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 ...pooled analysis compared the pharmacokinetics and glucodynamics between URLi and Humalog
®
in healthy subjects and patients with type 1 or type 2 diabetes mellitus.
Methods
The analysis included four randomized, double-blind, crossover, single-dose studies (healthy subjects
n
= 74, patients with type 1 diabetes
n
= 78, and type 2 diabetes
n
= 38) evaluating subcutaneous doses of 7, 15, or 30 U of URLi and Humalog during an 8- to 10-h euglycemic clamp procedure.
Results
The pooled analysis showed an ~ 5-min faster onset of appearance, an ~8-fold greater exposure in the first 15 min, a 43% reduction in exposure beyond 3 h, and a 68-min shorter exposure duration with URLi vs Humalog across all study populations and dose range. Compared with Humalog, URLi had a 10-min faster onset of action, a 3-fold greater insulin action in the first 30 min, a 35% reduction in insulin action beyond 4 h, and a 44-min shorter duration of action across all populations and dose range. Overall exposure and insulin action were similar between URLi and Humalog for each dose level and study population.
Conclusions
Across the studied populations and dose range, URLi consistently demonstrated a faster absorption, reduced late exposure, and overall shorter exposure duration compared with Humalog. Similarly, URLi demonstrated earlier insulin action while reducing late insulin action and shorter insulin action compared with Humalog across the study populations and dose range.
Clinical Trial Registration
NCT02942654 (registered: 21 October, 2016), NCT03286751 (registered: 15 September, 2017), NCT03166124 (registered: 23 May, 2017), and NCT03305822 (registered: 5 October, 2017).
Aims
To evaluate the efficacy and safety of ultra rapid lispro (URLi) versus lispro in adults with type 1 diabetes in a 26‐week, treat‐to‐target, phase 3 trial.
Materials and methods
After an 8‐week ...lead‐in to optimize basal insulin glargine or degludec, patients were randomized to double‐blind mealtime URLi (n = 451) or lispro (n = 442), or open‐label post‐meal URLi (n = 329). The primary endpoint was change from baseline glycated haemoglobin (HbA1c) to 26 weeks (non‐inferiority margin 0.4%), with multiplicity‐adjusted objectives for postprandial glucose (PPG) excursions after a meal test.
Results
Both mealtime and post‐meal URLi demonstrated non‐inferiority to lispro for HbA1c: estimated treatment difference (ETD) for mealtime URLi −0.08% 95% confidence interval (CI) −0.16, 0.00 and for post‐meal URLi +0.13% (95% CI 0.04, 0.22), with a significantly higher endpoint HbA1c for post‐meal URLi versus lispro (P = 0.003). Mealtime URLi was superior to lispro in reducing 1‐ and 2‐hour PPG excursions during the meal test: ETD −1.55 mmol/L (95% CI −1.96, −1.14) at 1 hour and − 1.73 mmol/L (95% CI −2.28, −1.18) at 2 hours (both P < 0.001). The rate and incidence of severe, documented and postprandial hypoglycaemia (<3.0 mmol/L) was similar between treatments, but mealtime URLi demonstrated a 37% lower rate in the period >4 hours after meals (P = 0.013). Injection site reactions were reported by 2.9% of patients on mealtime URLi, 2.4% on post‐meal URLi, and 0.2% on lispro. Overall, the incidence of treatment‐emergent adverse events was similar between treatments.
Conclusions
The results showed that URLi provided good glycaemic control, with non‐inferiority to lispro confirmed for both mealtime and post‐meal URLi, while superior PPG control was demonstrated with mealtime dosing.
Aims
To compare the pharmacokinetic (PK) and glucodynamic (GD) characteristics of ultra rapid lispro (URLi; Eli Lilly and Company, Indianapolis, Indiana), Fiasp® (Novo Nordisk, Bagsvaerd, Denmark), ...Humalog® (Eli Lilly and Company) and NovoRapid® (Novo Nordisk), in patients with type 1 diabetes (T1D).
