Elsevier

The Lancet

Volume 384, Issue 9943, 16–22 August 2014, Pages 626-635
The Lancet

Series
Triglycerides and cardiovascular disease

https://doi.org/10.1016/S0140-6736(14)61177-6Get rights and content

Summary

After the introduction of statins, clinical emphasis first focussed on LDL cholesterol-lowering, then on the potential for raising HDL cholesterol, with less focus on lowering triglycerides. However, the understanding from genetic studies and negative results from randomised trials that low HDL cholesterol might not cause cardiovascular disease as originally thought has now generated renewed interest in raised concentrations of triglycerides. This renewed interest has also been driven by epidemiological and genetic evidence supporting raised triglycerides, remnant cholesterol, or triglyceride-rich lipoproteins as an additional cause of cardiovascular disease and all-cause mortality. Triglycerides can be measured in the non-fasting or fasting states, with concentrations of 2–10 mmol/L conferring increased risk of cardiovascular disease, and concentrations greater than 10 mmol/L conferring increased risk of acute pancreatitis and possibly cardiovascular disease. Although randomised trials showing cardiovascular benefit of triglyceride reduction are scarce, new triglyceride-lowering drugs are being developed, and large-scale trials have been initiated that will hopefully provide conclusive evidence as to whether lowering triglycerides reduces the risk of cardiovascular disease.

Introduction

More than 25 years ago, mild–moderately high concentrations of triglycerides were regarded as a cardiovascular risk factor, similar to high total and LDL cholesterol.1, 2, 3 Both types of lipid fractions were treated by lipid specialists with the aim of preventing cardiovascular disease, and greatly increased concentrations of triglycerides were treated to prevent acute pancreatitis. These clinical practices were driven by clinicians seeing patients with raised triglycerides and severe cardiovascular disease such as those with remnant hyperlipidaemia, epidemiological evidence, and trials examining the benefit of triglyceride and cholesterol lowering. Equally important was Zilversmit's hypothesis that atherogenesis is a postprandial occurrence, and that raised concentrations of triglycerides and remnant lipoproteins are a main cause of atherosclerosis.4

Several scientific breakthroughs, however, lead to more focus on raised LDL cholesterol as the main lipid target for cardiovascular disease prevention. These included first, the identification of LDL receptor mutations as the cause of familial hypercholesterolemia by Brown and Goldstein5 (who won the Nobel prize in 1985). Second, the LDL-oxidation hypothesis promoted by Steinberg and colleagues that focused attention on LDL.6 Third, the discovery by Endo in 19767 of mevastatin as an inhibitor of HMG-CoA reductase, (the rate-limiting enzyme in cholesterol synthesis) that provided a very effective means of reducing LDL-cholesterol concentrations. This discovery prompted several pharmaceutical companies to develop and test statins, leading to the report of the 4S trial in 1994, which documented reduced cardiovascular disease and reduced all-cause mortality after LDL lowering with simvastatin.8 This study showed that raised concentrations of LDL cholesterol predisposes an individual to cardiovascular disease, and that LDL lowering is a prime lipid target.

4S and later statin trials also set the standard for evidence-based medicine,9 ie, treatment of cardiovascular risk factors should result in reduced cardiovascular disease and reduced all-cause mortality. These are valid but very hard criteria to meet. Therefore, as time went by the randomised evidence for treating raised triglycerides to prevent cardiovascular disease seemed weaker and weaker, not least because the expectations changed to include documentation of benefit of triglyceride reduction in patients who were already receiving a statin, evidence that naturally was not generated in the pre-statin era. Raised triglyceride concentrations are strongly associated with low concentrations of HDL cholesterol,10 and the past 15 years have been dominated by HDL research, with less focus on triglycerides. However, the understanding from genetic studies and randomised trials11, 12, 13, 14, 15, 16, 17, 18, 19, 20 that low HDL cholesterol might not be a cause of cardiovascular disease as originally thought, has generated renewed interest in raised triglycerides.

This Review focuses on the controversies regarding raised triglycerides with respect to their measurement, classification, role in cardiovascular disease, and treatment. It also emphasises novel developments in epidemiology, diagnostic techniques, genetics, understanding of disease mechanisms, and novel drug developments that aim to treat raised triglycerides for cardiovascular disease prevention. Other reviews detail other aspects of triglycerides and cardiovascular disease, including more comprehensive reference lists.21, 22, 23, 24, 25, 26, 27, 28, 29

Section snippets

Epidemiology

Unlike individuals with markedly raised cholesterol concentrations as seen in familial hypercholesterolaemia,5 many individuals with high triglyceride concentrations and so-called chylomicronaemia syndrome do not develop atherosclerosis and cardiovascular disease.30 This observation initially led to scepticism about the importance of triglycerides in cardiovascular disease; however, this paradox was accounted for by the fact that at greatly elevated concentrations (triglycerides >50 mmol/L),

Diagnostic techniques

A lipid profile includes measurement of the total amount of the two most important lipids in the plasma compartment–cholesterol and triglycerides. Similar to any other lipids, these are not soluble in the water phase of plasma, and are therefore carried in lipid particles kept in solution in association with proteins, the so-called lipoproteins. Lipoproteins include HDL—the smallest lipoproteins; LDL—medium-sized lipoproteins; and triglyceride-rich lipoproteins (remnants)—the largest

Non-fasting versus fasting concentrations

Traditionally, a lipid profile was taken in the fasting state and this is still the case in most countries. However, in some countries—eg, Denmark—a non-fasting lipid profile has been the standard since 2009;45 if non-fasting triglycerides are more than 4 mmol/L, then a subsequent fasting concentration reading can be requested by the attending physician.

