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Insulin degludec: Lower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300?U/mL in type 1 diabetes.

ABSTRACT: AIM:To compare day-to-day and within-day variability in glucose-lowering effect between insulin degludec (IDeg) and insulin glargine 300?U/mL (IGlar-U300) in type 1 diabetes. MATERIALS AND METHODS:In this double-blind, crossover study, patients were randomly assigned to 0.4?U/kg of IDeg or IGlar-U300 once daily for two treatment periods lasting 12?days each. Pharmacodynamic variables were assessed at steady-state from the glucose infusion rate profiles of three 24-hour euglycaemic glucose clamps (days 6, 9 and 12) during each treatment period. RESULTS:Overall, 57 patients completed both treatment periods (342 clamps). The potency of IGlar-U300 was 30% lower than IDeg (estimated ratio 0.70, 95% confidence interval [CI] 0.61; 0.80; P ?

SUBMITTER: Heise T

PROVIDER: S-EPMC5485013 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Insulin degludec: Lower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300 U/mL in type 1 diabetes.

Heise Tim T Nørskov Marianne M Nosek Leszek L Kaplan Kadriye K Famulla Susanne S Haahr Hanne L HL

Diabetes, obesity & metabolism 20170423 7

<h4>Aim</h4>To compare day-to-day and within-day variability in glucose-lowering effect between insulin degludec (IDeg) and insulin glargine 300 U/mL (IGlar-U300) in type 1 diabetes.<h4>Materials and methods</h4>In this double-blind, crossover study, patients were randomly assigned to 0.4 U/kg of IDeg or IGlar-U300 once daily for two treatment periods lasting 12 days each. Pharmacodynamic variables were assessed at steady-state from the glucose infusion rate profiles of three 24-hour euglycaemic ...[more]

PMID: 28295934

Similar Datasets

Low within- and between-day variability in exposure to new insulin glargine 300 U/ml.

Project description:To characterize the variability in exposure and metabolic effect of insulin glargine 300?U/ml (Gla-300) at steady state in people with type 1 diabetes (T1DM).A total of 50 participants with T1DM underwent two 24-h euglycaemic clamps in steady-state conditions after six once-daily administrations of 0.4?U/kg Gla-300 in a double-blind, randomized, two-treatment, two-period, crossover clamp study. Participants were randomized to receive Gla-300 as a standard cartridge formulation in the first treatment period, and as a formulation with enhanced stability through polysorbate-20 addition in the second treatment period, or vice versa. This design allowed the assessment of bioequivalence between formulations and, subsequently, within- and between-day variability.The cumulative exposure and effect of Gla-300 developed linearly over 24?h, and were evenly distributed across 6- and 12-h intervals. Diurnal fluctuation in exposure (within-day variability) was low; the peak-to-trough ratio of insulin concentration profiles was <2, and both the swing and peak-to-trough fluctuation were <1. Day-to-day reproducibility of exposure was high: the between-day within-subject coefficients of variation for total systemic exposure (area under the serum insulin glargine concentration time curve from time 0 to 24?h after dosing) and maximum insulin concentration were 17.4% [95% confidence interval (CI) 15-21] and 33.4% (95% CI 28-41), respectively. Reproducibility of the metabolic effect was lower than that of exposure.Gla-300 provides predictable, evenly distributed 24-h coverage as a result of low fluctuation and high reproducibility in insulin exposure, and appears suitable for effective basal insulin use.

| S-EPMC4674964 | biostudies-literature

In Silico Head-to-Head Comparison of Insulin Glargine 300?U/mL and Insulin Degludec 100?U/mL in Type 1 Diabetes.

Project description:Background: Second-generation long-acting insulin glargine 300?U/mL (Gla-300) and degludec 100?U/mL (Deg-100) provide novel basal insulin therapies for the treatment of type 1 diabetes (T1D). Both offer a flatter pharmacokinetic (PK) profile than the previous generation of long-acting insulins, thus improving glycemic control while reducing hypoglycemic events. This work describes an in silico head-to-head comparison of the two basal insulins on 24-h glucose profiles and was used to guide the design of a clinical trial. Materials and Methods: The Universities of Virginia (UVA)/Padova T1D simulator describes the intra-/interday variability of glucose-insulin dynamics and thus provides a robust bench-test for assessing glucose control for basal insulin therapies. A PK model describing subcutaneous absorption of Deg-100, in addition to the one already available for Gla-300, has been developed based on T1D clinical data and incorporated into the simulator. One hundred in silico T1D subjects received a basal insulin dose (Gla-300 or Deg-100) for 12 weeks (8 weeks uptitration, 4 weeks stable dosing) by morning or evening administration in a basal/bolus regimen. The virtual patients were uptitrated to their individual doses with two different titration rules. Results: The last 2-week simulated continuous glucose monitoring data were used to calculate various outcome metrics for both basal insulin treatments, with primary outcome being the percent time in glucose target (70-140?mg/dL). The simulations show no statistically significant difference for Gla-300 versus Deg-100 in the main endpoints. Conclusions: This work suggests comparable glucose control using either Gla-300 or Deg-100 and was used to guide the design of a clinical trial intended to compare second-generation long-acting insulin analogues.

