Previous changes

July 2025 — minor update. Quality statements updated in line with the updated NICE quality standard Cardiovascular risk assessment and lipid modification.

May 2025 — minor update. QOF indicators updated in line with the NHS England Quality and Outcomes Framework guidance for 2025/26.

March 2025 — minor update. Information added that the British HIV Association (BHIVA) recommends that all people living with HIV aged 40 years or older should be offered statin treatment for primary prevention of CVD irrespective of lipid profile or estimated CVD risk, and that this should be initiated and monitored in primary care, has been added to this topic. 

September 2024 — minor update. Added recommendation on adding icosapent ethyl.

July 2024 — reviewed. A literature search was conducted in May 2024 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. The scope of the topic has been clarified, and prescribing information sections have been added for bempedoic acid, inclisiran, alirocumab, evolocumab, and icosapent ethyl. No major changes to clinical recommendations have been made.  

December 2023 — minor update. Recommendations were updated in line with the National Institute for Health and Care Excellence (NICE) guideline Cardiovascular disease: risk assessment and reduction, including lipid modification, including a new recommendation on the target lipid level for secondary prevention of cardiovascular disease (CVD) in people taking lipid-lowering treatment. 

May 2023 — minor update. The Quality and Outcomes Framework (QoF) indicators have been updated in line with the Quality and Outcomes Framework guidance for 2023/24. The NICE Quality standards have also been updated in line with Cardiovascular risk assessment and lipid modification. Quality standard (QS100) [updated May 2023]. Recommendations have been updated to align with the updated NICE guideline Cardiovascular disease: risk assessment and reduction, including lipid modification. 

April 2023 — minor update. Added adverse effect that statins can induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia, and that treatment should be discontinued in case of aggravation or development of these symptoms.

January 2023 — minor update. Information regarding rosuvastatin interactions was added in line with the manufacturer's updated Summary of Product Characteristics (SPC).

October 2022 — minor update. Information regarding an interaction between ticagrelor and rosuvastatin was added in line with the manufacturer's updated SPC.

August 2022 — minor update. A recommendation to consider offering inclisiran has been added in line with the NICE technology appraisal Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidaemia.

July 2022 — minor update. A recommendation to consider offering icosapent ethyl has been added in line with the NICE technology appraisal Icosapent ethyl with statin therapy for reducing the risk of cardiovascular events in people with raised triglycerides.

January 2022 — minor update. Information that ezetimibe with bempedoic acid can be considered for people taking ezetimibe monotherapy if it does not control low-density lipoprotein cholesterol well enough has been added in line with the NHS England Summary of National Guidance for Lipid Management for Primary and Secondary Prevention of CVD.

May 2021 — minor update. A drug interaction between rosuvastatin and gemfibrozil was added in line with the manufacturer's updated SPC.

April 2021 — minor update. The scope of the topic has been clarified. 

October 2020 — minor update. The concurrent use of sofosbuvir/velpatasvir/voxilaprevir with rosuvastatin is contraindicated and has been added in line with the manufacturers' updated SPCs.

September 2020 — minor update. A drug interaction between simvastatin and ticagrelor was added in line with the updated SPC for simvastatin.

August 2020 — minor update. The section on the adverse effects of statins has been updated in line with the updated SPC for simvastatin, and broken URL links have been updated. 

July to August 2019 — reviewed. A literature search was conducted in July 2019 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials (RCTs) published since the last revision of the topic. No major changes have been made to the recommendations in this topic.

October 2015 — minor update. Immune-mediated necrotizing myopathy (IMNM) has been included as a very rare adverse effect of some statins following an update to the SPCs for atorvastatin and simvastatin.

July 2015 — minor update. Minor text change to remove the percentage equivalents of HbA1c mmol/mol values, which are no longer commonly used to diagnose diabetes mellitus.

June 2015 — minor update. Further clarification on the use of ezetimibe for the prevention of CVD.

May 2015 — minor update. Following an update to the SPC for atorvastatin, as advised by the European Medicines Agency (EMA), immune-mediated necrotizing myopathy has been added as a possible adverse effect during or after treatment with atorvastatin (and other statins).

April 2015 — minor update. The recommendations on the use of ezetimibe for the prevention of CVD have been amended to reflect recommendations in the NICE guideline Lipid modification: Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease and the NICE technology appraisal Ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia.

February 2015 — minor update. Typographical errors were corrected in the topic.

December 2014 — reviewed. The recommendations have been updated in line with the revised NICE guideline Lipid modification: Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Significant changes to the recommendations include advice on the following:

• When to offer treatment for the prevention of CVD:
  • If there is no established CVD, lipid modification treatment should be:
    • Offered to people aged 84 years and younger if their estimated 10-year risk of developing CVD using the QRISK^®2 assessment tool is 10% or more.
    • Offered (without the need for a formal risk assessment) to people with type 1 diabetes, chronic kidney disease, or familial hypercholesterolaemia.
    • Considered (without the need for a formal risk assessment) in people who are 85 years or older, considering the benefits and risks of treatment and any comorbidities that make treatment appropriate.
  • For people who have established CVD, lipid modification therapy should be advised for the secondary prevention of CVD.
• Lipid measurements: before starting lipid modification treatment for the prevention of CVD, at least one lipid sample should be taken to measure a full lipid profile. This should include measuring total cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, and triglycerides. A fasting sample is not needed. The aim of treatment is to achieve a greater than 40% reduction in non-HDL cholesterol.
• Creatine kinase: this should only be checked if the person has persistent generalized unexplained muscle pain (whether associated with previous lipid-lowering therapy or not). It should not be checked in asymptomatic people being considered for statin treatment. 
• Treatment to offer: high-intensity statin treatment should be offered for the primary and secondary prevention of CVD. Atorvastatin 20 mg is recommended first line for the primary prevention of CVD. Atorvastatin 80 mg is recommended first line for secondary prevention of CVD; however, a lower dose should be prescribed if there are adverse effects, increased risk of adverse effects, or if the person prefers a lower dose.
• Informed choice: the decision to start statin treatment should be made after an informed discussion with the person about the risks and benefits of treatment, considering factors such as co-morbidities, potential benefits from lifestyle intervention, the person's preference, and life expectancy.

June 2013 — minor update. The 2013 QOF options for local implementation have been added to this topic.

February 2013 — minor update. The 2013 QIPP options for local implementation have been added to this topic.

January 2013 — minor update. Colesevelam is no longer a black triangle drug, so the black triangle status has been removed. The text has been updated to reflect safety advice for simvastatin issued by the Medicines and Healthcare products Regulatory Agency (MHRA).

October 2012 — minor update. The 2012 QIPP options for local implementation have been added to this topic.

June 2012 — minor update. Minor formatting error corrected.

April 2012 — minor update. The 2012/2013 QOF indicators have been added to this topic. 

January 2012 — minor update. Information from the MHRA about the risk of hyperglycaemia and diabetes with statin use has been added. Issued in February 2012.

December 2011 — minor update. The MHRA warning on the interaction between systemic fusidic acid and statins has been included. 

September 2011 — minor update. Removed all references to Niaspan® m/r tablets (containing nicotinic acid) as they have been discontinued (in August 2011) and included information (and prescriptions) for Tredaptive® modified release tablets (containing laropiprant with nicotinic acid) and Olbetam® capsules (containing acipimox, a derivative of nicotinic acid). 

June 2011 — minor update. A typographical error was corrected. The 2011/2012 QOF indicators and the 2010/2011 QIPP options for local implementation have been added to this topic. 

March 2011 — the topic structure was revised to ensure consistency across CKS topics. No changes to clinical recommendations have been made.

December 2010 — minor update. The section on supporting evidence has been updated following the publication of the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial.

June 2010 — minor update. Following a review of the data from the SEARCH trial, the MHRA has advised that simvastatin 80 mg should be considered only in people 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. 

November 2009 — minor update. Added advice from the MHRA that treatment with any statin may be associated with depression, sleep disturbances, memory loss, sexual dysfunction or, very rarely, interstitial lung disease. 

