Hyperlipidaemia

Hyperlipidaemia is the term used to denote raised serum levels of one or more of total cholesterol, low-density lipoprotein cholesterol, triglycerides, or both total cholesterol and triglyceride (combined hyperlipidaemia). Dyslipidaemia is a wider term that also includes low levels of high-density lipoprotein cholesterol.¹ Many types of hyperlipidaemia carry an increased risk of cardiovascular disease (CVD). High-density-lipoprotein cholesterol (HDL-C) however confers protection. Generally the risk of coronary heart disease (CHD) rises as the ratio of total cholesterol (TC) to HDL-cholesterol (HDL-C) rises.

• The UK population has one of the highest average serum cholesterol levels in the world.¹
• Two-thirds of people have a serum cholesterol level greater than 5.2 mmol/L.²
• Low levels of high-density lipoprotein cholesterol are often associated with raised triglyceride levels (e.g. in familial combined hyperlipidaemia, and in dyslipidaemia in Type 2 diabetes).
• Heterozygous familial hypercholesterolaemia is one of the most common familial conditions, with a prevalence of about 1 in 500. Homozygous familial hypercholesterolaemia is rare. Familial combined hyperlipidaemia occurs in about 1 in 100 people.³

Epidemiological evidence suggests a:⁴

• 1% increase in CHD risk for each 1% increase in LDL cholesterol.
• 2-3% reduction in CHD risk for each 1% increase in HDL cholesterol.

Cholesterol and other lipid levels vary according to age, sex, nutrition, lifestyle and genetic factors. Most commonly, hypercholesterolaemia results from nutritional factors such as obesity and diets loaded with saturated fat, combined with an underlying polygenic predisposition.

More rarely, consider a genetic cause. Most familial dyslipidaemias go undiagnosed but if identified can enable more effective prevention and treatment in individuals and their families - where suspected, refer to secondary care.

• Medical conditions e.g. hypothyroidism, obstructive jaundice, Cushing's syndrome, anorexia nervosa, nephrotic syndrome, diabetes mellitus, renal failure
• Drugs e.g. thiazide diuretics, glucocorticoids, ciclosporin, anti-retroviral therapy, beta-blockers, combined oral contraceptive pill, atypical anti-psychotics, retinoic acid derivatives
• Pregnancy
• Obesity
• Alcohol abuse

Apoprotein disorders: lipids are insoluble in plasma. They combine with special proteins called apoproteins (apolipoproteins) to form lipoproteins which are soluble in plasma. There are some rare disorders of apoproteins which can also cause lipid disorders.⁸
Before considering pharmacological treatment of dyslipidaemias, always try to identify and correct/optimise any secondary or contributory causes.

• Total cholesterol: fasting samples are not strictly necessary. A mild or moderate elevation in LDL-cholesterol with a concomitant reduction in HDL-cholesterol can result in a normal total cholesterol level, which can be misleading. A fasting sample should however be taken in patients who have non-fasting cholesterol levels that would require treatment, or are being investigated for dyslipidaemia.
• LDL Cholesterol: a fasting sample is required for an accurate result. This is not a standardised test. The gold standard ultracentrifugal measurement of LDL is time consuming and expensive and requires specialist equipment. For this reason, LDL-cholesterol is commonly estimated from quantitative measurements of total and HDL-cholesterol and plasma triglycerides (TG) using the empirical relationship of Friedewald (all values in mmol/L):⁹

  LDL-cholesterol = (Total cholesterol) - (HDL-cholesterol) - (TG / 2.2)

  
  The Friedewald equation should not be used under the following circumstances:^10,11
  • when chylomicrons are present
  • when plasma triglyceride concentration exceeds 400 mg/dL (4.52 mmol/L)
  • in patients with dysbetalipoproteinemia (type III hyperlipoproteinemia).
• HDL Cholesterol: the measurement is not standardised and there are generally only small differences between normal and abnormal levels. However the ratio of total serum cholesterol:HDL cholesterol is used in the coronary risk prediction charts.
• Triglycerides: plasma triglycerides rise dramatically after a meal so a fasting sample is required.
• Fasting blood glucose: this should be done to exclude hyperlipidaemia secondary to diabetes mellitus.
• Renal function: this should be done to exclude chronic kidney disease.
• Liver function tests (transaminases): to rule out liver disease in the event of a statin having to be initiated (raised transaminases should not preclude the use of a statin if levels are less than three times the upper limit of normal).
• TSH: this should be done if dyslipidaemia is present, to exclude myxoedema.

