Triglyceride-rich lipoprotein cholesterol and small-dense LDL-c differently associated with future CV events

Triglyceride-Rich Lipoprotein Cholesterol, Small Dense LDL Cholesterol, and Incident Cardiovascular Disease

Literature - Duran EK, Aday AW, Cook NR et al., - J Am Coll Cardiol. 2020. doi: 10.1016/j.jacc.2020.02.059.

Introduction and methods

Lowering of LDL-c has a clear and well-defined benefit for atherosclerosis prevention [1,2]. Nevertheless, identification of other lipid targets that may be responsible for residual atherosclerotic risk remains a priority [3]. Previous studies have described strong associations between triglyceride-rich lipoprotein cholesterol (TRL-c) and small-dense low-density lipoprotein cholesterol (sdLDL-c) with incident coronary heart disease (CHD) [3-9]. Prospective data for TRL-C and sdLDL-c is however sparse for stroke and absent for peripheral artery disease (PAD) [10-12]. This case-cohort study evaluated whether TRL-c and sdLDL-c are atherogenic across different vascular beds among healthy subjects in the Womens Health Study (WHS).

The WHS is a completed randomized trial of aspirin and vitamin E in the primary prevention of CVD and cancer among 39,876 women aged ≥54 years [13,14]. Blood samples were available from 27,552 participants. The trial began in 1992 and was completed in 2004, after which women were invited to participate in observational follow-up. Participants were continuously followed for occurrence of incident myocardial infarction (MI), ischemic stroke (IS), CV death and PAD during a 15.7-year follow-up period. The study sample for the current study consisted of 480 women with incident total CVD (n-coronary and cerebrovascular disease [CCVD]=380, nPAD=114) and a subcohort of 496 women frequency-matched on age and smoking status. Risk associations were evaluated for the composite outcome of total CVD (MI, IS, PAD and CVD death), a composite outcome of CCVD (defined as MI, IS or CVD death), and individual outcomes (MI, IS, or PAD).

Main results

  • High TRL-c levels (in quartile [Q] 4) were associated with increased risk of total CVD, CCVD, MI and PAD after adjustment for CVD risk factors, baseline total LDL-c and hsCRP compared to TRL-c in Q1 (Total CVD: HR 1.87, 95%CI 1.14-3.06, P=0.013; CCVD: HR 1.79, 95%CI 1.04-3.07, P=0.036; MI: HR 3.05, 95%CI 1.46-6.39, P=0.002; PAD: HR 2.58, 95%CI 1.18-5.63, P=0.019). No significant association was found for IS.
  • The adjusted HR’s for total CVD and CCVD with elevated sdLDL-c levels (in Q4) were 1.67 (95%CI 0.95-2.95, P=0.025) and 1.82 (95%CI 0.97-3.39, P=0.021), respectively. These HR’s seemed to be mainly driven by an increased risk of MI (adjusted HR 3.71, 95%CI 1.59-8.63, P<0.001). No significant associations were found for IS and PAD.
  • Association patterns for TRL-c and sdLDL-c were similar when evaluated on a continuous scale.
  • Associations between TRL-c and CV events were also consistent when stratified by Apolipoprotein B levels (<100 mg/dl or ≥100 mg/dl).


Elevated TRL-c levels were associated with increased risk of MI and PAD, even among subjects with clinically normal Apolipoprotein B levels. Elevated sdLDL-c levels were associated with increased risk of MI alone. These findings are relevant for understanding residual CV risk and for finding novel targets for atherosclerosis prevention.

Editorial comment

In their editorial comment [15], Watts and Chan describe that several observational studies have shown that TRLs predict CVD events independent of LDL-c and that the causal role of TRLs have been confirmed by Mendelian randomization studies [16-18]. Independent effects of sdLDL on CVD events are present [19], but not as convincing as for TRLs [16]. The present study showed an association between TRL-c, but not sdLDL-c, with PAD. TRLs may have greater lipotoxicity and sub-endothelial retention that trigger inflammatory responses [16,20], which could explain the stronger association of TRL-c with PAD, than sdLDL-c. However, recent evidence suggests that all apoB containing lipoproteins are equally atherogenic [16,21,22].

LDL, TRL, and apoB are tightly correlated. This makes is very difficult to statistically address the independent contribution of each exposure to CVD outcomes. This issue is not overcome by the design of the present study. Furthermore, the present study was limited to women in primary prevention. Further studies will be necessary to confirm whether similar findings apply to men and people of different ethnicities. Moreover, predictive studies in high-risk patients on best standard of care are particularly relevant, according to Watts and Chan.

In risk assessment, hypertriglyceridemia, non-HDL-c and apoB may be useful risk enhances, for instance in the decision to initiate a statin (in patients with borderline or intermediate-risk) or whether other therapies should be added to maximally tolerated statins (in high-risk patients). Non-HDL-c and apoB have been proposed as treatment targets, secondary to LDL-c [23,24]. However, at present there is no hard evidence that treatments targeted at TRL-c, apoB or LDL particles specifically reduce CVD events and health care expenditure beyond reduction in LDL-c [24-26]. The benefits of TRL-c and sdLDL-c measurements should be demonstrated not only in observational studies, but also in interventional studies, according to the authors. In a broader context, several determinants of residual ASCVD risk need to be addressed, such as age, family history, smoking, hypertension, and diabetes. Furthermore, use of biomarkers of inflammation, coagulation, platelet function, and oxidative stress, as well as genetic indices are also relevant in the context of precision medicine [27-29].


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