Basal insulin has been an important treatment option for patients with diabetes mellitus (DM) and, along with prandial insulin, has undergone major improvements in terms of purity and similarity to the action of physiologic human insulin. (see The Evolution of Insulin Therapy in Diabetes Mellitus in this supplement.) Lente and Ultralente formulations were used for decades but are no longer available. The use of neutral protamine Hagedorn (NPH) insulin is also being replaced with the basal insulin analogs detemir and glargine.1 Basal insulin analogs generally cause less severe and nocturnal hypoglycemia compared with NPH insulin owing to their improved pharmacologic profiles.2-4 In comparison to NPH insulin, insulin glargine causes similar weight gain, whereas insulin detemir causes less weight gain.2-4 In addition, insulin detemir has been associated with a glucose-lowering effect that is more predictable than that of NPH insulin.5 Despite the improvements observed with basal insulin analogs, their time-action profiles are not completely flat and are shorter than 24 hours in many patients.5,6 In addition, severe hypoglycemia remains a concern, particularly in patients with type 1 DM (T1DM).7,8 Consequently, the search for a better basal insulin continues.
The ideal basal insulin should possess numerous attributes. While each of the attributes listed in the TABLE is important, an overarching difficulty with basal insulin therapy is the need for administration at the same time each day.9 This dosing limitation may be most difficult for those with busy or erratic schedules or who may forget to administer their insulin dose. This article will review the clinical experience with insulin degludec, an ultra–long-acting insulin under review by the US Food and Drug Administration (FDA).
Attributes of the ideal basal insulin9
|Delivers a steady, stable, peakless, continuous insulin concentration for at least 24 hours, in a predictable manner, with low intraindividual and interindividual variability|
|Does not cause side effects such as weight gain or hypoglycemia|
|Does not induce mitogenicity|
|Can be used as monotherapy, as part of basal-bolus therapy, or in combination with oral glucose-lowering therapy|
|Equally efficacious, safe, and well-tolerated in patients with type 1 or type 2 diabetes mellitus|
|Indian Journal of Endocrinology and Metabolism. Copyright 2011 by MEDKNOW PUBLICATIONS AND MEDIA PVT LTD. Reproduced with permission of MEDKNOW PUBLICATIONS AND MEDIA PVT LTD in the format Journal via Copyright Clearance Center.|
Clinical Pharmacology of Insulin Degludec
Removal of threonine at position 30 of the B chain of human insulin and the addition of a 16-carbon fatty diacid attached to lysine at position 29 of the B chain of human insulin via a glutamic acid spacer result in the insulin degludec molecule, which has several differences from available basal insulin analogs. Experimental investigations indicated that conditions mimicking subcutaneous injection of insulin degludec resulted in a reorganization of the insulin degludec molecule from dihexamers to multihexamer assemblies that remain in solution at physiologic pH.10 Slow release of zinc ions from the multihexamers leads to the slow release of insulin degludec monomers, which are easily absorbed into the systemic circulation.11 The result is a half-life of insulin degludec that is longer than 24 hours, with a level that is detectable in circulation for at least 96 hours after administration of the dose.10,12 The pharmacodynamic result is a relatively flat and consistent blood glucose–lowering effect with insulin degludec (FIGURE 1) reported to be longer than 24 hours in patients with T1DM or type 2 DM (T2DM).11,12
A randomized, double-blind, two-period, crossover comparison of insulin degludec and insulin glargine in patients with T1DM (N = 66) reported a half-life of 25.4 hours with insulin degludec compared with 12.5 hours with insulin glargine.13 The serum exposure of insulin degludec was similar between the first and second 12-hour period postdose. On the other hand, approximately 60% of the serum exposure to insulin glargine occurred over the first 12 hours following administration. These results highlight that insulin degludec is an ultra–long-acting insulin preparation with improved pharmacodynamic stability.
Analysis of data in 54 patients with T1DM reported that the within-subject pharmacodynamic variability was lower with insulin degludec compared with insulin glargine during a 24-hour euglycemic glucose clamp.14 Over 24 hours, the coefficient of variation (CV) with insulin degludec was lower for the area under the glucose infusion rate curve (AUCGIR) for total AUCGIR,0-24h (CV, 23% vs. 72%; P < .001), for GIRmax (CV, 21% vs. 53%; P < .0001), and for the fluctuation around the mean GIR value over 24 hours (CV, 31% vs. 62%; P < .001).