Lower Within-Subject Variability of Insulin Detemir in Comparison to NPH Insulin and Insulin Glargine in People With Type 1 Diabetes

Abstract

The aim of this randomized double-blind study was to compare the within-subject variability of the glucoselowering effect of a novel insulin analog, insulin detemir, with that of insulin glargine and NPH insulin in people with type 1 diabetes. Fifty-four subjects (32 males and 22 females, age 38 ؎ 10 years [ D aily clinical experience indicates that subcutaneous administration of insulin often does not result in a reproducible metabolic effect even when injected at the same dose under comparable conditions. Nonetheless, only few studies have assessed the variability of insulin absorption after subcutaneous administration (1-7), and even fewer have assessed the variability in the glucose-lowering effect of insulin. Thus, even though variability of the glucoselowering effect is regarded as a major obstacle to achieving optimal metabolic control (8 -10), our knowledge of the variability of insulin preparations is surprisingly scarce (11,12). This is particularly true for basal insulin preparations. The few studies available report coefficients of variation (CVs) for within-and between-subject variability in the pharmacodynamic action of long-acting zinc insulin preparations to be between 35 and 55% (9) and even greater for NPH insulin (13). Compared with these findings, the variability (CV) of short-acting insulin preparations, which are reported in the range of "only" 20 -30% (10,11), are less of a concern. The development of the new long-acting insulin analogs such as insulin detemir and insulin glargine has raised the hope of concurrent lower within-subject variability. However, insulin glargine does not appear to provide any improvement in the within-subject variability compared with NPH insulin (8).The aim of this study was to compare the within-subject variability in the glucose-lowering effect of the novel long-acting insulin analog insulin detemir with that of NPH insulin and insulin glargine. Insulin detemir [Lys B29 (N ε -tetradecanoyl) des(B30) human insulin] is the first of a new class of long-acting soluble insulin analogs. Its prolonged duration of action is attributable to a combination of increased self-association (hexamer stabilization and hexamer-hexamer interaction) and albumin binding due to acylation of the amino acid lysine in position B29 with a 14 C fatty acid (myristic acid). Insulin detemir is highly albumin bound in the interstitial fluid and in plasma (14) and has been shown to elicit a protracted metabolic action, with a slow onset of action and a less pronounced peak of action compared with that observed for NPH insulin (15,16).

Comparison of insulin detemir and insulin glargine in a basal—bolus regimen, with insulin aspart as the mealtime insulin, in patients with type 1 diabetes: A 52-week, multinational, randomized, open-label, parallel-group, Treat-to-Target noninferiority trial

“…10 In clamp studies in patients with T1DM 1 and type 2 DM, 11 the amount of within-patient variability in the blood glucose-lowering action of detemir was reported to be significantly lower than that of NPH or glargine as measured by the coefficient of variation for glucose infusion rate, area under curve. For patients with T1DM, CV was 27% for detemir versus 59% for NPH and 46% for glargine 1 , and for those with T2DM, CV was 47% versus 215% (detemir versus glargine) 2 (p<0.001 for all comparisons)…”

“…[1][2][3][4] This may make it difficult to achieve stable glycemic control over 24 hours, as both the variability and pronounced peak can result in unexpected hyperglycemia or hypoglycemia.…”

“…Both offer potential advantages over NPH insulin, including a flatter diurnal plasma glucose (PG) profile, a longer duration of action (up to 24 hours, depending on the dose), 5 and reduced within-patient variability. 1 However, only 1 study has directly compared the efficacy of these 2 basal insulins in patients with type 1 diabetes mellitus (T1DM). 6 *Trademark: Lantus ® , Sanofi Aventis, Paris, France † Trademark: Levemir ® Levemir ® , Novo Nordisk A/S, Copenhagen, Denmark…”

Tissue selectivity of insulin detemir action in vivo

“…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]. Due to the profile of action of insulin detemir and the fact that the albumin-bound insulin buffers against rapid changes of absorption, insulin detemir action is supposed to be more predictable in terms of the risk for hypoglycaemic episodes compared with other basal insulins [9][10][11].…”

To: Scholtz HE, Pretorius SG, Wessels DH, Becker RHA (2005) Pharmacokinetic and glucodynamic variability: assessment of insulin glargine, NPH insulin and insulin ultralente in healthy volunteers using a euglycaemic clamp technique. Diabetologia 48:1988–1995

“…The notion that the pharmacodynamic profile of insulin glargine is best characterised as waxing and waning is supported by the profiles shown in a paper comparing insulins NPH, glargine and detemir [2]. The idea that insulin glargine's profile is flat originates from a paper that is difficult to interpret unequivocally [3].…”