Study shows a combination of liraglutide and the genetically modified insulin analog degludec was safe and improved HbA1c levels, weight loss, and hypoglycemia outcomes in patients with type 2 diabetes.
A combination of liraglutide and the genetically modified insulin analog degludec was safe and more effective than either agent alone, according to results from a phase 3 trial released at the annual scientific sessions of the American Diabetes Association in Chicago. The study found that the combination improved results in terms of HbA1c levels, weight loss, and hypoglycemia by levels that were statistically highly significant, with values below 0.001, according to the abstract.
Insulin degludec was approved for marketing in the European Union, though the combination is experimental and has not been approved in the US.
“This is a pretty impressive performance for a single treatment,” said John B. Buse, MD, PhD, professor of medicine and chief of the Division of Endocrinology at the University of North Carolina School of Medicine in Chapel Hill.
“Achieving an HbA1c level of 6.4 percent is almost unheard of in patients who had failed an oral agent," said Buse, who discussed the study in an oral presentation called “IDegLira, a Novel Fixed Ratio Combination of Insulin Degludec and Liraglutide, is Efficacious and Safe in Subjects with Type 2 Diabetes: A Large, Randomized Phase 3 Trial.”
“The manufacturer applied for FDA approval for insulin degludec alone, but the FDA wanted additional studies on CV safety” citing cardiovascular safety concerns," Buse explained. “It’s biologically implausible that there’s a cardiovascular issue, and the European authorities decided that was the case.” The current study found no cardiovascular hazards with the combination, Buse noted.
In the study, type 2 diabetics who had been inadequately controlled on metformin with or without pioglitazone were randomized to three arms. The combination arm included 834 patients, while 414 patients received insulin degludec alone, and 415 patients received liraglutide alone, the abstract said.
Outcomes were measured at 26 weeks. The primary endpoint, HbA1c, decreased by 1.9 percent, from 8.3 percent to 6.4 percent, in those on the combination therapy, compared to a decrease by 1.4 percent, to 6.9 percent, for those on degludec alone and a decrease by 1.3 percent, to 7 percent, for those on liraglutide alone, with a p value below 0.001, according to the abstract. Of those on the combination therapy, 81 percent achieved an HbA1c level below 7 percent, compared to 65 percent of those on insulin degludec alone and 60 percent of those on liraglutide alone.
The combination therapy was also associated with greater weight loss than either agent taken alone. Those in the combination arm experienced a mean weight loss of -0.5 kg, as those on both agents lost 2.22 kilograms more than those on degludec alone; however, those on the combination therapy lost 2.44 kilograms less than those on liraglutide alone, according to the abstract.
Those on the combination treatment also had a 32 percent lower rate of hypoglycemia than those on degludec alone, according to the abstract. While rates of hypoglycemia were low, those on both therapies were 68 percent as likely to have hypoglycemia as those on degludec alone (with a p value of 0.023); however, those in the combination arm were more than seven times as likely to have hypoglycemia as those on liraglutide alone, with a hazard ratio of 7.61, and a p value of less than 0.0001, according to the abstract.
Of those on the combination therapy, 8.8 percent reported nausea, compared to 19.7 percent of those on liraglutide. In addition, 3.9 percent reported vomiting, compared to 8.5 percent of those on liraglutide, the abstract said.
GI side effects with IDegLira were less than with Lira (nausea: 8.8 percent vs. 19.7 percent; vomiting: 3.9 percent vs. 8.5 percent).
“While insulin works by opening fat and muscle cells to receive glucose, degludec has been genetically modified, so it has a longer duration of action, and minimizes the risk of hypoglycemia from peaks and valleys,” Buse explained.
Researchers are also conducting other studies in insulin degludec, such as a cardiovascular outcome study using degludec alone and another study of the combination therapy called JEWEL 2, which are intended for release at the International Diabetes Federation meeting in Melbourne this December, Buse said. That study is designed to assess the effects of the liraglutide portion, he added.