___________
1 31%–40%: medium intensity
2 Above 40%: high intensity
3 20%–30%: low intensity
4 Advice from the MHRA: there is an increased risk of myopathy associated with high-dose (80 mg) simvastatin. The 80 mg dose 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
For primary prevention, NICE Clinical Guideline 181 recommends that atorvastatin, a high-intensity statin (when prescribed at a dose of at least 20 mg/day), should be offered to those with a 10-year risk of cardiovascular disease of 10% or more; patients aged 85 years and over may benefit from atorvastatin to reduce the risk of non-fatal myocardial infarction. For secondary prevention, atorvastatin is also recommended. See Atorvastatin for recommended doses. Patients taking a low- or medium-intensity statin should discuss the benefits and risks of switching to a high intensity statin at their next medication review.
A statin should be considered for all adults with type 1 diabetes mellitus, particularly those aged 40 years and over, or who have had diabetes for more than 10 years, or who have established nephropathy, or other risk factors for cardiovascular disease. JBS3 recommendations44 in diabetes mellitus differ in certain respects from NICE Clinical Guideline 18143 — see JBS3 recommendations for further details. In type 2 diabetes, assess level of risk using the risk calculator and treat for primary prevention if necessary.
Total cholesterol, HDL-cholesterol, and non-HDL cholesterol concentrations should be checked 3 months after starting treatment with a high intensity statin. NICE Clinical Guideline 181 recommends aiming for a reduction in non-HDL cholesterol concentration greater than 40%; JBS3 recommends a target non-HDL cholesterol concentration below 2.5 mmol/litre. If these are not achieved, ensure lifestyle modifications are optimised and consider increasing the dose of the statin if started on less than atorvastatin 80 mg and the patient is judged to be at higher risk because of comorbidities, risk score or, using clinical judgement.
Specialist advice should be sought about treatment options for patients at high risk of cardiovascular disease or those with existing cardiovascular disease, who are intolerant of three different statins.
Fibrates should not be routinely used for primary or secondary prevention. Nicotinic acid, bile acid sequestrants, and omega-3 fatty acid compounds are not recommended for primary or secondary prevention.
Hypercholesterolaemia, hypertriglyceridaemia, and familial hypercholesterolaemia A statin is also the drug of first choice for treating hypercholesterolaemia and moderate hypertriglyceridaemia. Severe hyperlipidaemia not adequately controlled with a maximal dose of a statin may require the use of an additional lipid-regulating drug such as ezetimibe; such treatment should generally be supervised by a specialist.
A number of conditions, some familial, are characterised by very high LDL-cholesterol concentration, high triglyceride concentration, or both. Fenofibrate may be added to statin therapy if triglycerides remain high even after the LDL-cholesterol concentration has been reduced adequately; nicotinic acid may also be used to further lower triglyceride or LDL-cholesterol concentration.
Combination of a statin with a fibrate or with nicotinic acid carries an increased risk of side-effects (including rhabdomyolysis — see Muscle Effects) and should be used under specialist supervision; monitoring of liver function and creatine kinase should also be considered. The concomitant administration of gemfibrozil with a statin increases the risk of rhabdomyolysis considerably — this combination should not be used.
A statin is recommended for all patients with familial hypercholesterolaemia. A ‘high-intensity’ statin (as defined in NICE Clinical Guideline 7145 e.g. rosuvastatin (initiated by a specialist) or atorvastatin) should be considered in order to achieve the recommended reduction in LDL-cholesterol concentration of greater than 50% from baseline; a ‘high-intensity’ statin is one that produces a greater LDL-cholesterol reduction than simvastatin 40 mg. Patients with heterozygous familial hypercholesterolaemia who have contra-indications to, or are intolerant of, statins should receive ezetimibe. The combination of a statin and ezetimibe can be considered if a statin alone fails to provide adequate control (or if intolerance limits dose titration), and when a switch to an alternative statin is being considered. Patients for whom statins and ezetimibe are inappropriate, should be referred to a specialist for the consideration of treatment with a bile acid sequestrant, nicotinic acid, or a fibrate.
The prescribing of drug therapy in homozygous familial hypercholesterolaemia should be undertaken in a specialist centre. Lomitapide is licensed as an adjunct to dietary measures and other lipid-regulating drugs for the treatment of homozygous familial hypercholesterolaemia.
