Elevated LDL Triglycerides and Atherosclerotic Risk

Mie Balling, MD; Shoaib Afzal, MD, PHD, DMSC; George Davey Smith, MD, DSC; Anette Varbo, MD, PHD; Anne Langsted, MD, PHD; Pia R. Kamstrup, MD, PHD; Børge G. Nordestgaard, MD, DMSC

Disclosures

J Am Coll Cardiol. 2023;81(2):136-152.

Abstract and Introduction

Abstract

Background: It is unclear whether elevated low-density lipoprotein (LDL) triglycerides are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD).

Objectives: This study tested the hypothesis that elevated LDL triglycerides are associated with an increased risk of ASCVD and of each ASCVD component individually.

Methods: 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.

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).

Conclusions: 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.

Introduction

Elevated low-density lipoprotein (LDL) triglycerides may be associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and each ASCVD component individually.^[1–6] Related to this, elevated triglyceride-rich remnant lipoproteins are robustly associated with an increased risk of ASCVD in both mendelian randomization and conventional observational studies.^[7–12] These 2 observations may be tied together, with elevated LDL triglycerides as a marker of high concentrations of triglyceride-rich remnant lipoproteins, because cholesteryl ester transfer protein during hypertriglyceridemia transfers cholesteryl esters from LDL in exchange for triglycerides from triglyceride-rich remnant lipoproteins, thus leading to elevated levels of LDL triglycerides.^[13,14] Alternatively, elevated LDL triglycerides themselves may directly cause ASCVD, if triglycerides are degraded locally to tissue-toxic free fatty acids after LDL particles enter the intima, thereby leading to atherosclerosis with vulnerable plaques ultimately causing ASCVD and its components of ischemic heart disease, myocardial infarction, ischemic stroke, and peripheral artery disease.^[2,4,11,15] It is, however, unclear whether elevated LDL triglycerides are robustly associated with an increased risk of ASCVD and of each ASCVD component individually.

We tested the hypothesis that elevated LDL triglycerides are associated with an increased risk of ASCVD and each of its components individually, that is, ischemic heart disease, myocardial infarction, ischemic stroke, and peripheral artery disease. To do so, we conducted 2 prospective studies within the Copenhagen General Population Study. The first study included 38,081 individuals with direct LDL triglycerides measured on fresh samples using an automated assay from Denka (direct LDL triglycerides), whereas the second study included another 30,208 individuals with nuclear magnetic resonance (NMR) LDL triglycerides measured on samples that had been frozen (NMR LDL triglycerides). We included the 2 different studies to document the association in 2 different settings with different assays, to strengthen inference. Moreover, the associations between elevated LDL triglycerides and the risk of ASCVD and each ASCVD component individually were aggregated in meta-analyses adding 6 previous studies to our current data, totaling >110,000 individuals and >15,000 events.

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Table 1. Baseline Characteristics of Subpopulations in the Copenhagen General Population Study
	Individuals With Direct LDL Triglyceride Measurement	Individuals With NMR LDL Triglyceride Measurement
Number	38,081	30,208
Age, y	60 (51–70)	63 (52–73)
Women	21,217 (56)	15,416 (51)
Smokers	4,337 (11)	7,146 (24)
Systolic blood pressure, mm Hg	138 (125–153)	140 (129–157)
Lipid-lowering therapy	5,796 (15)	4,274 (14)
Atrial fibrillation	1,521 (4)	1,429 (5)
Direct LDL triglycerides
mmol/L	0.23 (0.19–0.29)	N/A
mg/dL	21 (17–26)	N/A
NMR LDL triglycerides
mmol/L	N/A	0.29 (0.25–0.34)
mg/dL	N/A	26 (22–31)
LDL cholesterol
mmol/L	2.9 (2.3–3.6)	3.2 (2.6–3.9)
mg/dL	113 (90–139)	124 (101–151)
Plasma total triglycerides
mmol/L	1.4 (0.94–2.0)	1.5 (1.0–2.2)
mg/dL	120 (83–179)	132 (91–194)
Plasma total cholesterol
mmol/L	5.2 (4.5–5.9)	5.6 (4.9–6.4)
mg/dL	201 (174–228)	217 (190–248)
Remnant cholesterol
mmol/L	0.61 (0.43–0.89)	0.67 (0.47–0.99)
mg/dL	24 (16–34)	26 (18–38)
Apolipoprotein B
g/L	0.97 (0.8–1.2)	1.1 (0.9–1.3)
mg/dL	97 (80–117)	110 (90–134)
HDL cholesterol
mmol/L	1.48 (1.15–1.86)	1.55 (1.22–1.92)
mg/dL	57 (45–72)	60 (47–74)