Materials and Methods
This was a randomized, double‐blind, four‐period, crossover study, conducted in 68 patients with T1D. Patients received the same individualized subcutaneous dose of each study drug immediately prior to a liquid test meal. For comparison, 12 healthy subjects received the same test meal.
Results
URLi had a significantly faster insulin absorption compared to the other insulins tested. Early half‐maximal drug concentration was reached 13 minutes after administration of URLi, which was 6 minutes faster than Fiasp, 13 minutes faster than Humalog, and 14 minutes faster than NovoRapid (all P <0.0001). Early insulin exposure was significantly greater and late insulin exposure was reduced after URLi compared to the other insulins. URLi achieved the greatest numerical reduction in postprandial glucose (PPG) at 2 hours post‐meal (7 mg/dL vs Fiasp) and was significantly different from Humalog (21 mg/dL) and Novo Rapid (29 mg/dL). Additionally, glucose excursions over the first 3 hours post‐meal with URLi were comparable to those in healthy subjects.
Conclusions
URLi demonstrated the fastest insulin absorption and the greatest numeric PPG‐lowering effect compared to the other insulins tested. URLi more closely matched the early physiological glucose control observed in healthy subjects.
Background
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 pharmacokinetics, glucodynamics, safety, and tolerability of URLi and Humalog
®
in patients with type 1 diabetes mellitus (T1DM).
Methods
This was a phase I, two-period, randomised, double-blind, crossover glucose clamp study in younger adult (aged 18–45 years;
n
= 41) and elderly (aged ≥65 years;
n
= 39) patients with T1DM. At each dosing visit, patients received either URLi or Humalog (15 units subcutaneously) followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured.
Results
Insulin lispro appeared in serum 6 min faster, and exposure was 7.2-fold greater over the first 15 min postdose with URLi versus Humalog in both age groups. Exposure beyond 3 h postdose was 39–41% lower, and exposure duration was reduced by 72–74 min with URLi versus Humalog in both age groups. Onset of insulin action was 11–12 min faster, and insulin action was 3-fold greater over the first 30 min postdose with URLi versus Humalog in both age groups. Insulin action beyond 4 h postdose was 44–54% lower, and duration of action was reduced by 34–44 min with URLi versus Humalog in both age groups. Overall exposure and total insulin action remained similar for both treatments. URLi and Humalog were well tolerated.
Conclusion
In patients with T1DM, URLi showed ultra-rapid pharmacokinetics and glucodynamics, with the differences between URLi and Humalog in elderly patients mirroring those in younger adults.
ClinicalTrials.gov identifier
: NCT03166124.
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
< 0.0001) and exposure was 6.4-fold greater in the first 15 min (
p
< 0.0001) with URLi versus Humalog. Exposure beyond 3 h postdose was 26% lower and the duration of exposure was 51 min shorter with URLi versus Humalog. Onset of insulin action was 13 min faster (
p
< 0.0001) and insulin action was 4.2-fold greater within the first 30 min (
p
< 0.0001) with URLi versus Humalog. Insulin action beyond 4 h postdose was 20% lower (
p
= 0.0099) with URLi versus Humalog. Overall insulin lispro exposure and total glucose infused were similar for URLi and Humalog. Both treatments were well tolerated.
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.
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 ...pharmacokinetic profile and glucodynamic response of URLi when administered subcutaneously into the abdomen, upper arm, or thigh. An intravenous (IV) bolus administration was included to determine the absolute bioavailability at each injection site.
In this Phase I, randomized, open-label, 4-period, crossover study, healthy subjects received a single dose of 15 U URLi subcutaneously into the abdomen, upper arm, or thigh, or by intravenous injection. Serum insulin lispro concentrations and glucodynamic response during a 10-hour euglycemic clamp procedure were assessed after URLi administration.
Total insulin lispro exposure was similar for the abdomen, upper arm, and thigh, and absolute bioavailability was ∼65% at each subcutaneous (SC) injection site. Total and peak insulin action were similar across these SC injection sites. The onset of appearance was <1 minute, and the time to early half-maximal drug concentration occurred at ∼10 minutes across these three SC injection sites. Onset of insulin action occurred at ∼22 minutes, and the early insulin action (for the first hour) was also similar across these SC injection sites. URLi was well tolerated after single SC injections and IV bolus administration.
