Ferreira_2025_Pharmaceutics_17_

Background/Objectives: Hypertriglyceridemia (HTG) is a common multifactorial metabolic disorder often with genetic predisposition. Multiple lines of evidence support a causal role of triglyceride-rich lipoproteins (TRLs) in atherosclerotic cardiovascular disease (ASCVD), with severe HTG leading to pancreatitis and hepatic steatosis. This review covers TRL metabolism, causes and consequences of HTG, current management, and emerging TRL-targeted therapies. Methods: A narrative review was conducted. Results: Pharmacologic therapy with fibrates and omega-3 fatty acids remains the standard treatment for HTG but its efficacy in preventing pancreatitis and ASCVD is limited. Genetic studies have identified apolipoprotein C-III (ApoC-III) and angiopoietin-like 3 (ANGPTL3), both inhibitors of lipoprotein lipase, as potential therapeutic targets for reducing TG levels and ASCVD risk. Monoclonal antibodies and RNA-based therapies have enabled the development of inhibitors of ApoC-III and ANGPTL3, with promising results in phase 2 and small phase 3 trials. Angiopoietin-like 4 inhibitors and Fibroblast growth factor 21 analogs are in early-stage clinical development. Conclusions: Current pharmacologic therapies exhibit notable limitations in effectively managing severe HTG and in reducing the risk of ASCVD. Emerging therapies targeting TRLs metabolism showed favourable results in initial clinical trials.