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Investigation and management of hypertriglyceridaemia
  1. G Ferns1,3,
  2. V Keti1,
  3. B Griffin2
  1. 1 Department of Clinical Biochemistry, Royal Surrey County Hospital, Guildford, Surrey, UK
  2. 2 Division of Nutritional Science, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK
  3. 3 Postgraduate Medical School, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK
  1. Professor Gordon Ferns, Postgraduate Medical School, Daphne Jackson Rd, Guildford, Surrey GU2 7WG, UK; g.ferns{at}


While the precise definition of hypertriglyceridaemia remains contentious, the condition is becoming more common in western populations as the prevalence of obesity and diabetes mellitus rise. Although there is strong epidemiological evidence that hypertriglyceridaemia is an independent risk factor for cardiovascular disease, it is has been difficult to demonstrate this by drug intervention studies, as drugs that reduce triglycerides also raise high density lipoprotein cholesterol. Precise target values have also been difficult to agree, although several of the new guidelines for coronary risk management now include triglycerides. The causes of hypertriglyceridaemia are numerous. The more severe forms have a genetic basis, and may lead to an increased risk of pancreatitis. Several types of hypertriglyceridaemia are familial and are associated with increased cardiovascular risk. Secondary causes of hypertriglyceridaemia are also numerous and it is important to exclude these before starting treatment with specific triglyceride-lowering agents. Lifestyle management is also very effective and includes weight reduction, restricted alcohol and fat intake and exercise.

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Hypertriglyceridaemia is characterised by increased plasma concentrations of either or both of the triglyceride-rich lipoproteins: pre-β lipoproteins (very low density lipoprotein, VLDL) and chylomicron (CM) particles. The majority of cases are due to increased concentrations of pre-β lipoproteins, derived from endogenous synthesis in the liver. (Hyper)chylomicronaemia is due to abnormalities in the metabolism of exogenous (dietary) fat. A summary of normal lipoprotein metabolism with an emphasis on the exogenous and endogenous metabolism of triglyceride rich particles is shown in fig 1. The prevalence of a fasting serum triglycerides of >1.7 mmol/l is approximately 30% in individuals >20 years of age, rising to approximately 43% for those >50 years.1 While hypertriglyceridaemia is common,1 its definition is contentious. Recent National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines identify a triglyceride of 2.3 mmol/l as an important threshold for triggering “therapeutic lifestyle change”, although a normal fasting plasma triglycerides is defined as ⩽1.7 mmol/l.2 The American Diabetic Association has recently recommended a triglyceride target of 1.7 mmol/l,3 and the Joint British Societies’ Guidelines indicate that a fasting triglyceride >1.7 mmol/l should be used as a cut-off value to modify the risk calculator.4 However there is evidence to suggest that abnormalities in postprandial lipid metabolism and adverse compositional changes in low density lipoprotein (LDL) and high density lipoprotein (HDL) occur at a concentration of 1.5 mmol/l.5 Although there have been a number of intervention trials using fibrates6 8 the effects of these agents on HDL cholesterol (HDL-C) confound any attempt to determine the specific benefit of triglyceride reduction on coronary risk management, and none of these studies has attempted to address the issue of an optimum triglyceride target. In its forthcoming Guideline on Cardiovascular Risk Assessment, the National Institute for Health and Clinical Excellence does not suggest an optimum triglyceride target, although it states that the measurement of a fasting lipid profile is unnecessary if a random triglyceride is <2 mmol/l. A consensus guideline is therefore probably required for UK laboratories. In the current text, the terms borderline (1.7–2.2 mmol/l), high (2.3–5.5 mmol/l) and very high (5.6–11.0 mmol/l) hypertriglyceridaemia are used, and correspond to the NCEP ATP III categories.2 An additional categogy of severe (>11 mmol/l) is also used as this may be more frequently associated with genetic dyslipidaemias and acute pancreatitits9