The pharmacokinetic and glucodynamic profiles of URLi were similar after a single SC dose into the abdomen, upper arm, or thigh. The rate of insulin lispro absorption and early insulin action were maintained regardless of the SC injection site. The current study supports SC injection of URLi into the abdomen, upper arm, and thigh. ClinicalTrials.gov identifier: NCT03232983.
Aims
To compare the pharmacokinetics (PK), glucodynamics (GD) and tolerability following single and multiple daily subcutaneous doses of ultra rapid lispro (URLi) and Humalog® in patients with type 2 ...diabetes mellitus (T2D).
Materials and Methods
This was a two‐part, randomized, double‐blind Phase 1b study. Part A used a six‐period crossover design to assess PK and GD response to a solid mixed meal tolerance test (MMTT) following a single dose of URLi or Humalog administered 15 minutes before, immediately before, or 15 minutes after the start of the meal. Part B evaluated URLi or Humalog during 2 weeks of multiple daily dosing with a parallel design. The PK and GD were assessed following MMTTs at the beginning and end of the 2 weeks when insulins were administered immediately before the start of the meal.
Results
URLi increased the insulin exposure within the first 30 minutes postdose by 2.2‐fold and reduced the time to the early half‐maximal drug concentration by 22.6% compared with Humalog. Overall, URLi resulted in better postprandial glucose lowering when dosed before, immediately before, or after a meal. In comparing the same meal‐to‐dose timing between the insulins, the postprandial glucose excursion over 5 hours was significantly reduced by 29%‐105% for all three dose timings (−15, 0 and +15 minutes) with URLi. The PK and GD were sustained after daily subcutaneous dosing for 2 weeks in patients with T2D. URLi had more hypoglycaemic events during the MMTTs; few events occurred for both treatments during the 2 weeks of outpatient dosing.
Conclusions
URLi demonstrated accelerated insulin lispro absorption and greater postprandial glucose reduction at different meal‐to‐dose timings compared with Humalog and was well tolerated in patients with T2D.
To investigate contributions of changes in fasting plasma glucose (FPG) and postprandial glucose (PPG) to changes in hemoglobin A1c (HbA1c) and time-in-range (TIR, 70-180 mg/dL) in people with type 1 ...diabetes (T1D) and type 2 diabetes (T2D) treated with multiple daily injections (MDI) of insulin lispro (rapid/ultra-rapid formulations).
Multivariate regression models were used to quantify the contributions of FPG and PPG reductions to change in HbA1c and TIR using data from the PRONTO-T1D (N = 1222) and PRONTO-T2D (N = 673) clinical trials. TIR was derived from 10-point self-monitored blood glucose (SMBG) profiles overall, as well as from continuous glucose monitoring (CGM) in the PRONTO-T1D CGM substudy (n = 269/1222).
A 1 mmol/L FPG reduction corresponded with a 0.09-0.12 % (95 % confidence interval CI 0.06-0.15 %) HbA1c reduction in PRONTO-T1D and 0.17-0.26 % (95 % CI 0.13-0.30 %) in PRONTO-T2D (both p < 0.0001). A 1 mmol/L PPG reduction corresponded with a 0.05-0.09 % (95 % CI 0.01-0.12 %) HbA1c reduction in PRONTO-T1D (p < 0.001) and 0.10-0.15 % (95 % CI 0.05-0.19 %) in PRONTO-T2D (p < 0.0001). Reductions in FPG and PPG were significantly associated with increased TIR whether derived from SMBG (7.87-12.95 % 95 % CI 6.81-14.23 %; all p < 0.0001) or CGM (3.35-4.18 % 95 % CI 2.11-5.39 %; all p < 0.05).
FPG and PPG significantly impact HbA1c and TIR. Balanced management of both FPG and PPG is important to achieve glycemic goals for people with diabetes on MDI insulin therapy.
