Pioglitazone

Pioglitazone is a thiazolidinedione PPARγ agonist approved for type 2 diabetes mellitus as an insulin sensitizer, acting primarily by promoting the differentiation and lipid uptake of adipocytes, thereby reducing ectopic fat deposition and improving systemic insulin sensitivity. PPARγ activation also modulates inflammatory gene expression and macrophage polarization towards anti-inflammatory phenotypes, which has generated interest in pioglitazone for age-related conditions beyond glycaemic control. The IRIS trial (Kernan et al., 2016, NEJM) demonstrated reduced cardiovascular events in non-diabetic patients with insulin resistance and prior stroke or TIA, providing evidence for cardiovascular benefit in a metabolically compromised but non-diabetic population. Nir Barzilai and colleagues have included pioglitazone in geroscience cohort discussions as a candidate that addresses metabolic and inflammatory hallmarks of aging. Long-term safety concerns include risk of congestive heart failure, bone loss, and a possible association with bladder cancer; France and Germany suspended use in 2011 following safety signals, and the EMA did not withdraw authorisation EU-wide but added contraindications (active or past bladder cancer, uninvestigated haematuria) and strict labelling restrictions, limiting its investigational use as a longevity agent.