Aims
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).
Methods
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.
Results
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.
Conclusions
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.
ABSTRACT
Aim
Assess the pharmacodynamics of lixisenatide once daily (QD) versus liraglutide QD in type 2 diabetes insufficiently controlled on metformin.
Methods
In this 28‐day, randomized, ...open‐label, parallel‐group, multicentre study (NCT01175473), patients (mean HbA1c 7.3%) received subcutaneous lixisenatide QD (10 µg weeks 1–2, then 20 µg; n = 77) or liraglutide QD (0.6 mg week 1, 1.2 mg week 2, then 1.8 mg; n = 71) 30 min before breakfast. Primary endpoint was change in postprandial plasma glucose (PPG) exposure from baseline to day 28 during a breakfast test meal.
Results
Lixisenatide reduced PPG significantly more than liraglutide mean change in AUC0:30–4:30h: −12.6 vs. −4.0 h·mmol/L, respectively; p < 0.0001 (0:30 h = start of meal). Change in maximum PPG excursion was −3.9 mmol/l vs. −1.4 mmol/l, respectively (p < 0.0001). More lixisenatide‐treated patients achieved 2‐h PPG <7.8 mmol/l (69% vs. 29%). Changes in fasting plasma glucose were greater with liraglutide (−0.3 vs. −1.3 mmol/l, p < 0.0001). Lixisenatide provided greater decreases in postprandial glucagon (p < 0.05), insulin (p < 0.0001) and C‐peptide (p < 0.0001). Mean HbA1c decreased in both treatment groups (from 7.2% to 6.9% with lixisenatide vs. 7.4% to 6.9% with liraglutide) as did body weight (−1.6 kg vs. −2.4 kg, respectively). Overall incidence of adverse events was lower with lixisenatide (55%) versus liraglutide (65%), with no serious events or hypoglycaemia reported.
Conclusions
Once daily prebreakfast lixisenatide provided a significantly greater reduction in PPG (AUC) during a morning test meal versus prebreakfast liraglutide. Lixisenatide provided significant decreases in postprandial insulin, C‐peptide (vs. an increase with liraglutide) and glucagon, and better gastrointestinal tolerability than liraglutide.
Aims
Glucagon‐like peptide‐1 (GLP‐1) receptor agonists improve blood glucose control by enhancing glucose‐sensitive insulin release, delaying gastric emptying and reducing postprandial glucagon ...secretion. The studies reported here investigated the insulin response to an intravenous (iv) glucose challenge after injection of lixisenatide (LIXI) 20 µg or placebo.
Methods
Two single‐centre, double‐blind, randomized, placebo‐controlled, single‐dose, crossover studies were performed in healthy subjects (HS) and people with type 2 diabetes mellitus (T2DM). Participants received subcutaneous LIXI or placebo 2 h before an iv glucose challenge. Study endpoints included first‐ and second‐phase insulin response, insulin concentration (INS), glucagon response and glucose disposal rate (Kglucose). LIXI exposure was measured over 12 h.
Results
LIXI 20 µg reached maximum concentration after 2 h and resensitized first‐phase insulin secretion by 2.8‐fold in T2DM to rates comparable with those in HS on placebo, and raised second‐phase insulin secretion by 1.6‐fold in T2DM. INS rose correspondingly and glucose disposal was accelerated by 1.8‐fold in T2DM. First‐phase insulin secretion and glucose disposal were also augmented by LIXI in HS, whereas second‐phase insulin secretion reduced blood glucose concentrations to below fasting levels and then ceased, accompanied by a rapid, short‐lasting rise in glucagon. Otherwise, suppression of glucagon release subsequent to augmentation of insulin release was unaffected in T2DM and in HS.
Conclusions
LIXI resensitized the insulin response to an iv glucose challenge in people with T2DM, thereby accelerating glucose disposal to nearly physiological intensity, and did not impair counter‐regulation to low glucose levels by glucagon.
