Dr Honor Merriman discusses how a recently published consensus guideline should help healthcare professionals to assess and manage patients with hypertriglyceridaemia
  • Hypertriglyceridaemia increases the risk of cardiovascular disease and acute pancreatitis
  • Hypertriglyceridaemia may be primary or secondary in origin
  • A triglyceride level of <1.7 mmol/l is desirable
  • Patients with a triglyceride level of >20 mmol/l should be referred to a specialist
  • Patients with hypertriglyceridaemia should undergo physical examination and laboratory investigations
  • Management strategies for patients is dependent on the nature of the hypertriglyceridaemia:
    • Isolated hypercholesterolaemia
    • Combined hypercholesterolaemia and hypertriglyceridaemia
    • Isolated hypertriglyceridaemia
  • Lifestyle advice should be provided to patients with hypertriglyceridaemia
  • Pharmacological therapy options for managing hypertriglyceridaemia include statins, omega-3-acid ethyl esters, fibrate, or nicotinic acid (minimise flushing)
  • Treatment efficacy should be reviewed 8 weeks after a change in therapy

Lipid profiles, which include triglycerides, are a frequently requested blood test in primary care and are part of the cardiovascular (CV) risk assessment performed in healthy people. The detection of hypertriglyceridaemia or a raised triglyceride level does not invariably prompt action in primary care because:

  • raised triglycerides are recognised to be a risk factor for cardiovascular disease (CVD), but are not included in the Framingham,1 ASSIGN,2 and QRISK3 risk calculators so the effect of reducing triglycerides on minimising CV risk is difficult to quantify
  • the NICE guideline on lipid modification does not recommend specific treatments for raised triglycerides;4 it sets treatment thresholds for the primary prevention of CVD based on cholesterol,
    low density lipoprotein (LDL), and high density lipoprotein (HDL) levels
  • no guidance on managing this condition has been published by any national body (e.g. NICE) even though very high levels of triglycerides are associated with increased risk of developing pancreatitis5
  • some medical conditions can cause raised levels of triglycerides and may be detected for the first time through hypertriglyceridaemia. These need recognition in their own right as they are in themselves a risk factor for CVD and need to be treated individually in addition to reducing triglyceride levels (e.g. poorly controlled diabetes causes a rise in triglycerides and these are both risk factors).

A consensus guideline was therefore developed to help GPs understand the consequences of abnormally high levels of triglycerides—increased risk of CVD and acute pancreatitis—and how best to manage them by:6

  • reviewing lipid metabolism and the different types of hypertriglyceridaemia
  • providing information about management options
  • signposting suitable resources.

What are triglycerides?

Triglycerides are lipid molecules that come from two main sources: dietary fats (which enter the circulation as chylomicrons) and those synthesised by the liver, which are carried in the circulation with cholesterol as very low density lipoprotein particles (VLDL). Triglycerides are broken down in the circulation by specific enzymes for use as fuel or for re-storage in adipose tissue. Raised triglycerides can result from increased production, decreased clearance, or both.

The risk associated with raised triglycerides depends partly on the type of lipoprotein they are packaged with.7 Chylomicrons are not known to be atherogenic, but as their carrier lipoproteins are broken down by lipases, the smaller remnants become small enough to penetrate artery walls and bind to macrophages stimulating their conversion to foam cells.7 A detailed diagram of the metabolism of triglycerides can be found in the consensus guideline and makes clear the principle that a raised triglyceride level reflects the presence of several different types of lipids, with varying biological effects, in the blood.6

Triglyceride levels

Triglycerides are traditionally measured after an overnight fast to allow the dietary component to be cleared; this is part of the routine lipid profile together with cholesterol and HDL.4 Healthcare professionals should note that very high triglycerides, as found in lipaemic plasma, can interfere with the measurement of serum electrolytes.

Fasting triglyceride levels correlate positively with CVD risk, although very recent evidence suggests that non-fasting triglyceride levels (reflecting post-prandial levels) may relate more closely to risk of CVD.8,9

The consensus guideline is based on fasting blood levels as there is not yet general acceptance that non-fasting levels are helpful in patient assessment. The consensus guideline adopted a pragmatic approach to the classification of triglyceride levels (see Table 1). The Prospective Cardiovascular Münster (PROCAM) study showed that the risk of CVD increased with the level of triglycerides up to 9 mmol/l, with a lower risk above this value.10

An increase in the risk of pancreatitis was shown at triglyceride levels of above 11 mmol/l in PROCAM and other studies.11 A level of 10 mmol/l was therefore made by pragmatic consensus as a crossover point between CV and pancreatitis risks, although there is considerable variation of risk in individuals.6

Table 1: Consensus classification of triglyceride levels6
Level (mmol/l)
Description
<1.7
Desirable level
1.7–9.9
Abnormal, moderately high
10–20
Abnormal, very high
>20
Abnormal, extremely high

Causes of hypertriglyceridaemia

Familial hypertriglyceridaemia affects approximately 1 in 150 individuals.12 The lipid profile varies in affected family members with some having isolated raised triglycerides, some mixed lipaemia, and others hypercholesterolaemia.

