Statins

MHRA Drug Safety Update (May 2014): Statins: benefits and risks

MHRA Drug Safety Update (September 2023): Statins: very infrequent reports of myasthenia gravis

Classification of Statins

NICE CG181 groups statins according to their lipid lowering capability (see below). The guideline recommends the use of a high intensity statin (greater than 40% LDL-c lowering) of low acquisition cost in primary and secondary prevention of cardiovascular disease (CVD). If a person cannot tolerate a high intensity statin, prescribers should aim to treat with the maximum tolerated dose.

High intensity = Greater than 40%

• Atorvastatin 20mg (43%), 40mg (49%), 80mg (55%)
• Rosuvastatin 10mg (43%), 20mg (48%), 40mg (53%)
• Simvastatin 80mg (42%) (non-formulary)

Medium intensity = 31-40%

• Atorvastatin 10mg (37%)
• Simvastatin 20mg (32%), 40mg (37%)
• Rosuvastatin 5mg (38%)
• Fluvastatin (non-formulary) 80mg (33%)

Low intensity = 20-30%

• Simvastatin 10mg (27%)
• Pravastatin (non-formulary) 10mg (20%), 20mg (24%), 40mg (29%)
• Fluvastatin (non-formulary) 20mg (21%), 40mg (27%)

Atorvastatin

• Tablets 10mg, 20mg, 40mg, 80mg (£1.64 = 20mg daily)

Indications and dose

• Primary prevention of cardiovascular events in patients at high risk of a first cardiovascular event (see Management of blood lipids):
  • 20mg once daily. Increase dose if necessary at 2-3 month interval; maximum 80mg daily.
  • Renal impairment: 20mg once daily. Agree the use of daily doses above 20mg with a renal specialist if eGFR less than 30mL/min/1.73m². Increase dose if necessary at 2-3 month intervals; maximum 80mg once daily
• Secondary prevention of cardiovascular events (off-label use). See Management of blood lipids:
  • 80mg once daily. If not tolerated at this dose, see Management of blood lipids.
  • Renal impairment: initially 20mg once daily. Agree the use of daily doses above 20mg with a renal specialist if eGFR less than 30mL/min/1.73m². Increase dose if necessary at 2-3 month intervals. Maximum 80mg once daily.
• Familial hypercholesterolaemia or mixed dyslipidaemia (see Management of blood lipids)
  • Primary or secondary prevention: see above
  • When combined with anion-exchange resin in heterozygous familial hypercholesterolaemia: 40mg once daily

Notes

1. Atorvastatin is a high intensity statin at daily doses of 20mg and above.
2. For patients with swallowing difficulties or nasogastric tube, consider rosuvastatin “hard” capsules (see entry below). Atorvastatin chewable tablets and atorvastatin liquid formulations are non-formulary as they are significantly more expensive.
3. The prescribing of atorvastatin for secondary prevention of cardiovascular disease is an off-label use.
4. The BNF states that the starting dose of 20mg once daily is not licensed for the primary prevention of cardiovascular events.
5. Interactions: Atorvastatin is metabolised by cytochrome P450 3A4 and is associated with other interactions common to statins. See the BNF or Summary of Product Characteristics for drugs to be avoided or requiring a dose adjustment for atorvastatin with concurrent use. The MHRA has issued Drug Safety Updates on specific interactions with atorvastatin (January 2008) and statins in general (September 2011).

Rosuvastatin

• Tablets 5mg, 10mg, 20mg, 40mg (£1.58 = 20mg daily)
• Hard capsules 5mg, 10mg, 20mg, 40mg – for patients with swallowing difficulties (see note 6 below) (£12.72 = 20mg daily)

Indications and dose

• Prevention of cardiovascular events in patients at high risk of a first cardiovascular event or secondary prevention of cardiovascular events (off-label use) (see Management of blood lipids)
  • 20mg once daily (see note 4)
  • In adults aged 70 years and over, or of Asian origin, or with statin intolerance, or with risk factors for myopathy and rhabdomyolysis (see note 2):
  • • Initially 5mg once daily, increase dose if necessary at 2-3 month intervals to 20mg once daily
  • Renal impairment:
  • • eGFR 30–60 mL/min/1.73 m²: Initially 5 mg once daily, increase dose if necessary at 2-3 month intervals. Do not exceed 20mg once daily.
  • • Contraindicated in patients with eGFR less than 30 mL/min/1.73 m²
• Familial hypercholesterolaemia or mixed hyperlipidaemia (See Management of blood lipids)
  • Primary or secondary prevention of cardiovascular events: see above.

