For primary prevention of cardiovascular disease (CVD):

• Offer lipid modification therapy if the person's estimated 10-year risk of developing cardiovascular disease (CVD) is 20% or more.
• Prescribe a statin, unless this is contraindicated. Simvastatin 40 mg daily is the first-line choice.
• Consider a lower dose of simvastatin or an alternative statin (e.g. pravastatin 40 mg daily) if there are potential drug interactions or simvastatin 40 mg is contraindicated.
• Consider offering a fibrate or a bile acid sequestrant if a statin is not suitable.
• Evidence supporting the use of these drugs for primary prevention is poor compared to statins.
• Repeating lipid measurement is unnecessary. A target for total or low-density lipoprotein (LDL) cholesterol is not recommended.

For secondary prevention of CVD:

• Offer lipid-modification therapy to all adults with cardiovascular disease.
• Prescribe a statin, unless this is contraindicated. Simvastatin 40 mg daily is the first-line choice.
• Consider a lower dose of simvastatin or an alternative statin (e.g. pravastatin 40 mg daily) if there are potential drug interactions or simvastatin 40 mg is contraindicated (e.g. in people with renal impairment).
• Higher intensity statins (simvastatin 80 mg or atorvastatin 80 mg) should only be considered first-line for people with acute coronary syndrome.
• Offer a fibrate, nicotinic acid or a bile acid sequestrant if a statin is not suitable.
• Evidence supporting the use of these drugs for secondary prevention is poor compared to statins.
• Consider the use of higher intensity lipid-modifying treatment if a target total cholesterol of less than 4 mmol/L, or an LDL cholesterol of less than 2 mmol/L, has not been achieved.
• Any decision to offer a higher intensity statin should take into account the person's preference and tolerability, comorbidities, multiple drug therapy, and the benefits and risks of treatment.

Advice:

• Advise the person to seek medical advice and to stop the lipid-modifying drug if they develop unexplained muscle symptoms (pain, tenderness, weakness).
• Check creatine kinase.
• Stop the lipid-modifying drug immediately if muscle symptoms are severe or if creatine kinase is five times or more the upper limit of normal.

When to refer:

• Refer people with suspected familial hypercholesterolaemia or other monogenic familial disorders for specialist management.
• Considering specialist advice when managing people e.g. with complex lipid disorders.

• Offer lipid-modification therapy if the person's estimated 10-year risk of developing cardiovascular disease (CVD) is 20% or more:
• If the person is less than 75 years of age and does not have Type 2 diabetes, see the CKS topic on CVD risk assessment and management for information on how to estimate CVD risk.
• If the person has Type 2 diabetes, see the CKS topic on Diabetes type 2.
• If the person is 75 years of age or older, assume they are at increased risk of CVD. The decision to offer lipid-modification therapy should be guided by the likely benefits and risks, comorbidities that may make treatment inappropriate, and informed individual preference.
• Refer people with suspected familial hypercholesterolaemia or other monogenic familial disorders for specialist management.

For people with a 10-year cardiovascular disease (CVD) risk of 20% or greater:

• The recommendation to offer lipid-modification therapy for these people is based on guidance issued by the National Institute for Health and Clinical Excellence (NICE) on lipid modification and an earlier NICE Technology Appraisal of statins for the prevention of cardiovascular events [NICE, 2006; NICE, 2008a].
• Taking into consideration the reductions in the cost of some statins, NICE found statins to be cost effective for all age groups (including people older than 75 years of age) at a 20% or greater 10-year risk of CVD.
• For further information, see First-line therapy.

For people with a 10-year CVD risk of less than 20% (without abnormal lipids profile or genetic lipid disorders):

• NICE does not recommend statins for primary prevention for these people because [NICE, 2006; NICE, 2008a]:
• Although analysis indicates that it might be cost effective to initiate statins in this group, NICE is concerned by the uncertainty of the evidence (most of the clinical trials did not include people at very low risk of a cardiovascular event) and the risk of adverse events associated with lifelong statin treatment in a large population at low risk of CVD.
• Consequently, given these considerations and the need to consider the effective use of NHS resources (considering the potentially large eligible population), NICE concluded that initiation of statins for primary prevention of CVD is most appropriate in people with a 20% or greater 10-year CVD risk.

For people (without genetic lipid disorders) with an elevated total cholesterol to high-density lipoprotein (HDL) cholesterol ratio and a 10-year CVD risk of less than 20%:

• CKS is unable to recommend a specific total cholesterol:HDL ratio threshold for initiating lipid modification therapy due to a lack of evidence and expert consensus. Consequently, the decision to offer treatment will based on clinical judgement and informed individual preference.
• The Joint British Societies (JBS) guideline recommend offering lipid modification therapy to people with a total cholesterol:HDL cholesterol ratio of 6.0 or more [British Cardiac Society et al, 2005]. This is based on expert opinion.
• However, the Scottish Intercollegiate Guidelines Network (SIGN) highlight that this, and other recommendations proposed by JBS for primary prevention, would widen the groups to be prescribed statins, raising a number of clinical and economic concerns (e.g. the lack of supporting evidence which is unlikely to be made available from clinical trials) [SIGN, 2007].
• Neither NICE or SIGN make any recommendation regarding an appropriate total cholesterol:HDL ratio target for initiating lipid modification therapy [SIGN, 2007; NICE, 2008a].
• Feedback from expert reviewers was conflicting.

• Measures to reduce the risk of cardiovascular disease are discussed in detail in the CKS topic on CVD risk assessment and management.
• Manage other modifiable risk factors, such as smoking, high blood pressure, and obesity.
• Wherever possible, the management of these modifiable risk factors should be optimized before offering lipid modification therapy.
• Manage secondary causes of dyslipidaemia (e.g. hypothyroidism).
• Consider whether antiplatelet treatment (e.g. low dose aspirin) is indicated (not licensed for primary prevention of CVD). For further information, see the CKS topic on Antiplatelet treatment.
• Provide lifestyle and dietary advice such as increased physical activity, reduction of alcohol consumption, and adoption of a cardioprotective diet.
• See the section lifestyle and dietary advice in the CKS topic on CVD risk assessment and management.

