Nordestgaard 2014: Triglycerides and Cardiovascular Disease

Background

Drs. Børge G. Nordestgaard and Anette Varbo from Copenhagen University Hospital published this comprehensive review in The Lancet (PMID: 25131982), establishing the causal role of triglyceride-rich lipoproteins in cardiovascular disease.

Study Design

Review synthesizing epidemiological evidence, Mendelian randomization studies, and clinical trial data on triglycerides and cardiovascular risk.

Key Findings

Evidence hierarchy for TG-CVD relationship:

Evidence Type	Findings
Observational	Strong, consistent association
Mendelian randomization	Confirms causal relationship
Genetic studies	Variants affecting TG also affect CVD
Treatment trials	TG-lowering reduces events in some studies

Remnant cholesterol (TG-rich lipoprotein cholesterol):

• •Calculated as: Total-C − LDL-C − HDL-C
• •Directly penetrates arterial wall
• •Associated with CVD independent of LDL-C

Mendelian randomization key finding: 1 mmol/L (39 mg/dL) genetic increase in non-fasting TG → 2.8-fold increased CVD risk

Mechanistic Insights

Triglyceride-rich lipoproteins cause atherosclerosis through:

1. •Remnant particles entering arterial intima
2. •Cholesterol deposition from remnants (more pro-inflammatory than LDL)
3. •Activation of inflammatory pathways
4. •Macrophage foam cell formation

Unlike LDL, remnants are taken up by macrophages without oxidation.

Clinical Implications

TG reduction is a valid therapeutic target for CVD prevention. Nonfasting triglycerides are acceptable for risk assessment. Elevated TG should prompt metabolic evaluation.

Metabolic Health Perspective

Triglycerides are a metabolic marker responding dramatically to dietary intervention. Carbohydrate restriction typically produces 40-50% TG reduction within weeks. The TG/HDL ratio integrates this information with HDL response.