Triglyceride-Rich Lipoproteins and Residual Atherosclerotic Risk: A Review of Genetic and Pharmacologic Studies

Abstract

Introduction: Elevated triglycerides (TG) correlate with cardiovascular events even when LDL-cholesterol is well controlled. Whether TG-rich lipoproteins (TRL) and their remnants are causal or merely bystanders remains contentious.
Methods: We performed a literature review of Mendelian randomization (MR) studies and randomized trials of TG-lowering agents (fibrates, omega-3, pemafibrate). Inclusion: adult populations with established CVD or high risk. Outcomes: major adverse cardiovascular events. Exclusion: trials of statins.
Results: 12 MR studies consistently showed that genetic variants affecting lipoprotein lipase function (e.g., LPL, APOA5, APOC3) influence TG levels and CVD risk. Each 1 mmol/L (88 mg/dL) genetically predicted higher TG was associated with OR 1.5 (1.3–1.7) for CVD. In contrast, fibrate trials (n=45,000) showed no significant MACE reduction overall (RR 0.96, 0.90–1.03) except in subgroup with TG >2.3 mmol/L and low HDL. The REDUCE-IT trial (high-dose icosapent ethyl) showed 25% MACE reduction (HR 0.75, 0.68–0.83), but results are debated due to comparator mineral oil effects.
Discussion: Genetic evidence supports causality of TRL remnants. Failure of fibrates may relate to incomplete TG lowering and off-target effects. Icosapent ethyl’s benefit may extend beyond TG reduction to anti-inflammatory effects. Limitations include trial heterogeneity.
Conclusions: TRL remnants are likely causal in atherosclerosis, but currently available TG-lowering drugs do not consistently reduce CVD risk except for high-dose icosapent ethyl in selected patients. Novel therapies targeting APOC3 and ANGPTL3 hold promise.