OBJECTIVE: The primary aim was to evaluate duration of action of a single 0.8 U/kg dose of insulin lispro protamine suspension (ILPS) in type 2 diabetes (T2DM) patients; secondarily to compare onset and duration of action of ILPS, glargine (G), and detemir (D) (0.8 U/kg) and evaluate pharmacokinetic (PK) and pharmacodynamic (PD) dose responses of ILPS. RESEARCH DESIGN AND METHODS: In a single-center, double-blind, five-arm crossover study, 34 patients were randomized to a treatment sequence which included a single subcutaneous 0.8 U/kg dose of G and D and three doses of ILPS (0.4 U/kg, 0.8 U/kg, and 1.2 U/kg) and were studied using 24-hour euglycemic glucose clamps. PRIMARY OUTCOME MEASURE: Duration of action was determined as the time to the last measurable glucose infusion rate (tR(last)) during glucose clamps. RESULTS: The duration of insulin action (tR(last)) for ILPS at 0.8 U/kg was >23 hours and was similar to G (p = 0.114) and D (p = 0.570). Post-hoc analysis demonstrated the probability of achieving 24 hours of glucose-lowering activity after a 0.8 U/kg dose: 48% (ILPS), 43% (G), and 26% (D). G(tot) and R(max) were significantly greater for ILPS versus G or D. The median ILPS time-dependent values demonstrated a significantly earlier maximum PD response (tR(max) and early 50% tR(max)) versus either G or D. ILPS demonstrated dose-dependent increases in PK and PD measures across the dose range. CONCLUSIONS: Following a single 0.8 U/kg dose in T2DM patients, ILPS, G, and D demonstrated similar durations of glucose-lowering activity and ILPS demonstrated significantly greater glucose-lowering activity (R(max) and G(tot)) and earlier maximum PD response. These results potentially support once-daily dosing of ILPS in T2DM. LIMITATIONS: The observed number of 24-hour censored observations was higher than expected and the wash-out period for basal insulin treated patients may have been too short to definitively rule out a carry-over effect; however, such an effect, if present, would potentially only affect onset of action and not the primary outcome measure.
RCT Entities:
OBJECTIVE: The primary aim was to evaluate duration of action of a single 0.8 U/kg dose of insulin lispro protamine suspension (ILPS) in type 2 diabetes (T2DM) patients; secondarily to compare onset and duration of action of ILPS, glargine (G), and detemir (D) (0.8 U/kg) and evaluate pharmacokinetic (PK) and pharmacodynamic (PD) dose responses of ILPS. RESEARCH DESIGN AND METHODS: In a single-center, double-blind, five-arm crossover study, 34 patients were randomized to a treatment sequence which included a single subcutaneous 0.8 U/kg dose of G and D and three doses of ILPS (0.4 U/kg, 0.8 U/kg, and 1.2 U/kg) and were studied using 24-hour euglycemic glucose clamps. PRIMARY OUTCOME MEASURE: Duration of action was determined as the time to the last measurable glucose infusion rate (tR(last)) during glucose clamps. RESULTS: The duration of insulin action (tR(last)) for ILPS at 0.8 U/kg was >23 hours and was similar to G (p = 0.114) and D (p = 0.570). Post-hoc analysis demonstrated the probability of achieving 24 hours of glucose-lowering activity after a 0.8 U/kg dose: 48% (ILPS), 43% (G), and 26% (D). G(tot) and R(max) were significantly greater for ILPS versus G or D. The median ILPS time-dependent values demonstrated a significantly earlier maximum PD response (tR(max) and early 50% tR(max)) versus either G or D. ILPS demonstrated dose-dependent increases in PK and PD measures across the dose range. CONCLUSIONS: Following a single 0.8 U/kg dose in T2DM patients, ILPS, G, and D demonstrated similar durations of glucose-lowering activity and ILPS demonstrated significantly greater glucose-lowering activity (R(max) and G(tot)) and earlier maximum PD response. These results potentially support once-daily dosing of ILPS in T2DM. LIMITATIONS: The observed number of 24-hour censored observations was higher than expected and the wash-out period for basal insulin treated patients may have been too short to definitively rule out a carry-over effect; however, such an effect, if present, would potentially only affect onset of action and not the primary outcome measure.
Authors: Zhihui Wang; Maka S Hedrington; Nino Gogitidze Joy; Vanessa J Briscoe; M Antoinette Richardson; Lisa Younk; Wendell Nicholson; Donna B Tate; Stephen N Davis Journal: Diabetes Care Date: 2010-03-31 Impact factor: 17.152