Elsevier

La Presse Médicale

Volume 47, Issue 9, September 2018, Pages 757-763
La Presse Médicale

Update
Is hypertriglyceridemia atherogenic?L’hypertriglycéridémie est-elle athérogène ?

https://doi.org/10.1016/j.lpm.2018.08.009Get rights and content

Key points

ASCVD reduction is based on LDL reduction, especially by statins.

Highly elevated TG could be harmful, especially because of the risk of pancreatitis.

Elevation of TG is mainly due to metabolic disorders and diabetes, alcohol intake and overweight. Genetic factors have been clearly identified in the most severe cases.

TG have been generally considered as bystanders for cardiovascular diseases (CVD).

Both biological and basic research provide strong data suggesting that TG-rich lipoproteins could be involved in the pathophysiology of CVD.

Recent epidemiological and genetics studies strongly corroborate the causal role of TG in CVD.

This paves the way for new approaches in the management of patients both for primary and secondary prevention.

Points essentiels

La prévention de la maladie athéroscléreuse est fondée sur la réduction du taux de LDL, particulièrement par l’utilisation de statines.

Des taux élevés de triglycérides (TG) peut être dangereuse, en particulier à cause du risque de pancréatite.

L’augmentation des TG est principalement liée aux anomalies métaboliques et au diabète, la consommation d’alcool et le surpoids. Des facteurs génétiques ont été identifiés dans les cas les plus sévères.

Les TG sont généralement considérés comme des témoins des maladies cardiovasculaires.

Les approches biologiques et la recherche fondamentale apportent des démonstrations suggérant que les lipoprotéines riches en TG pourraient être impliquées dans la physiopathologie des maladies cardiovasculaires.

Des études épidémiologiques et génétiques récentes confortent puissamment le rôle causal des TG dans les maladies cardiovasculaires.

Cela prépare le terrain pour des nouvelles approches thérapeutiques en prévention primaire et secondaire.

Introduction

Atherosclerosis is usually considered as a complex pathophysiological phenomenon involving dyslipidemia, oxidative stress, inflammation [1], etc. Among lipids, cholesterol has been identified for decades as an actor of atherosclerosis, in spite of recent controversies especially in our country [2]. Low-density lipoprotein (LDL) has been clearly identified as the main component determining cardiovascular disease (CVD) risk, with various types of evidences including notably the observation of patients with familial hypercholesterolemia with high LDL levels and premature atherosclerotic cardiovascular disease (ASCVD), leading to the Nobel Prize award to Brown and Goldstein in 1985 and the development of statins [3]. Above all, many large, randomized, double blind trials particularly with statins demonstrated that LDL reduction lead to reduce both LDL cholesterol and clinical events such as ASCVD and all-cause mortality [4].

For all these reasons, in clinical practice, the physician focuses on cholesterol, and more especially LDL cholesterol, because its role has been well established. Further, international guidelines clearly recommend management of dyslipidemia depending on the only plasmatic LDL cholesterol level.

However, not only initial data form the beginning of the lipids story, but also more recent studies suggest that other lipids, including Triglycerides-(TG) rich lipoproteins could be of importance. All together, these data suggest that these lipoproteins are not only bystanders to low high-density lipoproteins (HDL), but could also be actors involved in active pathophysiological pathways of atherosclerosis.

From a clinical point-of-view, the most important is to control and treat a cause of disease. Statins and other treatments lowering LDL have largely demonstrated clinical benefit, corroborating the importance of LDL in the pathophysiology, as a mirror. By contrast, there is no evidence that lowering TG-rich lipoproteins could provide clinical benefit. Importantly, several studies are currently ongoing on this topic.

Section snippets

Definitions

Figure 1 presents briefly what is measured. Remnant cholesterol can be estimated as: “total cholesterol – LDL cholesterol – HDL cholesterol”. When plasmatic level of TG is above >4 g/L, LDL cholesterol has to be directly measured.

In the fasting state, remnant cholesterol is mainly present in very low-density lipoprotein (VLDL) and intermediate-density lipoprotein, whereas in the non fasting state, cholesterol is also included in chylomicron remnants.

As TG are the main component of chylomicrons

Preliminary pathophysiological considerations

TG can be used for metabolic functions in all the cells, by contrast with CT (cholesterol). When increased, CT accumulates leading to the deposits in several organs, remaining the well-known cause for ASCVD. CT but not TG has been evidenced in plaques for decades. This is one of the main reasons why TG had not been suspected in ASCVD. Recently, pathophysiological considerations have moved to at least consider TG as a marker of high levels of cholesterol in TG-rich lipoproteins. The question

High TG and the risk of pancreatitis

Hypertriglyceridemia has many multifactorial causes summarized in the figure 2 [5]. Alcohol consumption, high fat intake and hyperglycemia have been identified as possibly reversible causes of elevated TG. As a consequence, lifestyle conditions have to be modified as first treatment. Independently of the CV risk, the risk of pancreatitis has to be underlined, justifying the dosage of TG per se. Indeed, the cardiologist has to keep in mind the significant risk of pancreatitis in case of severely

Historical point-of-view

Figure 3 presents the point-of view of the authors [6] on the common concepts on lipoproteins. Importantly, initially before the 90s, both LDL and TG were considered to have a significant role in the ASCVD, because of the post-prandial observations. Hence, it was considered important to treat in parallel both elevated TG and CT. Thereafter, a great interest has raised on elevated LDL and guidelines largely ignored mild-to-moderately elevated TG, even if some guidelines propose additional tables

Pathophysiology

TG could be involved at various levels in the pathophysiology of ASCVD, as shown in figure 6.

TG enter easily into the arterial intima, in the heart of the atherosclerotic plaque. It should be noticed that isolated elevated plasmatic TG levels do not induce ASCVD. Indeed, patients with chylomicronemia syndrome (leading to severe hyper TG) caused by lipoprotein lipase deficiency, do not present ASCVD. TG could then trigger various pathways. TG are hydrolyzed mainly by the lipoprotein lipase (LPL)

New genetics data

Various genetics approaches provide strong evidence supporting the causal role of TG in ASCVD [20]. Genetics approaches and evidences are extensively presented elsewhere [21]. Indeed, large-scale meta-analyses of cohorts and population-based sequencing studies have investigated if some variants in genes could be determinants of plasma TG levels and associated with ASCVD. Some candidates are clearly identified, including: lipoprotein lipase and proteins that interact with it, such as

Clinical trials

Until now, there are no strong data from clinical trials supporting the interest to treat TG for controlling the CVD. The main reason is that no trial evaluated the strategy of reducing TG-rich lipoproteins on ASCVD and all-cause mortality, in patients with elevated TG, except one [23]. Above all, the efficacy of statins in various trials overshadowed the potential interest of strategies targeting TG. Trials with fibrates could provide promising information when subgroups are considered.

Conclusions

TG are of importance for the management of patients. The cardiologist has to keep in mind that LDL alone cannot be the Holy Grail for ASCVD management (both in primary and secondary prevention). New data from biology and basic research but also from epidemiology, genetics and preliminary clinical trials are consistent to support the hypothesis that TG-rich lipoproteins could be causal factors for ASCVD. Here, we briefly presented these data and presently growing interest leading to large trials

Disclosure of interest

conflicts of interest as regards to the field of lipids in CVD: F.R. declares honoraria from M.S.D., Amgen, Sanofi. A.S. declare honoraria from M.S.D., Amgen, Sanofi.

M.A. received research grants from Edwards Lifescience and Medtronic.

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