I fibrati: dal loro impiego in terapia agli studi di farmacogenetica (Fibrates: from clinical practice to pharmacogenetic studies)

Over the last decades, the use of fibrates has been pursued as a strategy to reduce cardiovascular risk. These drugs are agonists of peroxisome proliferator-activated receptor-alpha (PPAR-a) - a transcription factor that regulates lipid metabolism via several routes, but mostly via direct up-regulation of specific PPAR-a target genes. The main effects of fibrates on lipid metabolism are a decrease in serum triglycerides (TG), an increase in HDL cholesterol, and an increase in the size of LDL particles, making them less atherogenic. Additionally, fibrates reduce systemic inflammation independently from their effect on lipid metabolism. Despite such beneficial effects, results from clinical trial have been overall disappointing, for this reason, their use in clinical practice for cardiovascular prevention is not generally recommended. At the same time, meta-analysis of post-hoc studies in specific subgroups of patients, i.e. subjects with atherogenic dyslipidemia (= high TG combined with low HDL cholesterol levels) have consistently showed a cardiovascular benefit of fibrates. For this reason, fenofibrate might be considered to reduce residual cardiovascular risk (aiming to reduce levels of non-HDL cholesterol) as second or third line treatments among patients with atherogenic dyslipidemia. Interest in these drugs have been increased also by recent genetic and epidemiological studies reinvigorating the possible beneficial effect of improving lipid profile beyond LDL-cholesterol reduction. Furthermore, pharmacogenetic studies suggest the possibilities of further optimizing fibrate therapy with a “precision medicine” approach based also on genetic markers. This approach looks promising but will need further confirmation before its translation in clinical practice.