Evolution of insulin development: focus on key parameters

Abstract

Introduction: Although insulin products and treatment strategies have improved significantly, clinical challenges still exist. Meeting glycemic goals while minimizing glucose variability and hypoglycemia is of utmost importance when considering existing insulin therapies and designing investigational insulin treatments.

Methods: A PubMed search identified relevant, peer-reviewed articles related to the evolution of insulin development for this nonsystematic review. Search terms included "animal insulin," "synthetic insulin," "regular human insulin," "insulin lispro," "insulin aspart," "insulin glulisine," "insulin glargine," "insulin detemir," "insulin degludec," "biphasic human insulin," "insulin premixes," "ultra-long acting," "oral insulin," and "inhaled insulin."

Results: While the discovery of animal insulin significantly decreased mortality rates from diabetes, issues with availability and large variability between batches led to difficulty in determining proper doses and, subsequently, challenges in achieving glycemic control and avoiding hypoglycemia. The development of synthetic insulin created a more readily available supply, but hypoglycemia still persisted. Recombinant DNA technology solved insulin production problems and allowed for the development of better retarding agents, but pharmacokinetic/pharmacodynamic profiles still did not mimic natural insulin. Insulin premixes offered improved glycemic control, decreased intrapatient variability versus self-mixing, and required fewer injections per day; however, patient adherence remained a problem due to the need to inject 30-60 minutes before a meal for optimal control. This prompted the development of rapid-acting insulin analogs that could be injected right before a meal and long-acting insulin analogs with flatter time-action profiles.

Conclusion: Despite advances in insulin development, a need to provide more physiologic basal insulin coverage and reduce hypoglycemic risk in patients with diabetes remains. Newer insulin analogs and more convenient routes of insulin delivery have shown promising safety and efficacy results. Many patients with diabetes have not reached glycemic goals on currently available insulins. Additional studies are necessary to tailor optimal insulin delivery strategies to specific subsets of diabetes patients.