The Fredrickson Classification (now seldom used) lists five types of hyperlipidaemia (Fredrickson I to V):

• Type I - Normal or slightly raised cholesterol with very high triglycerides, xanthoma, hepatosplenomegaly & pancreatitis. It is not usually associated with cardiovascular disease.
• Type IIa - High cholesterol with normal triglyceride levels, xanthoma, xanthelasma and corneal arcus. It is hereditary and carries a very high risk of premature cardiovascular disease.
• Type IIb - Similar to type IIa, raised cholesterol and triglycerides. It is also associated with premature development of arterial disease.
• Type III - Raised cholesterol and triglycerides, xanthomas, often associated with obesity, hyperuricaemia and an impaired GTT. There is an increased risk of coronary artery and peripheral vascular disease.
• Type IV - Raised triglycerides, atheroma, raised uric acid, xanthoma, liver and spleen enlargement and often an impaired GTT. It is induced by a high fat/carbohydrate diet and is associated with gout and nephrotic syndrome. It may be familial but more often is seen secondary to diabetes mellitus, obesity, pancreatitis, alcoholism and hypothyroidism.
• Type V - Raised triglycerides, xanthoma and often an abnormal glucose tolerance test. It is induced by a high fat/carbohydrate diet and may accompany diabetes mellitus, pancreatitis and alcoholism. It is not usually associated with premature cardiovascular disease.

Non-drug

• Diet can decrease both cholesterol and triglycerides levels.
  • Total fat intake should be 30% or less of total energy intake.
  • Saturated fats should be 10% of less of total energy intake.
  • Dietary cholesterol should be less than 300 mg/day.
  • Saturated fats should be replaced by monounsaturated or polyunsaturated fats.
  • Five portions of fruit and vegetables should be eaten per day.
  • Two portions of fish should be eaten per week, including a portion of oily fish.
  • Advise pregnant women to limit their intake of oily fish to two portions a week.
  • Do not routinely recommend omega-3 fatty acid supplements or plant sterols and stanols for primary prevention.
• Other appropriate measures include weight reduction, regular physical exercise, and, when appropriate, additional measures to reduce cardiovascular risk such as smoking cessation, alcohol reduction and blood pressure and blood glucose control.