Figure 1 A summary of triglyceride-rich lipoprotein metabolism. In the exogenous pathway, chylomicrons are synthesised in the intestine, and are derived from dietary triglycerides and cholesterol together with apolipoprotein (Apo)B-48, which is elaborated by the enterocyte. The chylomicron is secreted into the lymphatic system, reaching the systemic circulation via the thoracic duct. Postprandially, chylomicrons are the major form of circulating triglyceride. They are cleared rapidly (normal half-life is 10 min) by lipoprotein lipase (LPL) present on the endothelium of capillaries in skeletal muscle and adipose tissue. Chylomicron remnants are removed by liver via ApoB/E-receptor-mediated uptake. Endogenous triglyceride metabolism starts with the formation and secretion of very low density lipoprotein (VLDL) by the liver. This relies on de novo synthesis of triglycerides from free fatty acids (FFA) that may be derived from peripheral tissues (skeletal muscle and adipose tissue) by the action of hormone sensitive lipase. This is normally suppressed by insulin, and in situations associated with insulin resistance, or deficiency, the increase in FFA from these tissues drive increased VLDL synthesis. Each VLDL particle contains one ApoB-100 molecule and other surface apoproteins including ApoE, C-II and A-I. VLDL undergoes a similar process of lipolysis as chylomicrons, with LPL and hepatic lipase (HL) causing the release of FFA and ApoA-I and ApoC-II, which may then contribute to high density lipoprotein formation. Lipolysis of VLDL leads to the formation of intermediate density lipoprotein (IDL) and low density lipoprotein (LDL). The normal half-life of VLDL is approximately 9 h. The efficient clearance of the VLDL remnants relies on ApoE. Relative sizes of the lipoprotein particles: chylomicron, 77–1200 nm; VLDL, 30–80 nm; IDL, 25–35 nm; LDL, 18–25 nm.


The causes of a fasting hypertriglyceridaemia are broadly categorised into primary (genetic) and secondary causes, and are due to increased production of triglyceride-rich lipoproteins (endogenous (VLDL) or exogenous (CM)) and/or reduced catabolism of VLDL and CM. In clinical practice the often fine distinction between primary and secondary hypertriglyceridaemia may not greatly affect the approach to patient management.


The characteristics of the primary hypertriglyceridaemias are summarised in table 1. These are a diverse group of conditions that vary greatly in their prevalence, clinical manifestations and severity. Their phenotype is modified by other genetic and environmental factors. An absolute LPL deficiency is associated with reduced CM remnant formation, while impaired LPL activity results in increased plasma concentration of partially lipolysed triglyceride rich remnants.

Table 1 Primary hypertriglyceridaemias and lipoprotein abnormalities


A deficiency of the endothelial lipase LPL or its activating cofactor ApoC-II, or the presence of an inhibitor of LPL, may result in very high triglyceride levels, associated with chylomicronaemia (type I dyslipidaemia in the Fredrickson classification), an increased risk of acute pancreatitis and dermatological stigmata such as eruptive xanthomata. A deficiency of LPL impairs peripheral lipolysis leading to reduced formation of CM remnant particles and increased free fatty acid (FFA) delivery to the liver for VLDL formation. There is also a reduction in surface remnant release of ApoA-I and ApoA-II for HDL formation. Recent studies have indicated that genetic variants in ApoAV may be another important determinant of plasma triglyceride concentrations.10 ,11

Familial hypertriglyceridaemia

This is characterised by raised VLDL, normal or low LDL cholesterol (LDL-C) (<3.0 mmol/l) and low HDL-C (<1.0 mmol/l) levels. It has an apparent autosomal dominant mode of inheritance, though a single genetic locus has remained elusive and an oligogenetic aetiology is likely.12 Its expression is age dependent and is exacerbated by environmental factors including high-carbohydrate diets, alcohol and obesity. It is due to VLDL overproduction, though it may accompanied by reduced VLDL catabolism. The VLDL particles in familial hypertriglyceridaemia contain more triglyceride, are larger and have a higher ratio of triglyceride to ApoB (approximately 26 mg/mg or 0.29 mmol/mg) than the VLDL found in familial combined hyperlipidaemia or in normal individuals (approximately 10 mg/mg or 0.11 mmol/mg in both instances).13

Familial mixed hypertriglyceridaemia

This condition (type V dyslipidaemia in Fredrickson’s classification) is rare and characterised by elevated plasma levels of chylomicrons and VLDL due to increased synthesis and reduced catabolism. Severe hypertriglyceridaemia is usually present and individuals with this condition usually have similar clinical features as patients with familial hypertriglyceridaemia and familial hyperchylomicronaemia. Its mode of inheritance is unclear. Patients may have normal post-heparin lipoprotein lipase (LPL) and hepatic lipase activities,14 and this distinguishes it from type I dyslipidaemia. A high VLDL production is often associated with a high refined carbohydrate diet in these patients.15