Statins
The statins (atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin) competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, an enzyme involved in cholesterol synthesis, especially in the liver. Statins are more effective than other lipid-regulating drugs at lowering LDL-cholesterol concentration but they are less effective than the fibrates in reducing triglyceride concentration. However, statins reduce cardiovascular disease events and total mortality irrespective of the initial cholesterol concentration.
Statins are used for the primary and secondary prevention of cardiovascular disease (see Lipid-regulating drugs).
Cautions See Lipid-regulating drugs for details of the management of hypothyroidism and the monitoring recommended before starting treatment with a statin.
Statins should be used with caution in those with a history of liver disease or with a high alcohol intake — see also Hepatic impairment, below. There is little information available on a rational approach to liver-function monitoring; however, a NICE guideline46 suggests that liver enzymes should be measured before treatment, and repeated within 3 months and at 12 months of starting treatment, unless indicated at other times by signs or symptoms suggestive of hepatotoxicity. Those with serum transaminases that are raised, but less than 3 times the upper limit of the reference range, should not be routinely excluded from statin therapy. Those with serum transaminases of more than 3 times the upper limit of the reference range should discontinue statin therapy.
Statins should be used with caution in those with risk factors for myopathy or rhabdomyolysis (see Muscle Effects below); patients should be advised to report unexplained muscle pain. Before initiation of statin treatment, creatine kinase concentration should be measured in patients who have had persistent, generalised, unexplained muscle pain (whether associated or not with previous lipid-regulating drugs); if the concentration is more than 5 times the upper limit of normal, a repeat measurement should be taken after 7 days. If the repeat concentration remains above 5 times the upper limit, statin treatment should not be started; if concentrations are still raised but less than 5 times the upper limit, the statin should be started at a lower dose.
Patients at high risk of diabetes mellitus should have fasting blood-glucose concentration or HbA1C checked before starting statin treatment, and then repeated after 3 months (see Side-effects). Interactions: Appendix 1 (statins).
Hepatic impairment Statins should be used with caution in those with a history of liver disease and avoided in active liver disease or when there are unexplained persistent elevations in serum transaminases.
Pregnancy Statins should be avoided in pregnancy (discontinue 3 months before attempting to conceive) as congenital anomalies have been reported and the decreased synthesis of cholesterol possibly affects fetal development. Adequate contraception is required during treatment and for 1 month afterwards.
Breast-feeding The manufacturers of atorvastatin, fluvastatin, rosuvastatin, and simvastatin advise avoiding use in mothers who are breast-feeding as there is no information available. The manufacturers of pravastatin advise against use in breast-feeding mothers as a small amount of drug is present in breast milk.
Side-effects The statins have been associated with myalgia, myopathy, myositis, and rhabdomyolysis (see Muscle Effects below). Statins can alter liver function tests, and rarely cause hepatitis and jaundice; pancreatitis and hepatic failure have been reported very rarely. Other side-effects include gastro-intestinal disturbances, sleep disturbance, headache, dizziness, depression, paraesthesia, asthenia, peripheral neuropathy, amnesia, fatigue, sexual dysfunction, thrombocytopenia, arthralgia, visual disturbance, alopecia, and hypersensitivity reactions (including rash, pruritus, urticaria, and very rarely lupus erythematosus-like reactions). In very rare cases, statins can cause interstitial lung disease; if patients develop symptoms such as dyspnoea, cough, and weight loss, they should seek medical attention. Statins can cause hyperglycaemia and may be associated with the development of diabetes mellitus, particularly in those already at risk of the condition; statins should not be discontinued if there is an increase in the blood-glucose concentration or HbA1c as the benefits continue to outweigh the risks.