Notes

1. Rosuvastatin is a high intensity statin at doses of 10mg and above. There is no evidence to suggest that cardiovascular events are less common when patients are treated with rosuvastatin compared to other statins and it has a considerably higher cost. It should be used solely in patients where all other appropriate statins have been considered and have either been demonstrated to be insufficiently effective, poorly tolerated or contraindicated.
2. The starting dose is 5mg for patients with predisposing factors for myopathy/rhabdomyolysis. For a list of predisposing factors, see “Before treatment” under Skeletal Muscle Effects, section 4.4 Warnings and Precautions, Summary of Product Characteristics.
3. Rosuvastatin 5mg is a medium intensity statin. There is no evidence medium intensity rosuvastatin results in fewer cardiovascular events than other medium intensity statins and it has a considerably higher cost.
4. Rosuvastatin 40mg is contraindicated in patients with predisposing factors for myopathy/rhabdomyolysis, including patients of Asian ancestry (see Crestor 40mg SmPC). Due to an increased reporting rate of adverse reactions with the 40mg dose compared to lower doses, the maximum dose of 40mg should only be considered in patients with severe hypercholesterolaemia at high cardiovascular risk (in particular those with familiar hypercholesterolaemia) who do not achieve their treatment goal on 20mg. The Summary of Product Characteristics recommends initiation on specialist advice. Local specialists support the use of rosuvastatin 40mg/day for the prevention of cardiovascular disease for patients who are unable to reach their target on rosuvastatin 20mg/day if it is clinically appropriate for patients to receive the higher dose (see Crestor 40mg SmPC for contraindications and warnings and precautions). Advice from specialists may be sought if necessary.
5. Interactions: Rosuvastatin is not associated with cytochrome P450 interactions. There are interactions which are common to all statins. The MHRA has issued Drug Safety Updates which include interactions with rosuvastatin (January 2008) and statins in general (September 2011). See the BNF or Summary of Product Characteristics for drugs to be avoided or requiring a dose adjustment for rosuvastatin with concurrent use.
6. Rosuvastatin “hard” capsules are included only for use where there is a clear indication of swallowing difficulty or the patient has a nasogastric tube. The capsules may be opened and the content (granules) sprinkled onto one teaspoon of soft food and swallowed within 60 minutes followed by ingestion of at least 240ml of water. The mixture should not be saved for later use. The hard capsules are licensed for administering rosuvastatin through a nasogastric tube 8 French or larger, for instructions, see the Summary of Product Characteristics.
7. The prescribing of rosuvastatin for secondary prevention of cardiovascular disease is an off-label use.
8. The routine commissioning of rosuvastatin is accepted in Devon for the prevention of cardiovascular disease in patients who are intolerant of other appropriate statins (See Commissioning Policy for more information)

Simvastatin

• Tablets 10mg, 20mg, 40mg (£0.80 = 40mg daily)

Indications and dose

• Prevention of cardiovascular events in patients at high risk of a first cardiovascular event or secondary prevention of cardiovascular events (See Management of blood lipids)
  • 40mg once daily at night as alternative to high intensity statin if not tolerated.
  • Renal impairment: doses above 10mg once daily should be used with caution if eGFR < 30ml/min/1.72m²
• Familial hypercholesterolaemia or mixed hyperlipidaemia (See Management of blood lipids)
  • 40mg once daily at night, adjusted at intervals of at least 4 weeks; maximum 80mg once daily at night (non-formulary, see note 1)

Notes

1. Simvastatin 80mg is not routinely recommended, given the association of myopathy with simvastatin 80mg (See MHRA Drug Safety Update (May 2010): Simvastatin: increased risk of myopathy at high dose [80mg]) and the availability of alternative high intensity, lower acquisition cost statins. Prescribers should discuss the potential benefits and risks of changing to another statin with people currently treated with simvastatin 80mg.
2. For patients with swallowing difficulties or nasogastric tube, consider rosuvastatin “hard” capsules (see entry above). Simvastatin liquid formulations are non-formulary as they are significantly more expensive.
   