PRONTO-T1D ClinicalTrials.gov identifier: NCT03214367; PRONTO-T2D ClinicalTrials.gov Identifier: NCT03214380.
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 ...pharmacokinetic and glucodynamic parameters of URLi and Lispro (Humalog®) at 3 dose levels in healthy subjects.
This randomized, 6-period, subject- and investigator-blind, crossover study included 42 healthy subjects. At each period, subjects received a single subcutaneous dose of 7, 15, or 30 U of URLi or Lispro followed by a 10-h automated euglycemic clamp. Insulin lispro and blood glucose concentrations were measured.
Across all 3 doses, insulin lispro appeared in the serum 2–5 min faster, and exposure was 6- to 8-fold greater in the first 15 min, with URLi versus Lispro. Exposure beyond 3 h postdose was 45%–52% lower, and duration of exposure was 67–86 min shorter with URLi versus Lispro for all dose levels. Onset of insulin action was 7–9 min faster and insulin action was ~3-fold greater in the first 30 min with URLi versus Lispro across the dose levels. Insulin action beyond 4 h was reduced by 32%–45%, and duration of action was reduced by 47–67 min, with URLi versus Lispro for all 3 dose levels. Overall exposure and total glucose infused were similar between URLi and Lispro at each dose level. Dose proportionality was observed for maximum and overall exposure after URLi. Less than dose-proportional increases in maximum and total glucose infused were observed and were similar for both URLi and Lispro.
URLi exhibited ultra-rapid pharmacokinetic and glucodynamic parameters across all 3 dose levels studied and exhibited dose-proportional increases in exposure in healthy subjects. ClinicalTrials.gov identifier: NCT03286751.
•Insulin absorption was up to 7-fold faster with URLi vs Lispro for all doses.•Early glucose lowering was greater with URLi vs Lispro across all dose levels.•Late insulin exposure and action were reduced with URLi vs Lispro for all doses.•Dose proportional increases in exposure were observed for URLi.•Both URLi and Lispro showed less than dose proportional increases in insulin action.
Aims
To evaluate the efficacy and safety of ultra‐rapid lispro (URLi) versus lispro in a paediatric population with type 1 diabetes (T1D) in a Phase 3, treat‐to‐target study.
Materials and Methods
...After a 4‐week lead‐in to optimize basal insulin, participants were randomized to double‐blind URLi (n = 280) or lispro (n = 298) injected 0 to 2 minutes prior to meals (mealtime), or open‐label URLi (n = 138) injected up to 20 minutes after start of meals (postmeal). Participants remained on pre‐study basal insulin (degludec, detemir or glargine). The primary endpoint was glycated haemoglobin (HbA1c) change from baseline after 26 weeks (noninferiority margin 4.4 mmol/mol 0.4%).
Results
Both mealtime and postmeal URLi demonstrated noninferiority to lispro for HbA1c: estimated treatment difference (ETD) for mealtime URLi −0.23 mmol/mol (95% confidence interval CI −1.84, 1.39) and postmeal URLi −0.17 mmol/mol (95% CI −2.15, 1.81). Mealtime URLi reduced 1‐hour postprandial glucose (PPG) daily mean (P = 0.001) and premeal to 1 hour postmeal PPG excursion daily mean (P < 0.001) versus lispro. The rate and incidence of severe, nocturnal or documented hypoglycaemia (<3.0 mmol/L 54 mg/dL) were similar for all treatments. With mealtime URLi versus lispro, the rate of postdose hypoglycaemia (<3.0 mmol/L) was higher at ≤2 hours (P = 0.034). The incidence of treatment‐emergent adverse events was similar for all treatments. More participants reported an injection site reaction with mealtime URLi (7.9%) versus postmeal URLi (2.9%) and lispro (2.7%).
Conclusions
In children and adolescents with T1D, URLi demonstrated good glycaemic control, and noninferiority to lispro in HbA1c change for mealtime and postmeal URLi. When dosed at the beginning of meals, URLi reduced 1‐hour PPG and PPG excursions versus lispro.
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