Muscle effects The risk of myopathy, myositis, and rhabdomyolysis associated with statin use is rare. Although myalgia has been reported commonly in patients receiving statins, muscle toxicity truly attributable to statin use is rare. Muscle toxicity can occur with all statins, however the likelihood increases with higher doses and in certain patients (see below). Statins should be used with caution in patients at increased risk of muscle toxicity, including those with a personal or family history of muscular disorders, previous history of muscular toxicity, a high alcohol intake, renal impairment, hypothyroidism, and in the elderly. There is an increased incidence of myopathy if a statin is given at a high dose, or if it is given with a fibrate (the combination of a statin and gemfibrozil should preferably be avoided), with lipid-lowering doses of nicotinic acid, with fusidic acid (risk of rhabdomyolysis — the combination of a statin and fusidic acid should be avoided; temporarily discontinue statin and restart 7 days after last fusidic acid dose), or with drugs that increase the plasma-statin concentration, such as macrolide antibiotics, imidazole and triazole antifungals, and ciclosporin — see interactions: Appendix 1 (statins); close monitoring of liver function and, if muscular symptoms occur, of creatine kinase is necessary. In patients at increased risk of muscle effects, a statin should not usually be started if the baseline creatine kinase concentration is more than 5 times the upper limit of normal (some patients may present with an extremely elevated baseline creatine kinase concentration, for example because of a physical occupation or rigorous exercise — specialist advice should be sought regarding consideration of statin therapy in these patients).
If muscular symptoms or raised creatine kinase occur during treatment, other possible causes (e.g. rigorous physical activity, hypothyroidism, infection, recent trauma, and drug or alcohol addiction) should be excluded before statin therapy is implicated, particularly if statin treatment has previously been tolerated for more than 3 months. When a statin is suspected to be the cause of myopathy, and creatine kinase concentration is markedly elevated (more than 5 times upper limit of normal), or if muscular symptoms are severe, treatment should be discontinued. If symptoms resolve and creatine kinase concentrations return to normal, the statin should be reintroduced at a lower dose and the patient monitored closely; an alternative statin should be prescribed if unacceptable side-effects are experienced with a particular statin. Statins should not be discontinued in the event of small, asymptomatic elevations of creatine kinase. Routine monitoring of creatine kinase is unnecessary in asymptomatic patients.
Counselling Advise patient to report promptly unexplained muscle pain, tenderness, or weakness.
ATORVASTATIN
Indications primary hypercholesterolaemia, heterozygous familial hypercholesterolaemia, homozygous familial hypercholesterolaemia or combined (mixed) hyperlipidaemia in patients who have not responded adequately to diet and other appropriate measures; primary prevention of cardiovascular events in patients at high risk of a first cardiovascular event; secondary prevention of cardiovascular events [unlicensed]
Cautions see notes above; also haemorrhagic stroke
Hepatic impairment see notes above
Renal impairment in chronic kidney disease, for primary and secondary prevention of cardiovascular events [unlicensed starting dose in primary prevention; unlicensed in secondary prevention], initially 20 mg once daily, increased if necessary (on specialist advice if eGFR < 30 mL/minute/1.73m2); max. 80 mg once daily
Pregnancy see notes above
Breast-feeding see notes above
Side-effects see notes above; also nasopharyngitis, epistaxis, pharyngeolaryngeal pain, back pain, hyperglycaemia; less commonly blurred vision, pyrexia, anorexia, malaise, chest pain, weight gain, hypoglycaemia, tinnitus, peripheral oedema, neck pain; rarely cholestasis, Stevens-Johnson syndrome, toxic epidermal necrolysis; very rarely gynaecomastia, hearing loss
Dose
Primary hypercholesterolaemia and combined hyperlipidaemia, ADULT over 18 years, usually 10 mg once daily; if necessary, may be increased at intervals of at least 4 weeks to max. 80 mg once daily