Familial mixed dyslipidaemias

Familial combined hyperlipidaemia

Familial combined hyperlipidaemia is common, particularly among patients with coronary disease,16 ,17 of whom approximately 20% have this condition. It is associated with ApoB-100 overproduction, small dense LDL and delayed postprandial CM remnant clearance. At least three gene loci have been implicated,18 although the condition is likely to have a complex mode of inheritance with several other modifying genes and environmental determinants, and family members of a single pedigree may have different lipoprotein phenotypes: increased triglycerides, increased cholesterol, or both.19 The risks of coronary disease associated with familial combined dyslipidaemia and familial hypertriglyceridaemia appear to be similar, and both are associated with a high prevalence of metabolic syndrome.20

Familial dysbetalipoproteinaemia

Familial dysbetalipoproteinaemia, also termed type III dyslipidaemia, broad-β disease or remnant disease, is uncommon (<0.1% of the population). It is associated with mutations or a deficiency of ApoE and confers a significant risk of premature atherosclerosis.21 The dyslipidaemia is characterised by raised levels of intermediate density lipoprotein (IDL) that may be demonstrated on serum lipoprotein electrophoresis as a band extending between pre-β and β regions. Approximately 90% of patients with type III dyslipidaemia have an ApoE2E2 phenotype.22 This form of ApoE has a lower affinity for the LDL receptor (1%).23 However expression of the type III phenotype is dependent on the presence of a second abnormality that promotes remnant particle accumulation. This may include diabetes mellitus, excessive alcohol, obesity and pregnancy, and while approximately 1% of the population have an ApoE2E2 phenotype, only 1–2% of these individuals develop type III dyslipidaemia.24


There are a large number of causes of secondary hypertriglyceridaemia (table 2). Several of these are associated with abnormalities of insulin responsiveness, including insulin resistance, or deficiency and high levels of counter-regulatory hormones. Alcohol excess and obesity are perhaps the most prevalent causes of hypertriglyceridaemia.25

Table 2 Causes of secondary hypertriglyceridaemia

Metabolic syndrome

Metabolic syndrome is a common condition,26 with an estimated age-adjusted prevalence of 23.7% in the USA.1 Using ATP III criteria, the prevalence of metabolic syndrome in the UK is approximately 20% among Caucasians, and it is significantly higher among those from south Asia (approximately 30%).27 It appears to be increasing in prevalence worldwide. Hypertriglyceridaemia is a feature of the metabolic syndrome, that is defined by the co-existence of hypertension, central adiposity, insulin resistance with impaired glucose tolerance and low HDL-C.28 Metabolic syndrome is associated with an increased risk of cardiovascular disease (CVD), though it appears to be an even better predictor of type 2 diabetes mellitus29 and there has also been considerable debate about its clinical utility as a concept.30

In insulin resistance states, hypertriglyceridaemia is primarily due to increased hepatic VLDL production31 although increased intestinal triglyceride-rich lipoprotein production32 and a reduced clearance of VLDL as a result of impaired LPL activity33 ,34 have also been reported. There may also be an increased flux of FFAs from adipose tissue to the liver because insulin fails to suppress the activity of hormone sensitive lipase, and conversely activate LPL in adipose tissue.35 ,36

Diabetes mellitus

Patients with type 2 diabetes often have normal LDL cholesterol levels but have hypertriglyceridaemia, low HDL cholesterol,37 and increased numbers of small, dense LDL particles38 This pattern of abnormalities is likely to be due to a combination of defects including increased ApoB-VLDL secretion compounded by delayed clearance.39 In patients with uncontrolled type 1 diabetes there may be a deficiency of LPL which may cause hyperchylomicronaemia. Furthermore increased plasma FFA concentrations drive the hepatic production of triglyceride, while insulin resistance increases VLDL secretion. Insulin also controls the release of FFAs from adipose tissue and muscle via hormone sensitive lipase. In insulin resistance there is an increased secretion of triglyceride-rich VLDL (VLDL-1) and increased release of FFAs from adipose tissue and skeletal muscle.

