Glucose-lowering Effect of Insulin Degludec is Independent of Subcutaneous Injection Region

Nosek, Leszek; Coester, Hans-Veit; Thomsen, Henrik F.; Roepstorff, Carsten; Sin, Roxana; Heise, Tim

doi:10.1016/j.jcjd.2012.07.362

Cited by 7 publications

(10 citation statements)

References 17 publications

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“…As expected, exposure to both components of IDegLira was inversely correlated with body weight, but other covariates (time since start of treatment, treatment type [IDegLira, IDeg, or liraglutide], injection site, race, age group, and sex) were shown to have little or no effect on exposure. These results were largely consistent with the results seen in the individual IDeg and liraglutide clinical development programs …”

Section: Discussionsupporting

confidence: 89%

“…These results were largely consistent with the results seen in the individual IDeg and liraglutide clinical development programs. 25,[29][30][31] Dose/exposure-response analyses showed that across the entire range of doses and exposures, the effect of IDegLira on HbA 1c levels was larger than the effect of both IDeg and liraglutide administered alone. It can therefore be concluded that the IDeg and liraglutide components contribute distinctly to the glycemic effect of IDegLira throughout the studied dose and exposure ranges.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Preserved pharmacokinetic exposure and distinct glycemic effects of insulin degludec and liraglutide in IDegLira, a fixed‐ratio combination therapy

Kapitza

Bode

Ingwersen

et al. 2015

The Journal of Clinical Pharma

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Insulin degludec/liraglutide (IDegLira) is a novel fixed-ratio combination of the basal insulin insulin degludec (IDeg) and liraglutide, a glucagon-like peptide-1 analog. The pharmacokinetics (PK) and pharmacodynamics of IDegLira were assessed versus its components. A single-dose, randomized, 4-period crossover clinical pharmacology study in healthy subjects compared the bioavailability of IDegLira with its monocomponents. Dose proportionality, covariate effects on exposure, and exposure-response for change in glycated hemoglobin were analyzed based on data from a randomized treat-to-target phase 3 study in subjects with type 2 diabetes. Overall, the PK properties of IDeg and liraglutide were preserved for IDegLira. Liraglutide exposure was lower when dosed as IDegLira but met the criterion for equivalence. No relevant deviations from dose proportionality for the IDegLira components were observed. Covariate effects on exposure were consistent with previous results. Glycemic response to IDegLira was larger than with IDeg or liraglutide alone, reflecting their distinct glucose-lowering effects throughout the dose/exposure range. Keywords Clinical Pharmacology (CPH), Drug Interactions, Endocrinology (END), Pharmacodynamics (PDY), Population Pharmacokinetics Exposure-ResponseType 2 diabetes (T2D) is a progressive disease with an underlying complex pathophysiology involving multiple organs, necessitating a multitargeted approach to treatment.1 Accordingly, there is a need for therapies that have complementary mechanisms of action to help achieve improved glycemic control with fewer side effects than the currently available treatment options. 2IDegLira is a novel fixed-ratio combination of the basal insulin, insulin degludec (IDeg; 100 U/mL), and a once-daily glucagon-like peptide-1 (GLP-1) analog, liraglutide (3.6 mg/mL). IDegLira may be initiated and titrated, as performed with basal insulin, and administered in dose steps, in which 1 dose step is defined as 1 unit IDeg/0.036 mg liraglutide and can be titrated up to a maximum of 50 dose steps (50 units/1.8 mg). 3,4 IDeg is a new-generation basal insulin with an ultralong duration of action, providing a flat and stable glucose-lowering effect. [5][6][7][8] IDeg has been shown to be efficacious in lowering glycated hemoglobin (HbA 1c ) and fasting plasma glucose (FPG) levels in subjects with T2D, 9-11 with fewer hypoglycemic episodes, particularly nocturnal episodes, versus insulin glargine.12 The molecular structure of IDeg and its solubility at neutral pH (7) allow it to be coformulated with liraglutide.Liraglutide is an injectable, once-daily GLP-1 analog 13,14 that mimics the effects of native GLP-1 in restoring the insulin response to glucose, 15 providing both fasting and postprandial glycemic control 16,17 in a glucose-dependent manner. Liraglutide reduces body weight and body fat mass through mechanisms involving reduced hunger and lowered energy intake.18-22 Although GLP-1 receptor agonist treatment has been associated with a moderately increased risk...