• These recommendations are based on guidance issued by the National Institute for Health and Clinical Excellence (NICE) [NICE, 2008a].

• Perform the following tests (if not already done as part of the cardiovascular risk assessment):
• Two lipid measurements — at least one fasting lipid sample taken to measure total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides.
• A liver function test (transaminases): if these results are abnormal, further investigation is required to determine the cause of the abnormal test results (e.g. alcohol abuse).
• People who have liver enzymes that are elevated, but are less than three times the upper limit of normal, should not be routinely excluded from statin therapy.
• Renal function: chronic kidney disease does not preclude the use of a statin. However, the dose of some statins should be adjusted in people with moderate or severe renal insufficiency.
• Fasting blood glucose.
• Creatine kinase is recommended if the person is at high risk of muscle toxicity (e.g. older people, or when combining a statin with a drug known to increase myotoxicity) but this is not routinely necessary in other people.
• Serum thyroid stimulating hormone (if dyslipidaemia is present).

• These recommendations are based on guidance from the National Institute for Health and Clinical Excellence (NICE) and the Scottish Intercollegiate Guidelines Network (SIGN) [SIGN, 2007; NICE, 2008a].
• Repeated lipid measurement:
• The NICE Guidance Development Group (GDG) recognized that there is variability in lipid measurement due to day-to-day physiological, laboratory, and statistical variation [National Collaborating Centre for Primary Care, 2008a].
• Because of the individual variation in a single lipid measurement, repeated measurement will give greater precision. However, NICE accepted that, in routine practice, serial replicate testing is not feasible and clinicians often base monitoring decisions on one measurement, and treatment decisions on two measurements, accepting the imprecision.
• Need for a fasting lipid measurement before starting lipid modification treatment:
• This is based on the expert opinion of the NICE GDG which acknowledged that there was no substantive evidence to support the view that a fasting specimen is advantageous before starting treatment [National Collaborating Centre for Primary Care, 2008a].
• However, they recognized that many clinicians view low-density lipoprotein (LDL) cholesterol and triglycerides as an important adjunct to clinical management because they may inform diagnosis and are a baseline against which the progress and effectiveness of treatment can be judged.
• Liver function:
• This is to exclude possible contraindication to treatment with statins or other lipid–modifying drugs. Statins are contraindicated in people with active liver disease or persistently abnormal liver function tests.
• Pretreatment baseline creatine kinase (CK) only for people at high risk of muscle toxicity:
• NICE does not make any recommendation regarding the need for pretreatment, baseline CK measurement [NICE, 2008a].
• This recommendation is based on that from SIGN [SIGN, 2007], following the consensus recommendations issued by the National Lipid Association Statin Safety Task Force [McKenney et al, 2006; SIGN, 2007]. This recommendation was based on assessment of evidence from the US Food and Drug Administration (FDA), cohort and clinical trials, and administrative claims database information.
• Fasting blood glucose:
• Although it is not required for cardiovascular risk calculation, it is recommended for diagnosis of impaired glucose regulation and diabetes [British Cardiac Society et al, 2005].
• Serum thyroid stimulating hormone should be checked if dyslipidaemia is present because:
• Hypothyroidism is a recognized cause of dyslipidaemia [BTA et al, 2006].
• In addition, untreated hypothyroidism increases the risk of statin-induced myopathy [Bar et al, 2007].

• A target for total cholesterol or low-density lipoprotein (LDL) cholesterol is not recommended for primary prevention of cardiovascular disease.

• The National Institute for Health and Clinical Excellence (NICE) does not recommend the use of target levels of cholesterol for people taking statins for primary prevention of cardiovascular disease. This is because it found no clinical trials in primary prevention that have evaluated the relative and absolute benefits of achieving different cholesterol targets in relation to clinical events [National Collaborating Centre for Primary Care, 2008a; NICE, 2008a].

• Prescribe a statin, unless this is contraindicated.
• If statin treatment is appropriate, it should be offered as soon as practicable after a full risk assessment.
• Simvastatin 40 mg daily is the first-line choice.
• Consider a lower dose of simvastatin or an alternative statin (e.g. pravastatin 40 mg daily) if there are potential drug interactions or if simvastatin 40 mg is contraindicated (e.g. in people with renal impairment).
• Do not offer higher intensity statin therapy (e.g. simvastatin 80 mg daily), or a combination of a statin and other lipid-modifying treatment (including fish oil supplements), for the primary prevention of cardiovascular disease.