Renal disease

Patients with chronic renal disease often develop a secondary dyslipidaemia characterised by high plasma triglycerides (high VLDL and IDL) and low HDL cholesterol concentrations that confer increased cardiovascular risk.40 CVD is a major cause of mortality in patients with chronic renal failure, accounting for up to 40–50% of deaths in patients on renal replacement therapy.41 The mechanisms for hypertriglyceridaemia in chronic renal disease are likely to be multifactorial, being associated with increased VLDL ApoB-100 production42 and reduced clearance of triglyceride rich lipoproteins mediated by HL and LPL and the VLDL receptor40 It is evident that a substantial proportion of individuals with an estimated glomerular filtration rate <60 ml/min/1.73 m2 have high plasma triglyceride concentrations,43 moreover the latter also predicts the rate of decline in renal function.44

HIV and highly active antiviral therapy

HIV infection is associated with a dyslipidaemia that is similar to that seen in other chronic infections, consisting of decreased LDL and HDL and delayed rise in triglycerides.25 ,45 However highly active antiviral therapy (HAART) is associated with more profound abnormalities of lipid metabolism including severe hypertriglyceridaemia46 particularly in those who are genetically predisposed.47 Approximately 40% of AIDS patients on HAART develop lipodystrophy.48 These changes are often associated with insulin resistance and fat redistribution syndromes that can develop in patients on HAART49 and are associated with increased cardiovascular risk.50 The dyslipidaemia is predominantly mixed/combined and less commonly isolated hypertriglyceridaemia with low HDL, or isolated hypercholesterolaemia.25 It has been proposed that a dysregulation of fatty acid metabolism is the primary abnormality with an increased flux into skeletal muscles and liver, and this is associated with intramyocellular lipid accumulation and peripheral insulin resistance and hepatic steatosis and VLDL secretion.51


The lipodystrophies are rare inherited or acquired abnormalities associated with a selective loss of adipose tissue mass that can be generalised or localised to specific regions.52 They are often accompanied by metabolic complications such as diabetes mellitus, hepatic steatosis and dyslipidaemia. Severe hypertriglyceridaemia and low HDL have been reported in more than 70% of patients with generalised lipodystrophy.53 The precise cause of dyslipidaemia in the different forms of lipodystrophy is likely to vary.52


Hypertriglyceridaemia may be detected as an incidental finding in an asymptomatic patient in the clinical laboratory, where it may be the cause of interference in the determination of other blood analytes for example serum bilirubin and electrolytes;54 in severe cases it may be associated with pseudohyponatraemia, a spuriously low plasma sodium measurement when indirect methods, including those using ion-selective electrodes, are applied.55


Although rare, eruptive xanthomatosis occurs much more frequently in patients with hyperchylomicronaemia than in patients with elevated VLDL alone.56 It appears as clusters of maculopapular lesions on the knees, elbows, neck, trunk and buttocks, and resolves fairly rapidly when plasma triglyceride concentrations are reduced. Planar, or palmar xanthomas, appear as a yellow discolouration of the palmar creases of the hands, and are pathognomonic of the combined dyslipidaemia associated with broad-β disease (type III dyslipidaemia). Tuberous or tuboeruptive xanthomas are non-painful, raised, erythematous, nodular lesions approximately 0.5 cm in diameter that may also be found in type III dyslipidaemia. Hence hypertriglyceridaemia may have diverse dermatological presentations.

Lipaemia retinalis is a rare finding due to the lactescence of blood flowing through the retinal vessels and is characteristic of hyperchylomicronaemia. This is usually found as an incidental finding in a patient presenting with one of the other features of severe hypertriglyceridaemia.


