Research progress on the pathophysiological mechanisms of pioglitazone-induced heart failure: a review

Pioglitazone is thought to increase the risk of heart failure exacerbation in vulnerable individuals, primarily through fluid retention and plasma volume expansion. However, the precise molecular and cellular mechanisms remain incompletely understood. This narrative review aims to collect, organise, and evaluate current evidence on the pathophysiological mechanisms driving pioglitazone-related heart failure. We categorised preclinical and clinical data into key pathophysiological domains and graded evidence strength as high, moderate, or limited. The key domains implicated in this process include renal fluid retention, direct myocardial effects, altered energy metabolism, vascular changes, neurohormonal activation, and individual genetic susceptibility. While fluid retention and vascular changes demonstrate strong clinical evidence, direct myocardial toxicity remains primarily observed in vitro and lacks clinical confirmation. Neurohormonal activation and metabolic disturbances are supported by moderate evidence from animal models and cohort studies, whereas evidence for genetic susceptibility and direct cardiotoxicity remains limited. Overall, this review grades the strength of current evidence and provides a framework for the safe clinical use of pioglitazone and the design of targeted risk prevention strategies.