Targeting apoC-III and ANGPTL3 in the treatment of hypertriglyceridemia

The prevalence of hypertriglyceridemia (HTG) is increasing. Elevated triglyceride (TG) levels are associated with an increased cardiovascular disease (CVD) risk. Moreover, severe HTG results in an elevated risk of pancreatitis, especially in severe HTG with an up to 350-fold increased risk. Both problems emphasize the clinical need for effective TG lowering.The purpose of this review is to discuss the currently available therapies and to elaborate the most promising novel therapeutics for TG lowering.Conventional lipid lowering strategies do not efficiently lower plasma TG levels, leaving a residual CVD and pancreatitis risk. Both apolipoprotein C-III (apoC-III) and angiopoietin-like 3 (ANGPTL3) are important regulators in TG-rich lipoprotein (TRL) metabolism. Several novel agents targeting these linchpins have ended phase II/III trials. Volanesorsen targeting apoC-III has shown reductions in plasma TG levels up to 90%. Multiple ANGPLT3 inhibitors (evinacumab, IONIS-ANGPTL3-LRx, ARO-ANG3) effectuate TG reductions up to 70% with concomitant potent reduction in all other apoB containing lipoprotein fractions. We expect these therapeutics to become players in the treatment for (especially) severe HTG in the near future.