Insulin glulisine injection [3(B)-Lys, 29(B)-Glu-human insulin] is the newest human insulin analogue product for the control of mealtime blood sugar. As with insulin aspart and insulin lispro products, the insulin glulisine product displays faster absorption and onset of action, with a shorter duration of action than that of regular human insulin. The modifications of the amino acid sequence at positions 3 and 29 in the B chain of human insulin simultaneously provide stability to the molecular structure and render the insulin glulisine molecule less likely to self-associate, compared with human insulin, while still allowing the formation of dimers at pharmaceutical concentrations. Unlike other insulin analogue products, this allows for a viable drug product in the absence of hexamer-promoting zinc and, thus, provides immediate availability of insulin glulisine molecules at the injection site for absorption. Pharmacokinetic studies with insulin glulisine have shown an absorption profile with a peak insulin concentration approximately twice that of regular human insulin, which is reached in approximately half the time. Dose proportionality in early, maximum and total exposure is observed for insulin glulisine over the therapeutic relevant dose range up to 0.4 U/kg. The pharmacodynamic profile of insulin glulisine reflects the absorption kinetics by demonstrating a greater rate of glucose utilization, which is completed earlier and at equipotency on a molar base compared with regular human insulin. Dose-proportionality in glucose utilization has been established for insulin glulisine in patients with type 1 diabetes mellitus in the dose range of 0.075-0.15 U/kg, and a less than dose-proportional increase above 0.15 U/kg, indicating saturation of insulin action in general. The rapid absorption and action of insulin glulisine show similar low intrasubject variability compared with insulin lispro and regular human insulin when given repeatedly, and have been confirmed in healthy subjects of different body mass indices (BMIs) and ethnic groups, as well as adults and children with type 1 and type 2 diabetes. Furthermore, the early insulin exposure and action of insulin glulisine were slightly -- but consistently -- greater than those of insulin lispro in healthy volunteers across a wide range of BMIs.Meal studies in patients with type 1 diabetes show that insulin glulisine provides better postprandial blood glucose control than regular human insulin when administered immediately pre-meal, and equivalent control when given after the meal. In a study in patients with type 2 diabetes, the overall postprandial blood glucose excursions were lower with insulin glulisine than with insulin lispro. Therefore, by virtue of its primary structure, insulin glulisine demonstrates both low self-association in solution and stability for a viable insulin product in the absence of zinc, thereby maintaining immediate availability for absorption after subcutaneous injection. This confers the most rapid onset of glucose-lowering activity and...
Insulin glulisine and insulin lispro demonstrated substantially more rapid time-action profiles than regular human insulin in obese non-diabetic subjects, which prevailed with insulin glulisine irrespective of BMI and subcutaneous fat thickness.
Glulisine shows a faster onset of action than lispro, independent of BMI and dose.
OBJECTIVE -The aim of this study was to investigate the pharmacokinetics, postprandial blood glucose excursions, and safety of insulin glulisine as compared with regular human insulin (RHI), both administered immediately before meals in pediatric patients with type 1 diabetes. RESEARCH DESIGN AND METHODS-A total of 10 children (aged 5-11 years) and 10 adolescents (aged 12-17 years) were enrolled in a randomized, single-center, single-dose, double-blind, cross-over study. The blood glucose of fasting patients was stabilized with intravenous insulin, following which patients received 0.15 IU/kg of subcutaneously injected insulin glulisine or RHI 2 min before a weight-adjusted standardized liquid meal.RESULTS -For insulin glulisine versus RHI, maximum insulin concentrations (58 vs. 33 IU/ml, P Ͻ 0.05) and initial insulin concentrations (insulin [area under the curve] AUC 0 -2h 5,232 vs. 2,994 IU ⅐ min Ϫ1 ⅐ ml Ϫ1 , P Ͻ 0.05; data are geometric means) were higher after insulin glulisine than RHI. Both time to maximum insulin concentration (54 vs. 66 min) and mean residence time (88 vs. 137 min, P Ͻ 0.05) were shorter with insulin glulisine versus RHI. Postprandial glucose excursions after insulin glulisine were lower than after RHI (glucose AUC 0 -6h 641 vs. 801 mg ⅐ h Ϫ1 ⅐ dl Ϫ1 , P Ͻ 0.05). The pharmacokinetic profile for insulin glulisine was similar for children and adolescents, whereas the pharmacokinetic profile for RHI demonstrated a 64% higher concentration in adolescents. Insulin glulisine was safe and well tolerated.CONCLUSIONS -The rapid-acting properties of insulin glulisine that have been previously demonstrated in adults are also observed in children and adolescents with type 1 diabetes. Further, these initial data indicate that insulin glulisine is safe and well tolerated in this patient population. Diabetes Care 28:2100 -2105, 2005T he goal of basal-bolus insulin therapy in type 1 diabetes is to achieve near to normal glycemic control and reduce the risk of long-term clinical complications (1). Children and adolescents sometimes encounter difficulties in adjusting their daily activities to fixed intervals between insulin administration and meals, particularly with regular human insulin (RHI), which requires administration 30 -45 min before mealtime (2). The use of rapid-acting insulin analogs instead of RHI for prandial glycemic control is becoming increasingly accepted, since these insulins can be given much closer to mealtime (2-4). Thus, rapid-acting insulin analogs might offer advantages, particularly for very young children in whom the actual carbohydrate intake is often difficult to predict (5). It remains to be shown, however, whether the rapidacting properties of these analogs are preserved in children.Insulin glulisine ([LysB3, GluB29]-insulin) is a recombinant insulin analog designed to provide the same total glucodynamic effect as RHI after subcutaneous administration but with a faster onset and shorter duration of action (6), which has been demonstrated in adults (7-9). The altered absorpt...
