Role of Elevated Triglycerides in Heart Disease Development
Elevated triglycerides represent an important biomarker of cardiovascular disease risk primarily through their association with atherogenic remnant particles and apolipoprotein CIII, rather than being directly atherogenic themselves. 1
Pathophysiological Mechanisms
Elevated triglycerides alter lipoprotein metabolism, increasing cardiovascular disease risk through several mechanisms 2:
- Triglyceride-rich lipoproteins (TRLs) including chylomicrons and very low-density lipoproteins contribute to atherogenesis 1, 3
- When triglycerides are elevated, there is an increase in remnant cholesterol particles, which are causally linked to atherosclerosis 1, 3
- High triglycerides are associated with changes in LDL morphology to small, dense particles that are more susceptible to oxidation and therefore more atherogenic 4
- Elevated triglycerides typically coincide with decreased HDL-C levels, creating a particularly high-risk profile 2
Genetic evidence strongly suggests that remnants of triglyceride-rich lipoproteins are causal cardiovascular risk factors, not just markers 3
Epidemiological Evidence
- A long-standing association exists between elevated triglyceride levels and cardiovascular disease, though the direct causality has been debated for decades 1
- Approximately 31% of the adult US population has triglyceride levels ≥150 mg/dL, with varying prevalence among ethnic groups 1
- Current triglyceride classification designates levels as 1:
- Normal: <150 mg/dL
- Borderline high: 150-199 mg/dL
- High: 200-499 mg/dL
- Very high: ≥500 mg/dL
- The American Heart Association now suggests that optimal fasting triglyceride levels should be <100 mg/dL as a parameter of metabolic health 1, 5
Associated Risk Factors
Elevated triglycerides frequently cluster with other cardiovascular risk factors, creating a complex risk profile 2:
Mean triglyceride levels in the United States have risen since 1976, coinciding with the growing epidemic of obesity, insulin resistance, and type 2 diabetes mellitus 1
Clinical Significance
- Despite the use of statin therapy, ASCVD event rates remain high in patients with elevated triglycerides, suggesting they represent a marker of residual cardiovascular risk 1
- Elevated triglycerides are considered a "risk-enhancing factor" in primary ASCVD prevention according to the 2018 AHA/ACC/multisociety cholesterol guideline 1
- The risk appears to be greater for women than men 2
- Very high triglyceride levels (≥500 mg/dL) increase risk for pancreatitis, while moderate elevations (200-499 mg/dL) are more associated with atherosclerotic risk 1, 5
Management Implications
Treatment of elevated triglycerides should focus first on intensive therapeutic lifestyle changes 1:
- Weight reduction (5-10% weight loss can reduce triglycerides by approximately 20%) 1, 5
- Reducing carbohydrate intake, especially added sugars and fructose 1, 5
- Eliminating trans fats and restricting saturated fatty acids 1
- Increasing consumption of marine-based omega-3 products 1
- Regular aerobic physical activity 1
Pharmacological options for triglyceride reduction include 1:
Recent evidence from the REDUCE-IT trial showed that high-dose icosapent ethyl added to statin therapy led to significant reduction in ASCVD events in patients with elevated triglycerides 1
Important Caveats
- While triglyceride levels serve as a biomarker for cardiovascular risk, there is ongoing debate about whether they are directly causal or simply markers of other metabolic abnormalities 5, 6
- Non-HDL-C and apolipoprotein B measurements may be more useful than LDL-C alone in patients with elevated triglycerides, as LDL-C calculations can underestimate cardiovascular risk in these patients 1
- Secondary causes of hypertriglyceridemia should always be ruled out, including uncontrolled diabetes, alcohol consumption, and medications (corticosteroids, estrogens, antipsychotics, antiretrovirals) 5