3. Interactions: Simvastatin is associated with a significant number of interactions. Simvastatin is metabolised by cytochrome P450 34A and is associated with other interactions common to statins. The MHRA has issued Drug Safety Updates on specific interactions with simvastatin (January 2008) and (October 2012) and statins in general (September 2011). See the BNF or Summary of Product Characteristics for drugs to be avoided or requiring a dose adjustment for simvastatin with concurrent use.
4. Moderate intensity simvastatin (20mg, 40mg) or low intensity (10mg) should be considered for primary prevention of CVD where intolerance to high intensity treatment, interactions, or contraindications occur.
5. Discuss with people stable on moderate intensity statins (e.g. simvastatin 40mg) the potential risks and benefits of changing to a high intensity alternative statin at their next review.
6. Use of simvastatin for primary prevention is off-label with the exception of use in patients with diabetes mellitus.

Other oral-lowering lipid drugs

Ezetimibe

• Tablets 10mg (£3.17 = 10mg daily)

Indications and dose

• Treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia in line with NICE TA385:
  • 10mg once daily
  • Renal impairment: No dose adjustment required
  • Hepatic impairment: No dose adjustment required for mild hepatic impairment. Not recommended in moderate or severe hepatic impairment
• See Management of blood lipids

Notes

1. NICE TA385: Ezetimibe is recommended for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia (February 2016):
   1. Ezetimibe monotherapy is recommended as an option for treating primary (heterozygous-familial or non-familial) hypercholesterolaemia in adults in whom initial statin therapy is contraindicated.
   2. Ezetimibe monotherapy is recommended as an option for treating primary (heterozygous-familial or non-familial) hypercholesterolaemia in adults who cannot tolerate statin therapy.
   3. Ezetimibe, co-administered with initial statin therapy, is recommended as an option for treating primary (heterozygous-familial or non-familial) hypercholesterolaemia in adults who have started statin therapy when:
      1. serum total or low-density lipoprotein (LDL) cholesterol concentration is not appropriately controlled either after appropriate dose titration of initial statin therapy or because dose titration is limited by intolerance to the initial statin therapy and
      2. a change from initial statin therapy to an alternative statin is being considered.
   4. When prescribing ezetimibe co-administered with a statin, ezetimibe should be prescribed on the basis of lowest acquisition cost.

Bempedoic acid (with ezetimibe)

• Nilemdo tablets 180mg (£55.44 = 180mg daily)
• Nustendi tablets 180mg plus ezetimibe 10mg (£55.44 = 180mg/10mg daily)

Indications and dose

• In combination with ezetimibe, for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia or mixed dyslipidaemia in line with NICE TA694:
  • Bempedoic acid 180mg / ezetimibe 10mg once daily
  • Renal impairment: No dose adjustment required. Limited data in severe renal impairment (GFR <30ml/min/1.73m²)
  • Hepatic impairment: No dose adjustment required for mild hepatic impairment. Not recommended in moderate or severe hepatic impairment due to the unknown effects of the increased exposure to ezetimibe
• See Management of blood lipids

Notes

1. NICE TA694: Bempedoic acid with ezetimibe is recommended as an option for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia as an adjunct to diet in adults (April 2021), only if:
   1. statins are contraindicated or not tolerated,
   1. ezetimibe alone does not control low-density lipoprotein cholesterol well enough, and
   1. the company provides bempedoic acid and bempedoic acid with ezetimibe according to the commercial arrangement.
2. Bempedoic acid with ezetimibe can be used as separate tablets or a fixed-dose combination.