• These recommendations reflect guidance issued by the National Institute for Health and Clinical Excellence (NICE) [NICE, 2008a] and are based on an earlier NICE Technology Appraisal on statins for the prevention of cardiovascular events [NICE, 2006].
• Statins for primary prevention:
• When considering lipid modification therapy in primary prevention, preference was given by NICE to drugs for which there is evidence in clinical trials of a beneficial effect on cardiovascular morbidity and mortality.
• Statins are recommended first-line by NICE for primary prevention because there is good evidence from meta-analyses that statins are associated with a significant reduction (compared with placebo) in the risk of all-cause mortality, fatal and non-fatal myocardial infarction, stable angina, and a composite endpoint of coronary heart disease death plus non-fatal myocardial infarction.
• The evidence for other drugs (e.g. bile acid sequestrants, ezetimibe, and fibrates) is less robust.
• Safety of statin therapy:
• NICE found good safety data for the use of statins.
• Evidence from two large meta-analyses indicates that serious muscular (e.g. rhabdomyolysis, myopathy) and liver (e.g. abnormal liver function tests) adverse effects are infrequent with statin therapy.
• Evidence from another meta-analysis (involving 86,936 participants) found statins to have a neutral effect on cancer and cancer death risks. No type of cancer was affected by statin use, and no subtype of statin affected the risk of cancer.
• Choice of statin:
• NICE recommends that, when the decision has been made to prescribe a statin, therapy should usually be initiated with a drug with a low acquisition cost (taking into account the required daily dose and product price per dose) [NICE, 2008a].
• Cost effectiveness analysis undertaken by the NICE Guidance Development Group indicates both simvastatin 40 mg and pravastatin 40 mg to be cost effective options for the primary prevention of cardiovascular disease (CVD); these are considered to be the most effective preparations at the lowest acquisition cost [National Collaborating Centre for Primary Care, 2008a].
• Where there is potential for drug interactions, pravastatin is recommended as an alternative to simvastatin because, unlike simvastatin, it is not significantly metabolized by cytochrome P450 isoenzymes.
• Note: for pravastatin, the dose of 40 mg daily was the only studied starting and maintenance dose used in all the preventive morbidity and mortality trials [ABPI Medicines Compendium, 2005b].
• Higher intensity statin therapy and combination therapy with statin:
• These are not recommended because NICE found no evidence to support the clinical effectiveness of higher intensity statins (e.g. simvastatin 80 mg daily) and of combining statins with other lipid-modifying drugs (e.g. bile acid sequestrant, fibrate, nicotinic acid, or fish oil supplement) for primary prevention of CVD [National Collaborating Centre for Primary Care, 2008a].

• Consider offering a fibrate or a bile acid sequestrant if a statin is contraindicated or not tolerated.
• The decision to select a particular lipid-modifying drug should take into account patient preference and tolerability, comorbidities, multiple drug therapy, and the benefits and risks of treatment.
• Table 1 lists some of the factors influencing drug choice when considering an alternative to a statin.

• For more information on these drugs (e.g. preferred drug choice and dosage), see prescribing information for Bile acid sequestrants and Fibrates.

Fibrates and bile acid sequestrants:

• The National Institute for Health and Clinical Excellence (NICE) recommends that a fibrate or bile acid sequestrant should be considered for primary prevention of CV events if a person cannot tolerate a statin [NICE, 2007; NICE, 2008a].
• The evidence for bile acid sequestrants and fibrates is less robust than that for statins in the primary prevention of CV events [National Collaborating Centre for Primary Care, 2008a].
• NICE does not state any preference when deciding whether to offer a fibrate or a bile acid sequestrant [National Collaborating Centre for Primary Care, 2008a]. CKS recommends that choice be based on comorbidities, potential for drug interactions, possible adverse effects, and patient preference.

Nicotinic acid:

• Nicotinic acid preparations are not recommended because the NICE Guideline Development Group did not find any randomized controlled trials that compared nicotinic acid with placebo in people at high risk of CVD which reported cardiovascular event outcomes [National Collaborating Centre for Primary Care, 2008a].

Ezetimibe:

• CKS does not currently recommend the use of ezetimibe for primary prevention of CVD because:
• There is no evidence to support this use. Ezetimibe is not licensed for primary prevention of cardiovascular events.
• None of the trials (except one) reported any health-related quality of life or clinical endpoints such as cardiovascular morbidity and mortality.
• Only the SEAS trial reported cardiovascular outcomes [Rossebo et al, 2008]. However, it found no difference in major cardiovascular events, overall mortality and secondary outcomes between people (with mild-to-moderate asymptomatic aortic stenosis) who received simvastatin only or a combination of simvastatin and ezetimibe.
• There is some concern about the risk of cancer with ezetimibe. Although there is currently insufficient evidence to draw any conclusions about the effect of ezetimibe on cancer, the Commission on Human Medicines (CHM) will review this issue when the results of two large ongoing ezetimibe trials become available [MHRA, 2008]. Consequently, CKS advises caution until this issue is clarified.

Plant stanols and steroids:

• These are not recommended because the NICE Guideline Development Group did not identify any randomized controlled trials that investigated their effectiveness in the primary prevention of cardiovascular events [National Collaborating Centre for Primary Care, 2008a].

Omega-3 fatty acid supplements:

• These are not recommended by NICE because there is insufficient evidence to recommend omega-3 fatty acid supplementation for people at high risk of CVD.
• See the section Omega-3 fatty acid supplements in the CKS topic on CVD risk assessment and management.

• Repeat lipid measurement is unnecessary.
• However, clinical judgement and patient preference should guide the review of drug therapy and whether to review the lipid profile (e.g. to assess compliance).
• For people taking statins, recheck liver function tests (LFTs) within 3 months of starting treatment, and again at 12 months. Further monitoring is not necessary unless clinically indicated (e.g. symptoms or signs of hepatotoxicity).
• If LFTs are abnormal, see Abnormal LFT results regarding management.
• Monitor for adverse effects of lipid modification therapy:
• If they develop unexplained muscle symptoms (pain, tenderness, weakness):
• Check creatine kinase (CK).
• Stop the lipid-modifying drug immediately if muscle symptoms are severe or if CK is five times or more the upper limit of normal.
• For further information on managing abnormal CK results with statins, see Raised creatine kinase.
• Note: people should be advised to seek medical advice and to stop the lipid-modifying drug if they develop unexplained muscle symptoms.
• For people on a statin:
• Discontinue the statin and seek specialist advice if they develop unexplained peripheral neuropathy.
• Advise them to seek medical advice if they develop presenting features of interstitial lung disease such as dyspnoea, non-productive cough, and deterioration in general health (e.g. fatigue, weight loss, and fever).
• For further information, see Adverse effects.