OBJECTIVE -To assess the absorption profile of inhaled insulin in healthy, actively smoking subjects at baseline, after smoking cessation, and after smoking resumption and compare it with nonsmoking subjects.RESEARCH DESIGN AND METHODS -Insulin pharmacokinetics and glucodynamics were measured in 20 male smoking subjects (10 -20 cigarettes/day) and 10 matched nonsmoking subjects after receiving inhaled insulin (1 mg) or the approximate subcutaneous insulin equivalent (3 units) in a randomized cross-over fashion. All smokers then received inhaled insulin 12 h, 3 days, and 7 days into a smoking cessation period. They then resumed smoking for 2-3 days before again receiving inhaled insulin 1 h after the last cigarette.RESULTS -Before smoking cessation, maximum insulin concentration (C max ) and area under the curve (AUC) for insulin concentration time (AUC-Insulin 0 -360 ) with inhaled insulin were higher, and time to C max (t max ) shorter, in smokers than nonsmokers (C max 26.8 vs. 9.7 U/ml; AUC-Insulin 0 -360 2,583 vs. 1,645 U ⅐ ml Ϫ1 ⅐ min Ϫ1 ; t max 20 vs. 53 min, respectively; all P Ͻ 0.05), whereas with subcutaneous insulin, systemic exposure was unchanged (AUCInsulin 0 -360 2,324 vs. 2,269 U ⅐ ml Ϫ1 ⅐ min Ϫ1 ; P ϭ NS). After smoking cessation, AUCInsulin 0 -360 decreased with inhaled insulin by up to 50% within 1 week and approached nonsmoker levels. C max decreased and t max increased relative to baseline but were still not comparable with nonsmoker values. Smoking resumption completely reversed the effect of smoking cessation. Glucodynamics corroborated the observed findings in insulin pharmacokinetics.CONCLUSIONS -Cessation and resumption of smoking greatly altered the pharmacokinetics of inhaled insulin. As rapid changes in systemic insulin exposure increase hypoglycemia risk, inhaled insulin should not be used in people with diabetes who choose to continue smoking. This is consistent with recommendations that people with diabetes refrain from smoking altogether. Diabetes Care 29:277-282, 2006I nhaled insulin is being developed as an alternative method of insulin administration. It has a faster onset of action than either regular human insulin or insulin lispro injected subcutaneously but retains a duration of action that is longer than that of short-acting analogs of human insulin (1). These characteristics suggest that inhaled insulin is suitable for prandial insulin supplementation in patients with diabetes. Accordingly, the results of large-scale clinical trials show that inhaled insulin is effective and well tolerated in patients with type 1 and type 2 diabetes and that it may prove to be a novel and well-accepted component of diabetes therapy for many patients (2-5). In long-term extension trials, Ͼ80% of insulin-treated patients preferred an inhaled insulin regimen over standard subc u t a n e o u s i n s u l i n t h e r a p y ( 6 ) . Furthermore, the availability of inhaled insulin could, in theory, help to overcome patient aversion to insulin therapy in general (7).Pulmonary permeability determi...