An advantage of non-fasting rather than fasting lipid profile measurements is that the blood-sampling process is simplified for patients,

Population distribution

27% of individuals in the Copenhagen General Population Study had mild–moderately raised concentrations of triglycerides (2–10 mmol/L), and 0·1% had greatly raised concentrations (>10 mmol/L). For remnant cholesterol measurements, 45% of individuals had concentrations of 0·5–1 mmol/L, and 21% had concentrations of more than 1 mmol/L.

Previous classifications of raised triglyceride concentrations focused on phenotypical differences or different genetic subgroups.3, 27, 51 However, novel genetic

Remnant cholesterol

Remnant cholesterol is the cholesterol content of triglyceride-rich lipoproteins. Various methods for measuring remnants and remnant cholesterol exist; however, because lipoprotein remnants are different both in composition of lipids and apolipoproteins as a result of different stages of metabolism5, 21 a direct assay that measures all remnants at the same time has not yet been developed. Remnant cholesterol can, however, be calculated as non-fasting total cholesterol minus HDL cholesterol

Genetics and lifestyle

Mild–moderately high concentrations of triglycerides are typically multigenic, and result from the cumulative burden of variants in more than 30 genes together with lifestyle factors, most importantly being overweight or obese.27 Rare, autosomal, recessive, monogenic disorders can cause greately raised triglycerides through large-effect mutations in six different genes, ie, LPL, APOC2, APOA5, LMF1, GPIHBP1, and GPD1. However, the most common causes of markedly raised triglycerides also involve

The role of triglycerides in cardiovascular disease

Because triglycerides can be degraded by most cells, but cholesterol cannot be degraded by any, the cholesterol content of triglyceride-rich lipoproteins (remnant cholesterol) is more likely to be the cause of atherosclerosis and cardiovascular disease rather than raised triglycerides per se. Indeed, cholesterol not triglycerides accumulates in intimal foam cells and in atherosclerotic plaques, and remnant lipoproteins just like LDL can enter the arterial intima,4, 33, 34 but chylomicrons are

Genetics suggest causality

Experience with inherited disorders encountered in the clinic such as remnant hyperlipidaemia (type 3 hyperlipidaemia) or the so-called familial combined hyperlipidaemia, has for years suggested that raised concentrations of triglycerides and remnant cholesterol predisposes an individual to cardiovascular disease.3 However, large-scale evidence for this has not previously been available.

Mendelian randomisation studies, just like randomised intervention trials, are typically mainly free of

Treatment

Detailed advice on lifestyle modifications, including the role of aerobic exercise, dietary fructose, and the Mediterranean diet, and on drug choices to reduce triglycerides, are described elsewhere.21, 27, 51, 63 For mild–moderately raised triglycerides, the secondary causes of raised triglycerides should be ruled out and treated. Next, lifestyle modification is important, most often weight loss. Then, statin therapy or intensified statin therapy with a potent statin that lowers both

Lifestyle modification

For individuals with mild–moderately high concentrations of triglycerides, the most important lifestyle modification is to lose weight through eating less and exercising more.51 Thus, the aim is to reduce excess calories that otherwise would be deposited as excess fat in the body. Paradoxically, an increased intake of food and supplements that are rich in fish oils reduces triglycerides.21, 23 Reduced alcohol intake is important for people with high triglycerides and high alcohol intake, with

Drug therapies

No large-scale randomised trial has examined the effect of reducing triglycerides on cardiovascular disease risk in people with raised triglycerides. Conversely, most trials (including most statin trials) have excluded participants with triglyceride concentrations that are greater than 4·5 mmol/L. Therefore, results from most reported trials cannot show whether a reduction of triglycerides and remnant cholesterol provides cardiovascular benefit. Despite this, many meta-analyses and reviews have

Genetics suggest new drug targets

Evidence from genetic studies suggests potential drug targets for triglyceride reduction, including proteins with the most profound effect on plasma triglycerides such as apolipoprotein C3,71, 72, 73 apolipoprotein A5,10, 52, 59 and lipoprotein lipase.58, 74 Lipoprotein lipase is the key triglyceride-degrading enzyme in plasma-, and apolipoproteins C3 and A5 modulate lipoprotein lipase function and affect liver uptake of remnant cholesterol. Figure 5 shows that genetically reduced triglyceride

Novel drug therapies

Several new drugs with properties for lowering mild-to-moderately raised or very high concentrations of triglycerides are being developed or are already being tested in clinical trials,26 including some that are specifically aimed at reducing triglycerides. These drugs include n-3 fatty acids (fish oils), apolipoprotein C3 inhibitors, and LPL gene replacement therapy. Other new drugs in development have triglyceride-lowering properties among their functions; these drugs include proprotein

Conclusion

The evidence that raised concentrations of remnant cholesterol, marked by raised triglycerides, are an additional causal risk factor for cardiovascular disease and all-cause mortality, is increasing. However, randomised intervention trial evidence is urgently needed, that triglyceride-lowering reduces cardiovascular disease in patients with raised triglycerides. Most desirable would be a placebo-controlled, primary prevention trial of individuals with mild–moderately raised triglycerides

Search strategy and selection criteria

We searched the Cochrane Library (between Jan 1, 1988, and May 11, 2014) and the PubMed and Embase databases (between Jan 1, 1950, and May 11, 2014) with the search terms “triglyceride”, “triglyceride-rich lipoproteins”, or “remnant” in combination with “cardiovascular disease” or “atherosclerosis”. We mainly selected publications in the last 5 years, but did not exclude widely referenced and highly regarded older publications. We also searched the reference lists of articles identified

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