Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies

Area of Science:

• Cardiovascular Medicine
• Lipid Metabolism
• Pharmacology

Background:

• Residual cardiovascular disease (CVD) risk persists despite LDL-C reduction, particularly in patients with diabetes, metabolic syndrome, or chronic kidney disease.
• Triglycerides (TGs) and TG-rich lipoproteins (TRLs) play a significant role in this residual risk.
• Apolipoprotein B (ApoB) in remnant lipoproteins is implicated as a key driver of atherosclerotic CVD.

Purpose of the Study:

• To evaluate the evolving role of TGs and TRLs in cardiovascular disease (CVD) risk and prevention.
• To examine the mechanistic rationale, genetic, and epidemiological evidence for TG targeting in residual risk reduction.
• To assess the therapeutic potential of novel agents targeting TRLs in high-risk populations.

Main Methods:

• Review of mechanistic rationale, genetic, and epidemiological studies.
• Analysis of emerging data from Mendelian randomization studies and large clinical cohorts.
• Evaluation of clinical trial data for TG-lowering therapies, including ApoC-III and ANGPTL3 inhibitors, and PPAR modulators.

Main Results:

• Emerging evidence supports a causal link between elevated remnant lipoproteins and atherosclerotic CVD, with ApoB as a potential principal driver.
• Traditional TG-lowering agents have shown mixed results on cardiovascular outcomes.
• Novel therapies like ApoC-III and ANGPTL3 inhibitors demonstrate potent lipid-lowering effects, but outcome data are limited; PPAR modulators have not shown cardiovascular benefit thus far.

Conclusions:

• Targeting TRLs, particularly those decreasing ApoB, may offer clinical benefits for high-risk phenotypes with residual CVD risk.
• Ongoing clinical trials are crucial to determine the cardiovascular protective effects of emerging TG-lowering therapies.
• These findings may inform future guidelines for managing residual CVD risk.