October 2009 — minor update. A reminder from the MHRA that aspirin is not licensed for use in the primary prevention of vascular events has been added. 

May 2009 — the section on goals and outcome measures was updated to include the QOF indicators related to lipid modification. 

June to December 2008 — converted from CKS guidance to CKS topic structure. The evidence base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence. The recommendations on lipid modification have been updated in line with guidance issued by the NICE. Significant changes to the recommendations include:

• For primary prevention of CVD:
  • Repeat lipid measurement is unnecessary. A target for total or low-density lipoprotein (LDL) cholesterol is not recommended.
• For secondary prevention of CVD:
  • The use of higher intensity lipid-modifying treatment (simvastatin 80 mg) is recommended if a target total cholesterol of less than 4 mmol/L or a low-density lipoprotein (LDL) cholesterol of less than 2 mmol/L has not been achieved.
  • Other higher-intensity statin therapy (other than simvastatin 80 mg) is not recommended except for people with acute coronary syndrome (where the use of atorvastatin 80 mg is cost effective).

March 2008 — minor update. The MHRA has issued advice regarding several additional class adverse effects of statins. 

January 2008 — minor update. The MHRA has issued updated advice on interactions with statins. 

December 2007 — minor update to add new drug safety advice from the MHRA regarding fibrates. 

October 2007 — minor update to remove the black triangle status of rosuvastatin (effective from July 2007). 

March 2007 — minor update to clarify that the current national targets for lipid lowering are still the National Service Framework targets, not the Joint British Societies (JBS) targets. 

April to June 2006 — reviewed. Validated in September 2006 and issued in October 2006. This guidance has been rewritten following a full literature review and to take account of JBS 2, the Joint British Societies' guidelines on the prevention of cardiovascular disease in clinical practice. It incorporates and replaces the CKS guidance on Hyperlipidaemia and Diabetes type 2 — lipid management. The main changes relate to recommendations on:

• Screening people for CVD risk: all people over the age of 40 years and people at high risk for CVD under the age of 40 years.
• Indications for starting lipid-lowering treatment: now, equal priority is given to people requiring primary and secondary prevention of CVD.
• Targets for lipid-lowering treatment: lower absolute targets for LDL cholesterol and total cholesterol.

November 2005 — minor technical update. 

April 2005 — updated to include new advice on the maximum dose of rosuvastatin in people of Asian descent. 

February 2003 — reviewed. Validated in June 2003 and issued in July 2003.

September 2002 — written. Validated in December 2002 and issued in February 2003. Replaces previous guidance Hyperlipidaemia — primary prevention and Hyperlipidaemia — secondary prevention.

New evidence

Evidence-based guidelines

• Damman K, Ter Maaten JM, Mayne KJ, et al (2026) 2026 ESC Guidelines for the management of cardiovascular disease and chronic kidney disease, in collaboration with the European Renal Association (ERA). European Heart Journal. https://academic.oup.com/eurheartj [Free Full-text]

HTAs (Health Technology Assessments)

No new HTAs since 1 May 2024.

Economic appraisals

No new economic appraisals relevant to England since 1 May 2024.

Systematic reviews and meta-analyses

• Saad Cleto, A., Schirlo, J.M., Oliveira Gomes, V.H., et al. (2024) Inclisiran versus alirocumab in improving lipid profile parameters: A systematic review and meta-analysis. Diabetes Obesity and Metabolism. https://dom-pubs.pericles-prod.literatumonline.com/ [Abstract]

Primary evidence

• Nicholls, S.J., Ni, W., Rhodes, G.M., et al. (2024) Oral Muvalaplin for Lowering of Lipoprotein(a): A Randomized Clinical Trial. JAMA. https://jamanetwork.com [Free Full-text]
•  

New policies

No new national policies or guidelines since 1 May 2024.

New safety alerts

No new safety alerts since 1 May 2024.

Changes in product availability

• New product, rosuvastatin 10mg/5ml Oral Solution, is licensed for the prevention of major cardiovascular events in patients at high risk. See more here.

When should I offer lipid-lowering treatment for the primary prevention of cardiovascular disease?

• Primary prevention of cardiovascular disease (CVD) targets people who do not have established CVD but are at risk of a first cardiovascular event. This includes:
  • People with a 10-year QRISK3 score of 10% or more (including people with type 2 diabetes).
  • People with type 1 diabetes, chronic kidney disease (CKD), or familial hypercholesterolaemia (or other inherited disorders of lipid metabolism).
  • People aged 85 years and older.
• Before offering statin treatment for the primary prevention of CVD:
  • Discuss the benefits of lifestyle changes (such as physical activity and a cardioprotective diet). For information on lifestyle changes to reduce CVD risk, see the CKS topic on CVD risk assessment and management.
  • Recognize that the person may need support to change their lifestyle. To help with this, arrange referrals to programmes such as exercise referral schemes or weight management services. 
  • Where possible, optimize the management of all other modifiable CVD risk factors (such as hypertension and obesity). For more information, see the CKS topics on Hypertension and Obesity.
  • Where applicable, offer the person the opportunity to have their CVD risk assessed again after they have tried to change their lifestyle. For information on assessing CVD risk, see the CKS topic on CVD risk assessment and management.
  • Recognize that CVD risk tools may underestimate CVD risk in certain groups of people, including:
    • People treated for HIV. Note: the British HIV Association (BHIVA) recommends that all people living with HIV aged 40 years or older should be offered statin treatment for primary prevention of CVD irrespective of lipid profile or estimated CVD risk, and that this should be initiated and monitored in primary care [BHIVA, 2024].
    • People already taking medications to treat CVD risk factors.
    • People taking medications that can cause dyslipidaemia (such as antipsychotics, corticosteroids, or immunosuppressant drugs).
    • People who have recently stopped smoking.
    • People with severe mental illness.
    • People with autoimmune disorders or other systemic inflammatory disorders. 
• If lifestyle change alone is ineffective or inappropriate (for example, in people thought to be at higher risk of CVD based on comorbidities, risk scores, or clinical judgement):
  
  • Offer statin treatment for the primary prevention of CVD to people with a 10-year QRISK3 score of 10% or more, including those with type 2 diabetes. 
    • If the 10-year QRISK3 score is less than 10%, do not rule out statin treatment if the person has an informed preference for taking it or if there is concern that CVD risk may be underestimated.
  • Offer statin treatment for the primary prevention of CVD (without the need for a formal risk assessment) to:
    • People with type 1 diabetes who are aged over 40 years, have had diabetes for more than 10 years, have established nephropathy, or have other CVD risk factors.
    • People with CKD (estimated glomerular filtration rate less than 60 ml per minute per 1.73 m² and/or albuminuria).
    • People with familial hypercholesterolaemia. For more information, see the section on Lipid-modification treatment in adults with heterozygous FH in the CKS topic on Hypercholesterolaemia - familial. 
  •  Consider offering statin treatment for the primary prevention of CVD (without the need for a formal risk assessment) to:
    • People aged 85 and older, especially if they smoke or have raised blood pressure. Consider the potential benefits from lifestyle changes, as well as the person's preferences, comorbidities, current medications, general frailty, and life expectancy.
    • People aged 18–40 with type 1 diabetes, including those who have had diabetes for 10 years or less.
• Make decisions about starting statin treatment after an informed discussion with the person about the risks and benefits. For more information, see the section on Discussions and assessment before starting treatment.

What discussions and assessments are required before starting lipid-lowering treatment for the primary prevention of cardiovascular disease?