• Statins and other lipid-modifying drugs can rarely cause myopathy and rhabdomyolysis. The exact mechanism is uncertain, but risk factors include [CSM, 2004]:
• Underlying muscle disorders.
• Renal impairment.
• Untreated hypothyroidism.
• Alcohol abuse.
• Older age (more than 70 years of age).
• Concomitant use of other lipid modification therapy (i.e. fibrates, nicotinic acid).
• A history of myopathy with any lipid modification therapy.
• Drug interactions (e.g. with drugs inhibiting cytochrome P450 enzymes).

• These recommendations are based on those issued by the National Institute for Health and Clinical Excellence (NICE) [NICE, 2008a].
• Repeat lipid measurement:
• Repeat lipid measurement is unnecessary after initiating a statin or other lipid-modifying drug, because NICE does not recommend a target for total or low-density lipoprotein (LDL) cholesterol for people who are treated with a statin for primary prevention of cardiovascular disease (CVD). For further information, see Lipid targets.
• However, NICE does not exclude repeat lipid measurement, adding that clinical judgement and patient preference should guide the review of drug therapy and whether to review the lipid profile [NICE, 2008a].
• Muscular events (rhabdomyolysis and myopathy):
• These are rare but serious adverse effects of lipid-modifying drugs.
• The Commission on Human Medicines and NICE advise that people receiving a statin should be asked to report muscle pain, weakness, or cramps immediately and to stop treatment until this has been investigated [CSM, 2004; NICE, 2008a].
• CKS advises that the same warning should be used for other lipid-modifying drugs (except bile acid sequestrants) because rhabdomyolysis and myopathy have been reported for these drugs and the manufacturers advise similar warnings.
• Repeat liver function tests:
• The recommendation to repeat liver function tests within 3 months of starting statin treatment and again at 12 months is based on expert consensus of the NICE Guidance Development Group [NICE, 2008a].
• Evidence for the monitoring of liver function tests is sparse.
• Repeat liver function testing is also recommended by other experts [Smellie, 2006; Bhatnagar et al, 2008].
• CKS did not find any evidence to support the need for long-term monitoring of liver function in people taking a statin (e.g. for more than 12 months).

• Refer people with suspected familial hypercholesterolaemia (FH) or other monogenic familial disorders for specialist management.
• Consider the possibility of FH in adults with elevated cholesterol (total cholesterol typically greater than 7.5 mmol/L), especially when there is a personal or family history of premature coronary heart disease.
• A diagnosis of FH should be made using the Simon Broome criteria.
• Confirm the diagnosis by referral to a specialist.
• Consider a clinical diagnosis of homozygous FH in adults with a low-density lipoprotein cholesterol concentration greater than 13 mmol/L.
• Note: a CKS topic on familial hypercholesterolaemia is currently under development.
• Consider seeking specialist advice in managing people with:
• Severe hyperlipidaemia.
• Mixed hyperlipidaemia.
• Serum triglyceride level greater than 10 mmol/L.
• Resistant hyperlipidaemic states.
• Secondary hyperlipidaemia (see Clarification for further information).
• Abnormal pretreatment liver enzymes or creatine kinase activity.
• Multiple drug intolerance (to lipid-modifying drugs).
• Lipodystrophy syndromes.
• Dyslipidaemia related to HIV.
• People taking complex combinations of drugs with high risk of serious drug interaction with lipid modification therapy.

• Secondary hyperlipidaemia
• Causes of secondary hyperlipidaemia include [Bhatnagar et al, 2008]:
• Nephrotic syndrome
• Obstructive jaundice
• Hypothyroidism
• Cushing's syndrome
• Anorexia nervosa
• Thiazide diuretics
• Ciclosporin
• Consider seeking specialist advice regarding management where appropriate.

• People with severe hyperlipidaemia, suspected familial hypercholesterolaemia (FH) or other monogenic familial disorders:
• The recommendation to refer these people are based on the expert opinion of the National Institute for Health and Clinical Excellence (NICE) Guidance Development Group. NICE found no good evidence to guide which individuals, with which lipid disorders, should be referred for specialist assessment and management [National Collaborating Centre for Primary Care, 2008a].
• The criteria for diagnosing suspected familial hypercholesterolaemia are based on those issued by NICE (which include the use of Simon Broome diagnostic criteria) [NICE, 2008b].
• People with triglyceridaemia greater than 10 mmol/L:
• Specialist advice is recommended as these people have a very high risk of pancreatitis [British Cardiac Society et al, 2005]. They should be referred to lipid clinics for treatment [Bhatnagar et al, 2008].
• Other groups:
• The recommendation to seek specialist advice for the other patient groups is based on expert opinion [Bhatnagar et al, 2008].

• Offer lipid modification therapy to all adults with cardiovascular disease (e.g. people with a past or current history of myocardial infarction, angina, stroke, transient ischaemic attack, or peripheral arterial disease).

• These recommendations are based on those issued by the National Institute for Health and Clinical Excellence (NICE) [NICE, 2008a] which were based on an earlier NICE Technology Appraisal of statins for the prevention of cardiovascular events [NICE, 2006].
• NICE concluded that statins are clinically effective and cost effective for people with cardiovascular disease (CVD) [NICE, 2006]:
• There is good evidence that statins reduce all-cause mortality, CVD mortality, coronary heart disease mortality, fatal myocardial infarction, and coronary revascularization, when compared with placebo, in people with coronary heart disease.
• Sensitivity analysis undertaken by NICE indicates a high probability (greater than 85%) that statin therapy is cost effective for all people with a history of cardiovascular disease.

• Measures to reduce the risk of cardiovascular disease are discussed in detail in the CKS topic on CVD risk assessment and management.
• Manage other modifiable risk factors, such as smoking, high blood pressure, and obesity.
• Do not delay offering lipid-modification therapy by the management of these modifiable risk factors.
• Manage secondary causes of dyslipidaemia (e.g. hypothyroidism).
• Prescribe appropriate antiplatelet treatment (e.g. low dose aspirin: for further information, see the CKS topic on Antiplatelet treatment).
• Provide lifestyle and dietary advice such as increased physical activity, reduction of alcohol consumption, and adoption of a cardioprotective diet.
• See the section lifestyle and dietary advice in the CKS topic on CVD risk assessment and management.

