Basal insulin analogues in the management of diabetes mellitus: what progress have we made?

Abstract

Insulin remains the most effective and consistent means of controlling blood glucose levels in diabetes. Since 1946, neutral protamine Hagedorn (NPH) has been the predominant basal insulin in clinical use. However, absorption is variable due to the need for resuspension and the time-action profile (peak activity 4-6 h after subcutaneous administration) confers an increased propensity for between-meal and nocturnal hypoglycaemia. In the 1980s, recombinant DNA technology enabled modifications to the insulin molecule resulting in the soluble long-acting insulin analogues, glargine and detemir. Both exhibit a lower risk of hypoglycaemia compared with neutral protamine Hagedorn due to improved time-action profiles and reduced day-to-day glucose variability. Glargine is indicated for administration once daily and detemir once or twice daily. Degludec is the latest prolonged-acting insulin which forms long subcutaneous multi-hexamers that delay absorption. Recent phase III trials in type 1 and type 2 diabetes show that degludec was non-inferior to comparators (predominantly glargine) with a minimal although inconsistent reduction in overall hypoglycaemia and a small absolute difference in nocturnal hypoglycaemia. Newer developmental agents include LY2605541 and glargine U300. LY2605541 comprises insulin lispro combined with polyethylene glycol, thereby increasing its hydrodynamic size and retarding absorption from the subcutaneous tissue. Glargine U300 is a new formulation of glargine resulting in a flatter and more prolonged time-action profile than its predecessor. This article reviews recent advances in basal insulin analogues, including a critical appraisal of the degludec trials.

New Long-Acting Basal Insulins: Does Benefit Outweigh Cost?

“…In summary of these and findings from other comparative studies, the following practical, evidence-based notions become apparent (1,3,4,(9)(10)(11)(12)(13)(14)(16)(17)(18) to a reduced rate of overall hypoglycemia and less weight gain compared with therapies based on regular human insulin and NPH insulin. c In contrast to insulin detemir, insulin glargine typically lowers blood glucose for 24 h, thus allowing for a once-a-day basal insulin regimen in most patients.…”

“…In comparison, the duration of action of NPH insulin is considerably shorter, being up to 16 h and dose dependent, with a clear peak action after 4-6 h (1,3,4,(9)(10)(11)(12)(13)(14). The latter property may be responsible for nocturnal hypoglycemia sometime between 2:00 and 4:00 A.M., after the administration of NPH insulin at bedtime, or late morning hypoglycemia, when NPH insulin is given before breakfast and its peak action not sufficiently covered by an appropriate snack.…”

“…The latter property may be responsible for nocturnal hypoglycemia sometime between 2:00 and 4:00 A.M., after the administration of NPH insulin at bedtime, or late morning hypoglycemia, when NPH insulin is given before breakfast and its peak action not sufficiently covered by an appropriate snack. The long-acting insulin detemir has a flatter peak action profile than NPH at low doses, but at higher doses a peak action is evident 7-14 h after administration (1,3,4,(9)(10)(11)(12)(13)15). The long-acting insulin glargine has an even smoother peak action profile than insulin detemir but has a discernable peak action 3-4 h after administration while possessing a duration of action of 24 h or more, depending on the dose (1,3,4,(9)(10)(11)(12)(13)15).…”

“…The findings from the DEVOTE study in 7,500 high-risk individuals with type 2 diabetes will be invaluable owing to its prospective, double-blind design. Glargine U300 is a new higherstrength formulation of insulin glargine at 300 IU/mL rather than the usual glargine at 100 IU/mL, which alters its pharmacokinetic and pharmacodynamic properties (1,3,4,22,25,26,41,42). Glargine U300 forms a more compact subcutaneous depot with its surface area reduced by half and its volume by two-thirds (Fig.…”

“…2), thereby increasing the hydrodynamic size of the insulin-PEG complex (1,3,4,15,20,21,(45)(46)(47)(48). PegLispro has an even lower binding affinity for both the insulin receptor and IGF-1 receptor than lispro and a lower mitogenic potency than human insulin (45,47,48).…”