| S-EPMC7407002 | biostudies-literature

Comparison of insulin glargine 300 U/mL and insulin degludec using flash glucose monitoring: A randomized cross-over study.

Project description:Aims/introductionWe compared the efficacy and safety of insulin glargine 300 U/mL (Gla300) and insulin degludec U100 (Deg) using a flash glucose monitoring system.Materials and methodsA total of 24 Japanese patients with type 2 diabetes were randomized to receive once-daily Gla300 (n = 12) or Deg (n = 12) in the morning. The primary end-points were the mean percentage of time in the target glucose range (70-179 mg/dL) and hypoglycemia (<70 mg/dL), as measured using flash glucose monitoring during the last 7 days of each 14-day period.ResultsThe percentages of time with glucose levels <70 mg/dL were not significantly different between the two insulin treatments. No significant differences were observed in the percentages of time with glucose levels of 70-179 mg/dL or ≥180 mg/dL. The percentage of time with nocturnal hypoglycemia with Gla300 was significantly lower than that with Deg treatment (P = 0.021). This difference might be attributable to the difference in the duration of action between the two formulations, and the incidence of nocturnal hypoglycemia with Deg treatment was associated with the concomitant use of metformin (P = 0.035).ConclusionsThe two formulations were comparable in efficacy, whereas the incidence of nocturnal hypoglycemia was significantly lower with Gla300. Thus, the present study suggests that, although Gla300 and Deg are comparable long-acting insulin analogs, Gla300 is safer with respect to the incidence of hypoglycemia.

| S-EPMC6400163 | biostudies-literature

Efficacy and Safety of Degludec Compared to Glargine 300 Units/mL in Insulin-Experienced Patients With Type 2 Diabetes: Trial Protocol Amendment (NCT03078478).

Project description:BackgroundA head-to-head trial (NCT03078478) between insulin degludec and insulin glargine U300 with the primary objective of comparing the risk of hypoglycemia is being conducted. During trial conduct, safety concerns related to the glycemic data collection system led to a postinitiation protocol amendment, described here.MethodsThis randomized (1:1), open-label, treat-to-target, multinational trial was initiated in March 2017 with a planned treatment period of 52 weeks (16 weeks titration + 36 weeks maintenance). Overall, ~1600 insulin-experienced patients at risk of developing hypoglycemia based on predefined risk factors were included. The protocol amendment implemented in February 2018 resulted in assuring patient safety and an extension of the total treatment period up to 88 weeks (16 weeks titration + variable maintenance 1 + 36 weeks maintenance 2). The original glycemic data collection system (MyGlucoHealth blood glucose meter + electronic diary) was discontinued because of safety concerns and replaced with an Abbott blood glucose meter and paper diary to collect self-measured blood glucose and hypoglycemic episodes. The primary endpoint of number of severe or blood-glucose confirmed symptomatic hypoglycemic episodes will be evaluated with the same analysis duration and statistical methods as the original protocol. Only relevant changes were implemented to maintain patient safety while permitting evaluation of the scientific objectives of the trial.ConclusionsThese observations highlight the importance of safety surveillance during trial conduct despite the use of currently marketed glucose monitoring devices. The prompt protocol amendment and ensuing actions ensured that the scientific integrity of the trial was not compromised.

| S-EPMC6501520 | biostudies-literature

Investigational new insulin glargine 300 U/ml has the same metabolism as insulin glargine 100 U/ml.