Familial cases of hypertriglyceridaemia often have higher lipid levels than secondary causes. They are more prone to further rises in lipid level when ‘stressed’ by infection, excessive alcohol, or pregnancy, although all types of hypertriglyceridaemia can be affected by these factors. Pointers to these familial conditions are a family history of CVD and skin changes due to high lipid levels (e.g. eruptive xanthomas).6,7

Secondary hypertriglyceridaemia is much more common than primary hypertriglyceridaemia. Common secondary causes of hypertriglyceridaemia include:6

  • hypothyroidism
  • diabetes/impaired glucose tolerance
  • excessive alcohol consumption
  • obesity
  • smoking
  • liver disease
  • kidney disease
  • drugs (see Box 1).
Box 1: Medications implicated in secondary hypertriglyceridaemia6
  • Corticosteroids
  • Oestrogens (especially those taken orally, such as oestrogen replacement therapy and oral contraceptives)
  • Tamoxifen
  • Antihypertensive agents (e.g. non-cardioselective beta blockers and thiazides)
  • Retinoids (e.g. isotretinoin)
  • Bile acid-binding esters
  • Immunosuppressants (e.g. cyclophosphamide)
  • Antiretroviral regimens (especially those taken for human immunodeficiency virus infections, such as protease inhibitors)
  • Psychotropic medications (e.g. phenothiazines and second-generation antipsychotic drugs, such as chlorpromazine, clozapine, olanzapine, perphenazine, and risperidone)

Clinical assessment

Healthcare professionals should take into account the likely causes of hypertriglyceridaemia during patient assessment, which should include a history and examination to establish:6

  • smoking status
  • alcohol consumption
  • presence of family history suggestive of secondary cause of hypertriglyceridaemia
  • blood pressure
  • body mass index (BMI) or other measure of obesity
  • waist circumference13 (the consensus guideline has defined the maximum desirable circumference for different ethnic groups6)
  • skin changes suggestive of primary hyperlipidaemia
  • other signs (e.g. ankle oedema which would point to a secondary cause of hyperlipidaemia).

Investigations

The following investigations should be performed in a patient with hypertriglyceridaemia:6

  • Urine dipstick (protein could indicate nephrotic syndrome, glucose could indicate possible diabetes)
  • Blood tests:
  • fasting total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides (if fasting levels are not already available)
    • fasting blood glucose
    • renal function
    • liver function
    • thyroid-stimulating hormone
    • creatine kinase if considering fibrate therapy with or without a statin.

Lifestyle advice for people with raised triglycerides

Lifestyle interventions are the basis for managing raised triglycerides and are similar to those for people with other types of raised plasma lipid levels:4

  • Reduce waist circumference and BMI if appropriate14
  • Modify diet:
    • Reduce total calorie intake by minimising intake of carbohydrates and fats
    • Include at least two servings of fish each week, one of which should be oily fish
    • People whose triglyceride level is very high need to be on very low fat diets, which will require advice from specialist dieticians
  • Stop smoking (not only to reduce cardiovascular risk but also because smoking independently raises triglyceride levels)15
  • Increase physical activity
  • Reduce alcohol intake or abstain completely if possible.

Pharmacological management

For treatment purposes, patients with hypertriglyceridaemia can be divided into three categories:6

  • Isolated hypercholesterolaemia—increased levels of LDL cholesterol only
  • Combined hypercholesterolaemia and hypertriglyceridaemia—increased levels of LDL cholesterol and triglycerides
  • Isolated hypertriglyceridaemia—increased levels of triglycerides with relatively normal levels of cholesterol.

The management options for the above patient types are summarised in Figure 1 (see below). Patients with triglyceride levels >20 mmol/l should be referred straight away for specialist care.

Isolated hypercholesterolaemia
Patients with isolated hypercholesterolaemia should be managed according to the NICE guidelines on lipid modification and familial hypercholesterolaemia.4,16

Combined hypercholesterolaemia and hypertriglyceridaemia
Patients with triglyceride levels <20 mmol/l can be managed initially in primary care; those with higher levels should be referred straightaway for specialist care because of the high risk of acute pancreatitis. First-line treatment is with a statin (e.g. simvastatin 40 mg), which will reduce both cholesterol and triglyceride levels. Continue with this approach if statin therapy, control of concomitant conditions, and lifestyle change are effective in reducing the triglyceride level towards <1.7 mmol/l after 8 weeks.6

