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2 June 2020
Insights from the Women’s Health Study: Cholesterol in triglyceride-rich lipoproteins strongly associates with incident cardiovascular disease

Results from a prospective case-cohort study within the Women’s Health Study show that the cholesterol content of triglyceride-rich lipoproteins (TRLs) influences atherogenesis independently of low-density lipoprotein cholesterol.

Duran EK, Aday AW, Cook NR et al. Triglyceride-rich lipoprotein cholesterol, small dense LDL cholesterol, and incident cardiovascular disease. J Am Coll Cardiol 2020; 75:2122–35.
Summary
Comments & References
STUDY SUMMARY
Objective: To evaluate whether cholesterol deriving from TRLs and small dense low-density lipoprotein (sdLDL) is atherogenic across different vascular beds among healthy subjects
Study design: Prospective case-cohort study within the Women’s Health Study, a completed randomized trial of aspirin and vitamin E in the primary prevention of cardiovascular disease (CVD) and cancer.
Study population: The Women’s Health Study enrolled 39,876 female health professionals aged ≥45 years. This case-cohort study planned to include 500 CVD cases and controls stratified by age at enrolment and baseline smoking status. After accounting for missing key exposure data, the final study sample comprised 480 women with incident CVD and 496 matched controls.
Primary variable: Key endpoints: myocardial infarction (MI), ischemic stroke, peripheral artery disease (PAD), a composite of coronary and cerebral vascular disease (i.e. nonfatal MI, nonfatal ischaemic stroke, and death from CV causes), and total CVD events.
Methods: TRL-C and sdLDL-C were measured in baseline blood samples of cases and controls. Associations between these lipid variables and total CVD, coronary and cerebrovascular disease, and individual outcomes were evaluated using Cox proportional hazards models adjusted for traditional risk factors, LDL cholesterol (LDL-C), and high-sensitivity C-reactive protein.
Results:

Baseline TRL-C and sdLDL-C concentrations were higher in cases than controls (Table 1).

 

Table 1. Baseline lipid levels (mg/dL); geometric mean (95% confidence interval, CI)

 

Cases

Controls

 

MI

Ischemic stroke

PAD

TRL-C

55.4

(51.5 to 59.6)

47.8

(44.2 to 51.7)

50.3

(45.8 to 55.3)

39.6

(37.5 to 41.9)

sdLDL-C

49.0

(46.1 to 52.1)

42.6

(39.8 to 45.5)

41.2

(38.0 to 44.8)

35.3

(33.6 to 37.1)

 

TRL-C was significantly associated with MI and PAD, whereas sdLDL-C was significantly associated with MI alone (Table 2). Association patterns were similar for continuous exposures and, for TRL-C, among subjects with low atherogenic particle concentrations (apolipoprotein B <100 mg/dL).

 

Table 2. Association between lipids and CVD events

Lipid/endpoint

Hazard ratio (95% CI)*

p-value

TRL-C

 

 

Total CVD

1.87 (1.14–3.06)

0.013

Coronary and cerebrovascular disease

1.79 (1.04–3.07)

0.036

MI

3.05 (1.46–6.39)

0.002

Ischaemic stroke

1.31 (0.65–2.65)

0.453

PAD

2.58 (1.18–5.63)

0.019

 

 

 

SdLDL-C

 

 

Total CVD

1.67 (0.95–2.94)

0.025

Coronary and cerebrovascular disease

1.82 (0.97–3.39)

0.021

MI

3.71 (1.59–8.63)

<0.001

Ischaemic stroke

1.35 (0.58–3.13)

0.313

PAD

1.60 (0.67–3.83)

0.154

* For quartile 4 vs. quartile 1 (reference).

Median (range) for TRL-C 21.0 (<28.0) mg/dL for quartile 1 and 76 (>61.0) mg/dL for quartile 4. Median (range) for sdLDL-C 22.0 (<27.0) mg/dL for quartile 1 and 64 (>51.0) mg/dL for quartile 4.
Authors’ conclusion: TRL-C strongly associates with future MI and PAD events, whereas sdLDL-C strongly associates with MI alone. These findings signal that the cholesterol content of TRLs and sdLDL influence atherogenesis independently of LDL-C and hs-CRP, with potentially different potency across vascular beds.

COMMENT

Despite guideline-recommended treatment, including statins, ezetimibe and highly efficacious therapy to lower LDL-C, a high residual cardiovascular risk persists in individuals at high risk, as highlighted previously by the Residual Risk Reduction Initiative (1). Among the contenders for contributors to the lipid-related component of this residual risk, attention has focused on atherogenic dyslipidemia, characterized by the triad of reduced levels of high-density lipoprotein cholesterol (HDL-C), and elevations in TRLs and sdLDL particles (1,2). 

Mendelian randomization studies, genetic analyses and observational data have shown a causal role for TRLs in ischemic heart disease (3). There are, however, limited data for an association with other vascular territories such as PAD. Moreover, there has been discussion whether the cholesterol content of TRL (TRL-C or remnant cholesterol) is similarly atherogenic as that associated with LDL (4,5).

This analysis evaluated these questions using data from the Women’s Health Study. The results showed that increased levels of TRL-C  were associated with increased risk of incident CVD across multiple vascular territories, by about 2-fold for total CVD and coronary and cerebral vascular disease, 3-fold for MI, and 2.5-fold for PAD. The cholesterol contained in sdLDL-was not, however, significantly associated with PAD or ischemic stroke. The findings also reaffirm that it is the cholesterol content of TRL – and not TG - that are associated with CV risk. Taken together, the results of this study provide a basis for ongoing trials evaluating novel therapeutics that target elevated TG, a surrogate for TRL-C. An important study is PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in patients with Diabetes) (6), which is evaluating the effects of pemafibrate not only on fatal and nonfatal coronary and stroke events (the primary composite endpoint) but also on incident PAD as a key secondary endpoint. Thus, PROMINENT will provide critical information regarding the impact of reducing TRL-C across multiple vascular territories to reduce residual cardiovascular risk.

References

1. Fruchart JC, Sacks FM, Hermans MP, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patient. Diab Vasc Dis Res 2008;5:319–35.

2. Fruchart JC, Davignon J, Hermans MP, et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014 Jan 24;13:26.

3. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.

4. Lawler PR, Akinkuolie AO, Chu AY, et al. Atherogenic lipoprotein determinants of cardiovascular disease and residual risk among individuals with low low-density lipoprotein cholesterol. J Am Heart Assoc 2017;6:e005549.

5. Fruchart JC, Santos RD, Aguilar-Salinas C, et al. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential : A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation. Cardiovasc Diabetol 2019;18(1):71.

6. Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018;206:80-93.

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