If statin treatment is indicated:

• Make decisions about starting treatment after an informed discussion with the person about the risks and benefits of statins. 
  • Consider the potential benefits of lifestyle changes and the person's preferences, comorbidities, current medications, general frailty, and life expectancy.
  • Discuss possible adverse effects of statins, including muscle symptoms. Advise that the risk of muscle pain, tenderness, or weakness associated with statin use is small, and the rate of severe muscle adverse effects (rhabdomyolysis) is extremely low.
  • In women of childbearing potential, explain that because of the potential for serious adverse effects:
    
    • Adequate contraception is required during statin treatment.
    • Statins should be stopped 3 months before attempting to conceive and during pregnancy. 
    • Statins should not be restarted until breastfeeding has ended.
  • Explain that some foods, drinks (for example, grapefruit juice), medications, or supplements may interact with statins. Advise that they should check the patient information leaflet or get advice from a pharmacist or prescriber before taking other medications or supplements. 
  • The National Institute for Health and Care Excellence (NICE) Patient decision aid on statins may help facilitate the discussion.  
• Perform appropriate clinical assessments, including: 
  • Smoking status.
  • Alcohol consumption.
  • Blood pressure.
  • Body mass index.
• Measure a non-fasting full lipid profile (if it has not already been done as part of the cardiovascular risk assessment).   
  • Assess for and, where possible, treat comorbidities and secondary causes of dyslipidaemia (such as excess alcohol intake, uncontrolled diabetes, liver disease, and nephrotic syndrome).
  • Use clinical findings, the full lipid profile, and family history to judge the likelihood of a familial lipid disorder rather than using strict lipid cut-off values alone. For information on when to suspect (and how to manage) familial hypercholesterolaemia, see the CKS topic on Hypercholesterolaemia - familial. 
    • If the total blood cholesterol level is more than 9.0 mmol/L or non-high-density lipoprotein (non-HDL) cholesterol level is more than 7.5 mmol/L, even without a first-degree family history of premature coronary heart disease, arrange for specialist assessment.
    • If the triglyceride concentration is more than 20 mmol/L and does not result from excess alcohol intake or poor glycaemic control, refer for urgent specialist review.
    • If the triglyceride concentration is between 10 and 20 mmol/L, repeat the triglyceride measurement with a fasting test (after 5 days but within 2 weeks), review for potential secondary causes of hyperlipidaemia, and seek specialist advice if the triglyceride concentration remains above 10 mmol/L. 
    • If the triglyceride concentration is between 4.5 and 9.9 mmol/L, be aware that risk assessment tools may underestimate CVD risk. Optimize the management of other CVD risk factors, and seek specialist advice if the non-HDL cholesterol concentration is more than 7.5 mmol/L.
• Perform the following additional baseline blood tests (if they have not already been done as part of the cardiovascular risk assessment):
  
  • Liver transaminase level.
    • If alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is raised but is less than 3 times the upper limit of normal, do not routinely exclude the person from statin treatment. Start statin treatment and repeat liver function tests (LFTs) in 4 weeks. If ALT or AST remains elevated but is less than 3 times the upper limit of normal, continue statin treatment and repeat LFTs in 6 months.
    • If ALT or AST is greater than 3 times the upper limit of normal, do not start statin treatment. Repeat LFTs in 4 weeks. If ALT or AST is still greater than 3 times the upper limit of normal, do not start statin treatment. See the section on Lipid-lowering treatment for primary prevention for more information.
  • Diabetes status.
    
    • Do not withhold statin treatment because of an increase in HbA1c or blood glucose level. 
    • For information on how to manage hyperglycaemia, see the CKS topic on Diabetes - type 2.
  • Renal function (including estimated glomerular filtration rate).
    • Chronic kidney disease (CKD) does not preclude the use of statins, but specific doses are recommended depending on the stage of CKD.
• If the person has had persistent generalized unexplained muscle symptoms (pain, tenderness, or weakness), whether associated or not with previous lipid-lowering treatment, measure creatine kinase (CK).
  
  • If CK is raised but is less than 5 times the upper limit of normal, start statin treatment at a lower dose. 
  • If CK is more than 5 times the upper limit of normal, re-check after 7 days. If the level is still 5 times the upper limit of normal, do not start statin treatment. See the section on Lipid-lowering treatment for primary prevention for more information.
• If the person has symptoms of an underactive or overactive thyroid, measure thyroid-stimulating hormone levels.
  • For management information, see the CKS topic on Hypothyroidism or Hyperthyroidism.

Which lipid-lowering treatment should I offer for the primary prevention of cardiovascular disease?

• For the primary prevention of cardiovascular disease (CVD), offer high-intensity statin treatment with atorvastatin 20 mg to all people, including those with chronic kidney disease (estimated glomerular filtration rate less than 60 mL per minute per 1.73 m² and/or albuminuria).
• If statins are contraindicated or not tolerated, ezetimibe may be considered.
  • Consider referral to a specialist lipid management clinic according to local arrangements.
  • The Accelerated Access Collaborative (AAC) Statin Intolerance Pathway has additional information on managing statin intolerance in people at high risk of CVD.
• If the person declines lipid-lowering treatment:
  
  • Record their choice in their medical notes.
  • Advise that their CVD risk should be reassessed at a later date.
• Do not offer:
  • Coenzyme Q10 or vitamin D to increase adherence to statin treatment.
  • Fibrates routinely to prevent CVD.
  • Nicotinic acid (niacin), bile acid sequestrant (anion exchange resin), or omega-3 fatty acid compounds to prevent CVD.
  • A combination of a statin with a bile acid sequestrant (anion exchange resin), a fibrate, nicotinic acid, or an omega-3 fatty acid compound to prevent CVD.

How should I assess response to lipid-lowering treatment for the primary prevention of cardiovascular disease?

• Measure a non-fasting full lipid profile 2–3 months after starting (or changing) lipid-lowering treatment. 
  • The lipid target for primary prevention of cardiovascular disease (CVD) is a greater than 40% reduction in non-high-density lipoprotein (non-HDL) cholesterol. 
  • If the lipid target is met:
    • Continue lipid-lowering treatment if the shared decision is to continue.
    • Do not routinely de-escalate lipid-lowering treatments when levels are lower than the target, except if clinically indicated or based on the person's needs or preferences.
  • If the lipid target is not met:
    • Consider treatment optimization or escalation after an informed discussion with the person about the risks and benefits. For more information, see the section on Treatment optimization/escalation.
• Measure liver transaminase 2–3 months after starting (or changing) lipid-lowering treatment and again at 12 months. Further monitoring is not necessary unless clinically indicated (for example, if symptoms or signs of hepatotoxicity develop).
  • If alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is greater than 3 times the upper limit of normal, stop statin treatment and repeat liver function tests in 4 weeks.
  • If ALT or AST is still greater than 3 times the upper limit of normal, do not restart statin treatment. See the section on Lipid-lowering treatment for primary prevention for more information.
• Assess for other adverse effects of statins.
  • If the person reports muscle pain, tenderness, or weakness, check creatine kinase (CK).
    
    • If CK is less than 5 times the upper limit of normal, reassure the person that their symptoms are unlikely to be due to the statin and explore other possible causes. 
    • If CK is more than 5 times the upper limit of normal, stop statin treatment. See the section on Lipid-lowering treatment for primary prevention for more information.
    • Do not measure CK levels in asymptomatic people. 
  • If the person reports other adverse effects when taking a high-intensity statin, discuss the following strategies with them: 
    • Stopping the statin and trying again when the symptoms have resolved to check if the symptoms are related to the statin. 
    • Changing to a different statin in the same intensity group (for example, rosuvastatin if already receiving atorvastatin).
    • Reducing the dose of the statin. Advise that any statin at any dose reduces CVD risk.
    • Changing to a lower-intensity statin. 
  • If the person cannot tolerate a high-intensity statin, aim to treat with the maximum tolerated intensity and dose.  
  • If the person cannot tolerate statins daily, consider an alternate-day or twice-weekly dosing regimen. Rosuvastatin and atorvastatin have longer half-lives, permitting their use on non-daily treatment regimens.
  • If the person cannot tolerate statins at any dose, intensity, or regimen, see the section on Lipid-lowering treatment for primary prevention for more information.
• Provide annual medication reviews. 
  • During the medication review:
    
    • Discuss and encourage treatment adherence. Remind the person to remember to restart their statin if stopped because of drug interactions or to treat an intercurrent illness.
    • Assess for adverse effects of statins. Remind the person to seek medical advice if they develop adverse effects, such as unexplained muscle symptoms (pain, tenderness, or weakness). 
    • Discuss and encourage dietary and lifestyle changes. If appropriate, offer referrals to programmes such as exercise referral schemes or weight management services. 
    • Address other modifiable CVD risk factors, such as hypertension and type 2 diabetes. Do not withhold statin treatment because of an increase in blood glucose level or HbA1c.
    • If the person is stable on a low or medium-intensity statin, discuss the likely benefits and potential risks of changing to a high-intensity statin and agree with the person on whether a change is needed. 
  • Consider an annual full lipid profile to inform discussions on the primary prevention of CVD.

