The Mechanism of Protraction of Insulin Detemir, a Long-Acting, Acylated Analog of Human Insulin

Havelund, Svend; Plum, Anne; Ribel, Ulla; Jonassen, Inge; Vølund, Aage; Markussen, Jan; Kurtzhals, Peter

doi:10.1023/b:pham.0000036926.54824.37

Cited by 383 publications

(341 citation statements)

References 33 publications

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“…The primary analysis of whether glycemic control with detemir was noninferior to that with glargine after 52 weeks of treatment used a noninferiority margin of 0.4%, 10 consistent with FDA guidance. 13 The hypothesis was tested by fitting an ANCOVA model to the primary end point, with treatment and country as fixed factors and baseline (randomization) HbA 1c as a covariate.…”

Section: Discussionmentioning

confidence: 97%

“…Its action profile is the result of increased selfassociation at the injection site, together with reversible albumin binding via a fatty acid side chain. 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)…”

Section: Introductionmentioning

confidence: 99%

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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

Heller

Koenen

Bode

2009

Clinical Therapeutics

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Objective: The primary study objective was to determine whether insulin detemir (detemir) was noninferior to insulin glargine (glargine) as the basal insulin in a basalbolus regimen, with insulin aspart as the mealtime insulin, in terms of glycemic control at the end of 52 weeks in patients with type 1 diabetes mellitus (T1DM). Methods:This multinational, open-label, parallel-group, treat-to-target, noninferiority trial enrolled patients aged ≥18 years who had had T1DM for at least 12 months, had been taking a basal-bolus insulin regimen for at least 3 months, and had a glycosylated hemoglobin (HbA 1c ) value ≤11.0%. Patients were randomized in a 2:1 ratio to receive either detemir given once or twice daily or glargine given once daily for 52 weeks. The basal insulin was initially administered once daily (in the evening) in both groups; if patients in the detemir group were achieving the PG target before breakfast but not before dinner, they were switched to twice-daily administration. Each patient attended 13 study visits and received 16 scheduled telephone calls from the trial site.The primary efficacy end point was glycemic control (HbA 1c ) after 52 weeks of treatment. Secondary end points included the number of patients achieving an HbA 1c value ≤7.0%, with or without a major hypoglycemic episode in the last month of treatment; fasting plasma glucose (FPG); within-patient variation in self-monitored plasma glucose (SMPG) before breakfast and dinner; and 10-point SMPG profiles. The noninferiority margin was 0.4%, consistent with US Food and Drug Administration guidelines. significantly between the detemir and glargine groups (7.57% and 7.56%, respectively; mean difference, 0.01%; 95% CI, -0.13 to 0.16), consistent with the noninferiority of detemir to glargine. The corresponding estimated changes in HbA 1c were -0.53% and -0.54%. In the 90 patients who completed the trial on once-daily and the 173 patients who completed the trial on twice-daily detemir, the estimated changes in HbA 1c were -0.45% and -0.56%, respectively. After 52 weeks, there were no significant differences in the proportion of those receiving detemir and glargine who achieved an HbA 1c value ≤7.0% without major hypoglycemia (31.9% and 28.9%, respectively). In addition, there were no significant differences in estimated mean FPG (8.58 and 8.81 mmol/L; mean difference, -0.23; 95% CI,-1.04 to 0.58) or in basal insulin doses. The basal insulin dose was numerically higher in patients receiving detemir twice rather than once daily (0.47 vs 0.33 U/kg, respectively). The relative risks for total and nocturnal hypoglycemia with detemir versus glargine were 0.94 and 1.12, respectively (both, P = NS). Six patients (2.0%) in the detemir group and 4 (2.8%) in the glargine group withdrew due to adverse events. Results Conclusion

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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

Heller

Koenen

Bode

2009

Clinical Therapeutics

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“…To reach peripheral target cells (myocytes and adipocytes), insulin must pass through the capillary wall lined by a continuous endothelium, which limits the transfer of large molecules from the circulation into the extravascular space [2]. In contrast, the vascular sinusoids within the liver are lined by highly fenestrated epithelial cells with large pores between them and no basal lamina.…”

Section: Introductionmentioning

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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“…The characteristics are based on the fact that modification of the amino acid sequence of the insulin molecule results in distinguished hexamer formation and therefore altered absorption kinetics. Among conventional insulin analogues that are usually created by amino acid exchange, insulin detemir is the first analogue that is acylated with a fatty acid to enable reversible albumin binding [4][5][6][7]. 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].…”

Section: Introductionmentioning

confidence: 99%

Tissue selectivity of insulin detemir action in vivo

et al. 2006

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Aims/hypothesis: Recombinant DNA technology is a useful tool that can be used to create insulin analogues with modified absorption kinetics to improve glycaemic control in patients with type 1 and type 2 diabetes. Among conventional insulin analogues, which are usually created by amino acid exchange, insulin detemir is the first analogue to be acylated with a fatty acid to enable reversible albumin binding. In this study we determined activation of the insulin receptor (IR)-signalling cascade by insulin detemir at the level of IR and IR substrate (Irs) phosphorylation, as well as downstream signalling elements such as phosphatidylinositol 3-kinase and Akt, and performed epidural EEG in vivo. Methods: C57Bl/6 mice were injected i.v. with either insulin detemir or human insulin and Western blot analysis was performed on liver, muscle, hypothalamic and cerebrocortical tissues. Moreover, cerebrocortical activity was detected by EEG in awake mice and cerebral insulin concentrations were measured following human insulin and insulin detemir injection. Results: The time course and extent of IR phosphorylation in peripheral tissues were similar following insulin detemir treatment compared with human insulin, but insulin signalling in hypothalamic and cerebrocortical tissue determined by tyrosine-phosphorylation of the IR and Irs2 proteins occurred faster and was enhanced due to a higher insulin detemir concentration in the brain. Moreover, epidural EEG in mice displayed increased cortical activity using insulin detemir. Conclusions/interpretation: Taken together, these data suggest that insulin detemir has a tissue-selective action, with a relative preference for brain compared with peripheral tissues.

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The Mechanism of Protraction of Insulin Detemir, a Long-Acting, Acylated Analog of Human Insulin

Cited by 383 publications

References 33 publications

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

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

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

Tissue selectivity of insulin detemir action in vivo

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