Insulin degludec: a long-acting modern insulin analogue with a predictable pharmacokinetic/pharmacodynamic profile

Insulin degludec is, like insulin detemir, a product of coupling of Des-B30 threonine insulin to fatty acid side chains. After injection, degludec self associates, precipitating in subcutaneous tissue. There is a continuous and highly predictable slow dissociation of insulin monomers from this depot; insulin levels rise immediately reaching tmax at 10-12 hours, followed by a slow decline with a t½ of 17-21 hours, roughly double the duration of action of insulin glargine. An important property of degludec not shared by glargine is miscibility with rapid-acting insulin. Although the effect of coadministered insulin aspart is somewhat blunted by coformulation with degludec, a preparation of 70% degludec and 30% aspart has predictable pharmacodynamics. Daily administration of degludec has glucose-lowering benefits not different from those of glargine, with purportedly less hypoglycemia. Although degludec is approved and marketed in Europe under the brand name Tresiba®, the U.S. Food and Drug Administration, in a surprising development, challenged the assertion of lower tendency to hypoglycemia with degludec, and, more importantly, raised concerns that degludec may have a higher cardiovascular risk than glargine. Only a long-term study in a large patient population can resolve these questions. However, release of degludec for marketing to appropriate patients should proceed while awaiting the results of such a study.