How should I optimize or escalate lipid-lowering treatment for the primary prevention of cardiovascular disease?

The lipid target for primary prevention of cardiovascular disease (CVD) is a greater than 40% reduction in non-high-density lipoprotein (non-HDL) cholesterol. 

• If the lipid target is not met:
  • Discuss treatment adherence.
  • Discuss the timing of the statin dose (atorvastatin can be taken at any time of the day, but simvastatin, pravastatin, and fluvastatin should be taken in the evening). 
  • Encourage the person to continue improving their diet and lifestyle and make further changes if appropriate. 
  • If the person is thought to be at high risk of CVD (based on comorbidities, risk scores, or clinical judgement), consider treatment optimization (statin dose increase) or escalation (additional lipid-lowering treatment) after an informed discussion with the person about the risks and benefits. Consider the person's preferences, comorbidities, other medications, general frailty, and life expectancy. 
• If the lipid target is not met and the person is taking atorvastatin, increase the atorvastatin dose every 2–3 months up to a maximum daily dose of 80 mg.
  • If the estimated glomerular filtration rate (eGFR) is less than 30 ml per minute per 1.73 m², agree the use of higher doses with a renal specialist.
  • If the maximum tolerated statin dose does not achieve the lipid target after 2–3 months, consider adding ezetimibe.
• If the lipid target is not met and the person is taking ezetimibe monotherapy (due to statin contraindication or intolerance):
  • Consider adding bempedoic acid.
• If the lipid target is not met despite the maximum tolerated dose of lipid-lowering treatment:
  • Consider referral to a specialist lipid management clinic according to local arrangements.
• Do not offer:
  • Coenzyme Q10 or vitamin D to increase adherence to statin treatment.
  • Fibrates routinely to prevent CVD.
  • Nicotinic acid (niacin), bile acid sequestrant (anion exchange resin), or omega-3 fatty acid compounds to prevent CVD.
  • A combination of a statin with a bile acid sequestrant (anion exchange resin), a fibrate, or nicotinic acid to prevent CVD.
  • A combination of a statin with an omega-3 fatty acid compound to prevent CVD.
• Do not routinely de-escalate lipid-lowering treatments when levels are lower than the target, except if clinically indicated or based on the person’s needs or preferences.

When should I offer lipid-lowering treatment for secondary prevention of cardiovascular disease?

• Secondary prevention of cardiovascular disease (CVD) aims to reduce the risk of a recurrent cardiovascular event in people with established CVD.  
  • Offer lipid-lowering treatment for the secondary prevention of CVD to adults with established CVD, regardless of their cholesterol level.
  • Do not delay lipid-lowering treatment for secondary prevention of CVD, but discuss lifestyle changes at the same time if appropriate. For information on lifestyle changes to reduce CVD risk, see the CKS topic on CVD risk assessment and management. 
• Make decisions about starting statin treatment after an informed discussion with the person about the risks and benefits. For more information, see the section on Discussions and assessment before starting treatment. 

What discussions and assessments are required before starting lipid-lowering treatment for the secondary prevention of cardiovascular disease?

If statin treatment is indicated:

• Make decisions about starting treatment after an informed discussion with the person about the risks and benefits of statins. 
  • Consider the potential benefits of lifestyle changes and the person's preferences, comorbidities, current medications, general frailty, and life expectancy.
  • Discuss possible adverse effects of statins, including muscle symptoms. Advise that the risk of muscle pain, tenderness, or weakness associated with statin use is small, and the rate of severe muscle adverse effects (rhabdomyolysis) is extremely low.
  • In women of childbearing potential, explain that because of the potential for serious adverse effects:
    
    • Adequate contraception is required during statin treatment.
    • Statins should be stopped 3 months before attempting to conceive and during pregnancy. 
    • Statins should not be restarted until breastfeeding is finished.
  • Explain that some foods, drinks (for example, grapefruit juice), medications, or supplements may interact with statins. Advise that they should check the patient information leaflet or get advice from a pharmacist or prescriber before taking other drugs or supplements. 
  • The National Institute for Health and Care Excellence (NICE) Patient decision aid on statins may help facilitate the discussion.
• Perform appropriate clinical assessments, including: 
  • Smoking status.
  • Alcohol consumption.
  • Blood pressure.
  • Body mass index.
• Measure a non-fasting full lipid profile (if it has not already been done as part of the cardiovascular risk assessment).
  
  • Assess for and, where possible, treat comorbidities and secondary causes of dyslipidaemia (such as excess alcohol intake, uncontrolled diabetes, hypothyroidism, liver disease, and nephrotic syndrome).
  • Use clinical findings, the full lipid profile, and family history to judge the likelihood of a familial lipid disorder rather than using strict lipid cut-off values alone. For information on when to suspect (and how to manage) familial hypercholesterolaemia, see the CKS topic on Hypercholesterolaemia - familial. 
    • If the total blood cholesterol level is more than 9.0 mmol/L or non-high-density lipoprotein (non-HDL) cholesterol level is more than 7.5 mmol/L, even without a first-degree family history of premature coronary heart disease, arrange for specialist assessment.
    • If the triglyceride concentration is more than 20 mmol/L and does not result from excess alcohol intake or poor glycaemic control, refer for urgent specialist review.
    • If the triglyceride concentration is between 10 and 20 mmol/L, repeat the triglyceride measurement with a fasting test (after 5 days but within 2 weeks), review for potential secondary causes of hyperlipidemia, and seek specialist advice if the triglyceride concentration remains above 10 mmol/L. 
    • If the triglyceride concentration is between 4.5 and 9.9 mmol/L, be aware that risk assessment tools may underestimate CVD risk. Optimize the management of other CVD risk factors, and seek specialist advice if the non-HDL cholesterol concentration is more than 7.5 mmol/L.
• Perform the following additional baseline blood tests (if they have not already been done as part of the cardiovascular risk assessment):
  
  • Liver transaminase level.
    • If alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is raised but is less than 3 times the upper limit of normal, do not routinely exclude the person from statin treatment. Start statin treatment and repeat liver function tests (LFTs) in 4 weeks. If ALT or AST remains elevated but is less than 3 times the upper limit of normal, continue statin treatment and repeat LFTs in 6 months.
    • If ALT or AST is greater than 3 times the upper limit of normal, do not start statin treatment. Repeat LFTs in 4 weeks. If ALT or AST is still greater than 3 times the upper limit of normal, do not start statin treatment. See the section on Lipid-lowering treatment for secondary prevention for more information. 
  • Diabetes status.
    • Do not withhold statin treatment because of an increase in HbA1c or blood glucose level. 
    • For information on how to manage hyperglycaemia, see the CKS topic on Diabetes - type 2.
  • Renal function (including estimated glomerular filtration rate).
    • Chronic kidney disease (CKD) does not preclude the use of statins, but specific doses are recommended depending on the stage of CKD.
• If the person has a history of persistent generalized unexplained muscle symptoms (pain, tenderness, or weakness), whether associated or not with previous lipid-lowering treatment, measure creatine kinase (CK).
  • If CK is raised but is less than 5 times the upper limit of normal, start statin treatment at a lower dose. 
  • If CK is more than 5 times the upper limit of normal, re-check after 7 days. If the level is still 5 times the upper limit of normal, do not start statin treatment. See the section on Lipid-lowering treatment for secondary prevention for more information. 
• If the person has symptoms of an underactive or overactive thyroid:
  • Measure thyroid-stimulating hormone levels.
  • For management information, see the CKS topic on Hypothyroidism or Hyperthyroidism.

Which lipid-lowering treatment should I offer for the secondary prevention of cardiovascular disease?

