Engineering predictability and protraction in a basal insulin analogue: the pharmacology of insulin detemir

Abstract

The suboptimal nature of the absorption profiles of human insulin formulations following subcutaneous administration has prompted the development of insulin analogues better suited for therapeutic use in diabetes mellitus. A particular challenge has been to engineer long-acting agents that do not produce unduly variable responses from one injection to another. One recent approach that has met with success has been to acylate, the insulin molecule with a fatty acid, thereby enabling reversible albumin binding. The first clinically available agent of this type is insulin detemir. Pharmacological studies have established that this principle is effective in prolonging action, primarily by retarding absorption. The solubility of insulin detemir in the vial and after injection and an important buffering mechanism effected by plasma albumin binding explain a significant decrease in within-subject variability of pharmacodynamic response observed in repeat isoglycaemic clamp studies where insulin detemir was compared to other basal insulin products. Owing to the extremely high ratio of albumin-binding sites to insulin detemir molecules at therapeutic concentrations, no safety considerations have been identified pertaining to albumin binding. The insulin detemir molecule retains the molecular pharmacological properties of native human insulin, including a physiological balance between metabolic and mitogenic potencies. Thus, insulin detemir offers the promise of an improved tolerability:efficacy ratio in the clinical setting.

New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 2 Diabetes Using Oral Agents and Basal Insulin: Glucose Control and Hypoglycemia in a 6-Month Randomized Controlled Trial (EDITION 2)

“…This finding is consistent with results of EDITION 1, where the magnitude was comparable with that observed previously in studies comparing glargine and detemir insulins (16,17). Given that glycemic control and oral agents were comparable between the groups, these factors were not responsible for the difference.…”

Tissue selectivity of insulin detemir action in vivo

“…The characteristics are based on the fact that modification of the amino acid sequence of the insulin molecule results in distinguished hexamer formation and therefore altered absorption kinetics. Among conventional insulin analogues that are usually created by amino acid exchange, insulin detemir is the first analogue that is acylated with a fatty acid to enable reversible albumin binding [4][5][6][7]. Albumin binding is a common principle to delay absorption and results in retention of the insulin molecule in the s.c. depot for a longer period of time [8].…”

Insulin Analogues: Reviewing the Pros and Cons in Managing Diabetes Mellitus

“…Detemir, as a consequence of its fatty acyl chain, has a lower affinity for the insulin receptor [7]. However it dissociates from the insulin receptor 2-fold faster and is associated with reduced mitogenic potency compared to human insulin [7].…”

“…This slows both absorption and excretion however twice daily dosing is still often required. The fatty acid side-chain enhances self-association of monomers in the subcutaneous depot, which as well as contributing to prolongation of action reduces variability of the time effect profile [7].…”