Fixed-dose combination of insulin degludec and liraglutide yields superior results in type 2 diabetes

By Will Boggs MD

NEW YORK (Reuters Health) - The fixed-dose combination of insulin degludec and liraglutide (Xultophy) is more effective than either agent alone at lowering blood sugar in insulin-naïve patients with type 2 diabetes, according to the DUAL-I trial.

Xultophy was developed by Novo Nordisk as a once-daily injection for treating type 2 diabetes. Dr. Stephen Gough from NIHR Oxford Biomedical Research Centre in the UK and colleagues compared it with each of its components in an open-label, randomized phase 3 trial including 1,663 insulin-naïve patients.

The drop in HbA1c at 26 weeks, the primary endpoint, was 1.9 percentage point (to 6.4%) in the Xultophy group, 1.4 percentage points in the insulin degludec group (to 6.9%) and 1.3 percentage points in the liraglutide group (to 7.0%), the researchers found.

The change with Xultophy was non-inferior to that seen with insulin degludec and significantly greater than that seen with liraglutide alone, they report in The Lancet Diabetes & Endocrinology, online September 2.

Moreover, a significantly higher proportion of patients achieved an HbA1c of less than 7.0% and of 6.5% or less with Xultophy (81% and 70%, respectively) than with insulin degludec (65% and 47%) or with liraglutide (60% and 41%).

More patients achieved HbA1c targets without weight gain in the liraglutide group than in the Xultophy group and in the Xultophy group than in the insulin degludec group.

More patients withdrew from the liraglutide group than from the insulin degludec and Xultophy groups, primarily as a result of gastrointestinal adverse events.

About a third of those in the Xultophy group had confirmed hypoglycemia, compared with 39% of the insulin degludec group and 7% of the liraglutide group. Treatment-emergent adverse events occurred in 63% of Xultophy patients, 60% of insulin degludec patients, and 73% of liraglutide patients.

Serious adverse events were relatively uncommon (2% of the Xultophy group, 2% of the insulin degludec group, and 3% of the liraglutide group).

"Further studies and feedback about patient experience are needed to determine whether these benefits of combined treatment will be compelling to health-care providers and patients, compared with the existing approach of adding basal insulin to GLP-1 receptor agonist treatment," the authors conclude. "Based on the results of the paper published in The Lancet and in a twin paper in Diabetes Care, the use of (the) fixed combination was effective both in patients previously treated with oral agents (and in those) already taking a basal insulin," said Dr. Stefano Del Prato from the University of Pisa in Italy, who wrote a comment on the findings in the journal.

"Both studies show efficacy with an attenuation of the typical side effects of insulin (body weight gain and hypoglycemia) and those of liraglutide (mainly nausea and, less frequently, vomiting)," he told Reuters Health by email. "Based on this profile, the fixed combination may offer an opportunity in all those patients in whom no further gain in body weight is felt desirable and in those in whom risk of hypoglycemia should be minimized in spite of the need of therapy intensification with insulin."

"To further appreciate the potential of this treatment, we will need to determine the durability of the efficacy of this treatment," Dr. Del Prato said. "This is quite important, because, if the fixed-ratio combination of the 2 agents could ensure sustained glycemic control this may also offset any possible (hopefully) minor increase in price."

He added, "The other point is that, right now, the therapeutic armamentarium in diabetes is quite articulate. Therefore, it will be our task to learn how to get the best out of each therapeutic opportunity for the individual patient."

Dr. Ajay Kumar from Diabetes Care and Research Center in Bihar, India, who recently wrote a review of Xultophy, said the medication can be helpful when multiple oral drugs fail to control the disease.

"Subjects failing on basal insulin along with oral antidiabetic agents are also candidates," he told Reuters Health. "However, at this stage one should restrict its use to subjects already on complex insulin regimens."

While concerned about Xultophy's potentially high cost, Dr. Kumar said, "With time cost is likely to come down making it available for use in all subjects where indicated."

The European Medicines Agency has issued a positive opinion regarding Xultophy, but has yet to approve the drug formally. Regulatory filing in the U.S. is awaiting additional data requested by the Food and Drug Administration for insulin degludec.

Novo Nordisk funded the study, employed two of the authors and had various relationships with five other authors.

Dr. Gough did not respond to a request for comments.

SOURCE: http://bit.ly/1uqV0nw and http://bit.ly/1tG3hS6

Lancet Diabetes Endocrinol 2014.

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