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Hypertriglyceridaemia and risk of coronary artery disease

Key Points

  • The role of elevated blood triglycerides as an independent risk factor for cardiovascular disease (CVD) has been debated for more than half a century, but without resolution

  • One of the reasons for this uncertainty is that hypertriglyceridaemia is often associated with decreased HDL-cholesterol levels and an increased number of atherogenic small dense LDL particles

  • Large observational, epidemiological, genetic, and Mendelian randomization studies support the hypothesis that elevated blood triglyceride levels, either fasting or nonfasting, are independently associated with an increased risk of CVD

  • Therapeutic targeting of hypertriglyceridaemia might provide further benefit in reducing CVD and events, in addition to that achieved with LDL-cholesterol lowering

  • Hypertriglyceridaemia is currently treated with lifestyle interventions and with fibrates, which can be combined with high doses of omega-3 fatty acids, but CVD outcome studies have produced inconsistent results

  • Some novel drugs, such as pemafibrate and volanesorsen, are being tested, but clinical data are preliminary

Abstract

An elevated serum level of LDL cholesterol is a well-known risk factor for cardiovascular disease (CVD), but the role of elevated triglyceride levels is debated. Controversies regarding hypertriglyceridaemia as an independent risk factor for CVD have occurred partly because elevated triglyceride levels are often a component of atherogenic dyslipidaemia — they are associated with decreased levels of HDL cholesterol and increased levels of small dense LDL particles, which are highly atherogenic. Findings from several large studies indicate that elevated levels of triglycerides (either fasting or nonfasting) or, more specifically, triglyceride-rich lipoproteins and their remnants, are independently associated with increased risk of CVD. Possible mechanisms for this association include excessive free fatty acid release, production of proinflammatory cytokines, coagulation factors, and impairment of fibrinolysis. Therapeutic targeting of hypertriglyceridaemia could, therefore, reduce CVD and cardiovascular events, beyond the reduction achieved by LDL-cholesterol lowering. Elevated triglyceride levels are reduced with lifestyle interventions and fibrates, which can be combined with omega-3 fatty acids. Some new drugs are on the horizon, such as volanesorsen (which targets apolipoprotein C-III), pemafibrate, and others. However, CVD outcome studies with triglyceride-lowering agents have produced inconsistent results, meaning that no convincing evidence is available that lowering triglycerides by any approach can reduce mortality.

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Figure 1: Metabolism of triglycerides.
Figure 2: Possible mechanisms of atherogenesis by triglyceride-rich lipoprotein particles.

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Reiner, Ž. Hypertriglyceridaemia and risk of coronary artery disease. Nat Rev Cardiol 14, 401–411 (2017). https://doi.org/10.1038/nrcardio.2017.31

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