• For the secondary prevention of cardiovascular disease (CVD):
  • Offer high-intensity statin treatment with atorvastatin 80 mg.
  • Offer a lower dose of atorvastatin if any of the following apply:
    
    • The person has chronic kidney disease (estimated glomerular filtration rate less than 60 ml per minute per 1.73 m² and/or albuminuria) — offer atorvastatin 20 mg.
    • There are drug interactions. 
    • There is an increased risk of adverse effects. 
    • The person requests to start at a lower dose.
• If statins are contraindicated or not tolerated, offer ezetimibe monotherapy regardless of the person's cholesterol level. 
  
  • The Accelerated Access Collaborative (AAC) Statin Intolerance Pathway has additional information on managing statin intolerance in people at high risk of CVD.
• If the person declines lipid-lowering treatment:
  
  • Record their choice in their medical notes.
  • Advise that their CVD risk should be discussed again at a later date.
• Do not offer:
  • Coenzyme Q10 or vitamin D to increase adherence to statin treatment.
  • Fibrates routinely to prevent CVD.
  • Nicotinic acid (niacin), bile acid sequestrant (anion exchange resin), or omega 3 fatty acid compounds to prevent CVD.
  • A combination of a statin with a bile acid sequestrant (anion exchange resin), a fibrate, or nicotinic acid to prevent CVD.
  • A combination of a statin with an omega 3 fatty acid compound to prevent CVD, except icosapent ethyl if used as described in the National Institute for Health and Care Excellence (NICE) technology appraisal guidance.

How should I manage a person who is taking a different statin for secondary prevention of cardiovascular disease?

• If the person is stable on a low-intensity statin (such as simvastatin 10 mg) or a medium-intensity statin (such as simvastatin 20 or 40 mg):
  • Discuss the benefits of changing to high-intensity treatment with atorvastatin 80 mg (or lower if necessary).
  • If the person is unwilling to switch to atorvastatin 80 mg, reassure them that they will still benefit from their current treatment.
• If the person is stable on another high-intensity statin, manage as follows:
  • For simvastatin 80 mg: encourage them to switch to atorvastatin 80 mg (or lower if necessary). Advise that there is an increased risk of myopathy associated with simvastatin 80 mg. If the person is unwilling to switch to atorvastatin, advise them to continue their current treatment.
  • For rosuvastatin 10, 20, or 40 mg: advise the person to continue with rosuvastatin treatment.
• Follow up the person to assess the effectiveness and tolerability of the treatment.

How should I assess response to lipid-lowering treatment for the secondary prevention of cardiovascular disease?

• Measure a non-fasting full lipid profile 2–3 months after starting (or changing) lipid-lowering treatment.
  • The lipid target for the secondary prevention of cardiovascular disease (CVD) is low-density lipoprotein (LDL) cholesterol levels of 2.0 mmol/L or less or non-high-density lipoprotein (non-HDL) cholesterol levels of 2.6 mmol/L or less.
    
  • If the lipid target is met:
    • Continue lipid-lowering treatment if the shared decision is to continue.
    • Do not routinely de-escalate lipid-lowering treatments when levels are lower than the target, except if clinically indicated or based on the person’s needs or preferences.
    • Consider ezetimibe in addition to the maximum tolerated intensity and dose of statin to further reduce CVD risk.
  • If the lipid target is not met:
    • Consider treatment optimization or escalation after an informed discussion with the person about the risks and benefits. For more information, see the section on Treatment optimization/escalation.
• Measure liver transaminase 2–3 months after starting (or changing) lipid-lowering treatment and again at 12 months. Further monitoring is not necessary unless clinically indicated (for example, if symptoms or signs of hepatotoxicity develop).
  • If alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is greater than 3 times the upper limit of normal, stop statin treatment and repeat liver function tests in 4 weeks.
  • If ALT or AST is still greater than 3 times the upper limit of normal, do not restart statin treatment. See the section on Lipid-lowering treatment for secondary prevention for more information. 
• Assess for other adverse effects of statins.
  • If the person reports muscle pain, tenderness, or weakness while taking a statin, check creatine kinase (CK).
    • If CK is less than 5 times the upper limit of normal, reassure the person that their symptoms are unlikely to be due to the statin and explore other possible causes. 
    • If CK is more than 5 times the upper limit of normal, stop statin treatment. See the section on Lipid-lowering treatment for secondary prevention for more information. 
    • Do not measure CK levels in asymptomatic people. 
  • If the person reports other adverse effects when taking a high-intensity statin, discuss the following strategies with them: 
    • Stopping the statin and trying again when the symptoms have resolved to check if the symptoms are related to the statin. 
    • Changing to a different statin in the same intensity group.
    • Reducing the dose of the statin. Advise that any statin at any dose reduces CVD risk.
    • Changing to a lower-intensity statin. 
  • If the person cannot tolerate a high-intensity statin, aim to treat with the maximum tolerated intensity and dose.  
  • If the person cannot tolerate statins daily, consider an alternate-day or twice-weekly dosing regimen. Rosuvastatin and atorvastatin have longer half-lives, permitting their use on non-daily treatment regimens.
  • If the person cannot tolerate statins at any dose, intensity, or regimen, see the section on Lipid-lowering treatment for secondary prevention for more information. 
• Provide annual medication reviews. 
  • During the medication review:
    
    • Discuss and encourage treatment adherence. Remind the person to remember to restart their statin if stopped because of drug interactions or to treat an intercurrent illness.
    • Assess for adverse effects of statins. Remind the person to seek medical advice if they develop adverse effects, such as unexplained muscle symptoms (pain, tenderness, or weakness). 
    • Discuss and encourage dietary and lifestyle changes. If appropriate, offer referrals to programmes such as exercise referral schemes or weight management services. 
    • Address other modifiable CVD risk factors, such as hypertension and type 2 diabetes. Do not withhold statin treatment because of an increase in blood glucose level or HbA1c.
    • If the person is stable on a low or medium-intensity statin, discuss the likely benefits and potential risks of changing to a high-intensity statin and agree with the person on whether a change is needed. 
  • Offer an annual full lipid profile to inform discussions on secondary prevention of CVD.

How should I optimize or escalate lipid-lowering treatment for the secondary prevention of cardiovascular disease?

The lipid target for the secondary prevention of cardiovascular disease (CVD) is low-density lipoprotein (LDL) cholesterol levels of 2.0 mmol/L or less or non-high-density lipoprotein (non-HDL) cholesterol levels of 2.6 mmol/L or less.

• If the lipid target is not met:
  • Discuss treatment adherence.
  • Discuss the timing of the statin dose (atorvastatin can be taken at any time of the day, but simvastatin, pravastatin, and fluvastatin should be taken in the evening). 
  • Encourage the person to continue improving their diet and lifestyle and make further changes if appropriate. 
  • Consider treatment optimization (statin dose increase) or escalation (additional lipid-lowering treatment) after an informed discussion with the person about the risks and benefits. Consider the person's preferences, comorbidities, other medications, general frailty, and life expectancy. 
• If the lipid target is not met and the person is not taking a high-intensity statin at the maximum tolerated dose, consider increasing the statin intensity/dose.
  • If the estimated glomerular filtration rate (eGFR) is less than 30 ml per minute per 1.73 m², agree the use of higher doses with a renal specialist.
  • If the maximum tolerated dose/intensity of statin does not achieve the lipid target after 2–3 months, consider one of the following options:
    • Add ezetimibe.
    • Consider adding icosapent ethyl. 
    • Consider an injectable lipid-lowering treatment based on eligibility. For more information, see the sections on inclisiran, alirocumab, or evolocumab.
• If the lipid target is not met and the person is taking ezetimibe monotherapy (due to statin contraindication or intolerance), consider one of the following options:
  • Add bempedoic acid. 
  • Consider an injectable lipid-lowering treatment based on eligibility. For more information, see the sections on inclisiran, alirocumab, or evolocumab.    
• If the lipid target is not met despite the maximum tolerated dose of lipid-lowering treatment, consider referral to a specialist lipid management clinic according to local arrangements.
• Do not offer:
  • Coenzyme Q10 or vitamin D to increase adherence to statin treatment.
  • Fibrates routinely to prevent CVD.
  • Nicotinic acid (niacin), bile acid sequestrant (anion exchange resin), or omega 3 fatty acid compounds to prevent CVD.
  • A combination of a statin with a bile acid sequestrant (anion exchange resin), a fibrate, or nicotinic acid to prevent CVD.
  • A combination of a statin with an omega 3 fatty acid compound to prevent CVD, except icosapent ethyl if used as described in the National Institute for Health and Care Excellence (NICE) technology appraisal guidance.
• Do not routinely de-escalate lipid-lowering treatments when levels are lower than the target, except if clinically indicated or based on the person’s needs or preferences.

