Does Isolated Hypertriglyceridemia Cause Coronary Artery Disease?
Yes, isolated hypertriglyceridemia is an independent risk factor for coronary artery disease, though the evidence for direct causation remains debated and the relationship is complex. 1
Evidence for Independent Risk
Borderline high (150-199 mg/dL) and high (≥200 mg/dL) triglyceride levels have been established as independent risk factors for coronary heart disease through meta-analyses of prospective studies. 1, 2, 3
Patients with elevated triglyceride levels are at increased risk of atherosclerotic cardiovascular disease (ASCVD) events, as demonstrated in multiple clinical trials including the Scandinavian Simvastatin Survival Study (4S). 1
In the PROVE IT-TIMI 22 trial, on-treatment triglyceride levels <150 mg/dL were independently associated with lower risk of recurrent coronary heart disease events (HR: 0.80; 95% CI: 0.66-0.97; P = 0.025) even after adjustment for other factors. 1
Mechanistic Pathways Supporting Causation
Triglyceride-rich lipoproteins (TRLs) possess several atherogenic properties: 1
TRLs contain apolipoprotein B and cholesteryl esters, similar to classic atherogenic LDL particles. 1
Remnant lipoproteins (by-products of TRLs) can lead to foam cell formation in vessel walls analogous to modified LDL. 1
Lipoprotein lipase action on TRLs releases fatty acids in microcapillary beds, which can trigger pathophysiological responses in macrophages and endothelial cells. 1
Apolipoprotein CIII contained in TRLs promotes pro-atherogenic responses in both macrophages and endothelial cells. 1
TRLs have been directly associated with measures of coronary atherosclerosis in human observational studies. 1
The Complexity and Confounding Factors
Much of the association between triglycerides and coronary artery disease risk is related to clustering with other atherogenic factors: 1
Hypertriglyceridemia commonly coexists with diabetes, obesity, hypertension, high LDL cholesterol, and low HDL cholesterol. 1
Hypertriglyceridemia is often found with abnormalities in hemostatic factors. 1
The metabolic consequences of hypertriglyceridemia include formation of small, dense LDL particles and reduced HDL cholesterol through cholesteryl ester transfer protein-mediated exchange. 1
The heterogeneity of triglyceride-rich lipoproteins complicates the relationship: 4
Larger triglyceride-rich particles are thought not to be associated with coronary artery disease risk. 4
Smaller, denser particles are believed to be atherogenic. 4
Clinical Implications for Treatment
Despite the independent association, treatment decisions should prioritize LDL cholesterol as the primary target: 1, 2
In primary prevention patients with 10-year ASCVD risk ≥7.5% to <20%, persistent hypertriglyceridemia supports initiating moderate-intensity statin therapy (Class IIa recommendation). 1
For individuals with 10-year ASCVD risk 5% to <7.5% and persistent hypertriglyceridemia, patient-clinician discussion regarding moderate-intensity statin therapy is recommended (Class IIb recommendation). 1
After achieving LDL cholesterol goals, non-HDL cholesterol becomes the secondary target when triglycerides are ≥200 mg/dL, with a goal of <130 mg/dL. 1, 3
The evidence that lowering triglycerides alone improves cardiovascular outcomes beyond addressing LDL cholesterol remains insufficient. 2
Important Clinical Caveats
Triglyceride measurements vary considerably for individual patients, so decisions should not be based on a single measurement. 1, 2
The data for an independent association between triglyceride concentrations and coronary artery disease risk are equivocal, unlike the strong, consistent data for LDL and HDL cholesterol. 4
It remains controversial how much isolated hypertriglyceridemia correlates directly with coronary artery disease, and whether treatment for this condition alone leads to meaningful clinical outcomes requires further study. 5
Triglyceride overload is not a classic pathological feature of human atherosclerotic lesions, as the end product (free fatty acids) serves as an active energy source rather than accumulating in plaques. 1