New long-acting insulin analogs: from clamp studies to clinical practice.

Abstract

The NPH era started in 1946 and ended nearly 60 years later with the introduction to the market of the long-acting analogs, glargine in 2000 (1) and detemir in 2004 (2). More recently, a second-generation acylated long-acting insulin analog, degludec (3), has become available in some countries outside the U.S. In this issue of the journal, Becker et al. (4) report on pharmacokinetics (PK) and pharmacodynamics (PD) of a new long-acting insulin analog, glargine U300 (Gla-300). This is the same glargine molecule concentrated three times (300 units in 1 mL). It was approved by the U.S. Food and Drug Administration and received a positive opinion from the European Medicines Agency at the end of February 2015. Becker et al. (4) compared Gla-300 to the original glargine (Lantus, U-100; Gla-100) in a clamp experiment in subjects with type 1 diabetes (T1D). They studied the right population (absent endogenous insulin secretion) in which the observed PK/PD after subcutaneous (s.c.) injection of an insulin preparation are specifically attributable to the injected insulin. When clamp studies are instead run in subjects without diabetes or with type 2 diabetes (T2D), the PK/PD results are confounded by endogenous insulin secretion. Becker et al. (4) correctly studied the subjects after 1 week of treatment at “steady state.” However, they did use a fixed dose of basal insulin (0.4 units/kg/day glargine, either Gla-300 or Gla-100). This approach has the advantage of simplicity but the disadvantage of inducing a pharmacological overinsulinization with risk of hypoglycemia as the previously daily basal insulin dose used by the subjects with T1D was lower (mean 0.30 units/kg/day). Indeed, the majority of subjects needed a robust glucose infusion rate (GIR) during the 6 h prior to injection of glargine (time zero) to prevent hypoglycemia, and several subjects had baseline plasma insulin concentrations higher before …