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).

OBJECTIVE -Insulin detemir is a soluble basal insulin analog with a unique mechanism of protracted action designed to reduce the variability associated with conventional basal insulins. This trial compared the glycemic control, risk of hypoglycemia, and effect on body weight of insulin detemir and NPH insulin in patients with type 1 diabetes treated with rapid-acting insulin aspart at meals. RESEARCH DESIGN AND METHODS-This study was a 6-month multinational open parallel-group comparison conducted at 46 centers in five countries and included 448 patients with type 1 diabetes randomized 2:1 to insulin detemir or NPH insulin, respectively. RESULTS -After 6 months, comparable HbA 1c levels were found between the two treatment groups. Fasting plasma glucose tended to be lower in patients treated with insulin detemir, but this difference was not statistically significant (Ϫ0.76 mmol/l, P ϭ 0.097). Within-subject variation in self-measured fasting blood glucose was lower with insulin detemir than with NPH insulin (SD 3.37 vs. 3.78 mmol/l, P Ͻ 0.001). Risk of hypoglycemia was 22% lower with insulin detemir than with NPH insulin (P Ͻ 0.05) and 34% lower for nocturnal (2300 -0600) hypoglycemia (P Ͻ 0.005). Nightly plasma glucose profiles were smoother and more stable with insulin detemir (P ϭ 0.05). Body weight was significantly lower with insulin detemir at the end of the trial (P Ͻ 0.001).CONCLUSIONS -Treatment with insulin detemir resulted in more predictable glycemic control, with smoother plasma glucose profiles than NPH insulin and a significant reduction in the risk of hypoglycemia. The reduction in body weight with insulin detemir is a potential additional advantage. Regimens optimized for insulin detemir may be able to improve glycemic control beyond that possible with NPH insulin.

OBJECTIVE -To investigate the pharmacodynamic profile and duration of action for five subcutaneous doses of insulin detemir (0.1, 0.2, 0.4, 0.8, and 1.6 units/kg; 1 unit ϭ 24 nmol) and one subcutaneous dose of NPH insulin (0.3 IU/kg; 1 IU ϭ 6 nmol). RESEARCH DESIGN AND METHODS-This single-center, randomized, doubleblind, six-period, crossover study was carried out as a 24-h isoglycemic clamp (7.2 mmol/l) in 12 type 1 diabetic patients.RESULTS -Duration of action for insulin detemir was dose dependent and varied from 5.7, to 12.1, to 19.9, to 22.7, to 23.2 h for 0.1, 0.2, 0.4, 0.8, and 1.6 units/kg, respectively. Interpolation of the dose-response relationships for AUC GIR (area under the glucose infusion rate curve) revealed that a detemir dose of 0.29 units/kg would provide the same effect as 0.3 IU/kg NPH but has a longer duration of action (16.9 vs. 12.7 h, respectively). Lower between-subject variability was observed for insulin detemir on duration of action (0.4 units/kg insulin detemir vs. 0.3 IU/kg NPH, P Ͻ 0.05) and GIR max (maximal glucose infusion rate) (0.2 and 0.4 units/kg insulin detemir vs. 0.3 IU/kg NPH, both P Ͻ 0.05). Assessment of endogenous glucose production (EGP) and peripheral glucose uptake (PGU) resulted in an AOC EGP (area over the EGP curve) of 636 mg/kg (95% CI 279 -879) vs. 584 (323-846) and an AUC PGU (area under the PGU curve) of 173 (47-316) vs. 328 (39 -617) for 0.29 units/kg detemir vs. 0.3 IU/kg NPH, respectively.CONCLUSIONS -This study shows that insulin detemir provides a flat and protracted pharmacodynamic profile. Diabetes Care 28:1107-1112, 2005T raditional basal insulin formulations such as NPH or zinc insulin have limitations such as variability in insulin absorption after subcutaneous injection, resulting in an unpredictable action profile increasing the risk of hypoglycemic episodes, and a pharmacodynamic profile requiring several injections to cover 24 h (1-4).Recently, long-acting insulin analogs have been biologically engineered to overcome these limitations (5-9). These insulin analogs make use of different principles for achieving a protracted insulin profile, such as changing the isoelectric point (insulin glargine) or acylation of the insulin molecule (insulin detemir). Previous studies have confirmed both a delayed and a sustained blood glucoselowering effect with insulin detemir compared with NPH insulin in healthy subjects (10,11). However, the results show that a higher molar dose of insulin detemir is needed to achieve comparable glycemic control similar to that observed with NPH insulin (10).The objective of the present trial was to describe the 24-h pharmacodynamic profile, including duration of action and dose-response relationship, of insulin detemir in subjects with type 1 diabetes and to compare this with NPH insulin. RESEARCH DESIGN ANDMETHODS -In this single-center, double-blind, six-period, randomized, dose-response trial, isoglycemic (7.2 mmol/l) subjects were randomized to a specific treatment sequence encompassing five dose levels of insulin dete...

