Dataset Information

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog^® (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

ABSTRACT: Background and objective: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the insulin lispro pharmacokinetics and glucodynamics, safety and tolerability of URLi and Humalog^® after a single subcutaneous dose in patients with type 2 diabetes mellitus (T2DM).

Methods: This was a phase I, randomised, two-period, two-treatment, double-blind, crossover study in 38 patients with T2DM. At each dosing visit, patients received either 15 units of URLi or Humalog, followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured.

Results: Insulin lispro appeared in the serum 5 min faster (p?
Conclusions: This is the first study to investigate URLi in patients with T2DM using a euglycaemic clamp procedure. URLi demonstrated ultra-rapid pharmacokinetics and glucodynamics in patients with T2DM. CLINICALTRIALS.

Gov identifier: NCT03305822.

SUBMITTER: Leohr J

PROVIDER: S-EPMC7716902 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog<sup>®</sup> (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

Leohr Jennifer J Dellva Mary Anne MA Coutant David E DE LaBell Elizabeth E Heise Tim T Andersen Grit G Zijlstra Eric E Hermanski Lidia L Nosek Leszek L Linnebjerg Helle H

Clinical pharmacokinetics 20201201 12

<h4>Background and objective</h4>Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the insulin lispro pharmacokinetics and glucodynamics, safety and tolerability of URLi and Humalog<sup>®</sup> after a single subcutaneous dose in patients with type 2 diabetes mellitus (T2DM).<h4>Methods</h4>This was a phase I, randomised, two-period, two-treatment, double-bl ...[more]

PMID: 32468448

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Project description:IntroductionWe evaluated the efficacy and safety of ultra-rapid lispro (URLi) in comparison to lispro in a subgroup analysis of Japanese adults with type 1 diabetes mellitus from the phase 3 PRONTO-T1D trial.MethodsAfter an 8-week lead-in to optimize basal insulin treatment, patients were randomized to 52-week double-blind mealtime URLi or lispro, or 26-week open-label postmeal URLi. The primary endpoint was change in hemoglobin A1c (HbA1c) from baseline (week 0) to week 26 between mealtime URLi and lispro. The multiplicity adjusted objectives were 1- and 2-h postprandial glucose (PPG) excursions after a meal test between mealtime URLi and lispro, and change in HbA1c from baseline to week 26 between postmeal URLi and mealtime lispro.ResultsThis manuscript presents pre-specified exploratory analyses of 26-week data from Japanese patients randomized to double-blind URLi (n = 62) or lispro (n = 59), or open-label URLi (n = 46). Mean baseline HbA1c levels were 7.52% for mealtime URLi, 7.44% for lispro, and 7.51% for postmeal URLi at randomization. At week 26, the least squares mean (LSM) difference compared to lispro was 0.04% (95% confidence interval [CI] - 0.14 to 0.22) for mealtime URLi, and 0.16% (95% CI - 0.04 to 0.35) for postmeal URLi. In comparison to lispro, mealtime URLi resulted in statistically significantly lower 1- and 2-h PPG excursions during the mixed-meal tolerance test. LSM differences were - 40.5 mg/dL, 95% CI - 59.5 to 21.4 (- 2.25 mmol/L, 95% CI - 3.3 to - 1.2) for 1-h PPG excursions and - 51.7 mg/dL, 95% CI - 81.7 to - 21.8 (- 2.87 mmol/L, 95% CI - 4.5 to - 1.2) for 2-h PPG excursions at week 26. There were no significant treatment differences in rates of severe/overall hypoglycemia, or incidence of treatment-emergent adverse events.ConclusionsMealtime and postmeal URLi provide effective and comparable glycemic control in Japanese patients. Mealtime URLi demonstrated more effective PPG control compared to lispro.Trial registrationClinicalTrials.gov, NCT03214367.

Project description:IntroductionThe aim of this study was to evaluate the efficacy and safety of ultra-rapid lispro (URLi) versus lispro in a subgroup analysis of Japanese adults with type 2 diabetes mellitus (T2DM) from the phase 3 PRONTO-T2D trial.MethodsAfter an 8-week lead-in period during which patients transitioned to insulin lispro 3 times a day before main meals in association with basal insulin (glargine or degludec), the patients were randomized to 26 weeks of double-blind URLi or lispro injected immediately prior to meals. The primary endpoint was change in hemoglobin A1c (HbA1c) from baseline to week 26 between URLi and lispro. The multiplicity-adjusted objectives were 1- and 2-h postprandial glucose (PPG) excursions after a test meal and change in HbA1c from baseline to week 26 in the URLi and lispro groups.ResultsResults were obtained from prespecified exploratory analyses of 26-week data in Japanese patients randomized to receive URLi (n = 47) or lispro (n = 46). Mean baseline HbA1c levels significantly improved during the lead-in period to a baseline value of 7.50% and 7.60% in patients subsequently randomized to the URLi and lispro treatment groups, respectively. At week 26, the least squares mean (LSM) difference in HbAc1 between the URLi and lispro groups was 0.13% (95% confidence interval [CI] - 0.12 to 0.39) (1.4 mmol/mol, 95% CI - 1.3 to 4.2). Although there were no significant differences in PPG excursions at any time-point, numerically smaller PPG excursions were consistently observed from 30 min to 3 h during the mixed-meal tolerance test in patients on URLi compared to those on lispro. LSM differences in PPG excursions at week 26 were - 10.5 mg/dL (95% CI - 32.7 to 11.7) (- 0.58 mmol/L, 95% CI - 1.82 to 0.65) at 1 h and - 14.9 mg/dL (95% CI - 40.3 to 10.5) (- 0.83 mmol/L, 95% CI - 2.24 to 0.58) at 2 h. There were no significant differences between treatments in rates of severe/overall hypoglycemia or incidence of treatment-emergent adverse events.ConclusionsURLi administered as prandial insulin in combination with basal insulin provides effective glycemic control when administered immediately before a meal in Japanese patients with T2DM. URLi was well tolerated in this population.Trial registrationClinicalTrials.gov, NCT03214380.

