Hypertriglyceridemia and cardiovascular risk: a cautionary note about metabolic confounding

Triglycerides are the conventional tool to measure VLDLs, whereas LDL cholesterol (LDL-C) is the conventional tool to measure LDLs. Multiple epidemiological studies, including a series of genetically based analyses, have demonstrated that cardiovascular risk is related to triglycerides independently of LDL-C, and this has led to a series of new therapeutic agents designed specifically to reduce plasma triglycerides. The triglyceride hypothesis posits that increased levels of triglycerides increase cardiovascular risk and decreasing plasma triglycerides decreases cardiovascular risk. In this work, we will examine the validity of the triglyceride hypothesis by detailing the biological complexities associated with hypertriglyceridemia, the genetic epidemiological evidence in favor of hypertriglyceridemia, the evidence from the fibrate randomized clinical trials relating triglycerides and clinical outcomes, and the completeness of the evidence from the initial studies of novel mutations and the therapeutic agents based on these mutations that lower triglycerides. Because of the multiple metabolic links between VLDL and LDL, we will try to demonstrate that measuring triglycerides and LDL-C alone are inadequate to document the lipoprotein profile. We will try to demonstrate that apoB must be measured, as well as triglycerides and cholesterol, to have an accurate estimate of lipoprotein status. Triglycerides are the conventional tool to measure VLDLs, whereas LDL cholesterol (LDL-C) is the conventional tool to measure LDLs. Multiple epidemiological studies, including a series of genetically based analyses, have demonstrated that cardiovascular risk is related to triglycerides independently of LDL-C, and this has led to a series of new therapeutic agents designed specifically to reduce plasma triglycerides. The triglyceride hypothesis posits that increased levels of triglycerides increase cardiovascular risk and decreasing plasma triglycerides decreases cardiovascular risk. In this work, we will examine the validity of the triglyceride hypothesis by detailing the biological complexities associated with hypertriglyceridemia, the genetic epidemiological evidence in favor of hypertriglyceridemia, the evidence from the fibrate randomized clinical trials relating triglycerides and clinical outcomes, and the completeness of the evidence from the initial studies of novel mutations and the therapeutic agents based on these mutations that lower triglycerides. Because of the multiple metabolic links between VLDL and LDL, we will try to demonstrate that measuring triglycerides and LDL-C alone are inadequate to document the lipoprotein profile. We will try to demonstrate that apoB must be measured, as well as triglycerides and cholesterol, to have an accurate estimate of lipoprotein status. Multiple lines of epidemiological evidence, including most recently, Mendelian randomization studies (1.Jørgensen A.B. Frikke-Schmidt R. West A.S. Grande P. Nordestgaard B.G. Tybjaerg-Hansen A. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction.Eur. Heart J. 2013; 34: 1826-1833Crossref PubMed Scopus (287) Google Scholar, 2.Varbo A. Benn M. Tybjaerg-Hansen A. Jørgensen A.B. Frikke-Schmidt R. Nordestgaard B.G. Remnant cholesterol as a causal risk factor for ischemic heart disease.J. Am. Coll. Cardiol. 2013; 61: 427-436Crossref PubMed Scopus (629) Google Scholar, 3.Do R. Willer C.J. Schmidt E.M. Sengupta S. Gao C. Peloso G.M. Gustafsson S. Kanoni S. Ganna A. Chen J. et al.Common variants associated with plasma triglycerides and risk for coronary artery disease.Nat. Genet. 2013; 45: 1345-1352Crossref PubMed Scopus (616) Google Scholar), tie plasma triglycerides to the risk of atherosclerotic CVD. Conventionally, cholesterol and triglycerides have been regarded as markers that represent separate and distinct lipoprotein classes: triglycerides are the principal lipid constituent of VLDL particles and elevated triglycerides, therefore, identify elevated VLDL levels; whereas cholesterol is the principal lipid constituent of LDL particles and elevated LDL cholesterol (LDL-C), therefore, identifies elevated LDL levels. In this paradigm, the lipid component of a lipoprotein particle is accepted as fully informative of the atherogenic risk associated with the lipoprotein particle. Accordingly, based on the epidemiological evidence, novel therapeutic agents with major effects on triglyceride concentrations, but with little effect on LDL-C, are being developed. The operating assumption is that if LDL-C is not affected, clinical risk and benefit must relate to differences in plasma triglycerides, not to differences in LDL. However, hypertriglyceridemia may reflect increased numbers of one or more classes of triglyceride-rich lipoprotein particles, which have different relations to cardiovascular risk. Most VLDL apoB particles are small enough to enter the arterial wall. By contrast, most chylomicron particles are too large to enter the arterial wall and, therefore, the cholesterol and triglyceride they contain are no threat to the integrity of the arterial wall. Although VLDL particles do, in general, account for most of the mass of triglycerides in plasma, the mass of triglyceride per VLDL particle is not uniform. Accordingly, hypertriglyceridemia due to VLDL may be the