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BOSTON -- Type 1 diabetes patients taking three drugs -- dapagliflozin (Farxiga), liraglutide (Victoza), and insulin -- saw improved outcomes, but the benefit came at the apparent risk of ketoacidosis, according to a new pair of papers presented here.

Researchers looked at 30 patients with type 1 diabetes who were already on liraglutide and insulin; they then randomized the patients to receive either dapagliflozin -- a sodium-glucose cotransporter 2 (SGLT-2) inhibitor -- or placebo as an add-on for 12 weeks. HbA1c levels fell by 0.6% in the dapagliflozin group but did not change in the placebo group (P<0.01), and the average weekly glucose concentration decreased by 15 mg/dL (P<0.05 versus baseline and P=0.07 versus placebo), according to , at the State University of New York in Buffalo, and colleagues.

But there were serious safety concerns, with two patients who were on dapagliflozin suffering diabetic ketoacidosis 1 day after an increase in the dosage of the drug to 10mg. Both were withdrawn from the study, Ghanim reported at the Endocrine Society annual meeting.

In addition to the study, Ghanim presented results from a separate study on the .

"There's a need for additional improvement in glycemia," Ghanim stated. "In view of the fact that an overwhelming majority of patients with type 1 diabetes are not at the glycemic goal of HbA1c of <7%, it is imperative that novel approaches to its treatment are devised."

The Efficacy Trial

Patients were randomized 2:1 to either dapagliflozin or placebo as an add-on to liraglutide. Patients started on 5 mg of dapagliflozin but dosage was increased to 10 mg daily after the first week. All of the patients had type 1 diabetes for at least a year and were on 1.8 mg of liraglutide for at least 7 months.

Liraglutide suppresses glucagon and free fatty acids, and SGLT-2 increases glucagon, Ghanim explained, so the authors hoped that the combination of the drugs would be effective.

Patients were taking insulin therapy and had no detectable c-peptide in their plasma. The mean body weight was 182 lbs, mean HbA1c was 7.68, mean glucose levels were 163 mg/dL, mean age was 54, and mean age at the time of diabetes diagnosis was 29. Seventeen of the participants were female; only two were not white, with one African American in the study and one Asian. No significant differences between the groups existed at baseline.

Ghanim and colleagues found no statistical difference in hypoglycemia between the treatment and control groups (P=0.52). There also was no difference in total insulin dosage between the groups, but basal insulin dose fell by 0.72 from 33.7 units in the dapagliflozin group (P<0.05 versus placebo) while it increased by 1.9 units (P<0.01 versus baseline) in the placebo group.

In addition, those in the treatment group lost slightly more weight (-1.9 kg) than the placebo group, who didn't lose weight (P<0.05). Total cholesterol and LDL cholesterol increased by 6% and 8% in the dapagliflozin group, respectively, and by 11% and 17% in the placebo group (P<0.05 for both groups versus the baseline).

Ghanim said that the study has been accepted by Diabetes Care and is slated for publication in the near future.

Risk of Ketoacidosis

In the same patient population as the efficacy trial, one patient that dropped out had euglycemic diabetic ketoacidosis, while another had hyperglycemic ketoacidosis. The first patient saw a total insulin reduction from 33 to 26 units and the other did not change dose during the study. But both patients experienced ketoacidosis shortly after the dosage of dapagliflozin was increased to 10 mg.

Both patients had an arterial pH of <7.10, according to the authors. The urinary ketones acetoacetate and β-hydroxybutyrate increased significantly in the dapagliflozin group, from 0.68 to 1.28 µM/mg creatinine (P<0.05) compared with placebo. In addition, hormone sensitive lipase increased by 29% (P<0.05 versus placebo) and free fatty acids increased from 0.34 to 0.59 (P<0.05), but in the placebo group neither measure changed.

Serum β-hydroxybutyrate levels were related to FFA concentrations (r=0.374, P<0.05), Ghanim said. Both patients who had ketoacidosis were re-hydrated and treated with intravenous insulin and eventually began taking liraglutide and insulin again.

at Tulane University in New Orleans, session moderator, told MedPage Today that it is important that physicians understand the risks of putting type 1 diabetes patients on medications. He added that he is a co-author of a forthcoming consensus statement from the American Association of Clinical Endocrinologists (AACE) on managing ketoacidosis patients on GLP-1 receptor agonists.

"It's very comprehensive, it's an important topic, and there's a lot of misinformation and confusion around it," he said.