Understanding how pharmacokinetic and pharmacodynamic differences of basal analog insulins influence clinical practice

Abstract

This article reviews pharmacokinetic (PK) and pharmacodynamic (PD) concepts relating to the pharmacology of basal insulin analogs. Understanding the pharmacology of currently available long-acting basal insulins and the techniques used to assess PK and PD parameters (e.g. the euglycemic clamp method) is important when considering the efficacy and safety of these agents, and can help in understanding the rationale for specific dosing strategies when tailoring therapy for a specific patient. Basal insulins such as insulin glargine 100 units (U)/mL and insulin detemir show improved PK/PD characteristics compared with the intermediate-acting NPH insulin, with a longer duration of action, a more consistent glucose-lowering effect and less prominent concentration peaks. However, more recently developed basal insulins (insulin glargine 300 U/mL, and insulin degludec 100 U/mL and 200 U/mL) have PK/PD profiles closer to the physiologic profile of endogenous basal insulin owing to a more evenly distributed, predictable and prolonged time–action profile that exceeds 24 hours and improved within-patient variability in glucose-lowering effect. The clinical implications and relevance of these PK/PD profiles is explored, including the potential effect of PK/PD parameters on glycemic control and hypoglycemia, and the timing of dosing. The improved PK/PD properties of newer longer-acting basal insulins may translate into clinical benefits for patients with type 1 and type 2 diabetes, such as more consistent insulin levels in the blood over 24 hours, lower intra-patient variability, a reduced risk of nocturnal hypoglycemia, and more flexibility in dosing time, all of which are important to consider when choosing a basal insulin regimen.

Keywords:

• Insulins
• diabetes mellitus
• pharmacokinetics
• pharmacodynamics

Transparency

Declaration of funding

Writing/editorial support funded by Sanofi US Inc.

Author contributions: The contents of the paper and the opinions expressed within are those of the authors, and it was the decision of the authors to submit the manuscript for publication. All authors contributed to the writing of this manuscript, including critical review and editing of each draft, and approval of the submitted version. The authors received no honoraria related to the development of this publication.

Declaration of financial/other relationships

J.G. has disclosed that she has acted as a speaker for Novo Nordisk, Glaxo Smith Kline and Sanofi, and as a consultant for Becton Dickinson. J.P. has disclosed that he is a consultant for Dexcom, Novo Nordisk, Sanofi and Tandem Diabetes. T.H. has disclosed that he is a member of advisory panels for Novo Nordisk and received speaker honoraria and travel grants from Eli Lilly, Mylan and Novo Nordisk. His institution received research funds from Adocia, Astra Zeneca, BD, Biocon, Boehringer Ingelheim, Dance Pharmaceuticals, Grünenthal, Eli Lilly, Medtronic, Novo Nordisk, Novartis, Sanofi and Senseonics. C.K. has disclosed that he is a member of an advisory board for Sanofi and received speaker honoraria and travel grants from Sanofi. His institution received research funds from Adocia, Astra Zeneca, BD, Biocon, Boehringer Ingelheim, Dance Pharmaceuticals, Grünenthal, Eli Lilly, Medtronic, Novo Nordisk, Novartis, Sanofi and Senseonics.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgements

The authors received writing/editorial support in the preparation of this manuscript provided by Rosalie Gadiot, PhD, of Excerpta Medica, funded by Sanofi US Inc.