Insulin degludec, an ultralong-acting insulin now in clinical development, proved noninferior to insulin glargine in two parallel, phase III randomized trials sponsored by the manufacturer and reported in the April 21 issue of Lancet.
The new insulin was as effective as insulin glargine at reducing hemoglobin A1c levels in one study of patients with type 1 diabetes and in another of patients with type 2 diabetes. Patients reported significantly fewer episodes of hypoglycemia with insulin degludec, both research groups reported.
Fear of hypoglycemic events often interferes with patients’ initiating or intensifying their insulin therapy, and may be the leading cause of inadequate insulin dosing, the researchers noted.
When injected subcutaneously, insulin degludec forms a depot of soluble multihexamers that slowly and continuously release the drug into the circulation. Insulin degludec has a half-life of 25 hours (twice that of insulin glargine) and a duration of action of more than 40 hours.
In the first study, 629 adults who had longstanding type 1 diabetes and had been treated with basal-bolus insulin for at least 1 year were randomly assigned to take once-daily subcutaneous injections of either insulin degludec (472 subjects) or insulin glargine (157 subjects), as well as subcutaneous injections of insulin as part at every meal, a strategy known as basal-bolus treatment, said Dr. Simon Heller of the University of Sheffield (England) and his associates.
The trial was open label because the injection devices for the basal insulins were different, so subjects and researchers could not be blinded to treatment assignment.
The study subjects were treated and followed for 1 year at 79 sites in France, Germany, Russia, South Africa, the United Kingdom, and the United States. Novo Nordisk, the manufacturer of insulin degludec, designed the study, supplied products and equipment, and provided data monitoring and management, statistical analysis, and the written report of the trial results.
The primary efficacy outcome was the mean percent decrease in HbA1c levels from baseline values, which were less than or equal to 10% (86 mmol/mol). The mean percent reduction was 0.40% with insulin degludec and 0.39% with insulin glargine, demonstrating the noninferiority of the new insulin, the investigators said (Lancet 2012;379:1489-97).
Similar proportions of patients achieved target HbA1c levels with insulin degludec (40%) and insulin glargine (43%). Mean fasting plasma glucose levels also declined to the same degree in the two groups. Mean weight gain was similar, at 1.8 kg with insulin degludec and 1.6 kg with insulin glargine.
"At the end of the trial, the mean values for daily basal, daily bolus, and daily total insulin dose were significantly lower by 14%, 10%, and 11%, respectively, in the insulin degludec group relative to the insulin glargine group," Dr. Heller and his colleagues said. "This difference might be attributable to a requirement for higher doses of insulin glargine to achieve adequate 24-hour coverage when used once daily."
The rates of hypoglycemic episodes, of severe hypoglycemic episodes, and of daytime hypoglycemic episodes were not significantly different between the two study groups. The rate of nocturnal hypoglycemic episodes, however, was 25% lower with insulin degludec. In the first 12 hours after a once-daily injection, which many patients perform at bedtime, approximately 50% of insulin degludec and 60% of insulin glargine are released, the researchers explained.
The rates of other adverse events were similar between the two groups, and there were no significant differences in patient assessments of quality of life.
Dr. Heller and his colleagues cautioned that rates of severe hypoglycemia are much higher in real-world settings than in clinical trials – as much as 20 times higher in one large, observational study. "This difference is partly because patients with recurrent episodes are usually excluded from trials, but also because those in trials receive close supervision and are treated according to protocol. Whether reductions in hypoglycemia reported in clinical trials translate into benefits in clinical practice remains to be seen," they said.
The second phase III study was identical in design and differed only in the patient population, which was limited to patients with type 2 diabetes. These 1,006 subjects had a HbA1c of 7%-10% after 3 months or more of any insulin regimen (with or without oral antidiabetic drugs), and were treated and followed at 123 sites in Bulgaria, Germany, Honk Kong, Ireland, Italy, Romania, Russia, Slovakia, South Africa, Spain, Turkey, and the United States.
After 1 year, the mean HbA1c level had decreased by 1.10% with insulin degludec and by 1.18% with insulin glargine, confirming the noninferiority of insulin degludec, said Dr. Alan J. Garber of Baylor College of Medicine, Houston, and his associates.