Triweekly Insulin Degludec a Bad Idea; Stick With Daily Dose

Marlene Busko

July 11, 2013

In 2 phase 3 trials examining the concept of triweekly dosing with the long-acting insulin degludec (Tresiba, Novo Nordisk) in patients with type 2 diabetes, the recipients had inferior glucose control and an increased risk for hypoglycemia in the first 24 hours with this less frequent dosing regimen, compared with the comparator, daily insulin glargine (Lantus, Sanofi).

In a paper reporting these 2 trials, the authors conclude that the overall risk-to-benefit ratio does not support a 3-times-a-week dosing of insulin degludec, and this basal insulin should be used only in a once-daily dosing regimen.

"I was very anxious that these 2 phase 3 studies get published, because they don't support the phase 2 study [that suggested a benefit of triweekly dosing]," lead author Bernard Zinman, MD, from the Samuel Lunenfeld Research Center and the University of Toronto, Ontario, told Medscape Medical News. "The bottom line is this insulin is meant to be used daily."

The paper was published online July 9 in Lancet Diabetes- Endocrinology.

Insulin degludec is approved for once-daily dosing in Europe, Japan, and Mexico for use in adults with both type 1 and type 2 diabetes. In February, the US Food and Drug Administration declined to approve the drug, requesting cardiovascular data, and in Canada, the product is currently under review, Dr. Zinman noted.

Phase 2 Trials Hinted at Triweekly Dosing

Insulin degludec is a long-acting basal insulin that forms soluble multihexamers on subcutaneous injection. Its unique pharmacokinetics includes a "very flat" half-life, twice as long as currently available basal insulin products, with a 42-hour duration of effect, Dr. Zinman said.

"We know that on a once-a-day basis it is far superior to any other basal insulin and actually results in a lower fasting glucose but less nocturnal hypoglycemia for the same HbA1c," he commented.

A small proof-of-concept phase 2 study showed that insulin degludec given 3 times a week in type 2 diabetes patients "seemed to work" as well as daily insulin glargine, he noted. This led to these 2 larger, international, 26-week, open-label, noninferiority phase 3 studies: BEGIN: EASY AM and BEGIN: EASY PM .

The AM trial randomly assigned 460 insulin-naive participants with type 2 diabetes to receive either insulin degludec Monday, Wednesday, and Friday before breakfast or daily insulin glargine at a regular time.

Similarly, the PM trial randomly assigned 467 similar participants to receive the study drug with their evening meal on those days or to be injected with daily insulin glargine.

At the time of enrollment, the participants in both trials had a mean age of about 58 and had had type 2 diabetes for about 9 years. Their diabetes was uncontrolled by oral antidiabetic medications — they had an initial HbA1c level of about 8.3% — and they had not yet taken insulin.

Their insulin doses were titrated once a week, aiming for a prebreakfast plasma glucose level between 3.9 to less than 5.0 mmol/L. During the trial, the participants continued taking metformin with or without dipeptidyl peptidase (DPP)-4 inhibitors.

Waning Glycemic Control, Higher Risk of Hypoglycemia

After 26 weeks of treatment, insulin degludec did not provide at least a 0.4% greater decrease in HbA1c levels, the primary study outcome.

In the AM trial, HbA1c levels decreased by 0.9% with the study drug vs 1.3% with insulin glargine; in the PM trial, these levels decreased by 1.1% vs 1.4%, respectively. "You still got good effects, but not as good" with the study drug as with insulin glargine, Dr. Zinman said.

The patients' mean self-monitored blood glucose levels became progressively higher on the second and third mornings after an insulin degludec injection, which suggests that its effects waned over time.

In both trials, the number of overall and nocturnal confirmed hypoglycemic episodes was 2 to 3 times higher for insulin degludec in the first 24 hours after injection compared with the subsequent 24 hours.

"This distribution of hypoglycemic episodes suggests that when given in a 3-times-weekly schedule, insulin degludec plasma concentrations reach a peak within about 24 hours after dosing and then decline until the next injection is given," the researchers say.

In all other phase 3 trials, once-daily insulin degludec was not inferior to daily insulin glargine and was associated with a lower rate of hypoglycemia, especially nocturnal hypoglycemia.

Noting that all the approvals for this medication so far are for the once-daily dose, Dr. Zinman said: "I don't think the company is trying to approve it anywhere for anything less than once a day. It's clearly much better when it's used once a day."

The study was funded by Novo Nordisk. Dr. Zinman has served on advisory panels for Amylin, AstraZeneca, Boehringer Ingelheim, Lilly, Novo Nordisk, Bristol-Myers Squibb, Merck, and Sanofi and received research support from Boehringer Ingelheim, Novo Nordisk, and Merck. Disclosures for the coauthors are listed in the article.

Lancet Diabetes Endocrinol . Published online July 9, 2013. Abstract


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