Values are median (IQR) or n (%), unless otherwise indicated. Number of individuals in most parameters varies slightly according to availability of data.
HDL = high-density lipoprotein; LDL = low-density lipoprotein; N/A = not available; NMR = nuclear magnetic resonance.

Table 2. Correlation of LDL Triglycerides With Other Lipids, Lipoproteins, and Apolipoproteins
RCoefficients of Determination (R²)	Direct LDL Triglycerides	NMR LDL Triglycerides	LDL Cholesterol	Plasma Total Triglycerides	Plasma Total Cholesterol	Remnant Cholesterol	Apolipoprotein B	HDL Cholesterol
Direct LDL Triglycerides		N/A	0.33	0.37	0.34	0.37	0.44	−0.19
NMR LDL Triglycerides	N/A		0.56	0.62	0.71	0.62	0.74	−0.08
LDL Cholesterol	11%	31%		0.21	0.88	0.22	0.76	−0.08
Plasma Total Triglycerides	14%	38%	4%		0.26	0.98	0.62	−0.49
Plasma Total Cholesterol	11%	50%	78%	7%		0.27	0.73	0.23
Remnant Cholesterol	14%	38%	5%	96%	7%		0.62	−0.50
Apolipoprotein B	19%	58%	58%	39%	53%	39%		−0.29
HDL Cholesterol	4%	0.6%	0.6%	24%	5%	25%	8%

Number of individuals in most parameters varies slightly according to availability of data. All P values are <0.001.
Abbreviations as in Table 1.

Authors and Disclosures

Mie Balling, MD^a,b,c, Shoaib Afzal, MD, PHD, DMSC^a,b,c, George Davey Smith, MD, DSC^d,e, Anette Varbo, MD, PHD^a,b,c, Anne Langsted, MD, PHD^a,b,c, Pia R. Kamstrup, MD, PHD^a,b and Børge G. Nordestgaard, MD, DMSC^a,b,c

^aDepartment of Clinical Biochemistry, Copenhagen University Hospital, Herlev and Gentofte Hospital, Herlev, Denmark; ^bThe Copenhagen General Population Study, Copenhagen University Hospital, Herlev and Gentofte Hospital, Herlev, Denmark; ^cDepartment of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; ^dMRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, United Kingdom; and the ^ePopulation Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Address for Correspondence
Dr Børge G. Nordestgaard, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls vej 73, DK-2730 Herlev, Denmark. E-mail: boerge.nordestgaard@regionh.dk.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

Funding Support and Author Disclosures
This study was funded by the Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital; the Danish Heart Foundation (grant 18-R124-A8511-22089 MB); the Novo Nordisk Foundation (grant NNF18OC0052893 MB); and the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (grant MC_UU_00011/1 GDS). The funders did not participate in the design or conduct of the study; in the collection, analysis, or interpretation of data; and in preparation, review, or approval of the manuscript. Dr Davey Smith has served on the scientific advisory boards of Relation Therapeutics and insitro. Dr Varbo is employed by Novo Nordisk. Dr Kamstrup has received lecture honoraria from Physicians' Academy for Cardiovascular Education; and has served as a consultant for Silence Therapeutics and Novartis. Dr Nordestgaard has served as a consultant for Akcea, Amarin, Amgen, AstraZeneca, Abbott, Denka, Kowa, Novartis, Novo Nordisk, Sanofi, Regeneron, Esperion, and Silence Therapeutics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.