Dapagliflozin Plus Liraglutide and Insulin Effective in T1D (CME/CE)

Action Points

• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
• Dapagliflozin (Farxiga) was associated with improved HbA1c levels among patients with type 1 diabetes when it was added to liraglutide (Victoza) and insulin, researchers reported here, but the improvements came with significant side effects.
• Note that the triple combination therapy was also linked to improved weight, but two of 20 patients in the triple treatment arm developed diabetic ketoacidosis.

ORLANDO -- Dapagliflozin (Farxiga) was associated with improved HbA1c levels among patients with type 1 diabetes when it was added to liraglutide (Victoza) and insulin, researchers reported here, but the improvements came with significant side effects.

The triple combination therapy was also linked to improved weight, but two of 20 patients in the triple treatment arm developed diabetic ketoacidosis shortly after starting a higher dose of dapagliflozin and had to drop out.

There were no cases of ketoacidosis in the control group -- which was given liraglutide and insulin -- during the 12 week trial, according to Husam Ghanim, PhD, at the University of Buffalo in New York. Ghanim presented the findings here during a poster session at the annual meeting of the American Association of Clinical Endocrinologists, which runs through Sunday.

"The results were impressive," said Derek LeRoith, MD, PhD, at the Icahn School of Medicine in New York, in an interview with MedPage Today. "On the other hand, something that we've seen, particularly in type 1 diabetics, is that they develop ketosis, and this is worrisome in many respects because this often happens in association with a reduction in HbA1c levels -- the blood pressure gets better so patients will cut back on their insulin use."

LeRoith was not associated with the study.

Ghanim told MedPage Today that the reasoning behind adding a third agent to the patients' regimen -- they'd been on insulin and liraglutide therapy for at least 6 months -- was that the patients weren't achieving their targets. "We thought that we could add improvement, and maybe that the agents would synergistically reduce A1c and glycemia and improve the type 1 metabolic picture," said Ghanim.

The HbA1c levels did not change in the control arm (o%±0.02) but fell in the triple therapy group (-0.66%±0.08; P<0.01). But despite the improvement in HbA1c levels, the average glucose did not significantly differ between groups (3.1±6 in the controls versus -15±6; P=0.07), possibly due to the low number of participants, said Ghanim.

Body weight fell more in the triple therapy group (-1.9±0.54) than in the controls (-0.7 kg±1.5; P<0.05), but cholesterol increased in the triple therapy group. The class of drugs that dapagliflozin belongs to -- sodium-glucose transporter 2 (SGLT-2) inhibitors -- has been shown to be associated with ketoacidosis. The type 2 diabetes drug, along with the glucagon-like peptide 1 (GLP-1) agonist liraglutide, is sometimes used off-label to treat type 1 diabetes.

The 30 patients were on liraglutide and insulin for an average of 7 months. Most of the patients were taking 1.8 mg of liraglutide, and there were no significantly different baseline differences between the two groups. In addition to the two patients with ketoacidosis, one other patient dropped for "social reasons," said Ghanim, and one in the placebo group dropped as well, so nine patients in the placebo group and 17 in the treatment group were considered in the final analysis.

The insulin dose of the two patients who developed ketoacidosis was dropped significantly from baseline, to less than .5 units per kg, said Ghanim. One patient went from 33 to 26 units a day, and the other went from 40 to 26 units. One of those patients also developed a urinary tract infection.

"There have to be safety measures in place before using this regimen, and maybe every patient with type 1 diabetes won't be eligible for this regimen," said Ghanim. "We have to be careful with how we manage their ketogenesis."

LeRoith said that this early evidence merits further study. "We know more about the mechanisms whereby this is happening, but on the other hand we need to determine how common ketosis is going to be, because we need to explain to patients this danger and that they should be using this combination as to what could happen and what they should do," he said. "So many of us are a little weary of using it at the moment, and therefore further studies are definitely warranted."

• Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco

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Dapagliflozin Plus Liraglutide and Insulin Effective in T1D (CME/CE)