• These recommendations are based on guidance issued by the National Institute for Health and Clinical Excellence (NICE) [NICE, 2008a].

• Perform the following tests (if not already done as part of the cardiovascular risk assessment):
• Two lipid measurements — at least one fasting lipid sample taken to measure total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides.
• A liver function test (transaminases): if these results are abnormal, further investigation is required to determine the cause of the abnormal test results (e.g. alcohol abuse).
• People who have liver enzymes that are elevated, but are less than three times the upper limit of normal, should not be routinely excluded from statin therapy.
• Renal function: chronic kidney disease does not preclude the use of a statin. However, the dose of some statins should be adjusted in people with moderate or severe renal insufficiency.
• Fasting blood glucose.
• Creatine kinase is recommended if the person is at high risk of muscle toxicity (e.g. older people, or when combining a statin with a drug known to increase myotoxicity) but this is not routinely necessary in other people.
• Serum thyroid stimulating hormone (if dyslipidaemia is present).

• These recommendations are based on guidance from the National Institute for Health and Clinical Excellence (NICE) and the Scottish Intercollegiate Guidelines Network (SIGN) [SIGN, 2007; NICE, 2008a].
• Repeated lipid measurement:
• The NICE Guidance Development Group (GDG) recognized that there is variability in lipid measurement due to day-to-day physiological, laboratory, and statistical variation [National Collaborating Centre for Primary Care, 2008a].
• Because of the individual variation in a single lipid measurement, repeated measurement will give greater precision. However, NICE accepted that, in routine practice, serial replicate testing is not feasible and clinicians often base monitoring decisions on one measurement, and treatment decisions on two measurements, accepting the imprecision.
• Need for a fasting lipid measurement before starting lipid modification treatment:
• This is based on the expert opinion of the NICE GDG which acknowledged that there was no substantive evidence to support the view that a fasting specimen is advantageous before starting treatment [National Collaborating Centre for Primary Care, 2008a].
• However, they recognized that many clinicians view low-density lipoprotein (LDL) cholesterol and triglycerides as an important adjunct to clinical management because they may inform diagnosis and are a baseline against which the progress and effectiveness of treatment can be judged.
• Liver function:
• This is to exclude possible contraindication to treatment with statins or other lipid–modifying drugs. Statins are contraindicated in people with active liver disease or persistently abnormal liver function tests.
• Pretreatment baseline creatine kinase (CK) only for people at high risk of muscle toxicity:
• NICE does not make any recommendation regarding the need for pretreatment, baseline CK measurement [NICE, 2008a].
• This recommendation is based on that from SIGN [SIGN, 2007], following the consensus recommendations issued by the National Lipid Association Statin Safety Task Force [McKenney et al, 2006; SIGN, 2007]. This recommendation was based on assessment of evidence from the US Food and Drug Administration (FDA), cohort and clinical trials, and administrative claims database information.
• Fasting blood glucose:
• Although it is not required for cardiovascular risk calculation, it is recommended for diagnosis of impaired glucose regulation and diabetes [British Cardiac Society et al, 2005].
• Serum thyroid stimulating hormone should be checked if dyslipidaemia is present because:
• Hypothyroidism is a recognized cause of dyslipidaemia [BTA et al, 2006].
• In addition, untreated hypothyroidism increases the risk of statin-induced myopathy [Bar et al, 2007].

• Prescribe a statin, unless this is contraindicated.
• Simvastatin 40 mg daily is the first-line choice.
• Consider a lower dose of simvastatin or an alternative statin (e.g. pravastatin 40 mg daily) if there are potential drug interactions or simvastatin 40 mg is contraindicated (e.g. renal impairment).
• Higher intensity statin therapy (simvastatin 80 mg or atorvastatin 80 mg) should only be considered first-line for people with acute coronary syndrome. Treatment should be initiated in secondary care.

• Higher intensity statins are those that produce greater cholesterol lowering than simvastatin 40 mg (e.g. simvastatin 80 mg).
• For information on the use of omega-3 fatty acids in people who have had a myocardial infarction within 3 months, and who are not achieving an intake of 7 g of omega-3 fatty acids per week in their diet, see Cardioprotective diet in the CKS topic on CVD risk assessment and management.