Injectable lipid-lowering drugs

Inclisiran

• Solution for injection, pre-filled syringe 284mg/1.5ml

Indication and dose:

• Primary (heterozygous-familial and non-familial) hypercholesterolaemia or mixed dyslipidaemia in line with NICE TA733:
  • By subcutaneous injection, initial 284mg dose, followed by a 284mg dose three months later, thereafter 284mg every 6 months
  • Renal impairment: No dose adjustment required for mild, moderate, severe or end-stage renal impairment. Use with caution in severe renal impairment due to limited experience in this patient group
  • Hepatic impairment: No dose adjustment required for mild or moderate hepatic impairment. Use with caution in severe hepatic impairment due to lack of data
• See Management of blood lipids

Notes:

1. 2nd December 2021: The Royal College of General Practitioners and the British Medical Association has issued a statement on inclisiran which includes recommendations for the prescribing of inclisiran by GPs (see here)
2. Practices are asked to order inclisiran injection directly from the wholesaler (AAH)
3. To be administered by a healthcare professional (Summary of Product Characteristics). Inclisiran is for subcutaneous injection into the abdomen. Alternative injection sites include the upper arm or thigh. Not to be administered into areas of active skin disease or injury.
4. Missed doses:
   1. If a planned dose is missed by less than 3 months, administer inclisiran and continue according to patient's original schedule.
   2. If a planned dose is missed by more than 3 months, a new dosing schedule should be started – inclisiran should be administered initially, again at 3 months, followed by every 6 months.
5. NICE TA733: Inclisiran (Leqvio) is recommended as an option for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia as an adjunct to diet in adults (06 October 2021) only if:
   1. there is a history of any of the following cardiovascular events:
      • acute coronary syndrome (such as myocardial infarction or unstable angina needing hospitalisation)
      • coronary or other arterial revascularisation procedures
      • coronary heart disease
      • ischaemic stroke or
      • peripheral arterial disease, and
   2. low‑density lipoprotein cholesterol (LDL-C) concentrations are persistently 2.6 mmol/L or more, despite maximum tolerated lipid‑lowering therapy, that is
      • maximum tolerated statins with or without other lipid-lowering therapies or,
      • other lipid-lowering therapies when statins are not tolerated or are contraindicated, and
   3. the company provides inclisiran according to the commercial arrangement
   4. Inclisiran is recommended only in research for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia in adults who have no history of cardiovascular events. This research is in the form of a clinical trial currently in development.

Alirocumab

(See note 1)

• Solution for injection, pre-filled pen 75mg in 1ml, 150mg in 1ml, 300mg in 2ml

Indications and dose

• Primary hypercholesterolaemia and mixed dyslipidaemia in line with NICE TA393
  • To be administered by subcutaneous injection: usual starting dose is 75mg administered once every 2 weeks. Patients requiring larger LDL-C reduction (>60%) may be started on 150mg once every 2 weeks, or 300mg once every 4 weeks.
  • If additional LDL-C reduction is needed in patients treated with 75mg once every 2 weeks or 300mg once every 4 weeks, the dosage may be adjusted to the maximum dosage of 150mg once every 2 weeks.
• See Management of blood lipids

Notes

1. PCSK9 inhibitors should only be initiated by lipid specialists in secondary care (or cardiologists in the case of NDDH). For patients who are stabilised on treatment and are able to self-administer injections, prescribing may be continued by GPs in line with the Devon-wide guidance for the use and prescription of PCSK9 inhibitors.
2. An annual fasting lipid profile, including total cholesterol, LDL-C, HDL-C and triglyceride, is recommended.
3. Patients who are self-administering will need to be prescribed a suitable sharps container (e.g. Sharpsafe or Sharpsguard) to be disposed of in line with local practice for domestic/household clinical waste and sharps.
4. Note for community pharmacies: Alirocumab can be ordered through AAH or Phoenix.
5. NICE TA393: Alirocumab (Praluent) is recommended as an option for treating primary hypercholesterolaemia and mixed dyslipidaemia only when the criteria of the NICE TA are met (June 2016).

