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|Commentary on Hypertriglyceridaemia Consensus|
EAS Consensus Panel paper: Simplifying the definition of hypertriglyceridaemia
Molecular genetic analyses have facilitated dramatic progress in understanding the mechanisms potentially underlying hypertriglyceridaeridaemic states. Thus, the focus of the latest paper from the European Atherosclerosis Society (EAS) Consensus Panel on hypertriglyceridaemia is timely. The EAS Consensus Panel calls for a simplified dichotomous redefinition of hypertriglyceridaemia, recognising that the majority of cases have a polygenic basis. This simplified definition (see below) has important implications for the diagnosis and management of hypertriglyceridaemia, and is therefore critically relevant to a wide range of clinicians routinely involved in the management of dyslipidaemia.
According to Lead author, Robert A. Hegele, Distinguished Professor of Medicine and Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada:
‘Hypertriglyceridemia represents a diagnostic and therapeutic challenge for many health care providers. This consensus paper synthesizes recent epidemiologic, genetic and clinical evidence, streamlining the definition of hypertriglyceridaemia, which in turn serves as a simplified framework for diagnosis and management.’
The full paper is available for download HERE; the pdf will also be available as open access on Lancet Diabetes Endocrinology for February [at http://www.thelancet.com/journals/landia/article/PIIS2213-8587(13)70191-8/fulltext].
Triglycerides and cardiovascular disease
High levels of triglycerides, a marker for triglyceride-rich lipoproteins (TRLs) and their remnants, have a role in cardiovascular disease (CVD). Indeed, a previous EAS Consensus Panel position paper concluded that evidence from mechanistic and genetic studies, as well as epidemiological data supported a causal association of elevated TRLs and their remnants (with or without low high-density lipoprotein [HDL] cholesterol) with elevated CVD risk. Subsequent to that publication, there were supportive findings from a Mendelian randomisation study suggesting that lifelong exposure to remnant TRLs is causal for coronary heart disease risk, independent of low plasma concentrations of HDL cholesterol. Furthermore, a genetic study indicated a causal role for triglycerides, independent of confounding effects due to low-density lipoprotein (LDL) cholesterol or HDL cholesterol in the development of coronary artery disease. However, it is recognised that we still lack definitive evidence that targeting elevated triglycerides impacts CVD outcomes. This because the studies conducted to date have been flawed by inclusion of patients without clinically relevant hypertriglyceridaemia, and therefore, are not a true test of this hypothesis.
Understanding the genetic basis of hypertriglyceridaemia: monogenic versus polygenic
Historically, the phenotypic heterogeneity of hypertriglyceridaemia was defined according to qualitative and quantitative differences in plasma lipoproteins using the Fredrickson classification of hyperlipoproteinaemia phenotypes. It was implicit in this classification that differences between different hypertriglyceridaemic phenotypes were due to genetic differences.
It is recognised that hypertriglyceridaemia tends to cluster in families, implying a genetic component. However, recent genetic insights indicate that in more than 95% of cases of hypertriglyceridaemia, there is a polygenic or multigenic basis explaining this susceptibility.[2,6-10] The phenotypic heterogeneity of hypertriglyceridaemia reflects the cumulative burden associated with common small-effect genetic variants, as well as rare heterozygous large-effect variants of genes directly or indirectly associated with plasma triglycerides (Figure 1). Thus, while most cases of hypertriglyceridaemia are inherited, they are not monogenic.
Indeed, monogenic hypertriglyceridaemia is rare, thought to affect about one in a million people. Such individuals have markedly elevated triglyceride levels (>10 mmol/L or >885 mg/dL), usually evident from a young age. In many cases, these individuals are homozygous or compound heterozygous (i.e. with two recessive alleles for the same gene, but with those two alleles being different from each other) for large-effect loss of function mutations in 6 different genes that regulate the catabolism of TRLs (i.e. LPL, APOC2, APOA5, LMF1, GP1HBP1 and GPD1).