• The recommendation by the National Institute of Health and Clinical Excellence (NICE) to offer statins for secondary prevention is based on an earlier NICE Technology Appraisal of statins for the prevention of cardiovascular events [NICE, 2006; NICE, 2008a].
• Statins for secondary prevention:
• When considering lipid modification therapy in secondary prevention, preference was given by NICE to drugs for which there is evidence in clinical trials of a beneficial effect on cardiovascular disease (CVD) morbidity and mortality.
• Statins are recommended first-line for the secondary prevention of CVD because there is good evidence from a meta-analysis, undertaken by NICE, which found statin therapy was associated with a reduction in all-cause mortality, CVD mortality, coronary heart disease (CHD) mortality, fatal myocardial infarction (MI), and coronary revascularization, when compared with placebo, in people with coronary heart disease.
• The evidence for other drugs (e.g. bile acid sequestrants, ezetimibe, fibrates, and nicotinic acid) was less robust.
• Model studies undertaken by NICE showed a high probability (greater than 85%) that statin therapy is cost effective for all people with a history of CHD.
• Safety of statin therapy:
• NICE found good safety data to support the use of statins [National Collaborating Centre for Primary Care, 2008a]:
• Evidence from two large meta-analyses indicates that serious muscular (e.g. rhabdomyolysis, myopathy) and liver (e.g. abnormal liver function tests) adverse effects are infrequent with statin therapy.
• Evidence from another meta-analysis (involving 86,936 participants) found statins to have a neutral effect on cancer and cancer death risks. No type of cancer was affected by statin use and no subtype of statin affected the risk of cancer.
• Treatment initiation — low intensity versus high intensity statin therapy:
• Low intensity statin therapy is recommended for people with stable coronary artery disease because it is more likely to be more cost effective than high intensity statin therapy:
• Cost effectiveness analysis undertaken by the NICE Guidance Development Group indicated that, when compared with low intensity statins (simvastatin 40 mg), high intensity statins (atorvastatin 80 mg) were not cost effective in people with stable coronary artery disease. The probability that high intensity statins are cost effective is about 42% when compared with low intensity statins.
• Results from another cost effectiveness study undertaken by NICE indicate that the majority of people (69%) will reach a target of 5 mmol/L on simvastatin 40 mg. With a target of 4 mmol/L, 31% of people will reach this target on simvastatin 40 mg.
• However, higher intensive statin therapy is preferred for people with acute coronary syndrome (ACS) because it is more likely to be more cost effective than low intensity statin therapy:
• Modelling studies undertaken by NICE find fewer cardiovascular events occur in the population treated with higher intensity statins than with low intensity statins. The studies indicate a high probability (about 94%) that high intensity statins (both simvastatin and atorvastatin 80 mg) are cost effective in people with ACS.
• Effectiveness data of higher intensive statin therapy for ACS patients were drawn from two studies (one involving simvastatin [de Lemos et al, 2004] and the other with atorvastatin [Cannon et al, 2004]) which were meta-analysed.
• Pravastatin:
• Pravastatin is recommended as an alternative to simvastatin because, unlike simvastatin, it is not significantly metabolized by cytochrome P450 isoenzymes.
• A dose of pravastatin 40 mg daily is recommended because, in all preventive morbidity and mortality trials, this was the only studied starting and maintenance dose [ABPI Medicines Compendium, 2005b].

• Consider offering a fibrate, modified-release nicotinic acid, or a bile acid sequestrant if a statin is not suitable.
• The decision to select a particular lipid-modifying drug should take into account patient preference and tolerability, comorbidities, multiple drug therapy, and the benefits and risks of treatment.
• Table 1 lists some of the factors influencing drug choice when considering an alternative to a statin.

• For further information on these drugs (e.g. preferred drug choice and dosage), see prescribing information for Fibrates, Nicotinic acid, and Bile acid sequestrants.

Fibrates, nicotinic acid, and bile acid sequestrants:

• The National Institute for Health and Clinical Excellence (NICE) recommends that a fibrate, nicotinic acid, or a bile acid sequestrant should be considered for secondary prevention of CV events if a person cannot tolerate a statin [NICE, 2007; NICE, 2008a].
• The evidence for fibrates, nicotinic acid and bile acid sequestrants is less robust than that for statins in the secondary prevention of CV events [National Collaborating Centre for Primary Care, 2008a].
• NICE does not state any preference when deciding whether to offer a fibrate, nicotinic acid, or a bile acid sequestrant [National Collaborating Centre for Primary Care, 2008a]. CKS recommends that choice be based on comorbidities, potential for drug interactions, possible adverse effects, and patient preference.

Ezetimibe:

• CKS does not currently recommend the use of ezetimibe for secondary prevention of CVD because:
• There is no evidence to support this use. Ezetimibe is not licensed for secondary prevention of cardiovascular events.
• None of the trials (except one) reported any health-related quality of life or clinical endpoints such as cardiovascular morbidity and mortality.
• Only the SEAS trial reported cardiovascular outcomes [Rossebo et al, 2008]. However, it found no difference in major cardiovascular events, overall mortality and secondary outcomes between people (with mild-to-moderate asymptomatic aortic stenosis) who received simvastatin only or a combination of simvastatin and ezetimibe.
• There is some concern about the risk of cancer with ezetimibe. Although there is currently insufficient evidence to draw any conclusions about the effect of ezetimibe on cancer, the Commission on Human Medicines (CHM) will review this issue when the results of two large ongoing ezetimibe trials become available [MHRA, 2008]. Consequently, CKS advises caution until this issue is clarified.

Plant stanols and steroids:

• These are not recommended because the NICE Guideline Development Group did not identify any randomized controlled trials that investigated their effectiveness in the secondary prevention of cardiovascular events [National Collaborating Centre for Primary Care, 2008a].

Omega-3 fatty acid supplements:

• These are not recommended by NICE because there is insufficient evidence of benefit in people with angina, peripheral arterial disease, or stroke. See the section Omega-3 fatty acid supplements in the CKS topic on CVD risk assessment and management.
• For information on their use in people who have had a myocardial infarction within 3 months, and who are not achieving an intake of 7 g of omega-3 fatty acids per week in their diet, see Cardioprotective diet in the CKS topic on CVD risk assessment and management.

• Repeat lipid measurement:
• For people with acute coronary syndrome:
• Perform a fasting lipid measurement around 3 months after initiating statin therapy.
• For all other people taking a statin or other lipid-modifying drugs for secondary prevention:
• Check lipid profile around 8 (+/– 4) weeks after initiation, and after each adjustment to treatment.
• Lipid profile should be reviewed annually once the individual has reached an optimal, achievable target.
• For people taking statins, recheck liver function tests (LFTs) within 3 months of starting treatment and again at 12 months. Further monitoring is not necessary unless clinically indicated (e.g. symptoms or signs of hepatotoxicity).
• If LFTs are abnormal, see Abnormal LFT results.
• Monitor for adverse effects of lipid modification therapy:
• If they develop unexplained muscle symptoms (pain, tenderness, weakness):
• Check creatine kinase (CK).
• Stop the lipid-modifying drug immediately if muscle symptoms are severe or if CK is five times or more the upper limit of normal.
• For further information on managing abnormal CK results with statins, see Raised creatine kinase.
• Note: people should be advised to seek medical advice and to stop the lipid-modifying drug if they develop unexplained muscle symptoms.
• For people on a statin:
• Discontinue the statin and seek specialist advice if they develop unexplained peripheral neuropathy.
• Advise them to seek medical advice if they develop presenting features of interstitial lung disease such as dyspnoea, non-productive cough, and deterioration in general health (e.g. fatigue, weight loss, and fever).
• For further information, see Adverse effects.

