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.