New insulins: clinical dvances and future perspectives

Abstract

The therapeutic landscape of diabetes mellitus is undergoing substantial transformation, driven by the development of novel insulin formulations with improved pharmacokinetic and pharmacodynamic profiles. This presentation reviews the most relevant advances across four categories: inhaled insulins, once-weekly basal analogues, oral insulins, and glucose-responsive insulins (GRI).

Inhaled insulin Afrezza®, based on the Technosphere® delivery system, provides an ultra-rapid onset and brief duration of action, effectively reducing postprandial hyperglycemia and minimizing late hypoglycemia risk compared with injectable rapid-acting analogues³. Its respiratory safety profile nonetheless requires baseline and periodic spirometry, and its use is contraindicated in patients with chronic pulmonary disease.

Among once-weekly basal analogues, insulin Icodec achieves a half-life of approximately 196 hours through reversible albumin binding via a C20 fatty acid chain; the ONWARDS program demonstrated non-inferiority versus daily basal insulins, with comparable glycemic efficacy and safety and a marked reduction in injection burden¹. Insulin Efsitora Alfa, an insulin-IgG2 Fc fusion protein with a 17-day half-life, demonstrated non-inferiority versus degludec and glargine in the QWINT studies, with HbA1c reductions of up to 1.34% in type 2 diabetes and rates of clinically significant hypoglycemia that were similar or lower2. The GZR4 analogue showed detectable plasma concentrations up to 168 hours post-injection, positioning it as a promising weekly candidate still in early phases of clinical development.

Oral insulins remain challenging due to low bioavailability (approximately 3%), although absorption enhancers, nanocarriers, and enteric formulations offer encouraging prospects for improving therapeutic adherence. Finally, smart insulins (GRI), capable of modulating their activity according to circulating glucose levels through conformational changes (macrocycles), represent the most innovative frontier, with two candidates currently in advanced development phases aimed at reducing hypoglycemia in type 1 diabetes⁴.

These advances outline a scenario of increasing therapeutic personalization, with the potential to improve adherence, reduce the burden of administration, and decrease hypoglycemic events in individuals with type 1 and type 2 diabetes, redefining the standard of insulin treatment in the years ahead.