Aims
We assessed safety and efficacy of two selective 11β‐HSD1 inhibitors (RO5093151/RO‐151 and RO5027383/RO‐838) in this randomized, controlled study in metformin‐treated patients with type 2 ...diabetes.
Methods
Patients either received placebo (N = 21), RO‐151 BID 5 mg (N = 24) or 200 mg (N = 20) or RO‐838 QD 50 mg (N = 21) or 200 mg (N = 24) for 28 days. Metabolic assessments comprising of nine‐point plasma glucose profiles, oral glucose tolerance tests and determination of metabolic biomarkers including insulin, C‐peptide, glucagon, HbA1c and lipids were done at baseline and end of treatment.
Results
Despite the short treatment duration, both RO‐151 and RO‐838 showed trends for improved HbA1c and consistent reductions in body weight (–0.86 to –1.67 kg) exceeding those observed with placebo (–0.28 kg, p = 0.019 for 200 mg RO‐151 vs. placebo). Insulin sensitivity parameters (e.g. HOMA‐IR and Matsuda‐Index) improved non‐significantly with 200 mg RO‐151. Lipid parameters did not consistently improve with either compound, but RO‐838 led to non‐significant increases in triglycerides and VLDL‐cholesterol versus placebo. Both compounds were well tolerated and showed inhibitory effects on 11β‐HSD1 activity based on urinary corticosteroid excretion. As reported for other 11β‐HSD1‐inhibitors increased concentrations of ACTH and adrenal androgen precursors were found with RO‐151, but not with RO‐838.
Conclusions
Slight metabolic improvements were seen, in particular with RO‐151 high dose, however, the observed changes often did not reach statistical significance and were not clearly dose dependent. Studies of longer duration are needed to further investigate potential benefits and risks of these compounds.
Aim
To compare the pharmacokinetics (PK) and pharmacodynamics (PD) of 3 rapid‐acting insulin lispro products: SAR342434 solution, United States (US)‐approved Humalog and European Union (EU)‐approved ...Humalog.
Methods
In a single‐centre, randomized, double‐blind, 3‐treatment, 3‐period, 6‐sequence, crossover, euglycaemic clamp study (NCT02273258), adult male subjects with type 1 diabetes were randomized to receive 0.3 U/kg of SAR342434 solution, US‐approved and EU‐approved Humalog under fasted conditions. PK and PD (glucose infusion rate GIR) were assessed up to 12 hours.
Results
Of the 30 subjects randomized, 28 completed all 3 treatment periods. Mean concentration and GIR vs time profiles were similar for all 3 products. Exposure (INS‐Cmax, INS‐AUClast and INS‐AUC) and activity (GIRmax and GIR‐AUC0‐12h) of SAR342434, US‐approved and EU‐approved Humalog were similar in all comparisons (point estimates of treatment ratios, 0.95‐1.03 for PK parameters and 1.00‐1.07 for PD parameters), with 90% confidence intervals for the ratios of geometric least squares means within the pre‐specified bioequivalence limit (0.80‐1.25) and no significant differences in time‐related parameters. Within‐subject variability of exposure and activity was low across the 3 clamps, indicating high day‐to‐day reproducibility in clamp performance, irrespective of the individual product. Adverse events were similar for all 3 products. No safety concerns were noted in vital signs or in laboratory and electrocardiogram data.
Conclusions
The results of this study demonstrate similarity in insulin lispro exposure profiles and PD activity of SAR342434 solution to both US‐ and EU‐approved Humalog, and between both US‐ and EU‐approved Humalog, supporting the use of SAR342434 solution for injection as a follow‐on product.
Using the ARGUS detector at the DORIS II e+e− storage ring at DESY, we have obtained evidence for a new charmed resonance which decays into D*±(2010)π∓. The observed mass and width are 2420±6 MeV/c2 ...and 70±21 MeV/c2, respectively. The fragmentation function is found to be hard, as expected for a state containing a leading charm quark produced by nonresonant e+e− annihilation.
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