agency (EMA) last week. The EMA has reported 101 cases of DKA worldwide in patients with type 2 diabetes.

And in May, the US Food and Drug Administration (FDA) issued a similar warning about the drug class, noting 20 cases of euglycemic DKA linked to SGLT2-inhibitor use — most of those affected had type 2 diabetes.

SGLT2 inhibitors are a new class of drug for the treatment of type 2 diabetes, but they are also being used off label in patients with type 1 diabetes.

One of the most concerning aspects of this euglycemic DKA is that patients do not realize it is happening: because glucose levels are not significantly increased, they keep the insulin dose the same or even reduce it, possibly worsening the acidosis. In the cases reported, diagnosis and treatment were delayed for similar reasons.

The authors state: "Patients with type 1 or type 2 diabetes who experience nausea, vomiting, or malaise or develop a metabolic acidosis in the setting of SGLT2-inhibitor therapy should be promptly evaluated for the presence of [ketones in] urine and/or serum."

And SGLT2 inhibitors "should only be used with great caution, extensive counseling, and close monitoring in the setting of type 1 diabetes," they caution.

Another expert, Simeon Taylor, MD, PhD, professor of medicine at University of Maryland School of Medicine, who is the lead author of a new perspective on this topic(J Clin Endocrinol Metab. 2015; DOI:10.1210/jc.2015-1884), goes further and suggests this drug class not be used at all in those with type 1 diabetes, except in the setting of a clinical trial.

Euglycemic Ketoacidosis is Rare

SGLT2 inhibitors currently on the market in the United States and Europe include canagliflozin (Invokana, Janssen Pharmaceuticals), dapagliflozin (Farxiga/Forxiga, AstraZeneca Pharmaceuticals), and empagliflozin (Jardiance, Lilly/Boehringer). A number of combination products containing these agents are also marketed.

DKA is characterized by decreased insulin secretion along with increased secretion of cortisol, glucagon, catecholamines, and growth hormone. Common symptoms include headache, nausea, vomiting, malaise, and abdominal pain

Although DKA is well-recognized in type 1 diabetics, it rarely occurs in patients with type 2 diabetes. And DKA without marked hyperglycemia — euglycemia DKA — is thought to be rare.

SGLT2 inhibitors increase glucose loss through the urine and have also been linked to increased glucagon levels, which could cause gluconeogenesis, free-fatty-acid release, and increased serum-ketone levels. Volume depletion associated with SGLT2-inhibitor use could exacerbate the problem by further increasing glucagon, cortisol, and epinephrine, the case report authors suggest.

The Diabetes Care paper describes nine patients with 13 episodes of euglycemic DKA, some of whom had repeat episodes of ketosis on rechallenge with SGLT2 inhibitors.

In the two patients with type 2 diabetes, euglycemic DKA developed postoperatively. And in most of the seven patients with type 1 diabetes, euglycemic DKA developed in the setting of reduced insulin dose.

Contributing factors included recent illness, increased exercise, decreased food intake, and alcohol consumption, although a few patients had no identifiable contributing factors. Most patients were treated in the intensive-care unit; all responded well to intravenous fluids and insulin.

"The 'disconnect' between hepatic ketogenesis and blood glucose is not something we teach in medical school, and especially [not] in people with type 2 diabetes," explained the senior author of the case series report, Irl Hirsch, MD, professor of medicine at the University of Washington School of Medicine in Seattle.

"If insulin levels are low and glucagon and other counterregulatory hormones are high, a perfect storm exists, as renal glycosuria is masking the hepatic ketosis, and euglycemic DKA can occur," he told Medscape Medical News.

Don't Use SGLT2 Inhibitors in Those With Type 1 Diabetes

The two biggest concerns include patients having surgery and those with type 1 diabetes receiving SGLT2 inhibitors off label, according to Dr Hirsch.

He suggests stopping SGLT2 inhibitors 3 days before elective surgery. For urgent or emergent surgeries in patients on SGLT2 inhibitors, he advises anesthesiologists to infuse enough insulin and dextrose to ensure low or unmeasurable b-hydroxyburyrate levels.

The use of SGLT2 inhibitors in patients with recent-onset diabetes may also be concerning, according to Dr Hirsch.

"It is difficult to always know if an adult with new diabetes is type 1 or type 2, and we often see patients come into our clinic with an autoimmune form of diabetes with clear severe insulin deficiency," he explained, "The concern is euglycemic DKA could be seen in these patients, too."

Use of SGLT2 inhibitors in patients with type 1 diabetes is an especially concerning issue, Dr Taylor agrees.

One of the motivations for using SGLT2 inhibitors off label in patients with type 1 diabetes is to reduce the insulin dose and possibly decrease the risk of hypoglycemia, but Dr Taylor is skeptical.

"There may be a price to pay if the insulin dose is decreased. Insulin is also required to suppress lipolysis and ketone body synthesis. So, by decreasing insulin dosing, this has the potential to increase the risk of ketoacidosis," he explained.

Another issue that may be driving use of SGLT2 inhibitors off label in patients with type 1 diabetes is preliminary research that suggests this drug class may reduce the risk of diabetic kidney disease, Dr Taylor noted.

However, it would be "premature" and "ill-advised" to prescribe these drugs to patients with type 1 diabetes for kidney protection, he said, instead stressing that doctors should stick to approved drugs like ACE inhibitors and angiotensin-receptor blockers.

And while studies with SGLT2 inhibitors in patients with type 1 diabetes are ongoing, Dr Taylor emphasized: "SGTL2 inhibitors are not approved for treatment of type 1 diabetes. I personally strongly discourage off-label use in type 1 diabetic patients outside the context of an approved clinical-research trial."

This advice against off-label use "is motivated in great measure by concerns about the risk of ketoacidosis, but also by the absence of any proven benefit for patients with type 1 diabetes," he asserted.

DKA Rarer with SGLT2 Inhibitors in Type 2 Diabetes

It is likely, however, that the risk of DKA in patients with type 2 diabetes on SGLT2 inhibitors is quite low, probably numbering less than one in 1000 and possibly closer to one in 10,000, Dr Taylor said.

Still, he cautioned: "It is critically important for physicians to remember that [the case series] emphasized that a relatively normal level of plasma glucose does not exclude the presence of ketoacidosis. As reported…the presence of euglycemia appeared to delay correct diagnosis in some of the patients in their series."

Dr Peters reports having been an investigator, speaker, and/or consultant for Diabetes Care, Amgen, AstraZeneca, BD, Biodel, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen, Lexicon, Eli Lilly, Medtronic, Merck, Novo Nordisk, OptumRx, Sanofi, Takeda, and Thermalin. She is on the advisory board for Medscape. Dr Hirsch receives research grants from Sanofi, Novo Nordisk, and Halozyme and is a consultant for Abbott Diabetes Care, Roche, and Valeritas. Disclosures for the coauthors are listed in the article. Dr Taylor was formerly employed by Bristol-Myers Squibb and was on the research and development leading to dapagliflozin.

Diabetes Care. Published online June 15, 2015. Abstract