Project description:Insulin glargine is processed in vivo into soluble 21(A) -Gly-human insulin (M1), the principal moiety responsible for metabolic effects, and subsequently into M2. This sub-study compared metabolism and metabolite pharmacokinetic (PK) profiles of investigational new insulin glargine U300 (Gla-300) with insulin glargine 100 U/ml (Gla-100, Lantus®, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany) in people with type 1 diabetes. Participants received 0.4 (n = 18) or 0.6 U/kg Gla-300 (n = 12), and 0.4 U/kg Gla-100 (n = 30) once daily in randomized order for 8 days prior to a 36-h euglycaemic clamp. Metabolites were quantified using immunoaffinity enrichment and liquid chromatography tandem mass spectrometry (LC-MS/MS). Glargine metabolism was the same regardless of Gla-100 or Gla-300 administration; M1 was confirmed as the principal active moiety circulating in blood. Steady state concentrations of M1 were achieved after 2 days for Gla-100, and 4 days for Gla-300. Steady state M1 values defined prolonged and even flatter PK profiles after Gla-300 administration compared with M1 profiles after Gla-100.

| S-EPMC4237557 | biostudies-literature

Glycaemic control and hypoglycaemia risk with insulin glargine 300 U/mL and insulin degludec 100 U/mL in older participants in the BRIGHT trial.

Project description:AimTo evaluate the efficacy and safety of insulin glargine 300 U/mL (Gla-300) versus insulin degludec 100 U/mL (IDeg-100) in predefined (</≥65 years) and post hoc (</≥70 years) age groups of people with type 2 diabetes (T2D) in the BRIGHT trial.Materials and methodsBRIGHT was the first head-to-head randomized trial comparing Gla-300 and Deg-100 in insulin-naïve adults with T2D. In this subanalysis, endpoints were studied by predefined (</≥65 years, N = 596/333) and post hoc (</≥70 years, N = 768/161) age groups.ResultsHeterogeneity of treatment effect was observed for HbA1c reductions across the </≥70 years subgroups, but not across the </≥ 65 years subgroups, with greater HbA1c reductions with Gla-300 versus IDeg-100 in those 70 years or older (least squares mean -0.34% [95% confidence interval: -0.589% to -0.100%]). There was no significant heterogeneity of treatment effect for incidence and rates of confirmed (≤3.9 mmol/L [≤70 mg/dL]) hypoglycaemia across any age subgroups over 24 weeks, but numerically lower incidence and rates were consistently observed for Gla-300 versus IDeg-100 in the 65 years or older and 70 years or older age groups in the initial 12 weeks.ConclusionsGla-300 may be a suitable treatment option in the growing population of older people with T2D. Further investigation is required to determine Gla-300 glycaemic benefits in high-risk populations without increasing the risk of hypoglycaemia.

| S-EPMC8252805 | biostudies-literature

A comparative effectiveness study of degludec and insulin glargine 300 U/mL in insulin-naive patients with type 2 diabetes.

Project description:AimsTo compare the real-world effectiveness of insulin degludec (degludec) and glargine 300 units/mL (glargine U300) in insulin-naïve adult patients with type 2 diabetes in routine US clinical practice.Materials and methodsCONFIRM is a non-interventional comparative effectiveness study following US patients across the continuum of care, through electronic medical records from multiple health systems and integrated delivery networks. Propensity-score matching controlled for confounding. The primary endpoint, change in HbA1c from baseline to 180 days of follow-up, was estimated using a repeated-measure of covariance analysis with subject as random effect. Change in the rate of hypoglycaemic episodes (defined using International Classification of Diseases codes 9/10) and change in proportion of patients with hypoglycaemia were estimated using negative binomial and logistic regression, respectively. Time-to-discontinuation of the initial basal insulin/initiation with another prescribed basal insulin was analysed using a Cox Proportional Hazard model.ResultsData concerning 4056 patients were analysed. After matching, baseline characteristics were comparable (n = 2028 in each group). After 180 days of follow-up, degludec was associated with a larger reduction in HbA1c (estimated treatment difference, -0.27%; P = 0.03), greater reductions in change in rate (rate ratio, 0.70; P < 0.05) and greater reductions in change in the likelihood of hypoglycaemia (odds ratio, 0.64; P < 0.01]) compared with glargine U300. In addition, patients treated with degludec were 27% less likely to discontinue treatment at follow-up compared with those treated with glargine U300 (hazard ratio, 0.73; P < 0.001).ConclusionsSignificantly improved HbA1c, larger reductions in rates and likelihood of hypoglycaemia and lower risk of treatment discontinuation were demonstrated with degludec vs glargine U300.

| S-EPMC6590449 | biostudies-literature

Differential Effect of Hypoalbuminemia on Hypoglycemia on Type 2 Diabetes Patients Treated with Insulin Glargine 300 U/ml and Insulin Degludec.