• Statins and other lipid-modifying drugs can rarely cause myopathy and rhabdomyolysis. The exact mechanism is uncertain, but risk factors include [CSM, 2004]:
• Underlying muscle disorders.
• Renal impairment.
• Untreated hypothyroidism.
• Alcohol abuse.
• Older age (more than 70 years of age).
• Concomitant use of other lipid-modifying drugs (i.e. fibrates, nicotinic acid).
• A history of myopathy with any lipid modification therapy.
• Drug interactions (e.g. with drugs inhibiting cytochrome P450 enzymes).

• Repeat lipid monitoring:
• The recommendations for repeat lipid monitoring is based on expert opinion [Smellie, 2006; NICE, 2008a].
• Manufacturers of statins advise lipid monitoring should be done after an interval of at least 4 weeks, as the full effect usually occurs within this time.
• Repeat lipid monitoring for people with acute coronary syndrome (ACS) after statin initiation:
• The National Institute for Health and Clinical Excellence (NICE) recommends repeat lipid monitoring around 3 months after initiating statin therapy [NICE, 2008a].
• This recommendation is consistent with that recommended in the Joint British Societies guideline and is based on [British Cardiac Society et al, 2005]:
• At the time of ACS (especially myocardial infarction), total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol decrease (and triglycerides may increase).
• The reduction of total cholesterol following myocardial infarction generally lasts no longer than 6–8 weeks, but sometimes lasts longer if there is a complicated recovery.
• Consequently, a full fasting lipid profile should be performed around 3 months following the acute event (normally after statin treatment has been started). This should be used to assess response to therapy and investigate the presence of familial dyslipidaemia.
• Repeat liver function testing (after statin initiation):
• This recommendation is based on expert consensus of the NICE Guidance Development Group [NICE, 2008a]. Evidence for the monitoring of liver function is sparse.
• Repeat liver function testing is also recommended by other experts [Smellie, 2006; Bhatnagar et al, 2008].
• CKS did not find any evidence to support the need for long-term monitoring of liver function in people taking statins (for more than 12 months).
• Muscular events (rhabdomyolysis and myopathy):
• These are rare but serious adverse effects of lipid-modifying drugs.
• The Commission on Human medicines and NICE advise that people receiving statins should be asked to report muscle pain, weakness, or cramps immediately, and to stop treatment until this has been investigated [CSM, 2004; NICE, 2008a].
• CKS advises that the same warning should be applied to other lipid-modifying drugs (except for bile acid sequestrants) because rhabdomyolysis and myopathy have been reported for these drugs and the manufacturers advise similar warnings.

• Consider higher intensity lipid modification therapy if total cholesterol of less than 4 mmol/L or low-density lipoprotein (LDL) cholesterol of less than 2 mmol/L has not been achieved.
• Any decision to offer a higher intensity statin should take into account patient preference and tolerability, comorbidities, multiple drug therapy, and the benefits and risks of treatment.
• A target total cholesterol level of less than 5 mmol/L should be used as the minimum standard of care for all people with cardiovascular disease. Wherever possible, the optimal treatment targets should be achieved.

• These recommendations are based on guidance issued by the National Institute for Health and Clinical Excellence [NICE, 2008a].
• Advantages and disadvantages of targets:
• These were considered by the NICE Guidance Development Group (GDG) [National Collaborating Centre for Primary Care, 2008a]. For further information, see evidence on lipid targets for secondary prevention.
• The NICE GDG concluded that, for most people, a target can be helpful in guiding increases of lipid-modifying drugs as long as it is clear that this target is intended to guide treatment rather than be a level that all people are expected to achieve.
• For audit purposes, a target total cholesterol of less than 5 mmol/L is recommended to assess progress in populations or groups of people with cardiovascular disease, in recognition that more than a half of people will not achieve a total cholesterol of less than 4 mmol/L or low-density lipoprotein cholesterol of less than 2 mmol/L. This audit standard is the minimum standard of care for all high-risk people. Wherever possible, the optimal treatment targets should be achieved.
• Clinical evidence and safety of higher intensity statin therapy:
• This was reviewed by the NICE GDG [National Collaborating Centre for Primary Care, 2008a].
• A meta-analysis of four randomized controlled trials in people with coronary heart disease (CHD) found that, compared with lower intensity statin therapy, higher intensity statin therapy was associated with a reduction in the composite outcome of coronary death or myocardial infarction (MI), and with a reduction in the composite outcome of coronary death or any cardiovascular event (MI, stroke, hospitalization for unstable angina, or any revascularization).
• Higher intensity statin therapy was not associated with a reduction in all-cause mortality but there was a trend for significance in cardiovascular mortality compared with lower intensity statin therapy.
• Evidence from four large trials and one retrospective study found that higher intensity statin therapy was associated with an increased risk of elevated liver enzymes than lower intensity therapy, but not with a significant increase in clinical liver diseases.
• Higher intensity statin therapy with atorvastatin 80 mg daily (3 RCTs and one retrospective study) was not associated with an increase in rhabdomyolysis compared with lower intensity therapy.
• Higher intensity statin therapy with simvastatin 80 mg daily (1 RCT) was associated with a small increase in rhabdomyolysis (0.13%) compared with simvastatin 20 mg daily (0%) [de Lemos et al, 2004].
• The results of a subsequent RCT using simvastatin 80 mg daily, the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial [Clinical Trial Service Unit, 2008] also found a small increased risk of myopathy with simvastatin 80 mg (0.9%) compared with simvastatin 20 mg (0.02%). The Medicines and Healthcare products Regulatory Agency (MHRA) has recently reviewed these data and advised that simvastatin 80 mg should be considered only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks [MHRA, 2010].

