Time‐action profile of the soluble, fatty acid acylated, long‐acting insulin analogue NN304

Heinemann, Lutz; Sinha, K.; Weyer, Christian; Loftager, Mette; Hirschberger, S.; Heise, Tim

doi:10.1046/j.1464-5491.1999.00081.x

Cited by 146 publications

(87 citation statements)

References 5 publications

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“…This prolonged duration of action complements findings from kinetic studies showing that insulin detemir has a flatter timeaction profile than NPH (26), reaching a peak effect almost 90 min later than NPH (26). From these profiles, the duration of action of insulin detemir appears to be long enough to cover nighttime basal insulin requirements.…”

Section: Variability Of Glycemic Controlsupporting

confidence: 77%

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

Vague

Selam

Skeie³

et al. 2003

Diabetes Care

276

204

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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.

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Section: Variability Of Glycemic Controlsupporting

confidence: 77%

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

Vague

Selam

Skeie³

et al. 2003

Diabetes Care

276

204

View full text Add to dashboard Cite

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“…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).…”

mentioning

confidence: 75%

A Double-Blind, Randomized, Dose-Response Study Investigating the Pharmacodynamic and Pharmacokinetic Properties of the Long-Acting Insulin Analog Detemir

et al. 2005

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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...

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“…Analytical methods The total concentrations of free and bound insulin detemir in serum were measured with an insulin detemir-specific ELISA [13]. Concentrations of serum human insulin and C-peptide were analysed using an insulin ELISA assay (Dako, Glostrup, Denmark).…”

Section: Methodsmentioning

confidence: 99%

Differential effects of insulin detemir and neutral protamine Hagedorn (NPH) insulin on hepatic glucose production and peripheral glucose uptake during hypoglycaemia in type 1 diabetes

et al. 2009

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Aims/hypothesis We compared the symptoms of hypoglycaemia induced by insulin detemir (NN304) (B29Lys(ε-tetradecanoyl),desB30 human insulin) and equally effective doses of neutral protamine Hagedorn (NPH) insulin in relation to possible differential effects on hepatic glucose production and peripheral glucose uptake. Methods After overnight intravenous infusion of soluble human insulin 18 participants with type 1 diabetes received subcutaneous injections of NPH insulin or insulin detemir (0.5 U/kg body weight) on separate occasions in random order. During the ensuing gradual development of hypoglycaemia cognitive function and levels of counter-regulatory hormones were measured and rates of endogenous glucose production and peripheral glucose uptake continuously evaluated using a primed constant infusion of [6,6-2 H 2 ] glucose. The study was terminated when plasma glucose concentration had fallen to 2.4 mmol/l or had reached a minimum at a higher concentration. Results During the development of hypoglycaemia no difference between the two insulin preparations was observed in symptoms or hormonal responses. Significant differences were seen in rates of glucose flux. At and below plasma glucose concentrations of 3.5 mmol/l suppression of endogenous glucose production was greater with insulin detemir than with NPH insulin, whereas stimulation of peripheral glucose uptake was greater with NPH insulin than with insulin detemir. Conclusions/interpretation In participants with type 1 diabetes subcutaneously injected insulin detemir exhibits relative hepatoselectivity compared with NPH insulin, but symptoms of hypoglycaemia and hormonal counterregulation are similar.

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Time‐action profile of the soluble, fatty acid acylated, long‐acting insulin analogue NN304

Abstract: Injection of NN304 at different doses resulted in an increase in total NN304 concentration in a linear dose-response effect and a more even metabolic effect than NPH-insulin. However, we found no clear dose-response in its metabolic effect.

Cited by 146 publications

References 5 publications

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

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

A Double-Blind, Randomized, Dose-Response Study Investigating the Pharmacodynamic and Pharmacokinetic Properties of the Long-Acting Insulin Analog Detemir

Differential effects of insulin detemir and neutral protamine Hagedorn (NPH) insulin on hepatic glucose production and peripheral glucose uptake during hypoglycaemia in type 1 diabetes

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