New Horizons: Next-Generation Insulin Analogs: Structural Principles and Clinical Goals.

Design of "first-generation" insulin analogs over the past three decades has provided pharmaceutical formulations with tailored pharmacokinetic (PK) and pharmacodynamic (PD) properties. Application of a molecular tool-kit-integrating protein sequence, chemical modification and formulation-has thus led to improved prandial and basal formulations for the treatment of diabetes mellitus. Although PK/PD changes were modest in relation to prior formulations of human and animal insulins, significant clinical advantages in efficacy (mean glycemia) and safety (rates of hypoglycemia) were obtained. Continuing innovation is providing further improvements to achieve ultra-rapid and ultra-basal analog formulations in an effort to reduce glycemic variability and optimize time in range. Beyond such PK/PD metrics, next-generation insulin analogs seek to exploit therapeutic mechanisms: glucose-responsive ("smart") analogs, pathway-specific ("biased") analogs, and organ-targeted analogs. Smart insulin analogs and delivery systems promise to mitigate hypoglycemic risk, a critical barrier to glycemic control, whereas biased and organ-targeted insulin analogs may better recapitulate physiologic hormonal regulation. In each therapeutic class considerations of cost and stability will impact utilization and global distribution. This review highlights structural principles underlying next-generation design efforts, their respective biological rationale and potential clinical applications.