If triglyceride levels remain >5.6 mmol/l after 8 weeks, add omega-3-acid ethyl esters (1 g twice a day increasing to 2 g twice a day if needed) (fibrates may be considered for patients who cannot take fish-derived products or who are vegetarians).6

If triglyceride levels remain >5.6 mmol/l after another 8 weeks, a fibrate or nicotinic acid can be added.6

Fibrates reduce the synthesis of VLDL; however, there is an increased risk of myositis when a fibrate is used in combination with a statin and patients need to be aware of this.7

Nicotinic acid is an alternative to a fibrate and it also reduces VLDL, but often causes flushing. This side-effect may be minimised in a number of ways, including:6

  • starting at a low dose and titrating slowly
  • advising patients to eat a low-fat snack before taking nicotinic acid
  • advising patients to avoid alcohol and spicy foods before dosing
  • using modified-release preparations
  • advising the use of aspirin or another non-steroidal anti-inflammatory drug with (or 30 minutes before taking) nicotinic acid
  • the use of laropiprant (a combined preparation of this and nicotinic acid is available).

Isolated hypertriglyceridaemia
Refer patients who have a triglyceride level >20 mmol/l to a specialist. The treatment options for patients with levels <20 mmol/l are omega-3-acid ethyl esters and/or fibrate for 8 weeks. If triglyceride levels remain >5.6 mmol/l, replace the fibrate with modified-release nicotinic acid with or without laropiprant to minimise flushing.6

Indications for referral to secondary care

Refer if:6

  • there is a history suggestive of a familial hypertriglyceridaemia
  • initial triglyceride levels >20 mmol/l (after a repeat fasting sample)
  • there is treatment failure in primary care
  • there are problems with liver function or with raised creatine kinase where the use of primary care treatments may trigger liver disease or myositis
  • patient is pregnant with an already raised triglyceride level or where the level rises during pregnancy
  • patient is receiving treatment for human immunodeficiency virus, which can cause a rise in triglycerides.

Implementation

This consensus guideline will be invaluable to GPs who are receiving lipid results on patients who have had blood tests as part of a cardiovascular risk assessment. The guideline could be used as the basis for a practice protocol so that patients who have raised triglycerides are treated consistently by all members of the practice team.

The lifestyle changes needed to treat a patient with an abnormal triglyceride result are an essential part of patient management. It may be useful to refer patients, their carers, and families to the patient leaflet produced by NICE (www.nice.org.uk/guidance/CG67/PublicInfo/doc/English).

Summary

This new consensus guideline provides primary care clinicians with a framework so that they can:

  • define normal and abnormal levels of triglycerides
  • assess and further investigate patients to determine whether the condition is familial or secondary to another (possibly treatable) cause
  • arrange treatment for the secondary condition (e.g. kidney disease, diabetes)
  • manage patients with raised lipids levels both with lifestyle advice and with medication
  • refer patients with familial lipid disorders, those unresponsive to first-line medications, or those whose levels have been further raised by medications or pregnancy.

Ignoring an abnormal triglyceride result may result in the patient being put at increased risk of CVD or pancreatitis and so raised triglycerides should always provoke a response from the primary care clinician. This consensus guideline will help healthcare professionals who are uncertain about what action to take when their patients have abnormal blood lipid results.

Members of the working party guideline

  • Devaki Nair, Consultant Chemical Pathologist and Director, SAS Centre for Cardiovascular Biomarkers, Royal Free Hampstead NHS Trust, London
  • Honor Merriman, GP and CPD Tutor for Oxfordshire, Oxford
  • Jonathan Morrell, General Practitioner and Hospital Practitioner in Cardiology, Hastings
  • Michaela Nuttall, Cardiovascular Nurse Specialist, Bromley PCT, London
  • Vinod Patel, Consultant Physician in Endocrinology and Diabetes, George Eliot Hospital NHS Trust, Nuneaton, Warwickshire
  • Helen Williams, Consultant Pharmacist for Cardiovascular Disease, South London, Southwark Health and Social Care, London.

Acknowledgements

The author would like to thank Dr Devaki Nair, Chair of the working party guideline on Reducing the risk of cardiovascular events and acute pancreatitis through the effective management of triglycerides, for reviewing this article.

Figure 1: Algorithm for the management of hypertriglyceridaemia6
figure 1

* A review of the patient's family history is suggested if a familial nature to the disease is suspected
Fibrates can be used in place of omega-3-acid ethyl esters in vegetarians and other patients who are unable to take fish-derived products
If you are concerned about prescribing the combination of statin plus fibrate because of the increased risk of myopathy, consult your lipid clinic for advice
§ Measure creatine kinase and order liver function tests before initiating a fibrate and repeat after 8 weeks
| In patients with diabetes, nicotinic acid preparations may slightly increase levels of glycosylated haemoglobin (HbA1c) and glucose
CVD=cardiovascular disease


 

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