Targeting triglycerides for cardiovascular risk reduction

Residual cardiovascular risk persists in many patients despite optimal control of established factors such as low-density lipoprotein cholesterol (LDL-C), blood pressure and glycaemia. Mounting evidence indicates that hypertriglyceridemia (HTG) and triglyceride-rich lipoproteins (TRLs), including their remnant particles, contribute to atherogenesis and therefore constitute actionable targets for risk reduction. This narrative review summarizes current knowledge of TRL metabolism and its role in atherosclerotic cardiovascular disease (ASCVD), drawing on mechanistic studies, observational cohorts and Mendelian-randomization analyses. TRLs display pro-inflammatory and pro-thrombotic properties and are increasingly implicated in plaque initiation and progression. Traditional and emerging therapeutic strategies designed to lower TRL burden are critically examined with particular emphasis on their ability to address residual cardiovascular risk. Conventional interventions, fibrates and mixed omega-3 fatty-acid formulations, have yielded modest and inconsistent cardiovascular benefits. By contrast, icosapent ethyl, a highly purified ethyl ester of eicosapentaenoic acid, is the only TRL-targeted therapy that has demonstrated a significant reduction in major cardiovascular events in a large, randomized trial, irrespective of baseline triglyceride levels. Novel agents such as evinacumab (an ANGPTL3 monoclonal antibody) and antisense oligonucleotides against apolipoprotein C-III (volanesorsen, olezarsen, plozasiran) have produced marked decreases in triglycerides, apoB-containing lipoproteins and remnant cholesterol in recent clinical studies, even though cardiovascular outcome data are not yet available. Therefore, therapies targeting TRL metabolism represent a promising approach to reduce residual cardiovascular risk, particularly in high-risk or statin-treated patients.