However, most cases of hypertriglyceridaemia are polygenic, that is, the phenotype reflects the cumulative burden of common small-effect and rare large-effect variants of more than 30 genes involved in regulating the production or catabolism (or both) of TRLs. In other words, an increased burden of variants associated with triglyceride- raising translates to increased susceptibility to hypertriglyceridaemia. This substantially complicates tracing the hypertriglyceridaemic phenotype through families.
Moreover, susceptibility to elevated triglycerides is also impacted by secondary causes of hypertriglyceridaemia (see Box 1), which are themselves influenced by a genetic susceptibility component, leading to clustering in families. Notably obesity, metabolic syndrome, non-alcoholic fatty liver disease and diabetes, have their own susceptibility component.
Finally, It should be borne in mind that even among individuals with markedly elevated triglycerides (>10 mmol/L), the underlying genetic basis may be polygenic, compounded by secondary factors, if no monogenic cause is identified.
EAS Consensus Panel recommendations for redefinition of hypertriglyceridaemia
Taking account of these new genetic data, the EAS Consensus Panel therefore recommends a simplified redefinition of hypertriglyceridaemia, as either mild to moderate, or severe (Box 2). The Panel took the decision to use a diagnostic cutpoint of 2.0 mmol/L (175 mg/dL). However, it is recognised that this threshold is arbitrary, as consensus indicates that values ±0.3 mmol/L around this cutpoint may be also considered.
The EAS Consensus Panel recognises that there is inadequate evidence to define specific treatment targets for plasma triglycerides. In spite of this, both the EAS Consensus Panel and the European Society of Cardiology (ESC)/EAS guidelines for management of dyslipidaemia consider a triglyceride concentration <1.7 mmol/L (<150 mg/dL) as desirable, especially in the context of low plasma HDL cholesterol concentration.[2,11] Nonfasting lipid measurement may improve the efficiency of screening and diagnosis of hypertriglyceridaemia.
Non-HDL cholesterol and apolipoprotein B (apoB) (Table 1) are recommended secondary targets in defining desirable levels in individuals at high risk of CVD, consistent with current guidelines.[2,11-13]
There are two key aims in the management of hypertriglyceridaemia:
After addressing secondary causes (see Box 1), management of hypertriglyceridaemia should be in accordance with current guidelines (see Table 2).[11,13] Patients should be managed for their global CVD risk; a positive family history of CVD (at least one first degree relative or at least 2 second degree relatives with CVD) should be taken into account, independent of dyslipidaemia. As elevated LDL cholesterol is also part of the phenotype of combined hyperlipidaemia which exacerbates CVD risk, family members should be screened.
The primary priority for intervention is LDL cholesterol, with non-HDL cholesterol and apoB secondary treatment targets after attainment of LDL cholesterol goal. Lifestyle intervention is the mainstay of the management of hypertriglyceridaemia (after decreasing pancreatitis risk in patients with severe hypertriglyceridaemia). In terms of pharmacotherapy, statins are justifiably recommended for management of hypertriglyceridaemia due to i) proven efficacy in reducing CVD risk and ii) efficacy in lowering plasma triglycerides by up to 30% depending on baseline levels and dose. In Europe, the addition of a fibrate (especially in individuals with concomitant low plasma levels of HDL cholesterol), or omega-3 fatty acids may be considered, in accordance with current guidance.
* Reduce simple sugar and total carbohydrate intake; replace trans and saturated fat with monounsaturated fats; increase dietary omega-3 fatty acids;
** Nicotinic acid is no longer an option in Europe following the withdrawal of extended release niacin/laropiprant
Looking to the future
Expanding research is focused on elucidating the genetics of different forms of hypertriglyceridaemia, which may help in the identification of therapeutic targets. Ultimately these new research directions may offer the prospect of personalised medicine in the setting of hypertriglyceridaemia.
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