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Insulin degludec: New ultra-long-acting basal insulin

Issue: February 2013

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Before the release of insulin analogues, insulin products such as lente, ultralente and NPH were used as basal insulins in the management of type 1 and 2 diabetes. However, none of these products were physiologically ideal (too long-acting, too short-acting, significant peak effect, etc). More recently, insulin glargine and detemir have been primarily used as basal insulins. They offer improvements over the previous products, such as up to 24-hour duration of action and relatively stable concentrations throughout that duration. This leads to less nocturnal hypoglycemia and potentially fewer injections each day. These insulins are often described as peakless, although they do have a small peak a few hours after injection. They also do not last 24 hours in all patients. So, in some cases (more so with insulin detemir than glargine), patients must administer their basal insulin twice daily.

Insulin degludec is the newest basal insulin analogue, and it brings some new features to the table. After injection, insulin degludec is slowly released, allowing a half-life of more than 24 hours and detectable insulin levels at least 96 hours post-injection. The effect is also relatively flat over the duration of action. The prolonged effect is due to the formation of insulin degludec multi-hexamers after injection. Degludec monomers are slowly released from the multi-hexamers over time and easily absorbed into systemic circulation. Heise and colleagues compared degludec with glargine in 66 patients and found that the half-life of degludec was 25.4 hours vs. 12.5 hours for glargine. Also, the serum exposure of degludec was similar between the first and second 12-hour post-dose period. With glargine, 60% of the serum exposure occurred in the first 12 hours. It remains to be seen if this translates into clinically significant differences between the two insulins. In late 2012, insulin degludec received approval from an FDA advisory panel, with the stipulation that it evaluate postmarketing cardiovascular safety.

James R. Taylor

Similarly to the study by Heise and colleagues, Heller et al compared insulin degludec and glargine in 629 patients with type 1 diabetes over 12 months. Each basal insulin was administered once daily as part of a basal-bolus regimen (mealtime insulin aspart). After 1 year, HbA1c decreased similarly between the two groups (0.4% in degludec group vs. 0.39% in glargine group). Also, a similar number of patients in each group achieved HbA1c goal of <7%. Rates of nocturnal hypoglycemia were significantly lower in the degludec group (4.4 vs. 5.9 episodes/patient year; P=.021), although overall rates of hypoglycemia were comparable between the two groups (42.5 vs. 40.2 episodes/patient year; P=.48).

Garber et al compared insulin degludec with glargine in 1,006 patients with type 2 diabetes over 12 months in combination with insulin aspart plus or minus metformin, plus or minus pioglitazone. After 1 year, HbA1c and fasting glucose decreased similarly in both groups (1.1% and 41 mg/dL in the degludec group vs. 1.2% and 36 mg/dL in the glargine group). Overall rates of hypoglycemia were lower in the degludec group (11.1 vs. 13.6 episodes/patient year; P=.0359). Nocturnal hypoglycemia was also lower in the degludec group (1.4 vs. 1.8 episodes/patient year; P=.0399).

Finally, Heise et al compared two formulations of insulin degludec/insulin aspart (70%/30% and 55%/45%) and insulin glargine in 178 patients over 16 weeks with type 2 diabetes. All insulins were given in combination with metformin. After 16 weeks, HbA1c decreased in all groups by comparable levels. Additionally, a similar number of patients in each group achieved HbA1c goal <7%. The degludec/aspart 55%/45% group had the highest rates of hypoglycemia, and hypoglycemia rates between the other two groups were comparable.

Meneghini et al compared insulin degludec administered at various times each day (ie, patients would dose in morning one day, evening following day, and continue to cycle between AM and PM administration) to glargine given at the same time each day in 459 patients with type 2 diabetes. After 26 weeks, both insulins produced similar reductions in HbA1c (1.28% degludec group vs. 1.26% glargine group) and similar rates of hypoglycemia. The authors concluded that degludec offered more dosing flexibility while maintaining efficacy and safety, as compared with glargine given at the same time every day.

Based on the trials above, insulin degludec appears to offer similar efficacy to insulin glargine, while possibly reducing rates of hypoglycemia. It may also afford the opportunity for more flexible dosing, while maintaining efficacy. Any additional advantages/disadvantages remain to be seen.