Patients with type 2 diabetes, treated for 26 weeks with insulin detemir plus insulin aspart at mealtimes, experienced comparable glycaemic control but significantly lower within-subject variability and less weight gain compared to patients treated with NPH insulin and insulin aspart. Insulin detemir was well tolerated and had a similar safety profile to NPH insulin.

OBJECTIVE -Insulin detemir is a soluble long-acting basal insulin analog designed to overcome the limitations of conventional basal insulin formulations. Accordingly, insulin detemir has been compared with NPH insulin with respect to glycemic control (HbA 1c , prebreakfast glucose levels and variability, and hypoglycemia) and timing of administration.RESEARCH DESIGN AND METHODS -People with type 1 diabetes (n ϭ 408) were randomized in an open-label, parallel-group trial of 16-week treatment duration using either insulin detemir or NPH insulin. Insulin detemir was administered twice daily using two different regimens, either before breakfast and at bedtime (IDet mornϩbed ) or at a 12-h interval (IDet 12h ). NPH insulin was administered before breakfast and at bedtime. Mealtime insulin was given as the rapid-acting insulin analog insulin aspart.RESULTS -With both insulin detemir groups, clinic fasting plasma glucose was lower than with NPH insulin (IDet 12h vs. NPH, Ϫ1.5 mmol/l [95% CI Ϫ2.51 to Ϫ0.48], P ϭ 0.004; IDet mornϩbed vs. NPH, Ϫ2.3 mmol/l (Ϫ3.32 to Ϫ1.29), P Ͻ 0.001), as was self-measured prebreakfast plasma glucose (P ϭ 0.006 and P ϭ 0.004, respectively). The risk of minor hypoglycemia was lower in both insulin detemir groups (25%, P ϭ 0.046; 32%, P ϭ 0.002; respectively) compared with NPH insulin in the last 12 weeks of treatment, this being mainly attributable to a 53% reduction in nocturnal hypoglycemia in the IDet mornϩbed group (P Ͻ 0.001). Although HbA 1c for each insulin detemir group was not different from the NPH group, HbA 1c for the pooled insulin detemir groups was significantly lower than for the NPH group (mean difference Ϫ0.18% [Ϫ0.34 to Ϫ0.02], P ϭ 0.027). Within-person between-day variation in self-measured prebreakfast plasma glucose was lower for both detemir groups (both P Ͻ 0.001). The NPH group gained weight during the study, but there was no change in weight in either of the insulin detemir groups (IDet 12h vs. NPH, Ϫ0.8 kg [Ϫ1.44 to Ϫ0.24], P ϭ 0.006; IDet mornϩbed vs. NPH, Ϫ0.6 kg [Ϫ1.23 to Ϫ0.03], P ϭ 0.040).CONCLUSIONS -Overall glycemic control with insulin detemir was improved compared with NPH insulin. The data provide a basis for tailoring the timing of administration of insulin detemir to the individual person's needs. Diabetes Care 27:1081-1087, 2004L andmark studies show that intensive diabetes management delays progression of the late complications of type 1 diabetes (1,2). Although the introduction of rapid-acting insulin analogs has given improvement in postprandial blood glucose control, these analogs are not ideal for use with NPH insulin, which has inadequate duration of action to cover nighttime requirements and an undesirable peak effect ϳ5 h after administration (3). These problems, together with the high day-to-day variability in absorption (4,5), present a major barrier to achieving appropriate targets of blood glucose control.These limitations have stimulated the development of a soluble basal insulin analog that does not require resuspension before injection ...