OBJECTIVE -Insulin glulisine, a rapid-acting insulin analog, provides prandial insulin replacement. In this study, we compared postprandial blood glucose control after pre-and postmeal insulin glulisine with regular human insulin (RHI).RESEARCH DESIGN AND METHODS -In a single-dose, randomized, four-way complete cross-over study, subjects received standardized, 15-min meals, covered by subcutaneous injections of either insulin glulisine (immediately premeal or 15 min postmeal; 0.15 unit/kg per injection) or RHI (30 min or immediately premeal; 0.15 unit/kg per injection). Twenty-one patients with type 1 diabetes (mean age 36.4 years; mean BMI 26.0 kg/m 2 ) were enrolled; 20 patients completed the study. Postprandial baseline-subtracted blood glucose exposure, maximum excursion, maximum and minimum blood glucose concentrations, and time to the maximum excursion and minimum concentration were assessed, along with serum insulin concentrations.RESULTS -Lower maximum blood glucose excursion (65 vs. 89 mg/dl), total blood glucose exposure within 2 h (279 vs. 334 mg ⅐ h/dl, maximum blood glucose concentration (180 vs. 209 mg/dl), and less time to maximum blood glucose excursion (48 vs. 70 min) were seen with immediately premeal insulin glulisine versus immediately premeal RHI. The maximum serum concentration of insulin glulisine was almost double that of RHI (82 vs. 45 U/ml), achieved in approximately half the time (55 vs. 97 min). Conversely, insulin glulisine (15 min postmeal) versus RHI (immediately premeal) and RHI (30 min premeal) versus insulin glulisine (immediately premeal) resulted in comparable blood glucose control.CONCLUSIONS -Insulin glulisine renders postprandial glucose disposal closer to physiologic requirements compared with RHI and enables appropriate timing of prandial insulin administration. Diabetes Care 29:1812-1817, 2006T ight glycemic control is essential in patients who require insulin for the treatment of diabetes, and its benefits have been clearly demonstrated in several prospective clinical trials, including the Diabetes Control and Complications Trial (DCCT), the U.K. Prospective Diabetes Study (UKPDS), and the Stockholm Diabetes Intervention Study (SDIS) (1-3). Regimens involving multiple daily injections of insulin are designed to achieve tight glycemic control by attempting to mimic physiologic insulin secretion. Before the advent of rapid-acting insulin analogs, regular human insulin (RHI) was the best available treatment option to meet postprandial insulin needs. However, RHI demonstrates a delayed onset of activity after subcutaneous administration, resulting in a recommendation that it should be injected 30 min before a meal (4). Adherence to this recommendation can be inconvenient and has resulted in a substantial proportion of patients negligently injecting closer than 30 min to a meal (5,6).Insulin glulisine ([LysB3, GluB29] insulin) is a new, rapid-acting insulin analog that was developed to provide a more physiologic prandial insulin replacement compared with RHI to facilitate a...
Insulin glulisine is a new rapid-acting insulin analog. The aim of this study was to assess the glucodynamic efficacy of insulin glulisine compared with regular human insulin (RHI) using a manual euglycemic clamp technique. Steady-state pharmacokinetics of insulin glulisine, and its cardiac safety (ECG) and tolerability after intravenous administration, were also determined. This was a single center, randomized, open-label, two-way crossover study in healthy male subjects (n = 16). At the treatment visits subjects received an intravenous infusion of the study drug at a rate of 0.8 mU kg (-1) . min (-1) for 2 hours. Individual baseline glucose concentrations were targeted for euglycaemia and maintained with a manual adjusted 20 % glucose solution over the clamp period of a maximum 6 hours. A glulisine-specific antibody was used to quantify glulisine concentrations by radioimmunoassay, while a non-specific insulin antibody and C-peptide based correction for endogenous insulin was used to estimate exogenous human insulin (RHI). At steady state (90 - 120 min), insulin glulisine and RHI had equivalent glucose utilization (GIR-AUC (SS), 209 [corrected] mg . kg (-1) for glulisine, 214 [corrected] mg . kg (-1) for RHI) and infusion rates (GIR (SS), 7.0 and 7.2 [corrected] mg . kg (-1) . [corrected] min (-1) . kg (-1)). Both insulins also presented equal total glucose disposal (GIR-AUC (0 - clamp end), 995 and 1050 [corrected] mg . kg (-1)) and onset of activity within 20 min. Insulin glulisine and RHI showed parallel time concentration profiles with similar distribution and elimination, but the different antibodies employed for radioimmunoassay impeded a quantitative comparison. There were no noteworthy individual or within-group changes in cardiac repolarisation parameters measured by 12-lead ECG during insulin glulisine infusion. In conclusion, insulin glulisine and RHI show similar distribution and elimination profiles and equivalent glucodynamic efficacy on a molar, unit-per-unit basis.
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