Pharmacokinetics and pharmacodynamics of insulin lispro protamine suspension compared with insulin glargine and insulin detemir in type 2 diabetes

Abstract

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.

Key words: :

• Basal insulin analogs
• Pharmacodynamics
• Pharmacokinetics
• Type 2 diabetes mellitus

Transparency

Declaration of funding

This study was funded by Eli Lilly and Company.

Declaration of financial/other relationships

S.M.O., E.T.W., and S.J.J. have disclosed that they are employees and shareholders of Eli Lilly and Company. B.N.C. has disclosed that she was employed by Lilly at the time of the study and owns Lilly stock. M.H. and L.A.M. have disclosed that they are employees of Profil Institute for Clinical Research, an early phase clinical research services provider, which was sponsored by Lilly to conduct this trial. A.P.K. has disclosed that she is an employee of Johnson & Johnson and was employed by Profil at the time of the study.

Some peer reviewers receive honoraria from CMRO for their review work. One of the peer reviewers of this paper has disclosed that he/she owns stock in Merck. The other reviewer has no relevant financial relationships.

Acknowledgment

The authors thank Karen Shields, Inventiv Clinical Solutions, for technical assistance with the manuscript and Cate Jones, PhD, Eli Lilly and Company, for assistance with manuscript development.

Notes

* Humalog® Mix25™ and Humalog® Mix50™ (Humalog® Mix75/25™ and Humalog® Mix50/50™ in the USA) are registered trade names of Eli Lilly and Company, Indianapolis, Indiana, USA.

† Lantus® is a registered trade name of sanofi-aventis, Paris, France.

‡ Levemir® is a registered trade name of Novo Nordisk, Baegsvard, Denmark.