Triglycerides have long been considered a possible risk factor for atherosclerotic cardiovascular disease. (ASCVD). Trends emerged in early observational surveys (1), supported by later larger prospective studies (2,3). Concomitantly, there was strong interest in high-density lipoprotein cholesterol (HDL-C) as a protective risk factor, supported by extensive epidemiological evidence (4). This focus waned, however, as genetic studies and randomized clinical trials failed to show that raising HDL-C levels reduced cardiovascular events (5-7). Given the strong metabolic interaction with HDL and covariation the stage was set for a resurgence of interest in TG. Genetic studies, particularly those with a Mendelian randomization design, provided new insights into the association between elevated TG and ASCVD (8).
Against this scenario, and with innovative therapies for lowering TG in clinical development, reappraisal of the role of TG in ASCVD was a priority for the European Atherosclerosis Society (EAS) Consensus Panel. Plasma TG is, however, merely a surrogate for estimating the critical lipoproteins – TG-rich lipoproteins and their remnants. Therefore, this latest EAS Statement reviewed what is known about the structure, function, metabolism, and atherogenicity of TG-rich lipoproteins and their remnants, with the ultimate aim of identifying targeted therapeutic approaches to address residual cardiovascular risk associated with elevated TG levels (9). As such, this Statement should be regarded as essential reading for all involved in the management of patients with hypertriglyceridaemia.
This EAS Statement makes several important points. First, there is clarification of what is meant by TG, TG-rich lipoproteins, and remnants. Building on evidence, past consensus and guidelines, the Statement defines criteria for different TG ranges (Table 1) (8,10-13). Currently, these should be regarded as ‘working criteria’, particularly for when elevated TG become clinically relevant for ASCVD, given limited definitive evidence from randomized controlled trials.
|Table 1. Consensus definitions of normal triglycerides and hypertriglyceridaemia|
|Moderately elevated||1.7-5.7 (150-500)|
Second, this EAS Statement provides a framework for understanding how remnants of TG-rich lipoproteins are generated and cleared from the circulation. Plasma levels of TG-rich lipoproteins depend on the rate of production, the efficiency of removal of TG content by lipolysis, and hepatic clearance. Remnants result from partial lipolysis mainly by lipoprotein lipase; these accumulate if there is overproduction of TG-rich lipoproteins or compromised (albeit not absent) lipase action. Other proteins also play a role. Indeed, beyond the lipoprotein lipase cofactor apolipoprotein (apo) CII, recent studies have identified the relevance of apoCIII in controlling the efficiency of TG clearance, and angiopoietin-like protein 3 (ANGPTL3) in modulating lipoprotein lipase activity, suggesting potential as therapeutic targets (14,15).
There are two key questions that merit answers. How are elevated TG-rich lipoproteins linked to cardiovascular risk? What are the underlying mechanisms of atherogenicity? This EAS Statement provides a state-of-the art review of current thinking on how TG-rich lipoproteins and their remnants are retained in the arterial wall and promote maladaptive responses central to plaque initiation and progression. There is also exploration of the relative atherogenicity of TG-rich lipoproteins and their remnants versus LDL, with the caveat that precise definition of the nature of remnant particles is currently uncertain. Moreover, the Consensus Panel emphasise that LDL remains the priority for therapeutic intervention, consistent with guidelines (12).
Two key gaps in knowledge about TG-rich lipoproteins and remnants are highlighted. First, there is an unmet need for a standardised, readily applicable assay to measure remnants and to relate this to their atherogenic properties. Emerging approaches include measuring the cholesterol content of remnant particles, or TG-rich lipoprotein particle number or composition, although none of these is fully validated for their association with ASCVD risk. The Panel concludes that clinicians should continue to use plasma TG (either fasting or nonfasting) as a surrogate for quantitating TG-rich lipoproteins and remnants, as recommended by the 2019 European Society of Cardiology/EAS dyslipidaemia guidelines (12,16).
The other important challenge is for therapeutic options to lower circulating levels of remnants to reduce residual ASCVD risk. There is discussion of different therapeutic strategies for lowering TG-rich lipoproteins and their remnants – both currently available and novel treatments – that may potentially reduce cardiovascular risk. The pros and cons of targeting production, lipolysis, or hepatic clearance of these lipoproteins are elaborated. The answer to this challenge is unlikely to be as simple as for LDL, given the metabolic complexity of TG-rich lipoproteins and their remnants.
This new EAS Statement is an important contribution to understanding TG-rich lipoproteins and remnants and their association with ASCVD. Publication is also timely, with innovative therapies in clinical trials. The challenge for the future is translating mechanistic insights to reduction in residual cardiovascular risk in clinical practice.
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