Project description:IntroductionHypoglycemia resulting from insulin therapy for treatment of diabetes increases the risk of adverse cardiovascular events. Determining biomarkers that provide accurate estimation of hypoglycemia risk may allow for more accurate patient management and care. The purpose of this study was to determine the cutoff value of serum albumin (s-alb) that increases the risk of hypoglycemia in patients treated with insulin degludec.MethodsThis study used a crossover design and randomized 30 patients admitted for glycemic control to compare differences between insulin glargine 300 U/ml (Gla300) and degludec treatments.ResultsThe cutoff value of s-alb associated with 24-h hypoglycemia and nocturnal hypoglycemia in patients treated with degludec was 3.8 g/dl. In patients with s-alb levels < 3.8 g/dl, mean percentages of time with hypoglycemia, clinically important hypoglycemia, and nocturnal hypoglycemia were significantly lower in those treated with Gla300 compared with patients treated with degludec.ConclusionThis study identified a cutoff value for s-alb levels that indicates risk of hypoglycemia in patients treated with degludec. Monitoring s-alb levels in patients treated with degludec will help to mitigate the risk of hypoglycemia.Trial registrationUniversity Hospital Medical Information Network (UMIN 000031044).

| S-EPMC6612344 | biostudies-literature

Comparison of the efficacy and safety of insulin degludec/aspart (twice-daily injections), insulin glargine 300 U/mL, and insulin glulisine (basal-bolus therapy).

Project description:Aims/introductionWe compared the efficacy and safety of insulin degludec/aspart (IDegAsp) twice-daily injections with insulin glargine 300 U/mL and insulin glulisine basal-bolus therapy (Gla300/Glu) using insulin glargine 300 U/mL (Gla300) and insulin glulisine (Glu).Materials and methodsA total of 20 patients with type 2 diabetes mellitus were treated with IDegAsp twice-daily injections; achievement of target preprandial glucose concentration of 100-130 mg/dL at breakfast and supper was determined using a wearable flash glucose monitoring system. Patients were later switched to Gla300/Glu basal-bolus therapy before breakfast and before supper. Data were collected on days 2-4 and days 12-14 for each treatment period. The study's primary efficacy end-point was the mean percentage of time with a target glucose range of 70-180 mg/dL, and safety end-points were the mean percentage of time with hypoglycemia having glucose levels <70 mg/dL, clinically important hypoglycemia with glucose levels <54 mg/dL and nocturnal (00.00-06.00) hypoglycemia.ResultsConsidering efficacy, the mean percentage of time for the target glucose range of IDegAsp was significantly lower than that of Gla300/Glu (73.1 [69.4-81.1] vs 84.2 [80.2-93.1], P = 0.001). Considering safety, the mean percentages of hypoglycemia (<70 mg/dL; 2.1 [0.0-9.4] vs 14.4 [4.4-22.3]), clinically important hypoglycemia (<54 mg/dL; 0.0 [0.0-0.2] vs 1.9 [0.0-5.6]) and nocturnal (00.00-06.00 hours) hypoglycemia (0.5 [0.0-5.9] vs 8.9 [3.1-11.8]) of Gla300/Glu were significantly lower than those of IDegAsp (P = 0.012, 0.036 and 0.007, respectively).ConclusionsWhen compared with the IDegAsp twice-daily injections, Gla300/Glu basal-bolus therapy might achieve more effective glycemic control without hypoglycemic risk.

| S-EPMC6825933 | biostudies-literature

Insulin Degludec 200 Units/mL Is Associated With Lower Injection Frequency and Improved Patient-Reported Outcomes Compared With Insulin Glargine 100 Units/mL in Patients With Type 2 Diabetes Requiring High-Dose Insulin.

Project description:IN BRIEF Many patients with type 2 diabetes require high basal insulin doses, necessitating multiple injections, increasing patient burden, and resulting in reduced treatment adherence. This randomized, controlled, crossover trial compared the efficacy, safety, and patient-reported outcomes for a concentrated formulation of insulin degludec (200 units/mL) to those of insulin glargine in patients requiring high doses of basal insulin. By offering equivalent glycemic control while reducing the rate of confirmed hypoglycemia and the number of injections required for administration, insulin degludec 200 units/mL may be preferred by patients with type 2 diabetes who require high basal insulin doses.

| S-EPMC5391813 | biostudies-literature

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