Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

Abstract

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥ 1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal.

Figure 1

Upon entry into the circulation, chylomicrons (containing apo B-48) produced by the small intestine, and VLDL (containing apo B-100) produced by the liver undergo LPL–mediated lipolysis mainly in peripheral tissues, notably adipose tissue and muscle. Intravascular remodelling of TRL equally involves the actions of lipid transfer proteins (CETP, PLTP) and additional lipases (HL and EL) with the formation of remnant particles. TRL remnants are typically enriched in cholesterol and apo E, but depleted in triglyceride; they are principally catabolized in the liver upon uptake through the LRP and LDL receptor pathways. TRL remnants can contribute either directly to plaque formation following penetration of the arterial wall at sites of enhanced endothelial permeability, or potentially indirectly following liberation of lipolytic products (such as FFA and lysolecithin) which may activate pro-inflammatory signalling pathways in endothelial cells.^, Abbreviations: apo, apolipoprotein; CETP, cholesteryl ester transfer protein; EL, endothelial lipase; FFA, free fatty acids; HL, hepatic lipase; LDL, low-density lipoprotein; LPL, lipoprotein lipase; LRP, lipoprotein receptor-related protein; PLTP, phospholipid transfer protein; TRL, triglyceride-rich lipoprotein; VLDL, very-low density lipoprotein.

Figure 2

Metabolic pathways for HDL and triglyceride-rich lipoprotein remnants highlight their close interrelationship. De novo production of nascent HDL (discs) occurs in the liver and small intestine through the production of apo A-I (the major HDL protein) and lipidation (with cholesterol and phospholipids) of this protein by the ATP-binding cassette transporter (ABCA1) in these organs. Upon secretion, lecithin: cholesterol acyltransferase (LCAT) esterifies cholesterol on these discs which mature into spherical particles (due to the formation of a hydrophobic core resulting from generation of cholesteryl esters by LCAT). HDL undergoes extensive interconversion through triglyceride lipolysis (hepatic lipase, HL), phospholipid hydrolysis (endothelial lipase, EL), fusion (phospholipid transfer protein, PLTP), and lipid exchange among the HDL subpopulations (cholesteryl ester transfer protein, CETP). CETP also mediates major lipid transfer and exchange between HDL and triglyceride-rich lipoproteins (VLDL, chylomicrons) and their remnants [VLDL remnants = intermediate-density lipoproteins (IDLs), chylomicron remnants]. During this process, cholesteryl esters are transfered from HDL to VLDL and triglycrides move from VLDL to HDL. Chylomicrons also act as cholestery ester acceptors from LDL and HDL during the post-prandial phase. A second route that contributes to the plasma HDL pool involves hydrolysis of triglycerides in VLDL, IDL, and chylomicrons. In this process which is catalysed by lipoprotein lipase (LPL), phospholipids, as well as several apolipoproteins (such as apo CI, CII, CIII, AV) are transferred to HDL. PLTP contributes significantly to this remodelling process.

Figure 3

Lipoprotein cholesterol as a function of increasing levels of non-fasting triglycerides in the general population. Based on non-fasting samples from 36 160 men and women from the Copenhagen General Population Study collected over the period 2003–2007; 9% of men and 6% of women were on statins, mainly 40 mg/day simvastatin. Remnant cholesterol is calculated from a non-fasting lipid profile as total cholesterol minus HDL cholesterol minus LDL cholesterol; under these conditions, remnant cholesterol represents the total cholesterol transported in IDL, VLDL, and chylomicron remnants. Variable levels of chylomicrons are present in non-fasting samples and usually will only contribute minimally to the calculated remnant cholesterol. Nordestgaard BG 2010, unpublished results.

Figure 4

Hazard ratios for coronary heart disease and ischaemic stroke across quantiles of usual concentrations of triglycerides, HDL, and non-HDL cholesterol levels. Reproduced with permission from the Emerging Risk Factors Collaboration. Copyright© (2009) American Medical Association. All rights reserved.

Figure 5

Relationship of non-fasting triglycerides (up to and >5 mmol/L or 440 mg/dL) and risk of myocardial infarction, ischaemic stroke, and total mortality. Results are shown as age-adjusted hazard ratios from the Copenhagen City Heart Study with 26–31 years of follow-up. Reproduced with modification from Nordestgaard et al. and Freiberg et al. Copyright© (2007, 2008) American Medical Association. All rights reserved.

Figure 6

Proposed algorithm for the management of high-risk individuals with elevated triglycerides and/or low HDL cholesterol at LDL cholesterol goal. ^aLDL-C at goal as recommended by the most recent European guidelines (2007); <2.5 mmol/L in high-risk patients, decreasing to <2.0 mmol/L in very high risk patients. High-dose omega-3 fatty acids, fibrate, or niacin may be considered if the patient has very high TG (>5.0 mmol/L) to prevent pancreatitis. ^bIf the patient still has elevated TG (≥1.7 mmol/L, as recommended by the most recent European guidelines) and/or low HDL-C (<1.0 mmol/L) despite intensive lifestyle intervention, and addressing compliance with pharmacotherapy and secondary causes of dyslipidaemia, additional lipid-modifying therapy may be considered. ^cBased on clinical outcome data and safety considerations for combination statin–fibrate therapy, fenofibrate is the preferred fibrate. This fibrate may have particular value in patients with T2DM and mild-to-moderate retinopathy. ^dGreater LDL-C lowering may be achieved by the addition of ezetimibe to a statin. Ezetimibe has a dose-sparing advantage in patients intolerant of higher dose statins, although outcome evidence to support its use is awaited. Note: To convert LDL-C or HDL-C from mmol/L to mg/dL multiply by 38.7; to convert TG from mmol/L to mg/dL multiply by 88.5. Abbreviations: TG, triglycerides; HDL-C, high-density-lipoprotein cholesterol; LDL-C, low-density-lipoprotein cholesterol.