consequence of an increased mass of triglyceride per VLDL particle, an increase in the number of VLDL particles, or both. Moreover, VLDL particles are the metabolic precursors of LDL particles and the concentration of LDL particles in plasma depends upon the production rate of VLDL particles and the proportion that are converted to LDL particles, as well as the clearance rate of LDL particles (4.De Graaf J. Couture P. Sniderman A. ApoB in Clinical Care. Springer, Houten, The Netherlands2015Crossref Scopus (9) Google Scholar). All of these can vary independently and substantially. In addition, the composition of VLDL and LDL particles can change independently of their production rates: cholesterol ester transfer protein (CETP)-mediated exchanges and transfers of triglyceride and cholesterol ester between chylomicrons and VLDL particles, on the one hand, and LDL and HDL particles, on the other, produce VLDL, LDL, and HDL particles of variable size with variable masses of cholesterol and triglyceride. Higher plasma triglycerides lead to cholesterol-enriched VLDL particles and cholesterol-diminished LDL and HDL particles (4.De Graaf J. Couture P. Sniderman A. ApoB in Clinical Care. Springer, Houten, The Netherlands2015Crossref Scopus (9) Google Scholar), whereas lower triglycerides may be associated with cholesterol-enriched apoB particles. This variance in composition means that VLDL particle concentration cannot be reliably deduced from the concentration of triglyceride in plasma and LDL particle concentration cannot be reliably deduced from the concentration of LDL-C in plasma (4.De Graaf J. Couture P. Sniderman A. ApoB in Clinical Care. Springer, Houten, The Netherlands2015Crossref Scopus (9) Google Scholar). This discordance between lipid composition and particle number is important because there is considerable evidence that the atherogenic risk associated with the apoB lipoproteins more to the number of apoB particles with the mass of cholesterol between lipoprotein particle number and cholesterol an PubMed Scopus Google Scholar). Moreover, with the of the proportion of VLDL apoB LDL apoB particles is in with hypertriglyceridemia in LDL particles to account for the of apoB particles A. Graaf J. Couture P. of hypertriglyceridemia by PubMed Scopus Google Scholar). This means that clinical benefit from genetic mutations and that lower triglycerides be in on their effects on the number of LDL particles, effects that not be from of we that VLDL apoB is as accurate a of the risk due to VLDL particles as plasma triglycerides or VLDL cholesterol the agents that lower cardiovascular and lower plasma Moreover, their clinical benefit more to the in apoB to the in LDL-C or cholesterol R. Couture P. Graaf J. Sniderman A. of change in plasma levels of LDL-C, and apoB with risk from a of randomized Am. Heart PubMed Scopus Google Scholar, S. of of of lipoprotein cholesterol and lipoprotein cholesterol for cardiovascular risk in randomized J. Cardiol. PubMed Scopus Google Scholar). in the of the evidence from Mendelian randomization is that clinical benefit to the in not to the increase in or the in LDL-C C.J. C. et of genetic variants related to and with lipoprotein levels and cardiovascular PubMed Scopus Google Scholar). This means that in apoB particle number and their to in risk to be can be triglycerides are an risk factor for and agents that lower triglycerides are to and, if they do, Accordingly, this will the metabolic between the and apoB the evidence from the genetic mutations and Mendelian randomization that triglycerides are an risk factor for the evidence from randomized clinical trials that triglycerides clinical and, the of the evidence from the new series of agents as to their effect on the apoB lipoprotein profile. will be that of alone not a of lipoprotein status. apoB is of apoB particles the arterial wall is to the and of the atherosclerotic The of the different apoB lipoproteins to this is by their their and their to to of the the arterial wall J. The of arterial of lipoproteins in the of a of PubMed Scopus Google particles contain one of and are in plasma as or remnant particles between lipoprotein particle number and cholesterol an PubMed Scopus Google Scholar). of the a chylomicron particle to multiple of on the of and the of triglyceride are in and the of are by the and triglycerides, a metabolic which be if levels of are to be Moreover, as the chylomicron triglycerides are being the of the particle and transfer protein the of from the The of triglyceride and of the chylomicron particles, which are from the of the in and The remnant particle, which is the of the in chylomicron and a of the but the cholesterol, is by the The that the of LDL particles, the LDL have been in This with the for the of the apoB which to be more and chylomicron particles are too large to threat to the arterial wall plasma triglycerides are By contrast, they the of the they can an remnant particles are small enough to enter the arterial wall and contain of However, in there are more VLDL particles particles C. S. C. lipoprotein in PubMed Scopus Google Scholar, M. M. et concentration of in with and coronary artery 2013; PubMed Scopus Google Scholar, J. a in a PubMed Scopus Google Scholar). of these particles large of cholesterol and to atherogenic risk. VLDL particles are triglyceride-rich particles that from the to and (4.De Graaf J. Couture