Hypertriglyceridaemia has emerged as an independent risk factor for cardiovascular disease.57 It is also associated with increased plasma concentrations of VLDL remnant particles, small dense LDL particles and low HDL cholesterol levels.5 The latter is also associated with a change in HDL particle composition, reduction in HDL particle size and a low HDL cholesterol/ApoA-I ratio.58 The decrease in LDL and HDL particle size is the result of increased neutral lipid exchanges. Cholesteryl ester transfer protein mediates the exchange of cholesteryl esters for triglycerides on HDL and LDL, and triglycerides for cholesteryl esters on VLDL. The triglyceride-enriched LDL and HDL particles are converted to small dense LDL and HDL, respectively, through the action of HL.59

From their meta-analysis, Austin and colleagues found that the risk of cardiovascular disease increased with increasing serum triglyceride levels in men and women, even after adjustment for concentrations of HDL cholesterol.57 In a more recent metanalysis the adjusted odds ratio of coronary heart disease associated with a high serum triglyceride concentration was reported to be approximately 1.7 when comparing the upper with lower tertiles for serum triglycerides among men and women without a history of myocardial infacrtion.60 It was shown in the Copenhagen Male Study61 that the risk of coronary death rose as plasma triglycerides increased to up to 2.5 mmol/l, but decreased thereafter. Data from the PROCAM study62 have also shown that cardiovascular risk rises with plasma triglycerides up to a concentration of approximately 9 mmol/l and subsequently decreases. These findings probably reflect the predominant triglyceride-rich lipoprotein fraction associated with varying levels of serum triglycerides, there being a preponderance of non-atherogenic CM particles at higher serum triglyceride concentrations, while at lower concentrations raised triglycerides are associated with the generation of the pro-atherogenic small, dense LDL particle.63

Because there are no explicit treatment targets, fasting plasma triglyceride concentrations are often omitted in the management of patients in the primary care setting. There are however clinical action limits for serum triglycerides, and these are discussed further below.


Severe hypertriglyceridaemia (hyperchylomicronaemia associated with a plasma triglyceride >11 mmol/l) may present with acute pancreatitis.55 This is a potentially very serious complication of hypertriglyceridaemia, and is associated with a high mortality rate.64 It has been estimated to be the underlying cause of acute pancreatitis in up to 7% of cases in North America.65 A significant proportion of these cases has been shown to have mutations of the LPL or lecithin:cholesterol acyltransferase genes.66 69 While hypertriglyceridaemia-induced pancreatitis is considered to be rare unless plasma triglycerides exceed 20 mmol/l,70 the presence of a less severe form of hypertriglyceridaemia (2–20 mmol/l) is not an uncommon associated feature in patients with acute pancreatitis.71 The cause of the association between hypertriglyceridaemia and pancreatitis is uncertain, but experimental models suggest that high concentrations of chylomicra impair blood flow through the pancreatic microcirculation causing ischaemia and subsequent pancreatic lipase release. High local concentrations of FFAs are generated causing tissue inflammation and necrosis.72 ,73 The identification of the underlying hypertriglyceridaemia relies on being aware of the association, and a diagnosis is often only made after recurrent attacks. Less severe forms of recurrent abdominal pain that may be associated with nausea, vomiting or dyspnoea occur in what has been described as the chylomicronaemia syndrome74 which may also be associated with neurological sequelae.75


Non-alcoholic fatty liver disease is associated with primary and secondary hypertriglyceridaemia.76 It develops either because of reduced hepatic VLDL secretion, or increased triglyceride synthesis, and is characterised by a mild elevation of serum liver enzyme concentrations (usually more than two times the upper reference value), particularly serum alanine aminotransferase,77 and diffuse fatty infiltration on liver ultrasound.76 Recent data suggest that elevated levels of serum aspartate aminotransferase (>40 U/l), γGT (γ glutamyltransferase; >40 U/l) and alanine aminotransferase and triglycerides within the upper normal reference range may identify individuals who will subsequently develop frank diabetes.78 ,79



Hypertriglyceridaemia may be found during the routine evaluation of coronary risk, or because a patient’s clinical features are suggestive of a severe underlying dyslipidaemia. While general practitioners feel confident in treating hypercholesterolaemia, they are often unsure what to do about a combined dyslipidaemia, or an isolated elevated hypertriglyceridaemia, and usually refer such patients to a lipid specialist.

