A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir.

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 = 24 nmol) and one subcutaneous dose of NPH insulin (0.3 IU/kg; 1 IU = 6 nmol). RESEARCH DESIGN AND METHODS: This single-center, randomized, double-blind, 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 < 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 < 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.

Effects of QD insulin detemir or neutral protamine Hagedorn on blood glucose control in patients with type I diabetes mellitus using a basal-bolus regimen.

OBJECTIVE: The purpose of this trial was to compare the effects of QD basal insulin replacement using insulin detemir versus neutral protamine Hagedorn (NPH) insulin in basal-bolus therapy in combination with regular human insulin (HI) in patients with type 1 diabetes mellitus (DM). METHODS: This was a 6-month, prospective, randomized, open-label, controlled, parallel-group trial conducted at 92 sites in Europe and Australia. The trial population included men and women with type 1 DM for at least 1 year aged > or = 18 years with glycosylated hemoglobin (HbA(1c)) <== 12% already taking QD basal-bolus treatment with an intermediate- or long-acting insulin and a fast-acting human insulin or insulin analogue as bolus insulin. Patients were randomly assigned (2:1) to 6 months of treatment with insulin detemir or NPH at bedtime in combination with HI with main meals. Main outcome measures were blood glucose control as assessed by HbA(1c), fasting plasma glucose (FPG), 9-point self-monitored blood glucose (SMBG) profiles, 24-hour continuous blood glucose profiles, hypoglycemia, weight gain, and adverse events. RESULTS: Of the 749 patients randomized to treatment, 747 were exposed to trial products and included in the intent-to-treat analysis set. Seven hundred patients completed the trial: 465 (94.7%) in the insulin detemir group and 235 (91.8%) in the NPH group. After 6 months, FPG was lower with insulin detemir than with NPH (-1.16 mmol/L difference; P = 0.001), whereas HbA(1c) did not differ significantly between treatments (-0.12% [95% CI, -0.25 to 0.02]; P = NS). Day-to-day variability in self-measured fasting blood glucose was lower with insulin detemir (SD, 2.82 vs 3.60 mmol/L; P < 0.001). The overall shape of the 9-point SMBG profiles differed significantly between treatments (P = 0.006), with lower glucose levels before breakfast with insulin detemir than with NPH (P < 0.001). There was a 26% reduction in the relative risk of nocturnal hypoglycemia with insulin detemir compared with NPH (P = 0.003). Gain in body weight was significantly lower after 6 months with insulin detemir than with NPH (-0.54 kg difference; P = 0.024). The frequency and type of adverse events were similar between treatment groups. CONCLUSIONS: In this study, QD administration of insulin detemir at bedtime resulted in lower fasting blood glucose levels with less day-to-day variability and less fluctuation from ean blood glucose levels over 24 hours than NPH insulin, combined with an overall reduction in the risk of nocturnal hypoglycemia. These findings suggest that evening administration of insulin detemir may provide an opportunity to further improve fasting blood glucose targets.

Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes.

The aim of this randomized double-blind study was to compare the within-subject variability of the glucose-lowering 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 [mean +/- SD], BMI 24 +/- 2 kg/m(2), HbA(1c) 7.5 +/- 1.2%, diabetes duration 18 +/- 9 years) participated in this parallel group comparison. Each subject received four single subcutaneous doses of 0.4 units/kg of either insulin detemir (n = 18), insulin glargine (n = 16), or human NPH insulin (n = 17) under euglycemic glucose clamp conditions (target blood glucose concentration 5.5 mmol/l) on four identical study days. The pharmacodynamic (glucose infusion rates [GIRs]) and pharmacokinetic (serum concentrations of insulin detemir, human insulin, and insulin glargine) properties of the basal insulin preparations were recorded for 24 h postdosing. Insulin detemir was associated with significantly less within-subject variability than both NPH insulin and insulin glargine, as assessed by the coefficient of variation (CV) for the pharmacodynamic end points studied [GIR-AUC((0-12 h)) 27% (detemir) vs. 59% (NPH) vs. 46% (glargine); GIR-AUC((0-24 h)) 27 vs. 68 vs. 48%; GIR(max) 23 vs. 46 vs. 36%; P < 0.001 for all comparisons]. Insulin detemir also provided less within-subject variability in the pharmacokinetic end points: maximal concentration (C(max)) 18 vs. 24 vs. 34%; INS-AUC((0- infinity )) 14 vs. 28 vs. 33%. The results suggest that insulin detemir has a significantly more predictable glucose-lowering effect than both NPH insulin and insulin glargine.

Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes: a randomized clinical trial.

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 (HbA1c, prebreakfast glucose levels and variability, and hypoglycemia) and timing of administration. RESEARCH DESIGN AND METHODS: People with type 1 diabetes (n = 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(morn+bed)) 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, -1.5 mmol/l [95% CI -2.51 to -0.48], P = 0.004; IDet(morn+bed) vs. NPH, -2.3 mmol/l (-3.32 to -1.29), P < 0.001), as was self-measured prebreakfast plasma glucose (P = 0.006 and P = 0.004, respectively). The risk of minor hypoglycemia was lower in both insulin detemir groups (25%, P = 0.046; 32%, P = 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(morn+bed) group (P < 0.001). Although HbA1c for each insulin detemir group was not different from the NPH group, HbA1c for the pooled insulin detemir groups was significantly lower than for the NPH group (mean difference -0.18% [-0.34 to -0.02], P = 0.027). Within-person between-day variation in self-measured prebreakfast plasma glucose was lower for both detemir groups (both P < 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, -0.8 kg [-1.44 to -0.24], P = 0.006; IDet(morn+bed) vs. NPH, -0.6 kg [-1.23 to -0.03], P = 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.

Insulin detemir is associated with more predictable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on a basal-bolus regimen with premeal insulin aspart.

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 (-0.76 mmol/l, P = 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 < 0.001). Risk of hypoglycemia was 22% lower with insulin detemir than with NPH insulin (P < 0.05) and 34% lower for nocturnal (2300-0600) hypoglycemia (P < 0.005). Nightly plasma glucose profiles were smoother and more stable with insulin detemir (P = 0.05). Body weight was significantly lower with insulin detemir at the end of the trial (P < 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.