Lowering triglyceride levels
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Triglyceride Lowering: Key Medications and Mechanisms
Lowering triglyceride (TG) levels is important for reducing cardiovascular risk, especially in people with hypertriglyceridemia. Several therapies and mechanisms have been studied for their effectiveness and safety in lowering TGs.
Olezarsen and Apolipoprotein C-III Inhibition
Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III (APOC3), has shown strong effectiveness in lowering triglyceride levels. In clinical trials, olezarsen reduced TG levels by about 50%, along with reductions in apolipoprotein B and non-HDL cholesterol, without major safety concerns or significant side effects. These benefits were observed in patients with moderate to severe hypertriglyceridemia and high cardiovascular risk 16. Olezarsen also lowered other atherogenic lipoproteins, which may be important for reducing cardiovascular risk 16.
Omega-3 Fatty Acids and Triglyceride Reduction
Omega-3 fatty acids, commonly found in fish oil, lower triglycerides mainly by reducing the liver’s production of very-low-density lipoprotein (VLDL). Recent research has identified an additional mechanism: omega-3-derived N-acyl taurines (NATs) can inhibit intestinal triglyceride absorption, further lowering plasma TGs . High-dose eicosapentaenoic acid (EPA), a type of omega-3, has been linked to a reduction in major vascular events, while docosahexaenoic acid (DHA) does not show the same benefit . However, not all omega-3 formulations are equally effective; for example, icosapent ethyl (a purified EPA) reduced cardiovascular events in high-risk patients, but mixed omega-3 fatty acids did not 57.
Fibrates and Pemafibrate
Fibrates are commonly used to lower TGs, but their cardiovascular benefits are limited to specific subgroups. Pemafibrate, a newer fibrate, significantly lowers TGs and related lipoproteins, but did not reduce cardiovascular events in a large trial of patients with diabetes and hypertriglyceridemia. Pemafibrate was generally safe but had some increased risks for renal events and venous thromboembolism 410.
Bile Acids and FXR Pathway
Bile acids can lower triglyceride levels by activating the farnesoid X receptor (FXR) pathway, which reduces the expression of genes involved in fat production in the liver. This mechanism prevents hepatic TG accumulation and VLDL secretion, suggesting that increasing FXR activity could be a strategy for treating hypertriglyceridemia .
FGF21 and Lipoprotein Catabolism
FGF21, a hormone, lowers plasma TGs by reducing the release of fatty acids from fat tissue and increasing the breakdown of TG-rich lipoproteins in both white and brown fat. This dual action helps decrease liver fat and plasma TGs .
Triglyceride Lowering and Cardiovascular Outcomes
While lowering TGs is associated with reduced cardiovascular events and mortality in some studies, the benefit is not consistent across all therapies or patient groups. Meta-analyses show that TG-lowering therapy can reduce cardiovascular events and cardiovascular-specific mortality, especially in people with diabetes, but does not significantly reduce stroke or all-cause mortality 59. The reduction in cardiovascular risk appears to depend not just on lowering TGs, but also on reducing atherogenic lipoproteins such as apolipoprotein B 510.
Conclusion
Multiple therapies can effectively lower triglyceride levels, including olezarsen, omega-3 fatty acids (especially high-dose EPA), fibrates, bile acids, and FGF21. However, not all TG-lowering therapies reduce cardiovascular risk, and the greatest benefit may come from those that also lower atherogenic lipoproteins. Newer drugs targeting APOC3 show promise for both safety and efficacy, but further research is needed to confirm their impact on cardiovascular outcomes 1610.
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