An investigation algorithm for dyslipidaemia is shown in fig 2. The initial investigations aim to confirm the presence and type of dyslipidaemia after a 12 h fast, and to eliminate any treatable, secondary causes. The latter may include the identification of a drug-induced hypertrigyceridaemia80 (see table 2), which may require treatment with a lower dose of the drug or an alternative drug.25

Figure 2 Investigation protocol for hypertriglyceridaemia. BMI, body mass index; BP, blood pressure; CHD, coronary heart disease; cLDL, calculated low density lipoprotein cholesterol; FBG, fasting blood glucose; HDL, HDL cholesterol; LFTs, liver function tests (alanine aminotransferase); LPL, lipoprotein lipase; TC, total cholesterol; Tg, triglycerides; TSH, thyroid stimulating hormone; U&E, urea and electrolytes. Drug treatment cut-offs and targets will differ for patients with or without a family, or personal history of CHD, or features of severe dyslipidaemia. *These investigations will usually require to be sent to a specialist centre.

While non-fasting triglyceride concentrations have been shown to be associated with an increased risk of cardiovascular disease,81 their measurement is not currently recommended in routine practice as no reference values have been evaluated.9 The fast for 12 h is recommended because, although in healthy subjects plasma triglyceride levels attain basal values earlier than this,82 in patients with established coronary disease, or with other metabolic abnormalities, plasma triglyceride concentrations did not stabilise until at least 12 h.83 Furthermore, the utility of the triglyceride value for the determination of a calculated LDL becomes compromised (vide infra).

In patients with a severe fasting serum triglyceride concentration (>11 mmol/l), it may be useful to inspect the sample after overnight storage at 4°C. This will allow the detection of CM particles that settle as a creamy, floating layer. A type I dyslipidaemia is indicated when this is found in the presence of a clear infranatant layer and may require further non-routine investigations including assessment of post-heparin lipolytic activity and plasma ApoC-II analysis. A more precise estimation of the degree of turbidity using automated methods is probably unnecessary for classifying dyslipidaemia in patients.

A turbid serum is usually an indication of elevated levels of VLDL, and may require further non-routine investigations as indicated in fig 2. These may include ApoE genotyping for the diagnosis of type III dyslipidaemia24 and serum ApoB and lipoprotein subfractionation assays to allow discrimination between familial combined and familial hypertriglyceridaemia84 although the latter should probably be done in consultation with a lipid clinic as it requires ultracentrifugation using specialist equipment and skilled staff. After separation by ultracentrifugation the cholesterol and triglyceride content of the lipoprotein fractions may then be determined.

Management of hypertriglyceridaemia

As previously discussed, hypertriglyceridaemia is often associated with low plasma HDL-C concentrations and hence current interventions would intend to improve both abnormalities simultaneously.

Lifestyle change

Lifestyle changes including dietary modification are key features in the management of hypertrigylceridaemia. Weight control through energy restriction, a reduction in alcohol intake, and increased exercise are key components in the management of hypertriglyceridaemia and are often very effective in borderline hypertriglyceridaemia, and may be particularly useful when managing obesity.85 While a modest alcohol intake (2–3 units in men, 1–2 units in women) is acceptable in patients with borderline hypertriglyceridaemia,86 patients with very high-severe hypertriglyceridaemia should abstain from alcohol87 and may require psychological support to do so. The isoenergetic replacement of dietary fat with carbohydrate may not be effective in reducing plasma triglycerides, and indeed simple as opposed to complex dietary carbohydrates may exacerbate existing dyslipidaemia88 due to an increase in de novo triglyceride synthesis.89 This phenomenon has been termed carbohydrate induced hypertriglyceridaemia and is due to increased VLDL secretion and slower clearance.90 While a Mediterranean diet is associated with a reduction in cardiovascular events91 ,92 it does not consistently improve serum triglyceride concentrations,93 and it appears that weight loss is a major determinant of whether the lipid profile improves overall.94

Drug treatment

NCEP ATP III also recognised non-HDLC as a target for treatment in patients with triglycerides ⩾2.3 mmol/l and metabolic syndrome, because VLDL remnant particles also confer increased cardiovascular risk.95 Furthermore, the estimation of LDL-C using the Friedewald equation (LDL-C (mmol/l)  =  total cholesterol – HDL-C – total triglycerides/2.19) becomes increasingly inaccurate as triglycerides rise, and unusable for triglycerides above 4.5 mmol/l. In patients with borderline-high hypertriglyceridaemia (<5.5 mmol/l), and particularly diabetics, the principal therapeutic focus is on lowering of serum cholesterol with a statin (see table 3).96 While a fasting lipid profile is used to categorise dyslipidaemias, impaired postprandial lipid handling and enhanced postprandial hypertriglyceridaemia are recognised as important determinants of dyslipidaemia and cardiovascular risk, particularly in diabetics.97 Sadly, the measurement of postprandial lipids for diagnostic and therapeutic purposes has been severely restricted because of the difficulty in assessing postprandial lipid status in a routine clinical setting due to the large biological variation in plasma triglycerides.98