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Preserved pharmacokinetic exposure and distinct glycemic effects of insulin degludec and liraglutide in IDegLira, a fixed‐ratio combination therapy

Kapitza

Bode

Ingwersen

et al. 2015

The Journal of Clinical Pharma

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“… 17 The glucose-lowering effect of degludec U100 was not statistically affected by injection site (thigh, upper arm, or abdominal wall), although slightly reduced in the thigh. 18 …”

Section: Body Of Reviewmentioning

confidence: 99%

Concentrated insulins: the new basal insulins

Lamos

Younk

2016

TCRM

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IntroductionInsulin therapy plays a critical role in the treatment of type 1 and type 2 diabetes mellitus. However, there is still a need to find basal insulins with 24-hour coverage and reduced risk of hypoglycemia. Additionally, with increasing obesity and insulin resistance, the ability to provide clinically necessary high doses of insulin at low volume is also needed.Areas coveredThis review highlights the published reports of the pharmacokinetic (PK) and glucodynamic properties of concentrated insulins: Humulin-R U500, insulin degludec U200, and insulin glargine U300, describes the clinical efficacy, risk of hypoglycemic, and metabolic changes observed, and finally, discusses observations about the complexity of introducing a new generation of concentrated insulins to the therapeutic market.ConclusionHumulin-R U500 has a similar onset but longer duration of action compared with U100 regular insulin. Insulin glargine U300 has differential PK/pharmacodynamic effects when compared with insulin glargine U100. In noninferiority studies, glycemic control with degludec U200 and glargine U300 is similar to insulin glargine U100 and nocturnal hypoglycemia is reduced. Concentrated formulations appear to behave as separate molecular entities when compared with earlier U100 insulin analog compounds. In the review of available published data, newer concentrated basal insulins may offer an advantage in terms of reduced intraindividual variability as well as reducing the injection burden in individuals requiring high-dose and large volume insulin therapy. Understanding the PK and pharmacodynamic properties of this new generation of insulins is critical to safe dosing, dispensing, and administration.

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“…Moreover, when the GIR data were divided into values for sequential 2‐h intervals, the lower within‐subject variability of degludec was found to be consistent over time, whereas the variability of glargine was not only higher but also tended to increase substantially after 8 h. In terms of overall total glucose‐lowering effect, this study also showed degludec to have equal molar potency to glargine. Finally, the region of injection has been shown to have little effect on the overall PD effect of degludec, with overall PK exposure slightly reduced (by ∼6%) with administration into the thigh versus the abdomen or deltoid .…”

Section: An Ultra‐long and Stable Pharmacokinetic/pharmacodynamic Promentioning

confidence: 99%

Insulin degludec: overview of a novel ultra long‐acting basal insulin

Gough

Harris

Woo

et al. 2013

Diabetes Obesity Metabolism

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All the basal insulin products currently available have suboptimal pharmacokinetic (PK) properties, with none reliably providing a reproducible and peakless pharmacodynamic (PD) effect that endures over 24 h from once-daily dosing. Insulin degludec is a novel acylated basal insulin with a unique mechanism of protracted absorption involving the formation of a depot of soluble multihexamer chains after subcutaneous injection. PK/PD studies show that insulin degludec has a very long duration of action, with a half-life exceeding 25 h. Once-daily dosing produces a steady-state profile characterized by a near-constant effect, which varies little from injection to injection in a given patient. Clinically, insulin degludec has been shown consistently to carry a lower risk of nocturnal hypoglycaemia than once-daily insulin glargine, in both basal+bolus and basal-only insulin regimens. The constancy of the steady-state profile of insulin degludec also means that day-to-day irregularities at the time of injection have relatively little PD influence, thereby offering the possibility of greater treatment flexibility for patients.

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Glucose-lowering Effect of Insulin Degludec is Independent of Subcutaneous Injection Region

Cited by 7 publications

References 17 publications

Preserved pharmacokinetic exposure and distinct glycemic effects of insulin degludec and liraglutide in IDegLira, a fixed‐ratio combination therapy

Preserved pharmacokinetic exposure and distinct glycemic effects of insulin degludec and liraglutide in IDegLira, a fixed‐ratio combination therapy

Concentrated insulins: the new basal insulins

Insulin degludec: overview of a novel ultra long‐acting basal insulin

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