Comparison of pharmacodynamic intrasubject variability of insulin lispro protamine suspension and insulin glargine in subjects with type 1 diabetes

Abstract

Objective: The objective of the study was to evaluate pharmacodynamic (PD) intrasubject variability of a single, s.c. dose of insulin lispro protamine suspension (ILPS) compared with insulin glargine in subjects with type 1 diabetes mellitus and additionally, to compare the intrasubject variability of pharmacokinetic parameters of both insulins. Design: This was a single-center, investigator-blinded and subject-blinded, two-arm, parallel, randomized, four-period study. During the replicate visits, subjects received a single s.c. 0.6 U/kg dose of either ILPS or glargine, and underwent 24-h euglycemic glucose clamps. Results: The intrasubject variabilities of the primary PD parameters, total amount of glucose infused (G tot ) and maximum glucose infusion rate (GIR; R max ), were statistically significantly lower for ILPS when compared with glargine (P!0.0001). Least-square (LS) mean estimates for G tot and R max were 2512.7 mg/kg and 3.740 mg/min per kg respectively for ILPS, and 1291.9 mg/kg and 1.793 mg/min per kg respectively for glargine. The LS mean estimates for G tot and R max were statistically greater (PZ0.0010 and P!0.0001 respectively) for ILPS compared with glargine, suggesting that ILPS had greater 24-h glucose-lowering activity. Glargine demonstrated a flatter GIR-time curve, and ILPS demonstrated a significantly shorter time of maximum GIR (tR max ) and earlier time to half-maximal GIR before tR max and time to half-maximal GIR after tR max . ILPS administration resulted in significantly greater exposure compared with glargine (area under the baseline-corrected serum concentration versus time curve from time 0 to 24 h (AUC 0-24 ): 77 150 vs 53 111 pmol min/l; maximum serum insulin concentration (C max ): 119 vs 68 pmol/l; ILPS versus glargine respectively), but the intrasubject variabilities for AUC and C max were comparable. Conclusion: Although glargine demonstrated a flatter GIR-time profile, the lower PD intrasubject variability of ILPS may provide a more predictable response.

Pharmacokinetic and Pharmacodynamic Properties of Faster-Acting Insulin Aspart versus Insulin Aspart Across a Clinically Relevant Dose Range in Subjects with Type 1 Diabetes Mellitus

“…Insulin aspart has previously been shown to have a within-subject variability in glucose-lowering effect of approximately 15–25%, which is comparable to that of regular human insulin, insulin lispro and insulin glulisine [22–25]. This is in contrast to the somewhat higher within-subject variability in glucose-lowering effect of 48–99% reported for several basal insulin preparations, such as insulin glargine 100 U/mL, neutral protamine hagedorn (NPH) insulin and protaminated insulin lispro [26–28]. At the same time, it is on par with the within-subject variability of 20 and 27% shown for insulin degludec and insulin detemir, respectively [26, 27].…”

Comparison of insulin lispro protamine suspension versus insulin glargine once daily added to oral antihyperglycaemic medications and exenatide in type 2 diabetes: a prospective randomized open‐label trial

“…ILPS and glargine have different pharmacokinetic/pharmacodynamic (PK/PD) profiles [19, 20]. Therefore, different dose adjustments based on FPG levels were used for these two insulins in order to optimize treatment for patients in both groups.…”

A Review of Insulin Degludec/Insulin Aspart: Pharmacokinetic and Pharmacodynamic Properties and Their Implications in Clinical Use

“…IDeg had four-times lower within-subject variability in the total glucose-lowering effect (coefficient of variation 20 vs. 82 %; p  < 0.0001) compared with IGlar [52]. To put this further into context, previous studies in patients with T1DM have shown within-subject coefficients of variation for 24-h glucose-lowering effect of 68, 48 and 27 % for neutral protamine hagedorn (NPH) insulin, IGlar and IDet, respectively [53], and 99 and 48 % for IGlar and protaminated insulin lispro, respectively [54]. The relatively low within-subject variability for IDeg and IDet is likely because they are formulated as solutions, they stay in solution after subcutaneous injection, their protraction occurs via formation of multi-/dihexamers and they both bind reversibly to albumin in the circulation, thereby providing a buffer effect [55].…”