Familial hypercholesterolaemia, ADULT over 18 years, initially 10 mg daily, increased at intervals of at least 4 weeks to 40 mg once daily; if necessary, further increased to max. 80 mg once daily (or 40 mg once daily combined with anion-exchange resin in heterozygous familial hypercholesterolaemia)
Primary prevention of cardiovascular events, ADULT over 18 years, 20 mg once daily increased if necessary (see Lipid-Regulating Drugs) [unlicensed starting dose]
Secondary prevention of cardiovascular events [unlicensed], ADULT over 18 years, 80 mg once daily
CHILD under 18 years see BNF for Children
Note Max. 10 mg daily with concomitant ciclosporin, or tipranavir combined with ritonavir (see also Appendix 1)
Atorvastatin (Non-proprietary) 
Tablets, atorvastatin (as calcium trihydrate) 10 mg, net price 28-tab pack = £1.19; 20 mg, 28-tab pack = £1.45; 40 mg, 28-tab pack = £1.67; 80 mg, 28-tab pack = £2.68. Counselling, muscle effects, see notes above
Lipitor® (Pfizer) 
Chewable tablets
, atorvastatin (as calcium trihydrate) 10 mg, net price 30-tab pack = £13.80; 20 mg, 30-tab pack = £26.40. Label: 24, counselling, muscle effects, see notes above
Tablets, all f/c, atorvastatin (as calcium trihydrate) 10 mg, net price 28-tab pack = £13.00; 20 mg, 28-tab pack = £24.64; 40 mg 28-tab pack = £24.64; 80 mg, 28-tab pack = £28.21. Counselling, muscle effects, see notes above
FLUVASTATIN
Note The Scottish Medicines Consortium has advised (February 2004) that fluvastatin is accepted for restricted use for the secondary prevention of coronary events after percutaneous coronary angioplasty; if the patient has previously been receiving another statin, then there is no need to change the statin
Indications adjunct to diet in primary hypercholesterolaemia or combined (mixed) hyperlipidaemia (types IIa and IIb); prevention of coronary events after percutaneous coronary intervention
Cautions see notes above
Hepatic impairment see notes above
Renal impairment manufacturer advises doses above 40 mg daily should be initiated with caution if eGFR less than 30 mL/minute/1.73 m2
Pregnancy see notes above
Breast-feeding see notes above
Side-effects see notes above; also very rarely vasculitis
Dose
Hypercholesterolaemia or combined hyperlipidaemia, initially 20–40 mg daily in the evening, adjusted at intervals of at least 4 weeks; up to 80 mg daily (given in 2 divided doses) may be required; CHILD under 18 years see BNF for Children
Following percutaneous coronary intervention, 80 mg daily
Fluvastatin (Non-proprietary) 
Capsules, fluvastatin (as sodium salt) 20 mg, net price 28-cap pack = £2.41; 40 mg, 28-cap pack = £2.48. Counselling, muscle effects, see notes above
Lescol® (Novartis) 
Capsules, fluvastatin (as sodium salt) 20 mg (brown/yellow), net price 28-cap pack = £15.26; 40 mg (brown/orange), 28-cap pack = £15.26, 56-cap pack = £30.53. Counselling, muscle effects, see notes above
Modified release
Fluvastatin (Non-proprietary) 
Tablets, m/r, fluvastatin (as sodium salt) 80 mg, net price 28-tab pack = £19.20. Label: 25, counselling, muscle effects, see notes above
Brands include Dorisin®XL, Luvinsta® XL, Pinmactil®, Stefluvin® XL
Dose 80 mg once daily (dose form not appropriate for initial dose titration)
PRAVASTATIN SODIUM
Indications adjunct to diet for primary hypercholesterolaemia or combined (mixed) hyperlipidaemias in patients who have not responded adequately to dietary control; adjunct to diet to prevent cardiovascular events in patients with hypercholesterolaemia; prevention of cardiovascular events in patients with previous myocardial infarction or unstable angina; reduction of hyperlipidaemia in patients receiving immunosuppressive therapy following solid-organ transplantation
Cautions see notes above
Hepatic impairment see notes above
Renal impairment manufacturer advises initial dose of 10 mg once daily in moderate to severe impairment
Pregnancy see notes above
Breast-feeding see notes above
Side-effects see notes above; less commonly abnormal urination (including dysuria, nocturia and frequency); very rarely fulminant hepatic necrosis
Dose
Hypercholesterolaemia or combined hyperlipidaemias, 10–40 mg once daily at night, adjusted at intervals of at least 4 weeks; CHILD under 18 years see BNF for Children
Familial hypercholesterolaemia, CHILD under 18 years see BNF for Children
Prevention of cardiovascular events, 40 mg once daily at night
