Addressing dyslipidemic risk beyond LDL-cholesterol.

Area of Science:

• Cardiovascular Medicine
• Lipid Metabolism
• Pharmacology

Background:

• Cardiovascular disease (CVD) remains a significant health burden despite LDL-lowering therapies.
• Persistent dyslipidemia, marked by high triglyceride-rich lipoproteins (TRLs) and low HDL, contributes to residual CVD risk, exacerbated by obesity and metabolic syndrome.
• Accumulating evidence links impaired hepatic clearance of TRL remnants to arterial accumulation, foam cell formation, and inflammation, while low HDL may impair cholesterol efflux, worsening atherosclerosis.

Purpose of the Study:

• To explore novel therapeutic targets for managing dyslipidemia and reducing residual cardiovascular disease (CVD) risk.
• To investigate the potential of inhibiting apolipoprotein C3 (APOC3) and angiopoietin-like 3 (ANGPTL3) as strategies for TRL reduction.
• To highlight the unmet need for new approaches beyond fibrates and fish oils for CVD prevention in dyslipidemic patients.

Main Methods:

• Review of accumulating evidence on TRL remnant accumulation and HDL function in atherosclerosis.
• Analysis of genetic variants associated with reduced triglyceride levels and CVD.
• Evaluation of emerging therapeutic targets, APOC3 and ANGPTL3, for inhibition via antibody, antisense, or RNAi approaches.

Main Results:

• Inhibition of APOC3 lowers TRLs and raises HDL levels.
• Inhibition of ANGPTL3 lowers TRLs and lowers HDL levels.
• Rare genetic variants that lower triglycerides through lipolysis activation are associated with reduced CVD risk, suggesting therapeutic potential.

Conclusions:

• Targeting APOC3 and ANGPTL3 represents a promising new avenue for treating dyslipidemia and reducing cardiovascular disease (CVD) risk.
• Further large-scale clinical trials are necessary to validate the efficacy of APOC3 and ANGPTL3 inhibitors in high-risk CVD patients with elevated TRLs.