• For people already taking simvastatin 40 mg daily:
• Increase the dose to simvastatin 80 mg daily or a drug of similar efficacy and acquisition cost if tolerated.
• For people already taking pravastatin 40 mg or less than simvastatin 40 mg daily:
• Check if there is any contraindication or a history of intolerability to simvastatin 40 mg.
• If there are no contraindications or a history of intolerability to simvastatin 40 mg:
• Consider increasing or changing to simvastatin 40 mg.
• If targets are still not met with simvastatin 40 mg daily, increase to simvastatin 80 mg if tolerated.
• For people with acute coronary syndrome and already on simvastatin 80mg daily:
• Switch to atorvastatin 80 mg daily.
• For people initiated with a fibrate or a bile acid sequestrant or nicotinic acid (i.e. statin not suitable):
• Consider increasing the dose of initial drug to maximum licensed or tolerated dose.
• If this is ineffective, consider adding a second lipid-modifying drug from a different class (other than a statin). See Therapy if statins not suitable for a summary of these drugs.

• These recommendations reflect guidance issued by the National Institute for Health and Clinical Excellence (NICE) on lipid modification [NICE, 2008a; National Collaborating Centre for Primary Care, 2008a] and licensed indications of lipid-modifying drugs.
• Clinical evidence and safety of higher intensity statin therapy:
• These have been reviewed by the NICE Guidance Development Group (GDG) [National Collaborating Centre for Primary Care, 2008a].
• For further information, see When to intensify therapy.
• For people with stable coronary artery disease:
• Titrating statin treatment to a threshold target of total cholesterol 4 mmol/L using simvastatin 80 mg (or a drug of similar efficacy and acquisition cost) is recommended because a cost effectiveness study undertaken by NICE GDG indicates that dose titration using a threshold target of total cholesterol 4 mmol/L is cost effective, providing titration stops at simvastatin 80 mg.
• The model indicates that it would not be cost effective to push a higher proportion of people to target using drugs such as atorvastatin 80 mg, at its current price.
• For people with acute coronary syndrome (ACS):
• Atorvastatin is recommended because modelling studies undertaken by NICE GDG indicate a high probability (about 94%) that both simvastatin and atorvastatin 80 mg are cost effective in people with ACS.
• For people initiated on a bile acid sequestrant or a fibrate, or nicotinic acid (i.e. people in whom a statin is not suitable):
• NICE does not offer any recommendation regarding more intensive lipid modification therapy if these people fail to reach lipid targets.
• For non-statin combinations, CKS could not find any trials that reported health-related quality of life or clinical endpoints such as cardiovascular morbidity and mortality.
• The treatment options offered are based on recommendations issued by the manufacturers of lipid-modifying drugs (e.g. the combination of fenofibrate with other complementary or different therapeutic measures) [ABPI Medicines Compendium, 2007e].
• Ezetimibe:
• CKS does not currently recommend the use of ezetimibe (alone or in combination with other lipid-modifying drugs) for secondary prevention. For further information, see Therapy if statins not suitable.

• Refer people with suspected familial hypercholesterolaemia (FH) or other monogenic familial disorders for specialist management.
• Consider the possibility of FH in adults with elevated cholesterol (total cholesterol typically greater than 7.5 mmol/L), especially when there is a personal or family history of premature coronary heart disease.
• A diagnosis of FH should be made using the Simon Broome criteria.
• Confirm the diagnosis by referral to a specialist.
• Consider a clinical diagnosis of homozygous FH in adults with a low-density lipoprotein cholesterol concentration greater than 13 mmol/L.
• Note: a CKS topic on familial hypercholesterolaemia is currently under development.
• Consider seeking specialist advice in managing people with:
• Severe hyperlipidaemia.
• Mixed hyperlipidaemia.
• Serum triglyceride level greater than 10 mmol/L.
• Resistant hyperlipidaemic states.
• Secondary hyperlipidaemia (see Clarification for further information).
• Abnormal pretreatment liver enzymes or creatine kinase activity.
• Multiple drug intolerance (to lipid-modifying drugs).
• Lipodystrophy syndromes.
• Dyslipidaemia related to HIV.
• People taking complex combinations of drugs with high risk of serious drug interaction with lipid modification therapy.

• Secondary hyperlipidaemia
• Causes of secondary hyperlipidaemia include [Bhatnagar et al, 2008]:
• Nephrotic syndrome
• Obstructive jaundice
• Hypothyroidism
• Cushing's syndrome
• Anorexia nervosa
• Thiazide diuretics
• Ciclosporin
• Consider seeking specialist advice regarding management where appropriate.

• People with severe hyperlipidaemia, suspected familial hypercholesterolaemia (FH) or other monogenic familial disorders:
• The recommendation to refer these people are based on the expert opinion of the National Institute for Health and Clinical Excellence (NICE) Guidance Development Group. NICE found no good evidence to guide which individuals, with which lipid disorders, should be referred for specialist assessment and management [National Collaborating Centre for Primary Care, 2008a].
• The criteria for diagnosing suspected familial hypercholesterolaemia are based on those issued by NICE (which include the use of Simon Broome diagnostic criteria) [NICE, 2008b].
• People with triglyceridaemia greater than 10 mmol/L:
• Specialist advice is recommended as these people have a very high risk of pancreatitis [British Cardiac Society et al, 2005]. They should be referred to lipid clinics for treatment [Bhatnagar et al, 2008].
• Other groups:
• The recommendation to seek specialist advice for the other patient groups is based on expert opinion [Bhatnagar et al, 2008].