Table 3 National Cholesterol Education Program Adult Treatment Panel (ATP) III treatment goals in patients with raised plasma triglycerides (modified from Jacobson et al 96)

Specific triglyceride-lowering therapy is utilised in situations where lifestyle change alone has had, or is likely to have, insufficient impact on plasma triglyceride concentrations in patients at high risk of cardiovascular disease or pancreatitis. It may also be necessary in patients with severe dermatological manifestations of dyslipidaemia, such as tuberous xanthomata. In these circumstances, agents such as fibrates, niacin and long chain n-3 fatty acids are usually required and may need to be used cautiously in combination with each other, or with a statin. A summary of the available drug treatment options, their modes of action and efficacy is shown in table 4.

Table 4 Drugs used to reduce plasma triglycerides

When used at a high dose (4 g per day) long chain n-3 fatty acids reduce serum triglycerides substantially in patients with severe hypertriglyceridaemia.99 It appears to work by at least three mechanisms: reduced hepatic triglyceride synthesis through acyl CoA 1,2-diacylglycerol-O-transferase, enhanced peroxisomal β-oxidation in the liver mediated by peroxisome proliferator-activated receptor (PPAR)γ, and increased LPL activity (reviewed by McKinney and Sica99) and adipose tissue LPL expression.100 When used in patients with type 2 diabetes, fish oil was associated with a significant reduction in serum triglycerides and a mild elevation of LDL cholesterol101 although the reported effects on LDL particle size in diabetics are inconsistent.101 ,102

Nicotinic acid appears to act in part via a newly discovered nicotinic acid receptor.103 105 It inhibits the catabolism of ApoA-I, extending its half-life, while also inhibiting intracellular lipolysis within adipocytes, and triglyceride synthesis.106 It is thereby effective in reducing the production of triglyceride-rich lipoproteins.107 Nicotinic acid may be associated with facial flushing, an effect that is mediated by the G-protein-coupled nicotinic acid receptor and may be blocked by a prostaglandin D2 receptor antagonist.108 ,109 This has led to the prospect of a preparation with reduced flushing, currently in late clinical trials.

The PPARα activators (bezafibrate, fenofibrate, ciprofibrate and gemfibrozil) reduce triglycerides and increase HDL-C, and have a variable effect on LDL-C, though they are all less potent than statins. The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPARα-dependent stimulation of LPL and of ApoAV, and to an inhibition of ApoC-III expression, whereas the increase in plasma HDL-C depends on an increased expression of ApoA-I and ApoA-II.110 However, fibrates may be associated with an increased risk of side effects, such as myositis or frank myopathy, when used in combination with statin therapy111 and this has probably limited their wider use.112 Of the available fibrates, gemfibrozil appears most likely to be the cause of muscle-related side effects.113


Hypertriglyceridaemia is common and increasing in prevalence globally. Its aetiology is often complicated, being due to a combination of genetic and lifestyle factors. It is important to detect hypertriglyceridaemia because of its clinical sequelae, which include cardiovascular disease and pancreatitis. In addition to the benefits of therapeutic lifestyle changes, including weight loss, alcohol and dietary restriction, the treatment of hypertriglyceridaemia will often require the use of several combinations of drugs, although clinical endpoint data for such combination therapy are very limited.

Take-home messages

  • Hypertriglyceridaemia is a common heterogeneous condition predisposing to cardiovascular disease and pancreatitis.

  • It may be primary, due to genetic abnormalities, or secondary to other metabolic conditions such as diabetes or renal disease.

  • It is often associated with low levels of high density lipoprotein cholesterol.

  • Management usually requires attention to the secondary causes of the condition, changes in lifestyle and perhaps the use of triglyceride-lowering drugs.

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  • Competing interests: None.