The role of the PPAR system in diabetic cardiovascular risk and beyond

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate metabolic homeostasis and play a key role in the management of a number of metabolic disorders (e.g. diabetes and liver steatosis). This review aims to provide an overview on the impact of the three isoforms, PPAR-α, PPAR-β/δ and PPAR-γ, on diabetic-driven metabolic diseases.

The lack of clinical benefit observed in the PROMINENT trial with pemafibrate (a selective PPAR-α agonist) has raised questions regarding the therapeutic potential of PPAR-α activation in the prevention of major cardiovascular events. Conversely, evidence suggests a possible therapeutic role in peripheral artery disease. To reduce the adverse effects occurring consequently to PPAR-γ activation, partial agonists or selective PPAR-γ modulators (SPPARγMs) have been developed. In the context of metabolic dysfunction associated steatohepatitis, pan-PPAR agonism appears necessary to achieve significant improvements in histological endpoints.

These diversified effects, albeit with a limited risk of significant side effects, make PPAR agonists an area of growing interest and with an expanding range of potential applications.