What is the mechanism of action of statins?

• Statins reduce the synthesis of cholesterol in the liver by competitively inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting enzyme of cholesterol biosynthesis. Reduction in intracellular cholesterol promotes increased low-density lipoprotein (LDL) receptor expression at the surface of the hepatocytes, resulting in increased uptake of LDL from the blood and decreased plasma concentrations of LDL- and other ApoB-containing lipoproteins. 

 [Mach, 2020; BNF, 2024]

What are the contraindications and cautions of statins?

• Do not prescribe statins to:
  • People with:
    • Active liver disease.
    • Unexplained persistent elevations of transaminases that are 3 or more times the upper limit of normal.
  • Women of childbearing potential who are not using appropriate contraception.
  • Women who are pregnant or breastfeeding.
    
    • Statins should be stopped 3 months before attempting to conceive and during pregnancy.
    • Statins should not be restarted until breastfeeding is finished.
• Prescribe statins with caution to people with:
  • Risk factors for muscle toxicity.
    
    • Muscle toxicity, including myopathy or rhabdomyolysis, can occur with all statins; however, the likelihood increases with higher doses and in certain people.
    • Predisposing factors for rhabdomyolysis include advanced age (especially older than 70–80 years), personal or family history of muscular disorders, history of muscle toxicity or unexplained persistent muscle pain, liver or kidney disease, high alcohol intake, known genetic polymorphisms, strenuous exercise, hypothyroidism, and the use of certain medications.
  • History of haemorrhagic stroke.

 [EMC, 2023; NICE, 2023a; BNF, 2024] 

What are the adverse effects of statins?

• Elevated serum transaminases have been reported in people taking statins.
  • These changes are usually mild and transient and do not require interruption of treatment.
  • Do not prescribe statins to people with unexplained persistent elevations of transaminases that are 3 or more times the upper limit of normal.
  • Do not routinely exclude from statin treatment people who have liver transaminase levels that are raised but are less than 3 times the upper limit of normal.
• Myalgia has been reported commonly in people taking statins; however, muscle toxicity truly attributable to statin use is rare.
  • The risk of muscle pain, tenderness, or weakness associated with statin use is small, and the rate of severe muscle adverse effects (rhabdomyolysis) due to statins is extremely low.
  • Advise people on statins to seek medical advice if they develop unexplained muscle symptoms (pain, tenderness, or weakness). 
  • If unexplained muscle symptoms occur, measure creatine kinase (CK):
    • If CK is more than 5 times the upper limit of normal, stop statin treatment. 
    • If CK is less than 5 times the upper limit of normal, reassure the person that their symptoms are unlikely to be due to the statin and explore other possible causes. 
• Hyperglycaemia has been reported during treatment with statins.
  • However, the risk is outweighed by the reduced vascular risk with statins.
  • Do not withhold statin treatment because of an increase in HbA1c or blood glucose level. 
• Interstitial lung disease has been reported with some statins, especially with long-term treatment.
  • Presenting features can include dyspnoea, non-productive cough, and deterioration in general health (fatigue, weight loss, and fever).
  • If interstitial lung disease is suspected, discontinue statin treatment.
• Myasthenia gravis or ocular myasthenia (new-onset or exacerbation of pre-existing cases) has been associated with statin use, albeit very infrequent and with no reported fatalities.
  • In most cases, people recovered after stopping statin treatment. However, a minority continued to experience symptoms, some of which recurred on rechallenge with the same or an alternative statin. Symptom onset ranges from a few days to 3 months after starting statin treatment.
  • Before starting statin treatment, ask whether the person has a history of myasthenia gravis or ocular myasthenia, as statin treatment may exacerbate their symptoms.
  • Advise people on statins to:
    
    • Seek medical advice if they experience symptoms such as weakness in the arms or legs that worsens after activity, double vision, drooping of the eyelids, difficulty swallowing, or shortness of breath.
    • Seek immediate medical attention if they develop severe breathing or swallowing problems.
  • Refer people who present with suspected new-onset myasthenia gravis symptoms after starting a statin to a neurologist. The statin may need to be discontinued if the risks outweigh the benefits.
• Other possible adverse effects include:
  • For atorvastatin:
    • Common or very common — epistaxis, hypersensitivity, joint swelling, laryngeal pain, and nasopharyngitis.
    • Uncommon — altered taste, burping, chest pain, decreased appetite, fever, hypoglycaemia, malaise, numbness, peripheral oedema, tinnitus, vision disorders, and weight gain.
    • Rare or very rare — angioedema, gynaecomastia, hearing loss, and severe cutaneous adverse reactions (SCARs).
  • For all statins:
    • Common or very common — arthralgia, asthenia, constipation, diarrhoea, dizziness, flatulence, gastrointestinal discomfort, headache, nausea, sleep disorders, and thrombocytopenia.
    • Uncommon — alopecia, hepatic disorders, memory loss, pancreatitis, paraesthesia, sexual dysfunction, skin reactions, and vomiting.
    • Rare or very rare — lupus-like syndrome, myopathy, peripheral neuropathy, and tendon disorders.
    • Unknown frequency — depression and neuromuscular dysfunction.

[Mach, 2020; NICE, 2023a; BNF, 2024]

What are the key drug interactions of atorvastatin?

• Key drug interactions with atorvastatin include:
  • Amlodipine — atorvastatin concentrations may be increased by amlodipine; a case of rhabdomyolysis has been reported.
    • Advise the person to report any muscle pain, tenderness, or weakness.
  • Azole antifungals — atorvastatin concentrations may be increased by azole antifungals (such as fluconazole, ketoconazole, voriconazole, itraconazole, and posaconazole), which might lead to rhabdomyolysis.
    • Temporarily withhold atorvastatin for the duration of the antifungal treatment.
    • If concurrent use is necessary, give the lowest possible dose of atorvastatin and advise the person to report any muscle pain, tenderness, or weakness.
  • Calcium channel blockers — atorvastatin concentrations may be increased by amiodarone, diltiazem, or verapamil; myopathy and rhabdomyolysis have been reported.
    • If concurrent use is unavoidable, consider reducing the atorvastatin dose. Advise the person to report any muscle pain, tenderness, or weakness.
  • Ciclosporin — atorvastatin concentrations can be markedly (or very markedly) increased by cyclosporin. Atorvastatin may cause a small increase in the exposure to ciclosporin.
    • If concurrent use is unavoidable, do not exceed 10 mg of atorvastatin daily. Advise the person to report any muscle pain, tenderness, or weakness.
  • Clarithromycin or erythromycin — clarithromycin and erythromycin are potent CYP3A4 enzyme inhibitors. Concurrent use with a statin metabolized by CYP3A4 will increase the plasma concentrations of the statin, leading to an increased risk of myopathy (including rhabdomyolysis).
    • Atorvastatin is moderately metabolized by CYP3A4.
    • If the antibiotic course is short, consider withholding atorvastatin for the duration of the treatment.
    • If concurrent use with clarithromycin cannot be avoided, do not exceed 20 mg of atorvastatin daily. Advise the person to report any muscle pain, tenderness, or weakness.
    • If concurrent use with erythromycin cannot be avoided, consider a lower maximum dose of atorvastatin. Advise the person to report any muscle pain, tenderness, or weakness.
  • Colchicine — cases of rhabdomyolysis and myopathy have been reported in people taking statins and colchicine. 
    • The general significance of these case reports is unclear; however, advise people to report any unexplained muscle pain, tenderness, or weakness.
  • Dalteparin, enoxaparin, or tinzaparin — concurrent use with statins may increase the risk of hepatotoxicity, especially in high doses.
    • Monitor for signs and symptoms of hepatotoxicity.
  • Danazol — rhabdomyolysis has occurred in people taking simvastatin and danazol. It seems possible that atorvastatin might interact similarly.
    