Drugs^3,5

• Statins:
  • NICE recommends simvastatin as first line therapy, but allows for use of other statins with similar acquisition costs. Other options include atorvastatin, fluvastatin, pravastatin, and rosuvastatin.
  • Simvastatin should be initiated at a dose of 40 mg unless potential drug interactions or contra-indications are an issue, in which case a lower dose of simvastatin or pravastatin should be offered.
  • Statins reduce coronary events, all cardiovascular events, and total mortality. They should be considered for primary and secondary prevention (see table above for categories of patients).
  • Statins produce benefits irrespective of the initial cholesterol concentration but patients with a total serum-cholesterol concentration of 5 mmol/L or greater are likely to benefit most.¹⁴
• Fibrates: bezafibrate, ciprofibrate, fenofibrate and gemfibrozil.
  • These should be considered in patients in whom statins are not tolerated.
  • Mainly decrease serum triglycerides, with variable effects on LDL-cholesterol.
  • They may reduce the risk of coronary heart disease events in those with low HDL-cholesterol or with raised triglycerides.
  • All can cause a myositis-like syndrome, especially in patients with impaired renal function. There is an increased risk of rhabdomyolysis when used in combination with a statin.¹⁴
  • Results from trials relating to use of fibrates in diabetic patients have been disappointing.
• Ezetimibe:¹⁵
  • Ezetimibe works by Inhibiting the intestinal absorption of cholesterol.
  • Ezetimibe monotherapy is recommended as an option for the treatment of adults with primary (heterozygous-familial or non-familial hypercholesterolaemia who cannot tolerate statin therapy or in whom they are contraindicated.
  • It can be co-prescribed with statin therapy in patients with primary hypercholesterolaemia when the serum total or low-density lipoprotein (LDL) cholesterol concentration is not appropriately controlled after appropriate dose titration of initial statin therapy or because dose titration is limited by intolerance to the initial statin.
• Anion-exchange resins:¹⁴
  • Cholestyramine and colestipol act by binding bile acids, preventing their reabsorption. The resultant increased LDL-receptor activity of liver cells increases the clearance of LDL-cholesterol.
  • Both drugs effectively reduce LDL-cholesterol but can aggravate hypertriglyceridaemia.
  • They can be offered as an alternative for primary and secondary prevention to patients where statins are not tolerated or contraindicated.⁵
• Nicotinic acid:
  • Role in treatment is limited by its side-effects, especially vasodilatation.
  • NICE advise that nicotinic acid may have a role in secondary prevention of CVD in patients intolerant of statins, but it should not be prescribed for primary prevention.⁵
  • Acipimox has fewer side-effects than nicotinic acid but may be less effective in its lipid-modulating capabilities.¹⁴ It is not mentioned in the NICE guidance on lipid modification.
• Omega-3 fatty acid compounds (commonly known as fish oils):¹⁴ NICE advise that these should not be offered routinely either alone or in combination with a statin for the primary prevention of CVD.⁵
• Plant sterols and stanols:⁵
  NICE do not recommend that these are prescribed routinely for the primary prevention of CVD. Although sterols and stanols have been shown to reduce total cholesterol, further research is required to demonstrate whether this translates into a reduction in CVD.

• Consider reducing dosage or stopping statin treatment if there is a temporary likelihood of drug interaction or concomitant illness that interferes with the metabolic pathway.
• Creatine kinase should be measured in people complaining of muscle symptoms, but not as a matter of routine.
• Baseline LFTs should be measured at start of treatment and then three months and twelve months after initiation. Further measurements are not necessary unless clinically indicated.
• People who have liver enzymes (transaminases) that are raised but are less than 3 times the upper limit of normal should not be routinely excluded from statin therapy.
• Patients who are on statins and who develop peripheral neuropathy should be referred to a specialist.
• Once patients have been started on lipid therapy for primary prevention, repeat testing is not necessary. Review of medication and further testing should be guided by patient preference and clinical judgement.

Other notes⁵

• Combinations of a statin with an anion exchange resin, nicotinic acid or a fibrate carry an increased risk of side-effects (including rhabdomyolysis) and NICE does not recommend them for the primary prevention of CVD.
• NICE considers that the case for the cost effectiveness (including adverse events) of higher intensity statins (either alone or in combination with other classes of drug) to reduce CVD events by treating to target levels of total cholesterol of either 5 mmol/L or 4 mmol/L (or comparable LDL cholesterol levels) has yet to be proved.

• About 46% of deaths due to coronary heart disease (CHD) may be attributable to raised serum cholesterol.
• People with heterozygous familial hypercholesterolaemia have a four-fold increased risk of CHD.
• People with familial combined hyperlipidaemia also have an increased risk of CHD, but CHD usually only presents after the age of 60 years.
• Very severe hypertriglyceridaemia (more than 10 mmol/L) is a risk factor for pancreatitis.
• Decreased levels of serum HDL cholesterol (HDL-C) are also an independent risk factor for CHD.

These include:

• Suspected familial hypercholesterolaemia: TC greater than 7.5 mmol/L (or LDL-C greater than 4.9 mmol/L) and at least one of the following:
  • Tendon xanthomata in patient or in a first- or second-degree relative
  • Family history of premature coronary heart disease
  • Family history of TC greater than 7.5 mmol/L
• Suspected familial combined hyperlipidaemia, i.e. mixed hyperlipidaemia and a family history of hyperlipidaemia or premature CHD
• Failure of therapy: failure to meet target lipid reduction despite maximally tolerated therapy
• Severe hypercholesterolaemia: initial TC greater than 10 mmol/L
• Very severe hypertriglyceridaemia: triglycerides greater than 10 mmol/L