PHILADELPHIA – The investigational ultralong-acting insulin, degludec, improved glycemic control while incurring lower risks of hypoglycemia in several studies of diabetes patients, many of them obese with high insulin requirements.
Novo Nordisk’s insulin degludec (IDeg), which is under consideration for approval by the Food and Drug Administration, is a basal insulin that forms soluble multihexamers after subcutaneous injection, extending its half-life significantly longer than 24 hours. The resulting steady blood levels of insulin confer a significantly lower risk of hypoglycemia in type 1 and type 2 patients taking degludec, compared with those taking insulin glargine, the comparator in many clinical trials, according to Dr. Helena W. Rodbard, an endocrinologist who practices in Rockville, Md.
About a third of patients with type 2 diabetes in the United States require more than 60 U just as the basal component, with quite a few requiring 80 or 100 U of insulin, noted Dr. Richard M. Bergenstal, executive director of the International Diabetes Center at Park Nicollet, Minneapolis. This demand for ever-increasing units has led to the development of new basal insulins that are even longer-acting, smoother, and flatter in terms of their pharmacokinetic and pharmacodynamic profiles, he said.
Dr. Rodbard presented the results of a meta-analysis of five phase IIIA, open-label, randomized, treat-to-target, confirmatory, 26- or 52-week trials in which a total of 2,262 type 2 diabetes patients received degludec and 1,110 received glargine, both injected once daily. Among those, 35% of the degludec group and 34% of the glargine group required more than 60 U of basal insulin per day by the end of the trials.
At study completion, hemoglobin A1c values were similar in both groups, with an insignificant estimated treatment difference (ETD) of just 0.05% (P = .44). The mean fasting plasma glucose values at the end of the trials were lower with degludec than with glargine, with an ETD of –5.9 mg/dL, Dr. Rodbard reported.
Overall confirmed and nocturnal hypoglycemia rates were lower in patients requiring more than 60 U of insulin on degludec than on glargine, with confirmed hypoglycemia defined as self-measured blood glucose less than 56 mg/dL (plasma calibrated) or any episode requiring assistance. Nocturnal confirmed hypoglycemia was defined as any confirmed episode with onset between midnight and 6:00 a.m.
Compared with glargine, there was a 21% lower rate of overall confirmed hypoglycemic episodes with degludec (P = .02) and a 52% lower rate of nocturnal confirmed hypoglycemic episodes (P less than.0001).
The reduction of risk of hypoglycemia with degludec was particularly significant for nocturnal hypoglycemia, the "important area of concern," Dr. Rodbard said in an interview.
Novo Nordisk is also developing a 200 U/mL formulation of insulin degludec specifically for patients with high insulin requirements. This formulation, known as IDeg U200, contains equal units of insulin in half the volume of the 100-U/mL formulation, thus allowing larger insulin doses (up to 160 U) to be administered in a single injection with a prefilled pen device.
Dr. Bergenstal presented data from a 26-week, open-label, treat-to-target trial that compared the efficacy and safety of once-daily IDeg U200 vs. 100 U/mL of insulin glargine, both in combination with oral antidiabetic drugs, in a total of 457 insulin-naive type 2 diabetes patients who qualified for insulin treatment. They were randomized to either IDeg U200 or glargine, both in combination with metformin and some also using other medications.
By 26 weeks, IDeg U200 reduced HbA1c by 1.30 percentage points (from a baseline of 8.3%) and was noninferior to glargine, with an estimated treatment difference of 0.04 percentage points.
Fasting glucose levels were similarly equally reduced. Rates of overall confirmed hypoglycemia (defined as less than 56 mg/dL, or having an episode requiring assistance) were lower with IDeg U200, at 1.22 episodes per patient per year, compared with 1.42 for glargine.
Rates of nocturnal confirmed hypoglycemia (defined as occurring between midnight and 6:00 a.m.) also were lower with IDeg U200 (0.18 vs. 0.28 episodes per patient-year, respectively). There were no severe hypoglycemic reactions in either group.
Mean daily basal insulin dose was similar after 26 weeks (0.62 U/kg for IDeg U200; 0.66 U/Kg for glargine). Weight gain occurred with a reduction in HbA1c in both groups, by 1.9 kg with IDeg U200 and 1.5 kg with glargine. Adverse events were similar and infrequent in both groups, said Dr. Bergenstal, who is the president of medicine and science at the American Diabetes Association.
"Insulin degludec 200 U/mL allows patients who require larger daily doses of basal insulin [to] use prefilled pen devices to administer up to 160 U in a single injection," he concluded.