Evolocumab

(See note 1)

• Solution for injection, pre-filled pen 140mg in 1ml (£340.20 = 2 pens)
• Solution for injection, pre-filled syringe 140mg in 1ml

Indications and dose

• Primary hypercholesterolaemia and mixed dyslipidaemia in line with NICE TA394
  • To be administered by subcutaneous injection: 140 mg every two weeks
• See Management of blood lipids

Notes

1. PCSK9 inhibitors should only be initiated by lipid specialists in secondary care (or cardiologists in the case of NDDH). For patients who are stabilised on treatment and are able to self-administer injections, prescribing may be continued by GPs in line with the Devon-wide guidance for the use and prescription of PCSK9 inhibitors.
2. An annual fasting lipid profile, including total cholesterol, LDL-C, HDL-C and triglyceride, is recommended.
3. Patients who are self-administering will need to be prescribed a suitable sharps container (e.g. Sharpsafe or Sharpsguard) to be disposed of in line with local practice for domestic/household clinical waste and sharps.
4. Note for community pharmacies: Evolocumab can be ordered through AAH.
5. NICE TA394: Evolocumab (Repatha) is recommended as an option for treating primary hypercholesterolaemia and mixed dyslipidaemia only when the criteria of the NICE TA are met (June 2016).

Volanesorsen

• Solution for injection, pre-filled syringes 285mg in 1.5ml

Notes

1. NICE HST13: Volanesorsen (Waylivra) is recommended, within its marketing authorisation, as an option for treating familial chylomicronaemia syndrome in adults with genetically confirmed familial chylomicronaemia syndrome who are at high risk of pancreatitis, and when response to diet and triglyceride-lowering therapy has been inadequate (October 2020)

Fibrates

The combination of a fibrate with a statin increases the risk of serious muscle toxicity, especially rhabdomyolysis, and should be used with caution.

MHRA Drug Safety Update (December 2010): Fibrates: first-line treatment not recommended.

NICE guidance (CG181) Cardiovascular disease: risk assessment and reduction, including lipid modification states "Do not routinely offer fibrates for the prevention of CVD to people being treated for primary or secondary prevention, people with CKD or type 1 diabetes or type 2 diabetes."

NICE guidance (CG71) Familial hypercholesterolaemia indicates the decision to offer a fibrate should be taken by a specialist.

Bezafibrate

• Immediate-release tablets 200mg (£7.25 = 200mg three times daily)
• Modified-release tablets 400mg (£7.12 = 400mg once daily)

Indications and dose

• Adjunct to diet and other appropriate measures in mixed hyperlipidaemia if statin contra-indicated or not tolerated, or in severe hypertriglyceridaemia:
  • Immediate-release: 200mg three times daily
  • Modified-release: 400mg once daily

Fenofibrate micronised

• Capsules 67mg (£23.23 = 90 capsules)
• Capsules 200mg, 267mg (£2.65 = 200mg once daily; £3.13 = 267mg once daily),
• Tablets 160mg (£2.94 = one daily)

Indications

• Adjunct to diet and other appropriate measures in mixed hyperlipidaemia if statin contra-indicated or not tolerated, or in severe hypertriglyceridaemia;
• Adjunct to statin in mixed hyperlipidaemia if triglycerides and HDL-cholesterol inadequately controlled in patients at high cardiovascular risk

Dose

• 67mg: initially 3 capsules daily, increased if necessary to 4 capsules daily (max 3 daily if used with statin)
• 200mg, 267mg: one capsule daily (maximum 200mg daily with statin)
• 160mg: one tablet daily

Omega-3 fatty acid compounds

Icosapent ethyl

Capsules 998mg (£134.60 = 4 capsules daily)

Indication and dose

• In combination with a statin for raised fasting triglyceride in patients with established cardiovascular disease in line with NICE TA805:
  • Two capsules twice daily in combination with a statin