    • Advise the person to report any unexplained muscle pain, tenderness, or weakness.
  • Ezetimibe — ezetimibe alone is associated with muscle-related adverse effects, including rhabdomyolysis. Therefore, the risk of these events may increase with concurrent statin use. 
    •  Advise the person to report any unexplained muscle pain, tenderness, or weakness.
  • Fusidic acid — cases of rhabdomyolysis have been reported in people taking systemic fusidic acid and statins.
    • Avoid concurrent use with statins. 
    • If fusidic acid is essential, stop treatment with the statin and resume 7 days after the last dose of fusidic acid. Advise the person to seek medical advice immediately if they experience any symptoms of muscle weakness, pain, or tenderness.
  • Grapefruit juice — atorvastatin concentrations are moderately increased by large quantities of grapefruit juice; smaller quantities and separating administration by 12 hours reduces this effect.  
    • Advise the person to avoid large quantities (greater than 1.2 litres) of grapefruit juice and to seek medical advice immediately if they experience any symptoms of muscle weakness, pain, or tenderness.
  • Ranolazine — ranolazine is predicted to increase exposure to atorvastatin; a case of myopathy has been reported with concurrent use.
    • Advise people to report any unexplained muscle pain, tenderness, or weakness.
  • Ticagrelor — atorvastatin concentrations are slightly increased by ticagrelor; cases of rhabdomyolysis have been reported with concurrent use. Atorvastatin does not affect the pharmacokinetics of ticagrelor.
    • Advise people to report any unexplained muscle pain, tenderness, or weakness.
  • HIV protease inhibitors —  the plasma concentrations of atorvastatin may be increased by HIV protease inhibitors.
    • Atazanavir, indinavir, or ritonavir: if concurrent use is unavoidable, use the lowest possible dose of atorvastatin. Advise the person to report any unexplained muscle pain, tenderness, or weakness.
    • Darunavir, fosamprenavir, or saquinavir: if concurrent use is unavoidable, give the lowest possible dose of atorvastatin. Monitor for adverse effects of statin, particularly in people taking atorvastatin doses greater than 40 mg daily. Advise the person to report any unexplained muscle pain, tenderness, or weakness.
    • Lopinavir: if concurrent use is unavoidable, give the lowest possible atorvastatin dose and monitor for statin adverse effects, particularly in people taking lopinavir boosted with ritonavir and atorvastatin doses exceeding 20 mg daily. Advise the person to report any unexplained muscle pain, tenderness, or weakness.
    • Tipranavir: if concurrent use is unavoidable, a maximum dose of atorvastatin 10 mg daily is advised. Advise the person to report any unexplained muscle pain, tenderness, or weakness.
• For a complete list of possible drug interactions of atorvastatin and other statins, see the electronic Medicines Compendium (eMC) or the British National Formulary (BNF).

[MHRA, 2014b; EMC, 2023; NICE, 2023a; BNF, 2024; Preston, 2024]

What is the mechanism of action, and when should it be considered?

• Ezetimibe inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. By inhibiting cholesterol absorption, ezetimibe reduces the amount of cholesterol delivered to the liver. Reduced cholesterol delivery promotes increased low-density lipoprotein (LDL) receptor expression, leading to increased clearance of LDL cholesterol from the blood.
• Ezetimibe is taken orally. The recommended dosage is 10 mg once daily. 
• The National Institute for Health and Care Excellence (NICE) technology appraisal guidance recommends [NICE, 2016a]:
  
  • Ezetimibe monotherapy as an option for treating primary (heterozygous‑familial or non‑familial) hypercholesterolaemia in adults in whom initial statin therapy is contraindicated.
  • Ezetimibe monotherapy as an option for treating primary (heterozygous‑familial or non‑familial) hypercholesterolaemia in adults who cannot tolerate statin therapy (defined as the presence of clinically significant adverse effects that represent an unacceptable risk to the person or that may reduce treatment compliance).
  • Ezetimibe, co‑administered with initial statin therapy, as an option for treating primary (heterozygous‑familial or non‑familial) hypercholesterolaemia in adults who have started statin therapy when:
    • Serum total or 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.
    • A change from initial statin therapy to an alternative statin is being considered.

 [Mach, 2020; EMC, 2022c; BNF, 2024]

What are the contraindications and cautions of ezetimibe?

• Do not prescribe ezetimibe to:
  • Breastfeeding women — it is not known if ezetimibe is secreted into human breast milk, but it is present in milk in animal studies. 
  • People with moderate or severe hepatic impairment.
  • People who are also taking a statin and:
    • Are pregnancy or breastfeeding.
    • Have active liver disease.
    • Have unexplained persistent elevations in serum transaminases.
  • People taking certain medications.
• Prescribe ezetimibe with caution to:
  • Pregnant women — use only if necessary. No clinical data are available on the use of ezetimibe during pregnancy. Animal studies on ezetimibe monotherapy have shown no evidence of direct or indirect harmful effects on pregnancy, embryofoetal development, or birth or postnatal development.
  • People with predisposing factors for rhabdomyolysis.
    • Predisposing factors for rhabdomyolysis include older age, personal or family history of muscle disorders, history of muscular toxicity or unexplained persistent muscle pain, liver or kidney disease, high alcohol intake, strenuous exercise, hypothyroidism, and the use of certain medications.

[EMC, 2022c; BNF, 2024]

What are the adverse effects of ezetimibe?

• Cases of myopathy and rhabdomyolysis have been reported in post-marketing experience with ezetimibe.
  • Most people who developed rhabdomyolysis were also taking a statin. However, rhabdomyolysis has been reported very rarely with ezetimibe monotherapy and with the addition of ezetimibe to other medications known to be associated with an increased risk of rhabdomyolysis.
  • If the person develops unexplained muscle symptoms (pain, tenderness, or weakness) during treatment, measure creatine kinase (CK):
    • If CK is less than 5 times the upper limit of normal, reassure the person that their symptoms are unlikely to be due to their lipid-lowering treatment(s) and explore other possible causes.
    • If CK is 5 or more times the upper limit of normal, stop ezetimibe. 
• Other adverse effects of ezetimibe include:
  • Common or very common — asthenia, diarrhoea, gastrointestinal discomfort, gastrointestinal disorders, headache, and muscle complaints.
  • Uncommon — arthralgia, chest pain, cough, decreased appetite, dry mouth, hot flush, hypertension, muscle weakness, nausea, pain, paraesthesia, peripheral oedema, and skin reactions.
  • Frequency not known — constipation, depression, dizziness, dyspnoea, hepatitis, myopathy, pancreatitis, and thrombocytopenia.

[EMC, 2022c; BNF, 2024]

What are the key drug interactions of ezetimibe?

• Key drug interactions of ezetimibe include:
  • Ciclosporin — ciclosporin moderately increases the exposure to ezetimibe, and ezetimibe slightly increases the exposure to ciclosporin.
    • Monitor ciclosporin concentrations closely.
  • Fibrates — concurrent use with ezetimibe is predicted to increase the risk of gallstones.
    • Discontinue treatment if gallstones develop.
  • Statins — although studies do not demonstrate an increased risk of myopathy when ezetimibe is combined with statins compared with statins alone, safety reports have described cases of myopathy (ezetimibe and atorvastatin), creatine kinase increases (ezetimibe and fluvastatin), and rhabdomyolysis (ezetimibe and simvastatin).
    • Monitor concurrent use closely.
  • Warfarin — there have been post-marketing reports of increased international normalized ratio (INR) during concurrent treatment with ezetimibe.
    • If concurrent treatment is necessary, monitor INR closely.
• For a complete list of possible drug interactions of ezetimibe, see the electronic Medicines Compendium (eMC) or the British National Formulary (BNF).

[EMC, 2022c; BNF, 2024; Preston, 2024]

What is the mechanism of action, and when should it be considered?

