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It is unclear whether elevated low-density lipoprotein (LDL) triglycerides are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD).
This study tested the hypothesis that elevated LDL triglycerides are associated with an increased risk of ASCVD and of each ASCVD component individually.
The study investigators used the Copenhagen General Population Study, which measured LDL triglycerides in 38,081 individuals with a direct automated assay (direct LDL triglycerides) and in another 30,208 individuals with nuclear magnetic resonance (NMR) spectroscopy (NMR LDL triglycerides). Meta-analyses aggregated the present findings with previously reported results.
During a median follow-up of 3.0 and 9.2 years, respectively, 872 and 5,766 individuals in the 2 cohorts received a diagnosis of ASCVD. Per 0.1 mmol/L (9 mg/dL) higher direct LDL triglycerides, HRs were 1.26 (95% CI: 1.17-1.35) for ASCVD, 1.27 (95% CI: 1.16-1.39) for ischemic heart disease, 1.28 (95% CI: 1.11-1.48) for myocardial infarction, 1.22 (95% CI: 1.08-1.38) for ischemic stroke, and 1.38 (95% CI: 1.21-1.58) for peripheral artery disease. Corresponding HRs for NMR LDL triglycerides were 1.26 (95% CI: 1.20-1.33), 1.33 (95% CI: 1.25-1.41), 1.41 (95% CI: 1.31-1.52), 1.13 (95% CI: 1.05-1.23), and 1.26 (95% CI: 1.10-1.43), respectively. The foregoing results were not entirely statistically explained by apolipoprotein B levels. In meta-analyses for the highest quartile vs the lowest quartile of LDL triglycerides, random-effects risk ratios were 1.50 (95% CI: 1.35-1.66) for ASCVD (4 studies; 71,526 individuals; 8,576 events), 1.62 (95% CI: 1.37-1.93) for ischemic heart disease (6 studies; 107,538 individuals; 9,734 events), 1.30 (95% CI: 1.13-1.49) for ischemic stroke (4 studies; 78,026 individuals; 4,273 events), and 1.53 (95% CI: 1.29-1.81) for peripheral artery disease (4 studies; 107,511 individuals; 1,848 events).
Elevated LDL triglycerides were robustly associated with an increased risk of ASCVD and of each ASCVD component individually in 2 prospective cohort studies and in meta-analyses of previous and present studies combined.
Disclosure statements are available on the authors' profiles:
Elevated LDL Triglycerides and Atherosclerotic RiskJ Am Coll Cardiol 2023 Jan 17;81(2)136-152, M Balling, S Afzal, G Davey Smith, A Varbo, A Langsted, PR Kamstrup, BG Nordestgaard
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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Low-density lipoprotein (LDL) particles carry cholesterol and triglycerides. There is extensive evidence on the established causal relationship between LDL cholesterol and atherosclerotic cardiovascular disease (ASCVD); however, knowledge on the association of LDL triglycerides with ASCVD is limited. In a recent study by Balling and colleagues based on two subpopulations within the Copenhagen General Population Study, LDL triglycerides were measured using direct assay in 30,081 individuals and nuclear magnetic resonance (NMR) spectroscopy in 30,208 individuals. The median follow-up times were 3.0 and 9.2 years, during which 872 and 5766 individuals developed ASCVD, in the direct assay group and NMR spectroscopy group, respectively. Per 0.1 mmol/L (0.9 mg/dL) higher levels of direct LDL triglycerides and NMR LDL triglycerides were both associated with a 26% higher risk of ASCVD. The corresponding values for the subcomponents of ASCVD were 28% and 33% for myocardial infarction, 22% and 13% for ischemic stroke, and 38% and 26% for peripheral artery disease. Also, meta-analyses of eight studies, comprising >110,000 individuals and >15.000 events, confirmed the association between higher levels of LDL triglycerides and ASCVD and its different subcomponents, showing that individuals in the highest versus the lowest quartile of LDL triglycerides had a higher risk amounting to 50% for ASCVD, 62% for ischemic heart disease, 30% for ischemic stroke, and 53% for peripheral artery disease.
The findings from the study are all observational, and no conclusions regarding causality can be drawn. We speculate on two alternative mechanisms. The first is that high levels of LDL triglycerides might lead to low-grade inflammation in the intima caused by toxic free fatty acids after degradation of triglycerides. The second is that high levels of LDL triglycerides may be a marker of high levels of remnant cholesterol. This is reasonable to speculate on since, during hypertriglyceridemia, a protein called cholesteryl ester transfer protein transfers cholesteryl esters from LDL in exchange for triglycerides from remnants. Future genetic studies are needed to examine whether the relationship between high levels of LDL triglycerides and ASCVD and its subcomponents are causal in nature.
The clinical use of finding a robust association between higher levels of LDL triglycerides and an increased risk of ASCVD and its subcomponents could potentially be an inclusion of LDL triglycerides in the lipid guidelines as an additional marker of increased ASCVD risk, alongside LDL cholesterol, apolipoprotein B, triglycerides, and high-sensitivity C-reactive protein.