Notes

1. Icosapent ethyl contains soya lecithin. Patients who are allergic to soya or peanut should not be given icosapent ethyl.
2. In patients with hepatic impairment, ALT should be monitored as clinically indicated before the start of treatment and at appropriate intervals during treatment.
3. Atrial fibrillation: Icosapent ethyl was associated with an increased risk of atrial fibrillation or flutter requiring hospitalisation in a double-blind placebo-controlled trial; the incidence was greater in patients with a previous history of atrial fibrillation or flutter. For further information, see the SmPC.
4. Patients taking icosapent ethyl with antiplatelet agents and/or anticoagulants may be at increased risk of bleeding.
5. NICE TA805: Icosapent ethyl (Vazkepa) is recommended as an option for reducing the risk of cardiovascular events in adults. It is recommended if they have a high risk of cardiovascular events and raised fasting triglycerides (1.7 mmol/litre or above) and are taking statins (13 July 2022), but only if they have:
   1. established cardiovascular disease (secondary prevention), defined as a history of any of the following:
      • acute coronary syndrome (such as myocardial infarction or unstable angina needing hospitalisation)
      • coronary or other arterial revascularisation procedures
      • coronary heart disease
      • ischaemic stroke
      • peripheral arterial disease, and
   2. low-density lipoprotein cholesterol (LDL C) levels above 1.04 mmol/litre and below or equal to 2.60 mmol/litre

Omega-3-acid ethyl esters

• Capsules 1g (each containing eicosapentaenoic acid 460mg and decosahexaenoic acid 380mg) (£28.48 = 2 capsules daily)

Indications

• Adjunct to diet and statin in IIb or III hypertriglyceridaemia; adjunct to diet in type IV hypertriglyceridaemia

Notes

1. Some preparations may contain soya lecithin. Patients who are allergic to soya or peanut should not be given omega-3-acid ethyl ester products containing soya lecithin.
2. Do not offer omega-3 fatty acids for the prevention of CVD to patients being treated for primary or secondary prevention, people with CKD, type 1 diabetes or type 2 diabetes (NICE CG181). This does not apply to icosapent ethyl when used in line with NICE TA805.
3. People with familial hypercholesterolaemia should not be routinely recommended omega-3 fatty acids (NICE CG71).
4. A European Medicines Agency (EMA) review confirms omega-3 fatty acid medicines are not effective in preventing further heart problems after a heart attack, for more information see here. Icosapent ethyl (see above) was licensed after this review was issued.
5. Omega-3 fatty acids are recommended only for people with severe hypertriglyceridaemia (>10mmol/l) who cannot tolerate a fibrate or in whom a fibrate has not sufficiently controlled triglyceride concentrations to a satisfactory level.
6. Patients taking omega-3 fatty acids with antiplatelet agents and/or anticoagulants may be at increased risk of bleeding.
7. MHRA Drug Safety Update (January 2024): Omega-3-acid ethyl ester medicines (Omacor/Teromeg 1000mg capsules): dose-dependent increased risk of atrial fibrillation in patients with established cardiovascular diseases or cardiovascular risk factors
   1. Atrial fibrillation is now listed as an adverse drug reaction with a “common” frequency (may affect up to 1 in 10 people) for medicines containing omega-3-acid ethyl esters licensed for the treatment of hypertriglyceridaemia.
   2. Advise patients taking omega-3-acid ethyl ester medicines to seek medical attention if they develop symptoms of atrial fibrillation.
   3. If a patient develops atrial fibrillation whilst taking these medicines then the medicine should be discontinued permanently.
   4. Refer to the Drug Safety Update for advice to give to patients.

Bile acid sequestrants

NICE guidance (CG181) Cardiovascular disease: risk assessment and reduction, including lipid modification states “Do not offer a bile acid sequestrant (anion exchange resin) for the prevention of CVD to people being treated for primary or secondary prevention, people with CKD or type 1 diabetes or type 2 diabetes”

For use in familial hypercholesterolaemia, see NICE guidance (CG71) Familial hypercholesterolaemia.

Colestyramine - for further information and preparations, see 1.9.2 Bile acid sequestrants)