Project description:IntroductionThe PRONTO-T1D study, which evaluated the efficacy and safety of ultra rapid lispro (URLi) versus lispro in adults with type 1 diabetes (T1D), met the primary endpoint of noninferiority of HbA1c change from baseline compared to lispro at 26 weeks. We present results of an additional 26-week treatment phase evaluating long-term efficacy and safety of URLi.MethodsIn this phase 3, treat-to-target study, subjects were randomized to double-blind mealtime URLi, lispro, or open-label postmeal URLi with insulin degludec or glargine for 26 weeks. Subjects in the double-blind URLi (n = 451) and lispro (n = 442) groups continued for another 26 weeks to assess long-term efficacy and safety.ResultsHbA1c increased marginally during the long-term maintenance period (week 26-52) in both groups to 7.47% (URLi) and 7.54% (lispro). At week 52, there were no statistically significant treatment differences in change from baseline HbA1c with a least-squares mean treatment difference (95% confidence interval) of - 0.06% (- 0.16, 0.03). Proportions of patients with HbA1c < 7% at week 52 were similar (URLi, 26.8%; lispro, 24.5%). Self-monitored blood glucose (SMBG) showed that 1-h (9.23 versus 10.14 mmol/L) and 2-h (8.40 versus 9.53 mmol/L) postmeal daily mean glucose was statistically significantly (p < 0.001) lower with URLi than lispro. The rate and incidence of severe, documented, and postprandial hypoglycemia (< 54 mg/dl [3.0 mmol/L]) were similar between treatments, but URLi demonstrated a 31% lower rate in the period more than 4 h after meals, (p = 0.023). Injection site reactions were reported by 3.3% of patients on URLi and 0.9% on lispro. The incidence of treatment-emergent adverse events was similar between treatments.ConclusionOverall glycemic control and improved postprandial glucose via SMBG were maintained after 52 weeks with URLi versus lispro, suggesting that the efficacy of URLi is preserved during long-term treatment in patients with T1D. No long-term safety issues were identified with URLi.Trial registrationClinicalTrials.gov, NCT03214367.

Project description:IntroductionTo assess time in range (TIR) (70-180 mg/dL) with postprandial glucose (PPG)-focused titration of ultra rapid lispro (URLi; Lyumjev®) in combination with insulin degludec in people with type 1 diabetes (T1D).MethodsThis phase 2, single-group, open-label, exploratory study was conducted in 31 participants with T1D on multiple daily injection therapy. Participants were treated with insulin degludec and Lispro for an 11-day lead-in and then URLi for a 46-day treatment period consisting of 35-day titration and 11-day endpoint maintenance period. Glucose targets for the titration period were PPG < 140 mg/dL or < 20% increase from premeal, fasting glucose 80-110 mg/dL, and overnight excursion ± 30 mg/dL or less. Participants used the InPen™ bolus calculator and Dexcom G6 continuous glucose monitoring (CGM).ResultsPrimary endpoint mean TIR (70-180 mg/dL) with URLi during the maintenance period was 70.2%. TIR (70-180 mg/dL) and times below/above range were not significantly different with URLi (maintenance) versus lispro (lead-in). HbA1c decreased from 7.1% at screening to 6.8% at endpoint (least squares mean [LSM] change from baseline, - 0.36%; P < 0.001). Fructosamine and 1,5-anhydroglucitol improved (P < 0.001). Mean hourly glucose using CGM was reduced from 8:00 AM to 4:00 PM with URLi. Overall highest PPG excursion across meals was significantly reduced at URLi endpoint compared with lispro lead-in (mean 56.5 vs 72.4 mg/dL; P < 0.001). Insulin-to-carbohydrate ratio (U/X g) was reduced (more insulin given) at breakfast at URLi endpoint vs lead-in (LSM 9.0 vs 9.7 g; P = 0.002) and numerically decreased at other meals. Total daily insulin dose (TDD) was higher at URLi endpoint compared with lispro lead-in (mean 50.2 vs 47.0 U; P = 0.046) with similar prandial/TDD ratio (mean 52.1% vs 51.2%). There were no severe hypoglycemia events during the study.ConclusionsURLi in a basal-bolus regimen focusing on PPG targets demonstrated improved overall glycemic control and reduced PPG excursions without increased hypoglycemia in participants with T1D.Trial registrationClinicalTrial.gov, NCT04585776.

Dataset Information

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog^® (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

Publications

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog<sup>®</sup> (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

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Dataset Information

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog® (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

Publications

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog<sup>®</sup> (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog^® (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.