Diabetic Ketoacidosis With SGLT2 Inhibitors Is Manageable

Miriam E Tucker

September 07, 2015

The euglycemic diabetic ketoacidosis (DKA) that has recently been associated with the use of sodium–glucose cotransporter 2 (SGLT2) inhibitors will probably turn out to be very infrequent in patients with type 2 diabetes and "predictable, detectable, and preventable" in those with type 1 diabetes, two leading clinical trialists assert in a new editorial published in the September issue of Diabetes Care.

The piece ― by Julio Rosenstock, MD, of the Dallas Diabetes and Endocrine Center at Medical City, Texas, and Ele Ferrannini, MD, of the Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche, Pisa, Italy ― accompanies the published versions of two related articles that had previously appeared online: a Janssen article demonstrating a low (but not zero) risk for DKA in a clinical-trial program of canagliflozin (Invokana, Janssen Pharmaceuticals, Inc), and a case series report of 13 episodes of euglycemic DKA in nine patients, seven with type 1 diabetes and two with type 2 diabetes, who developed the condition postoperatively.

The issue initially came to light in May 2015, when the US Food and Drug Administration issued a notice on the basis of 20 cases of DKA associated with SGLT2 inhibitors reported to the agency's adverse-event reporting system database. A month later, the European Medicines Agency initiated a review and identified 101 cases worldwide associated with type 2 diabetes.

Dr Rosenstock and Dr Ferrannini provide unpublished data from the other manufacturers of SGLT2 inhibitors on the US market, suggesting rates of DKA symptoms of 0.1% or less in randomized trials in more than 18,000 patients receiving dapagliflozin (multiple brands) and 7000 patients receiving empagliflozin (Jardiance, Boehringer Ingelheim).

They point out that there has been in increase in the use of SGLT2 inhibitors in patients with type 1 diabetes, although the agents are currently approved only for type 2 diabetes.

But the drugs have been shown to help improve glycemic control in type 1 diabetes, often enabling a reduction in insulin dose, and producing weight loss, so "it is not surprising that given the burden of type 1 diabetes and its challenging unmet needs, the pharmacological properties of SGLT2 inhibitors prompted clinical development programs seeking regulatory approval and attracted off-label use in type 1 diabetes," Dr Rosenstock and Dr Ferrannini say.

However, other experts have strongly discouraged such off-label use in light of the DKA findings, as Medscape Medical News has previously reported.

A Different Entity

Dr Rosenstock and Dr Ferrannini provide a detailed explanation of the pathophysiologic differences between classic DKA seen in patients with type 1 diabetes and that associated with SGLT2-inhibitor use.

The former has been described as occurring at blood glucose levels of less than 300 mg/dL in young and often female type 1 diabetes patients, often caused by reduced availability of carbohydrates and possibly in conjunction with reduced insulin doses.

In contrast, in SGLT2 inhibitor–induced euglycemic DKA, insulin deficiency and insulin resistance are milder, and insulin resistance may be improved. As a result, glucose overproduction and underutilization are less than in type 1 diabetes–associated DKA. More importantly, the authors say, renal glucose clearance ― ie, the ratio of glycosuria to prevailing glycemia ― is twice as great with euglycemic DKA as with classic DKA.

Although the incidence of euglycemic DKA in type 2 patients will probably turn out to be very low, physicians need to be aware that the risk may be increased in those with disease of long duration and beta-cell insufficiency, in adults with latent autoimmune diabetes, and in postsurgical patients, Dr Rosenstock and Dr Ferrannini advise.

Use in Patients With Type 1 Diabetes

For patients with type 1 disease, the authors say that SGLT2-inhibitor–related euglycemic DKA is "predictable, detectable, and preventable" (or can be mitigated), "so that the balance of benefits and risks favors the use of SGLT2 inhibitors in the type 1 diabetes population, which is in desperate need of adjunct therapies."

On the basis of case series reports, it appears that a common scenario occurs when the type 1 patient experiences mild nausea, checks his or her blood glucose, sees that it is only mildly elevated, and so reduces the insulin dose to avoid hypoglycemia, because the patient is not eating. This would then accelerate the ketone production and metabolic compensation toward DKA, potentially made worse by the volume depletion caused by the persistent glycosuria and vomiting.

To counter this, all patients taking SGLT2 inhibitors should be advised to check their ketone levels whenever they feel unwell, regardless of their glucose level.

If detected, patients should increase and maintain their fluid intake and consume carbohydrates to allow for their full insulin doses until the ketosis resolves. They should also temporarily stop the SGLT2 inhibitor and contact their medical provider, Dr Rosenstock and Dr Ferrannini say.

"In any event, type 1 diabetes patients who choose to take this medication off-label should sign an ad hoc informed consent that makes them fully aware of the potential for [euglycemic DKA], the precipitating factors, the warning symptoms and signs, and the preventive measures to adopt," they write.

For the future, ongoing long-term, randomized, placebo-controlled studies will provide information on the safety and efficacy of SGLT2 inhibitors in both type 1 and insulin-treated type 2 patients, and regulators will evaluate the risks vs benefits.

Dr Rosenstock and Dr Ferrannini conclude, "Hopefully, these clinical development programs will quickly expand so as to offer to patients and physicians a potential adjunct against the day-to-day management challenges of such a demanding disease."

Dr Rosenstock has participated in advisory boards and received honoraria or consulting fees from Merck, Sanofi, Novo Nordisk, Eli Lilly, MannKind, GlaxoSmithKline, Takeda, Daiichi Sankyo, Boehringer Ingelheim, Janssen, Lexicon, and Intarcia and has received research grants from Merck, Pfizer, Sanofi, Novo Nordisk, Eli Lilly, GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Janssen, Daiichi Sankyo, MannKind, Bristol-Myers Squibb, Boehringer Ingelheim, Lexicon, and Intarcia. Dr Ferrannini has been a member of the scientific advisory board or a speaker for Boehringer Ingelheim, Merck, AstraZeneca, Eli Lilly, Johnson & Johnson, Takeda, Novo Nordisk, GlaxoSmithKline, and Sanofi and has received research grant support from Eli Lilly and Boehringer Ingelheim.

Diabetes Care. 2015;38:1638-1642. Full text

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