Post-transplantation hyperlipidaemia, initially 20 mg once daily at night, increased if necessary (under close medical supervision) to max. 40 mg once daily at night
Pravastatin (Non-proprietary) 
Tablets, pravastatin sodium 10 mg, net price 28-tab pack = £1.43; 20 mg, 28-tab pack = £1.65; 40 mg, 28-tab pack = £2.00. Counselling, muscle effects, see notes above
ROSUVASTATIN
Indications primary hypercholesterolaemia (type IIa including heterozygous familial hypercholesterolaemia), mixed dyslipidaemia (type IIb), or homozygous familial hypercholesterolaemia in patients who have not responded adequately to diet and other appropriate measures; prevention of cardiovascular events in patients at high risk of a first cardiovascular event
Cautions see notes above; patients of Asian origin (see under Dose); patients with risk factors for myopathy or rhabdomyolysis, including personal or family history of muscular disorders or toxicity (see under Dose)
Hepatic impairment see notes above
Renal impairment initially 5 mg once daily (do not exceed 20 mg daily) if eGFR 30–60 mL/minute/1.73 m2; avoid if eGFR less than 30 mL/minute/1.73 m2
Pregnancy see notes above
Breast-feeding see notes above
Side-effects see notes above; also proteinuria; very rarely gynaecomastia, haematuria; also reported oedema, Stevens-Johnson syndrome
Dose
Hypercholesterolaemia, initially 5–10 mg once daily increased if necessary at intervals of at least 4 weeks to 20 mg once daily, increased after further 4 weeks to 40 mg daily only in severe hypercholesterolaemia with high cardiovascular risk and under specialist supervision; ELDERLY over 70 years, initially 5 mg once daily; patient of ASIAN origin or with risk factors for myopathy or rhabdomyolysis, initially 5 mg once daily increased if necessary to max. 20 mg daily; CHILD under 18 years see BNF for Children
Prevention of cardiovascular events, 20 mg once daily; ELDERLY over 70 years, patient of ASIAN origin or with risk factors for myopathy or rhabdomyolysis, initially 5 mg once daily increased if necessary to max. 20 mg daily
Note Initially 5 mg once daily with concomitant fibrate increased if necessary to max. 20 mg daily. For dose adjustments with concomitant atazanavir, clopidogrel, darunavir, dronedarone, eltrombopag, ezetimibe, itraconazole, lopinavir, or tipranavir, consult product literature
Crestor® (AstraZeneca) 
Tablets, f/c, rosuvastatin (as calcium salt) 5 mg (yellow), net price 28-tab pack = £18.03; 10 mg (pink), 28-tab pack = £18.03; 20 mg (pink), 28-tab pack = £26.02; 40 mg (pink), 28-tab pack = £29.69. Counselling, muscle effects, see notes above
SIMVASTATIN
Indications primary hypercholesterolaemia, homozygous familial hypercholesterolaemia or combined (mixed) hyperlipidaemia in patients who have not responded adequately to diet and other appropriate measures; prevention of cardiovascular events in patients with atherosclerotic cardiovascular disease or diabetes mellitus
Cautions see notes above; also 80-mg dose only for those with severe hypercholesterolaemia and at high risk of cardiovascular complications
Hepatic impairment see notes above
Renal impairment doses above 10 mg daily should be used with caution if eGFR less than 30 mL/minute/1.73 m2
Pregnancy see notes above
Breast-feeding see notes above
Side-effects see notes above; also rarely anaemia; also reported tendinopathy
Dose
Primary hypercholesterolaemia, combined hyperlipidaemia, 10–20 mg daily at night, adjusted at intervals of at least 4 weeks; max. 80 mg once daily at night; CHILD under 18 years see BNF for Children
Homozygous familial hypercholesterolaemia, initially 40 mg daily at night, adjusted at intervals of at least 4 weeks; max. 80 mg once daily at night
Heterozygous familial hypercholesterolaemia, CHILD under 18 years see BNF for Children
Prevention of cardiovascular events, initially 20–40 mg once daily at night, adjusted at intervals of at least 4 weeks; max. 80 mg once daily at night
Note Max. 10 mg daily with concomitant bezafibrate or ciprofibrate (see also Appendix 1). Max. 20 mg daily with concomitant amiodarone, verapamil, diltiazem, amlodipine, or ranolazine. Max. 40 mg daily with concomitant lomitapide
47Simvastatin (Non-proprietary) 
Tablets, simvastatin 10 mg, net price 28-tab pack = 90p, 20 mg, 28-tab pack = 98p; 40 mg, 28-tab pack = £1.23; 80 mg, 28-tab pack = £1.81. Counselling, muscle effects, see notes above
Brands include Simvador®
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