What is the relationship between hypertriglyceridemia and coronary artery disease?

Hypertriglyceridemia and Coronary Artery Disease

Hypertriglyceridemia is independently associated with increased coronary artery disease risk, though this association is partially attenuated when adjusted for other cardiovascular risk factors, and elevated triglycerides serve as a marker for multiple atherogenic abnormalities including remnant cholesterol particles and the atherogenic lipoprotein phenotype. 1

Pathophysiological Mechanisms

Triglyceride-rich lipoproteins (TRLs) and their remnant particles are directly atherogenic. 2 When triglycerides are elevated, there is an increase in remnant cholesterol particles that are causally linked to atherosclerosis. 1 The atherogenic mechanisms include:

• Small, dense LDL particles form when triglycerides are elevated, which are more susceptible to oxidation and more atherogenic than large, buoyant LDL particles 2
• Increased remnant lipoproteins accumulate and contribute directly to plaque formation 1
• The "lipid triad" (elevated triglycerides, low HDL-C, small dense LDL) represents a particularly atherogenic profile 2, 3

Epidemiological Evidence and Risk Quantification

Approximately 31% of US adults have triglyceride levels ≥150 mg/dL, with the American Heart Association suggesting optimal levels should be <100 mg/dL. 1 The relationship between triglycerides and CAD shows:

• Primary isolated hypertriglyceridemia (triglycerides ≥500 mg/dL) increases coronary heart disease risk by 53% (HR 1.53,95% CI 1.06-2.20) after adjustment for conventional cardiovascular risk factors 4
• The association is stronger in certain subgroups, particularly women aged 50-69 years and patients with diabetes 5
• Elevated triglycerides were associated with myocardial infarction and stroke risk in NHANES III 2
• The "hypertriglyceridemic waist" phenotype (elevated triglycerides plus increased waist circumference) shows strong association with angiographic CAD 2

Clinical Context and Confounding Factors

The independent effect of triglycerides on CAD risk remains somewhat controversial because hypertriglyceridemia clusters with multiple other metabolic abnormalities. 6, 5 Important considerations:

• In metabolic syndrome, other factors (low HDL-C, elevated glucose, elevated blood pressure) independently predicted CVD and all-cause mortality more strongly than triglycerides alone in randomized controlled trials 2
• The heterogeneity of triglyceride-rich lipoproteins matters: larger particles are not associated with CAD risk, whereas smaller, denser particles are atherogenic 5
• Triglycerides function as a "risk-enhancing factor" in primary ASCVD prevention according to 2018 AHA/ACC guidelines 1

Risk Stratification by Triglyceride Level

Different triglyceride thresholds carry distinct clinical implications:

• Normal: <150 mg/dL 1
• Borderline high: 150-199 mg/dL - associated with atherosclerotic risk 1
• High: 200-499 mg/dL - more strongly associated with atherosclerotic risk 1
• Very high: ≥500 mg/dL - primary concern shifts to pancreatitis risk, though CAD risk remains elevated 1, 6

Treatment Evidence and CAD Outcomes

Statin trials show benefit in patients with hypertriglyceridemia when LDL-C merits treatment, with subgroups having elevated baseline triglycerides showing increased CVD risk in 4S, CARE, WOSCOPS, AFCAPS/TexCAPS, and TNT studies. 2 However:

• Each 89-mg/dL decrease in on-treatment triglyceride level with pravastatin decreased CVD risk by 11% in the LIPID trial 2
• Fibrates show greater benefit in subgroups with increased triglyceride levels in the Helsinki Heart Study and Bezafibrate Infarction Prevention study 2
• High-dose icosapent ethyl (REDUCE-IT trial) added to statin therapy led to significant ASCVD event reduction in patients with elevated triglycerides 1

Clinical Management Implications

Non-HDL cholesterol should be assessed as a secondary treatment target when triglycerides ≥200 mg/dL persist after achieving LDL-C goals, with the non-HDL-C target set 30 mg/dL higher than the LDL-C target. 2 This approach captures the atherogenic burden of all apolipoprotein B-containing particles. 2

Awareness and control of primary isolated hypertriglyceridemia remain inadequate: only 60% have the diagnosis recorded, 46% receive lipid-lowering medication for primary prevention, and only 24.1% achieve triglyceride levels <150 mg/dL. 4

Common Pitfalls

• Do not dismiss hypertriglyceridemia as merely a marker - the association with CAD persists even after adjustment for other risk factors, supporting a causal role 4
• Do not ignore triglycerides in patients already on statins - elevated triglycerides represent residual cardiovascular risk despite statin therapy 1
• Do not assume all triglyceride-rich particles are equally atherogenic - smaller, denser remnant particles drive the risk 5
• Do not overlook secondary causes including diabetes, hypothyroidism, medications (beta-blockers, thiazides, estrogens), and excessive alcohol intake 2, 6