Understanding concentrated insulins: a systematic review of randomized controlled trials

Abstract

Objective: To compile, analyze, and summarize the literature on concentrated insulins (i.e. concentrations >100 units/mL) from randomized controlled trials and derive guidance on appropriate use of these agents.

Methods: Searches were conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, Trialtrove (through April 2016) and ClinicalTrials.gov (through April 2017) for phase 1–4 clinical studies using concentrated insulins. Selected studies included multiple-arm, randomized controlled trials evaluating subcutaneously administered concentrated insulins. Trial registration numbers (selected studies) were searched in Medline, Embase and Google Scholar (through April 2017). Late-phase studies were graded using guidance from the Agency for Healthcare Research and Quality.

Results: Thirty-eight completed trials (7900 participants) and 34 qualifying publications were identified. Four marketed concentrated insulins were evaluated: two long-acting basal (insulin glargine 300 units/mL and insulin degludec 200 units/mL [IDeg200]), one rapid-acting prandial (insulin lispro 200 units/mL [ILis200]), and one prandial/basal (human regular insulin 500 units/mL). Early-phase trials established bioequivalence for IDeg200 and ILis200 with the corresponding 100 units/mL formulations. Efficacy studies showed noninferior glycemic control between comparators for long-acting basal and prandial/basal products with generally low severe hypoglycemia. Six additional concentrated insulins with completed early-phase development were also identified.

Conclusion: Concentrated-insulin products demonstrated efficacious and safe outcomes in appropriate patients. Clinical findings (HbA1c and hypoglycemia) and methodology (initiation and titration), patient factors (insulin experience and dosing requirements) and treatment characteristics (bioequivalence, potency and device features) are important considerations. This overview of these and other factors provides essential information and guidance for using concentrated insulins in clinical practice.

Keywords:

• Bioequivalence
• concentrated insulin
• diabetes mellitus
• euglycemic clamp
• insulin devices

Transparency

Declaration of funding

This study was funded by Lilly USA LLC, Indianapolis, IN, USA. The funding organization participated in study design, data collection and analysis, and manuscript preparation and approval for publication.

Author contributions: All authors contributed to the conception and/or design of the study, analysis and/or interpretation of data, drafting and/or critical review of the manuscript, and final approval for publication. F.O., J.A.J. and T.M.M. additionally contributed to study selection, data extraction and trial assessment. All authors agree to be accountable for all aspects of the work.

Declaration of financial/other relationships

F.O. has disclosed that he is a member of speaker’s bureaus for Janssen and Novo Nordisk; is an advisory panel/consultant for Eli Lilly and Company, Novo Nordisk, Janssen and Sanofi; and has received research support from National Institutes of Health, Juvenile Diabetes Research Foundation, University of Alabama at Birmingham, Merck, AstraZeneca, Sanofi, Novo Nordisk, Glaxo Smith Kline, Janssen, Eli Lilly and Company, Medtronic, Pfizer and GI Dynamics. A.R.S. has disclosed that she is on advisory boards for Eli Lilly and Company and Boehringer-Ingelheim. J.E.A. has disclosed that he is a member of speaker’s bureaus for Eli Lilly and Company, Astra Zeneca, Boehringer-Ingelheim, Janssen, Pam Lab and Sanofi and a consultant for Eli Lilly and Company, Astra Zeneca, Boehringer-Ingelheim, Intarcia Therapeutics, Janssen, Sanofi and Abbott Diabetes. M.R.C. has disclosed that his organization (ISMP) has received newsletter and fellowship sponsorships from Baxter, Fresenius Kabi and Novartis. T.M.M. has disclosed that she is an employee of Eli Lilly and Company and former employee of Boehringer-Ingelheim. J.A.J. has disclosed that he is an employee of Eli Lilly and Company (subsidiary) and minor stockholder in Eli Lilly and Company.

Acknowledgements

The authors thank Charles E. Carroll MA, Eli Lilly and Company, for assistance with the Ovid/STN literature search; Robin Custeau MA, Pharma Intelligence, Informa, for assistance with the search of the Trialtrove clinical trial database; and Parag Garhyan PhD, Eli Lilly and Company, for a critical review of the manuscript and helpful insight and suggestions on PK/PD content.