Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease

Figures & data

Figure 1 Overview of triglyceride-rich lipoprotein metabolism.

Abbreviations: Apo, apolipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LPL, lipoprotein lipase; VLDL, very low-density lipoprotein.

Figure 2 Proposed pathophysiology of triglyceride-rich lipoproteins in the progression of atherosclerosis.

Note: Adapted by permission from Macmillan Publishers Ltd: [Nature Reviews Cardiology] Watts GF, Ooi EM, Chan DC. Demystifying the management of hypertriglyceridaemia. Nat Rev Cardiol. 2013;10(11):648–661,¹²⁶ Copyright © 2013.
Abbreviations: LPL, lipoprotein lipase; TRL, triglyceride-rich lipoproteins; TRL-R, triglyceride-rich lipoprotein remnants.

Table 1 Key studies investigating the association between triglycerides and cardiovascular disease

Study	Population (sample size)	Key findings
ERFC: individual record analysis of 68 long-term prospective studies^Citation64	No prior CHD (n=302,430)	After adjustment for nonlipid risk factors, TG levels were significantly associated with the incidence of CHD (HR 1.37, 95% CI 1.31–1.42). The association was no longer significant after adjustment for HDL-C and non-HDL-C (HR 0.99, 95% CI 0.94–1.05).
Post hoc analysis of two statin trials: IDEAL and TNT^Citation65	CHD and ACS, on potent statin therapy (n=15,779)	Risk of CVE occurring after the first year of the trials increased as a function of increasing on-treatment TG, with patients in the 5th quintile of TG having a 63% increase in events versus patients in the first quintile after adjusting for age and sex (P<0.001). After adjustment for HDL-C and apoB/apoAI, the association was attenuated (P=0.044).
PROVE IT-TIMI 22^Citation10	Hospitalized for ACS, on potent statin therapy (n=4,162)	On-treatment fasting TG <150 mg/dL was associated with a reduction in CHD risk versus high TG (HR 0.73, 95% CI 0.62–0.87; P<0.001). For each on-treatment 10-mg/dL decrement in TG, the incidence of death, MI, and recurrent ACS was lowered by 1.6% or 1.4% after adjustment for LDL-C (P<0.001) or non-HDL-C (P=0.01), respectively.
Prospective Copenhagen City Heart Study: ischemic stroke^Citation66	General population of Denmark (n=13,956)	The cumulative incidence of ischemic stroke increased with increasing levels of baseline nonfasting TG in both sexes (P<0.001). For men, age-adjusted HRs ranged from 1.4 (95% CI 0.9–2.1) in those with baseline TG of 89–176 mg/dL to 3.2 (95% CI 1.7–6.2) in those with TG ≥443 mg/dL versus men with TG <89 mg/dL. For women, HRs ranged from 1.3 (95% CI 1.0–1.8) in those with baseline TG of 89–176 mg/dL to 5.1 (95% CI 1.7–14.8) in those with TG ≥443 mg/dL versus women with TG <89 mg/dL.
Women’s Health Study^Citation67	Healthy US women (n=26,509)	Baseline fasting and nonfasting TG were both strongly associated with CVE. Fasting TG was not significantly associated with CVE after adjustment for TC and HDL-C and measures of insulin resistance. However, nonfasting TG remained significantly associated with CVE after adjustment for TC and HDL-C (P=0.006).
Prospective Copenhagen City Heart Study: MI, IHD, and all-cause mortality^Citation68	General population of Copenhagen, Denmark (n=13,981)	Levels of remnant lipoprotein cholesterol increased with increasing non-fasting TG. The cumulative incidence of MI, IHD, and all-cause mortality increased with increasing nonfasting TG (P<0.001). For men, HRs for MI increased from 1.6 (95% CI 1.1–2.3) for TG of 88.5–176.1 mg/dL to 4.6 (95% CI 2.7–8.0) for TG ≥442.5 mg/dL versus those with TG <88.5 mg/dL. For women, HRs for MI increased from 2.2 (95% CI 1.6–3.2) for TG of 88.5–176.1 mg/dL to 16.8 (95% CI 6.8–41.6) for TG ≥442.5 mg/dL versus those with TG <88.5 mg/dL.
Post hoc analysis of the Framingham Heart Study^Citation119	Participants of the Framingham Heart Study without CVD at baseline (n=3,501)	High plasma TG levels (>150 mg/dL), in the absence of high LDL-C (>130 mg/dL) or low HDL-C (<40 mg/dL) levels, were not significantly associated with an increased risk of CVD events (P=0.13).
ARIC study^Citation120	Participants of the ARIC Study without CVD at baseline (n=12,339)	In women, TG was significantly associated with CHD risk after adjustment for age, race, LDL-C, apoB, apoA-1, and HDL-C subfractions (RR 1.29, P<0.01). However, TG was not significantly associated with CHD risk in men.
PROCAM study^Citation121	Men and women aged 16–65 years (n=19,698)	In a logistic function analysis, log-transformed TG levels showed a significant association with CHD incidence (P<0.01). However, after adjustment for HDL-C, this association was no longer significant.

Abbreviations: ACS, acute coronary syndrome; apo, apolipoprotein; ARIC, The Atherosclerosis Risk in Communities; CHD, coronary heart disease; CI, confidence interval; CVD, cardiovascular disease; CVE, cardiovascular events; ERFC, Emerging Risk Factors Collaboration; HDL-C, high-density lipoprotein cholesterol; HR, hazard ratio; IDEAL, Incremental Decrease in End Points through Aggressive Lipid Lowering; IHD, ischemic heart disease; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; non-HDL-C, non-high-density lipoprotein cholesterol; PROCAM, Prospective Cardiovascular Munster; PROVE IT-TIMI 22, Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22; RR, relative risk; TC, total cholesterol; TG, triglyceride; TNT, Treating to New Targets.

Table 2 Summary of available triglyceride-lowering therapies

TG-lowering agent	Proposed mechanisms of action	Lipid-modifying effects (%)
		TG	Non-HDL-C	HDL-C	LDL-C
Fibrates^Citation2,Citation72,Citation73	Weak agonists of PPAR-α Decrease production of apoC-III Increase LPL expression Increase VLDL, IDL, and LDL apoB100 catabolism Decrease CETP activity Increase HDL2a and HDL3a	−36	−6 to −16	10	−8
Niacin^Citation72,Citation73,Citation122	Decrease TG synthesis Inhibit hepatic DGAT-2 Accelerate hepatic apoB degradation Decrease hepatic secretion of VLDL and LDL Decrease hepatic apoAI catabolism Inhibit removal of HDL-apoAI Inhibit oxidative stress and vascular inflammatory genes	−20	−7 to −39	16	−12
Omega-3 fatty acids (EPA and DHA)^Citation103,Citation105,Citation108,Citation123^–^Citation125	Decrease TG synthesis Inhibit DGAT-2 Increase LPL activity Decrease hepatic lipogenesis Increase hepatic β-oxidation Decrease Lp-PLA2 Decrease apoC-III	−25 to −34	−8	1–3	5–11

Abbreviations: apo, apolipoprotein; CETP, cholesteryl ester transfer protein; DGAT-2, diacylglycerol acyltransferase 2; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HDL, high-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; LPL, lipoprotein lipase; Lp-PLA2, lipoprotein-associated phospholipase A2; non-HDL-C, non-high-density lipoprotein cholesterol; PPARα, peroxisome proliferator-activated receptor alpha; TG, triglyceride; VLDL, very low-density lipoprotein.

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