Insulin glargine: the first clinically useful extended-acting insulin in half a century?

Abstract

Insulin glargine (HOE 901) appears to be the first clinically useful extended-acting insulin preparation for 50 years. A combination of a di-arginine addition to the C-terminal of the insulin B-chain, and a glycine substitution in the A-chain, produce an insulin which is soluble at acid pH, but precipitates in sc. tissue at neutral pH after injection. This new insulin analogue has slightly lower receptor binding affinity compared to human insulin, but equal potency in vivo. Prolonged receptor binding is not found, and IGF-1 binding is not significantly different from human insulin. Glucose clamp and sc. disappearance studies confirm that insulin glargine has a much slower onset of effect than NPH (Neutral Protamine Hagedorn) insulin, and a much more protracted profile of action. Variability of absorption is difficult to assess from published studies, but is not dissimilar to NPH insulin. Patient studies in Type 1 and Type 2 diabetes published to date are inconclusive, but appear to confirm differences in pharmacokinetics between insulin glargine and NPH, with significantly lower fasting plasma glucose levels or reduction in night hypoglycaemia. No safety concerns have emerged. It thus appears that insulin glargine is a genuinely new addition to the insulin family, and with further clinical experience it may well be possible to achieve better basal blood glucose control (without enhanced risk of hypoglycaemia), particularly at night or in conjunction with rapid-acting insulin analogues.

Insulin analogues and their potential in the management of diabetes mellitus

“…Similar results have been observed in a 28-week randomized trial in 518 patients with Type II diabetes [141]. Taken together, these data suggest that the majority of patients with Type I and perhaps also Type II diabetes might benefit from insulin glargine [142].…”

Physiological responses during hypoglycaemia induced by regular human insulin or a novel human analogue, insulin glargine

“…In addition, there may be some differences between insulin glargine and human insulin with regard to their interaction with insulin receptors and the IGF‐1 receptors. Glargine binds insulin receptors with a lower affinity compared with native human insulin[1]. In contrast, studies in H9 cardiac myoblasts (a cell line expressing abundant IGF‐1 receptors with undetectable insulin receptors) showed a higher IGF‐1 binding affinity for glargine than regular human insulin[28].…”

“…In contrast, studies in H9 cardiac myoblasts (a cell line expressing abundant IGF‐1 receptors with undetectable insulin receptors) showed a higher IGF‐1 binding affinity for glargine than regular human insulin[28]. However, glargine and regular human insulin are equipotent in their effects on mitogenesis[1,28,29].…”

“…In contrast, studies in H9 cardiac myoblasts (a cell line expressing abundant IGF-1 receptors with undetectable insulin receptors) showed a higher IGF-1 binding af®nity for glargine than regular human insulin [28]. However, glargine and regular human insulin are equipotent in their effects on mitogenesis [1,28,29]. The present study evaluated physiological symptoms, counter-regulatory hormones, and glucose disposal during hypoglycaemia induced by either regular human insulin or insulin glargine in healthy subjects and in patients with type 1 diabetes mellitus.…”

“…Insulin glargine (HOE 901) is a human insulin analogue obtained through recombinant DNA modification of native human insulin. The molecular substitutions shift the isoelectric point from pH 5.4 in native insulin to 7.0 in insulin glargine, and result in an insulin analogue that is absorbed more slowly from subcutaneous sites, compared with native insulin[1]. The objective of the present study was to compare the physiological symptoms and counter‐regulatory hormones during hypoglycaemia induced by either regular human insulin or insulin glargine in healthy subjects and in patients with type 1 diabetes mellitus.…”