September 27, 2013

BARCELONA, Spain — A fixed-ratio combination therapy that includes insulin degludec (Tresiba, Novo Nordisk) and liraglutide (Victoza, Novo Nordisk) significantly improves glycemic control in patients with type 2 diabetes mellitus compared with either drug alone, according to the results of a new study.

Prof. Stephen Gough, from the University of Oxford, United Kingdom, presented the results of the phase 3 randomized controlled trial at the European Association for the Study of Diabetes (EASD) 2013 Meeting and said the combination drug, which was given to patients inadequately controlled on the oral agents metformin and pioglitazone, was also shown to have a low risk for hypoglycemia, weight gain, and gastrointestinal side effects.

The results of the study, known as the DUAL I trial, were first presented at the American Diabetes Association 2013 Scientific Sessions in June. John Buse, MD, from the University of North Carolina, Chapel Hill, presented the results of the study then and raved about the findings to Medscape Medical News. He was impressed with the lack of side effects, particularly the reduced risk for nausea, weight gain, and hypoglycemia. "In my mind, this is a demonstration of a sort-of souped-up insulin — I hate to say it, but 'insulin on steroids.' "

Despite the positive results, Frits Holleman, PhD, from the Academic Medical Center, Amsterdam, the Netherlands, the moderator of the EASD session, was somewhat tepid about the data, particularly in the treatment approach.

"It seems to work, but you can't help but wonder, particularly in this patient group, which is patients with type 2 diabetes on metformin, why you'd start both [insulin and liraglutide] at the same time," he told Medscape Medical News. "Why not go sequentially? Starting 2 things at the same time always gives double the chance of trouble."

The fixed-ratio combination (Ideglira, Novo Nordisk) combines a long-acting basal insulin with liraglutide, a glucagonlike peptide-1 (GLP-1) agonist, in a single-injection delivery device for patients with type 2 diabetes. In combining the drugs, one unit of insulin degludec is combined with 0.036 mg of liraglutide. The maximum doses available for the combination would include 50 units of insulin degludec with 1.8 mg of liraglutide.

In the 26-week study, all patients were treated with metformin and pioglitazone and randomized to 1 of the following:

  • Insulin degludec/liraglutide (834 patients).

  • Insulin degludec (414 patients).

  • 1.8 mg of liraglutide (415 patients).

The average doses of liraglutide and insulin degludec that were combined for use in the Ideglira-treated patients were 38 units and 1.4 mg, respectively. For those randomized to receive insulin degludec with metformin and pioglitazone, the average dose was 53 units.

HbA1c levels for the insulin degludec/liraglutide-treated patients declined 1.9%, down from 8.3% to 6.4%, at the end of the trial. For those who received liraglutide, the change in HbA1c was a 1.44% reduction, down from 8.3% to 6.9%. Among those who received insulin degludec, the reduction was 1.28%, down from 8.3% to 7.0%. More than 80% of patients treated with insulin degludec/liraglutide achieved the target of HbA1c <7.0%, and 70% reached HbA1c levels <6.5%. Fasting plasma glucose levels were also significantly improved.

There was a modest reduction in body weight with insulin degludec/liraglutide and a significant reduction in the risk for hypoglycemia compared with patients who received basal insulin.

To Medscape Medical News, Dr. Holleman said the researchers achieved excellent levels of HbA1c, but he is not sure diabetes patients need to be treated to levels <6.5%. In Holland, he said physicians still use metformin and a sulfonylurea. If the patient is not at goal with that combination, insulin is added. They are mindful, however, of older or frailer patients who might be vulnerable to hypoglycemia, so the goal with them is to not lower their HbA1c levels as aggressively.

"I must say, though, I am impressed with the data," he said. "The effect was very good. On the one hand, it's what you'd expect because 2 drugs will always give you better HbA1c. But the effect on hypoglycemia is also quite interesting. Maybe we'll do this eventually, but I'm still a little bit confused about whether we really need all these new drugs coming out. Generally speaking, the side effects of [sulfonylureas], particularly hypoglycemia, are usually overemphasized."

Dr. Holleman said that even with basal insulin, the risk for hypoglycemia is quite low, and this can be treated easily with a can of soda. "This is the reason for switching to all these new drugs?" asked Holleman. "I'm skeptical of what the drugs bring."

Liraglutide is approved in the US and Europe, while insulin degludec is approved only in Europe. Earlier this year, the US Food and Drug Administration said large-scale cardiovascular studies would be required before insulin degludec can be approved. Novo Nordisk is seeking approval for Ideglira in Europe.

The study was sponsored by Novo Nordisk.

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