P. Sniderman A. ApoB in Clinical Care. Springer, Houten, The Netherlands2015Crossref Scopus (9) Google Scholar). most of the triglycerides in plasma are in VLDL particles, but the mass of triglyceride per VLDL particle and, therefore, the size of VLDL particles and between are multiple for this variance in composition of VLDL particles by the can with the more particles more triglyceride the particles J. C. Couture P. effect of and on in of and in with with PubMed Scopus Google Scholar, S. S. M. A. of on and in 45: PubMed Scopus Google Scholar, J. of lipoprotein by and in with the metabolic PubMed Scopus Google Scholar). because the which of these particles is may the rate of triglyceride by the will vary to the rate of of VLDL particles. as VLDL particles by in the and their triglyceride will be and their therefore, will lipid will to increase the cholesterol the triglyceride of VLDL particles. the metabolic of VLDL particles is more chylomicron particles. The VLDL particles that are and of of their triglyceride by may be from the plasma by the or converted to and LDL particles. one the is not and a in of apoB and atherogenic risk. In most a small of VLDL particles are converted to LDL particles. the in which of VLDL to LDL is a major metabolic of VLDL are to because these have large numbers of LDL particles. to this of the agents that will be to this This to their effects on VLDL and LDL particle and remnant lipoprotein particles may be in clearance of VLDL and chylomicron particles by the lipid which in increased numbers of cholesterol-enriched remnant particles the PubMed Scopus Google Scholar, an of remnant PubMed Scopus Google Scholar). In remnant particles VLDL remnant particles are in or more the concentration of remnant particles C. S. C. lipoprotein in PubMed Scopus Google Scholar, M. M. et concentration of in with and coronary artery 2013; PubMed Scopus Google Scholar, J. Couture P. The of plasma of lipoproteins in is of PubMed Scopus Google Scholar). This risk of in are and can be based on cholesterol, and apoB A. A. J. C. Couture P. of from plasma cholesterol, and PubMed Scopus Google Scholar). apoB particles with a of as particles, whereas with a of as LDL particles. However, this is not and apoB particles with a between and are LDL particles. LDL-C the cholesterol as well as the cholesterol LDL. The evidence to that the mass of cholesterol the LDL particle not change the atherogenic of the particles are as atherogenic as more LDL particles S. M. P. LDL particle LDL particle and in the of PubMed Scopus Google Scholar). However, for cholesterol a concentration of LDL particles more LDL particles to the cholesterol in the in to risk be from the the lipid of LDL particles not to their atherogenic the of to the particle may increase atherogenic J. lipoproteins and the risk of coronary heart PubMed Scopus Google Scholar), of may this risk J. in VLDL and LDL with is associated with a lower risk of coronary heart disease.J. Am. Heart 2013; PubMed Scopus Google Scholar). particles are LDL particles to which a of has been is evidence that the risk of in to the of lipoprotein a that is of LDL-C or apoB S. in and Am. Coll. Cardiol. PubMed Scopus Google Scholar, M. new from PubMed Scopus Google Scholar). the of VLDL apoB to LDL apoB in with hypertriglyceridemia and is variable is not triglyceride VLDL particles of apoB with hypertriglyceridemia they of apoB but with to hypertriglyceridemia they of apoB A. Graaf J. Couture P. of hypertriglyceridemia by PubMed Scopus Google Scholar). with by J. C. Couture P. effect of and on in of and in with with PubMed Scopus Google Scholar, S. S. M. A. of on and in 45: PubMed Scopus Google Scholar, J. of lipoprotein by and in with the metabolic PubMed Scopus Google Scholar). the proportion of apoB particles that are VLDL particles as triglyceride levels the number of LDL particles the number of VLDL particles. as VLDL particle number atherogenic risk. because the triglyceride of VLDL apoB particles is plasma apoB cannot be from plasma triglycerides. This is from which triglycerides apoB in of and Graaf J. Couture P. of LDL PubMed Scopus Google Scholar). is no between the a between VLDL apoB and plasma triglycerides. apoB cannot be reliably from plasma triglycerides. This is because multiple studies have that cardiovascular risk in but with elevated in but with apoB M. and lipoprotein levels in and with PubMed Scopus Google Scholar, A. of hypertriglyceridemia on the of plasma and LDL PubMed Scopus Google Scholar, C. of with hypertriglyceridemia and PubMed Scopus Google Scholar, M. J. and and lipoproteins in with and myocardial Heart J. PubMed Scopus Google Scholar, M. of and in coronary artery Heart J. PubMed Scopus Google Scholar, M. Clinical of of and in with and coronary artery PubMed Scopus Google Scholar). This in the Heart which a epidemiological S. of in ischemic heart from the J. Cardiol. PubMed Scopus Google Scholar). the in LDL particle number and, therefore, apoB cardiovascular risk is in with in with hypertriglyceridemia in the of PubMed Scopus Google Scholar). By contrast, as in there is a between plasma triglycerides and This means that the cardiovascular risk associated with these markers be if not to one from the conventional epidemiological have demonstrated a between plasma triglycerides and coronary heart risk. 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