• Bempedoic acid inhibits adenosine triphosphate citrate lyase (ACL), a key regulatory enzyme of cholesterol and fatty acid synthesis. Inhibition of ACL reduces cholesterol synthesis in the liver, leading to increased low-density lipoprotein (LDL) receptor expression and increased clearance of LDL cholesterol from the blood.
• Bempedoic acid is currently available as 180 mg oral tablets (Nilemdo® 180 mg film-coated tablets) to be taken once daily and in fixed combination with ezetimibe 10 mg (Nustendi® 180 mg/10 mg film-coated tablets) to be taken once daily.
• The National Institute for Health and Care Excellence (NICE) technology appraisal guidance recommends bempedoic acid with ezetimibe as an option for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia as an adjunct to diet in adults if [NICE, 2021a]:
  
  • Statins are contraindicated or not tolerated.
  • Ezetimibe alone does not control low-density lipoprotein cholesterol well enough.

 [BNF, 2024; Chandramahanti, 2024; EMC, 2024a]

• Do not prescribe bempedoic acid to:
  • Pregnant women — there is no data to inform on the safety of bempedoic acid use in human pregnancy, and animal studies conducted in rats have shown reproductive toxicity (decreased foetal viability and skeletal abnormalities). The manufacturer advises that:
    • Bempedoic acid should be discontinued before conception or as soon as pregnancy is recognized.
    • Women of childbearing potential must use effective contraception during treatment with bempedoic acid.
    • Women should be advised to stop taking bempedoic acid before stopping contraceptive measures if they plan to become pregnant.
  • Breastfeeding women — it is unknown whether bempedoic acid is secreted into human breast milk. The manufacturer advises that women taking bempedoic acid should not breast feed their infants because of the potential for serious adverse effects.
• Prescribe bempedoic acid with caution to people with:
  • History of gout (or predisposed to gout) — bempedoic acid may cause or exacerbate hyperuricaemia and precipitate gout.
  • Severe renal impairment — there is limited experience with bempedoic acid in people with severe renal impairment. Additional monitoring for adverse reactions may be warranted during treatment.
  • Severe hepatic impairment — the use of bempedoic acid in people with severe hepatic impairment (Child-Pugh C) has not been studied. Periodic liver function tests should be considered during treatment.

[BNF, 2024; EMC, 2024a]

What are the adverse effects of bempedoic acid?

• Bempedoic acid may cause or exacerbate hyperuricaemia and precipitate gout.
  • Discontinue treatment with bempedoic acid if hyperuricaemia accompanied by symptoms of gout appear.
• Elevations in the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been reported with bempedoic acid.
  • These elevations have been asymptomatic, not associated with elevations of 2 or more times the upper limit of normal in bilirubin or with cholestasis, and have returned to baseline with continued treatment or after treatment discontinuation.
  • Discontinue treatment if transaminase levels increase and persist at 3 times the upper limit of normal.
• Other adverse effects of bempedoic acid include:
  • Common or very common — anaemia and pain in the extremities.
  • Unknown frequency — diarrhoea, muscle spasms, and nausea.

[BNF, 2024; EMC, 2024a]

What are the drug interactions of bempedoic acid?

• Bempedoic acid does not appear to have a clinically relevant effect on exposure to atorvastatin but may increase exposure to other statins (pravastatin and simvastatin) [BNF, 2024; EMC, 2024a; Preston, 2024].
• For a complete list of possible drug interactions of bempedoic acid, see the electronic Medicines Compendium (eMC) or the British National Formulary (BNF).

What is the mechanism of action, and when should it be considered?

What are the contraindications and cautions for inclisiran?

• Do not prescribe inclisiran to:
  • Pregnant women — there is no human data on the safety of inclisiran use during pregnancy, and animal studies do not indicate direct or indirect harmful effects. However, the manufacturer recommends avoiding it on a precautionary basis.
  • Breastfeeding women — there is no human data on the safety of inclisiran use during breastfeeding, but animal studies have demonstrated its excretion in milk. Therefore, the manufacturer recommends avoiding it on a precautionary basis.
• Prescribe inclisiran with caution to:
  • People with severe hepatic or renal impairment.
  • People undergoing haemodialysis — the manufacturer advises that because inclisiran is eliminated renally, haemodialysis should not be performed for at least 72 hours after inclisiran dosing.

[EMC, 2022b; BNF, 2024]

What are the adverse effects of inclisiran?

• Common adverse effects of inclisiran include injection site reaction, injection site pain, injection site erythema, and injection site rash. These adverse reactions are mild or moderate in severity, transient, and resolve without sequelae.

[EMC, 2022b]

What are the drug interactions of inclisiran?

• No drug interactions have been identified for inclisiran.
  • Inclisiran is not a substrate for common drug transporters and is not anticipated to be a substrate for cytochrome P450.
  • The manufacturer states that inclisiran is not expected to have clinically significant interactions with other medicinal products.

[EMC, 2022b; Preston, 2024]

What is their mechanism of action, and when should they be considered?

• Alirocumab and evolocumab are monoclonal antibodies that inhibit proprotein convertase subtilisin/kextin type 9 (PCSK9), an enzyme involved in the down-regulation of low-density lipoprotein (LDL) receptors. Inhibition of PCSK9 stops low-density lipoprotein (LDL) receptors in the liver from degrading; receptor numbers increase, resulting in increased uptake of LDL cholesterol from the blood [NICE, 2016b; BNF, 2024].
• Alirocumab and evolocumab are given by subcutaneous injection and may be available for prescribing in primary care, depending on local initiation pathways [AAC, 2024].
• The National Institute for Health and Care Excellence (NICE) technology appraisal guidance recommends:
  
  • Alirocumab as an option for treating primary hypercholesterolaemia or mixed dyslipidaemia only if LDL cholesterol concentrations are persistently above the thresholds specified in Table 2 despite maximal tolerated lipid-lowering treatment (that is, either the maximum dose has been reached or further titration is limited by intolerance) [NICE, 2016b].
  • Evolocumab as an option for treating primary hypercholesterolaemia or mixed dyslipidaemia only if the dosage is 140 mg every 2 weeks and LDL cholesterol concentrations are persistently above the thresholds specified in Table 2 despite maximal tolerated lipid-lowering treatment [NICE, 2019].

Table 2: LDL cholesterol concentration thresholds for alirocumab and evolocumab.

What is the mechanism of action, and when should it be considered?

• Icosapent ethyl is a stable ethyl ester of the omega 3 fatty acid eicosapentaenoic acid. It improves the lipoprotein profile by suppressing cholesterol-, fatty acid-, and triglyceride-synthesising enzymes, increasing fatty acid β-oxidation, and reducing microsomal triglyceride transfer (MTP) protein, resulting in decreased hepatic triglyceride and very low-density lipoprotein (VLDL) synthesis and release. It also increases the expression of lipoprotein lipase, leading to increased triglyceride removal from circulating VLDL and chylomicron particles. In people with elevated triglyceride levels, icosapent ethyl lowers triglyceride, VLDL, remnant lipoprotein cholesterol, and levels of inflammatory markers, such as C-reactive protein. However, triglyceride reduction appears to provide only a minor contribution to the reduction in risk of cardiovascular events with icosapent ethyl [EMC, 2024b].
• Icosapent ethyl is taken orally and is available as 998 mg soft capsules. The recommended dosage is 1.996 g (2 capsules) twice daily. 
• The National Institute for Health and Care (NICE) technology appraisal guidance recommends icosapent ethyl as an option for reducing the risk of cardiovascular events in adults taking statins who have a high risk of cardiovascular events, raised fasting triglycerides (1.7 mmol/L or above), and the following [NICE, 2022]: 
  • Established cardiovascular disease, defined as a history of acute coronary syndrome (such as myocardial infarction or unstable angina requiring hospitalization), coronary or other arterial revascularization procedures, coronary heart disease, ischaemic stroke, or peripheral arterial disease.
  • Low-density lipoprotein (LDL) cholesterol levels above 1.04 mmol/L and less than or equal to 2.60 mmol/L.