Low DKA Risk Seen With Canagliflozin in Company Trials

Miriam E Tucker

August 12, 2015

The rate of diabetic ketoacidosis (DKA) occurring among patients with type 2 diabetes taking the sodium glucose cotransporter-2 (SGLT2) inhibitor canagliflozin (Invokana, Johnson & Johnson/ Janssen) was low in Janssen's clinical-trial program for the drug, new data from the company show.

The analysis, by Gary E Meininger, MD, vice president, franchise medical leader, metabolism, and Janssen colleagues, was published online July 22, 2015 in Diabetes Care.

Overall rates of DKA and related serious adverse events (metabolic acidosis, acidosis, and ketoacidosis) occurred in less than 1% of 17,596 patients.

"DKA and related events occurred at a low frequency in patients participating in the randomized, controlled, canagliflozin type 2 diabetes clinical-trial program," Dr Meininger told Medscape Medical News, adding that at this rate the incidence of DKA was not significant and is unlikely "to be clinically meaningful."

However, one expert said that despite the low numbers, there is still reason for concern.

"These data are not reassuring. Canagliflozin was associated with a dose-dependent increase in the risk of treatment-emergent DKA, with more than a threefold increase at the 300-mg dose," said Simeon I Taylor, MD, PhD, professor of medicine at University of Maryland School of Medicine, Baltimore, and author of a recent perspective on this topic (J Clin Endocrinol Metab. 2015;100:2849-2852).

DKA: A New Concern for SGLT2-Inhibitor Use

On May 15, 2015, the US Food and Drug Administration (FDA) issued a notice based on 20 cases of diabetic ketoacidosis associated with diabetes medications in the SGLT2-inhibitor class reported to the agency's Adverse Event Reporting System database. The warning applied to canagliflozin, as well as dapagliflozin (Farxiga/Forxiga, AstraZeneca), empagliflozin (Jardiance, Lilly/Boehringer), and several combination products that include an SGLT2 inhibitor.

Just a month later, the European Medicines Agency initiated a review of SGLT2 inhibitors to evaluate the risk of DKA and reported that a total of 101 cases of diabetic ketoacidosis had been reported worldwide in patients treated with SGLT2 inhibitors for type 2 diabetes. Canada has also launched a similar investigation.

The reports are of great concern because DKA is uncommon among people with type 2 diabetes and because in several of the cases the DKA occurred in the setting of only mildly elevated blood glucose levels (less than 200 mg/dL).

On July 9, 2015, Janssen sent a letter to healthcare providers advising them to assess for ketoacidosis in diabetes patients who present with typical symptoms including nausea, vomiting, excessive thirst, and/or difficulty breathing.

One subsequent analysis has suggested that some of the DKA is occurring in type 1 patients in whom the drug is prescribed off-label, and experts have recommended against this practice until more is known about this phenomenon.

Is the DKA Risk Significant?

In the new Janssen analysis, rates of serious DKA events were 0.07% for 100-mg/day canagliflozin and 0.11% for the 300-mg/day dose vs 0.03% with comparators. There were 12 cases in all.

Dr Meininger said, "While numerically there were more cases with canagliflozin 300 mg vs canagliflozin 100 mg, given the small number of cases, these differences are not statistically significant and not likely to be clinically meaningful."

The Janssen investigators also suggest that some of the DKA cases could be occurring in adults with autoimmune diabetes misdiagnosed as type 2.

While Dr Taylor doesn't dispute that this could be the explanation in some cases, he pointed to a phase 2 study of a different SGLT2 inhibitor that showed a statistically significant, dose-dependent increase in serum ketone body levels in a Japanese type 2 diabetes population (Cardiovasc Diabetol. 2014;13:65).

"This occurred in Japanese patients—a population in whom autoimmune diabetes is relatively uncommon.…Furthermore, the clinical data strongly suggest that an increase in serum ketone body levels is intrinsic to the mechanism of action of selective SGLT2 inhibitors, possibly mediated by the well-demonstrated ability of the drugs to increase glucagon levels," Dr Taylor told Medscape.

He added, "It seems likely that a drug-induced increase in serum ketone body levels would render patients more vulnerable to develop overt ketoacidosis in response to other risk factors for DKA, such as intercurrent illnesses or stress associated with surgery."

Should Autoimmune Diabetes Be Screened Out?

Of the total 12 patients who developed DKA in the canagliflozin trials, half were found to have autoimmune diabetes after they experienced the DKA. And, in contrast to the FDA reports, blood glucose levels were above 300 mg/dL for all 10 patients in whom the levels were known.

However, Dr Meininger said it wouldn't make sense to require antibody screening in order to rule out autoimmune diabetes before prescribing canagliflozin.

Approximately 5% of patients diagnosed with type 2 diabetes actually have latent autoimmune diabetes of adulthood (LADA), he explained.

That means, based upon the ~17,000 subjects included in the current analysis, approximately 850 subjects — including about 600 exposed to canagliflozin — in the trials could be antibody positive, yet only six were found to have DKA.

"Furthermore, the incidence of DKA in patients with LADA is low. Therefore, testing for antibodies for LADA is unlikely to be predictive of a risk for DKA," Dr Meininger said.

Dr Taylor concurred. "It's expensive to screen for these autoantibodies and probably would not be cost-effective."

Janssen is currently considering ways to better understand the risk of DKA in patients with diabetes, Dr Meininger told Medscape Medical News.

In the meantime, Dr Taylor advised, SGLT2 inhibitors should not be prescribed off-label to patients with type 1 diabetes.

And for those with type 2 diabetes taking the drugs, the approach in the provider letter is probably the best bet: "Monitor for clinical signs and symptoms of DKA and maintain a high index of suspicion about the risk of DKA in SGTL2-inhibitor–treated patients."

Dr Meininger is an employee of Janssen. Disclosures for the coauthors are listed in the article. Dr Taylor was employed by Bristol-Myers Squibb during 2002–2013 where, as vice president of cardiovascular and metabolic disease research, he participated in research and development leading to the approval of dapagliflozin, which is currently marketed by AstraZeneca.

Diabetes Care. Published online July 22, 2015. Abstract


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