Baseline measurements and monitoring:

HbA1c no longer required at baseline. Check patient’s diabetes status.

Primary prevention: risk assessment:

• QRISK3 is the current version of the calculator. QRISK2 can be used if QRISK3 is not available. QRISK3 has been updated with indicators for certain patient groups to incorporate disease or medication specific risks of cardiovascular (CVD). QRISK3 (on-line version if necessary) should be used for the following patient groups:
  • people taking corticosteroids or atypical antipsychotics or people with systemic lupus erythematosus, migraine, severe mental illness (schizophrenia, bipolar disorder or other psychoses), or erectile dysfunction
• Consider using QRISK3-lifetime to inform discussions on CVD risk and to motivate lifestyle changes particularly for people with a 10-year QRISK3 score less than 10%, and people under 40 who have CVD risk factors.

Secondary prevention:

• New target lipid level: LDL-C 2.0 mmol/L or less, or non-HDL-C 2.6 mmol/L or less.
• Consider ezetimibe in addition to maximum tolerated intensity and dose of statin to reduce CVD risk further, even if the lipid target for secondary prevention of CVD is met.

Familial hypercholesterolaemia:

Simon Broome and Dutch Lipid Clinic Network criteria removed, refer to clinical referral guidance for assessment and referral criteria.

Baseline measurements and clinical assessment

• Smoking status, alcohol consumption, BP, BMI, diabetes status.
• Non-fasting full lipid profile (total cholesterol, HDL-C, non-HDL-C, triglycerides).
• Renal, thyroid and liver profiles (including albumin) to exclude secondary causes and co-morbidities. 
  • Possible common secondary causes include excess alcohol, uncontrolled diabetes, hypothyroidism, liver disease, pregnancy and nephrotic syndrome.
• Baseline liver transaminase (ALT or AST) before starting a statin.
  • If ALT or AST are ≥3x ULN, do not start a statin and repeat the LFTs in a month.
  • Do not routinely exclude from statin therapy if ALT or AST are raised but <3x ULN.
• Measure CK if patient has had persistent generalised unexplained muscle pain, tenderness or weakness, whether associated or not with previous lipid-lowering therapy. Do not measure CK level if the patient is asymptomatic.
  • If CK level ≥5x ULN, re-measure CK after 7 days.
  • If CK still 5x ULN, do not start treatment.

Severe hyperlipidaemia

Refer to clinical referral guidance (below) for assessment and referral criteria for familial hypercholesterolaemia if:

• Personal or family history of confirmed coronary heart disease (event before 60 years in index individual or 1st degree relative) and with no secondary causes, or
• Any of the following criteria are met, regardless of family history:
  • Total cholesterol >9.0mmol/L, or
  • LDL-C >6.5mmol/L, or
  • Non-HDL-C >7.5mmol/L.

Do not use the QRISK assessment tool. 

Clinical referral guidance: South Devon; West Devon

If non-fasting triglyceride >4.5mmol/L

Greater than 20mmol/L

• Refer to lipid clinic for urgent specialist review if not a result of excess alcohol or poor glycaemic control. At risk of acute pancreatitis.

10 - 20mmol/L

• Repeat the triglyceride measurement with a fasting test (after an interval of 5 days, but within 2 weeks) and review for potential secondary causes of hyperlipidaemia.
• Seek specialist advice if the triglyceride concentration remains > 10mmol/L. At risk of acute pancreatitis

4.5 - 9.9mmol/L

• Triglyceride >4.5mmol/L, repeat with a fasting triglyceride measurement.
• Be aware that CVD risk may be underestimated by risk assessment tools, optimise the management of other CVD risk factors* present and seek specialist advice if non-HDL-C concentration is >7.5 mmol/L.

*See additional risk factors listed under the following subsection 'Primary prevention: risk assessment'.

Monitoring

Lipids

• Measure non-fasting lipid profile within 2 to 3 months of starting treatment with an ORAL lipid-lowering drug, and then within 2 to 3 months of each up-titration of dose or addition of a further ORAL lipid-lowering drug.
• Measure fasting full lipid profile (including LDL-C) within 2 to 3 months of starting treatment with INCLISIRAN.

Liver transaminases

• Measure AST or ALT within 3 months of starting treatment with a statin, and within 3 months of addition of ezetimibe, and then again at 12 months.
• AST or ALT is not required again unless clinically indicated.
  • If ALT or AST are ≥3x ULN, do not discontinue statin and repeat the LFTs in a month. If they remain ≥3x ULN, temporarily discontinue statin and reassess.
  • If ALT or AST are elevated but are <3x ULN, continue the statin and repeat in a month. If they remain elevated but <3x ULN, continue statin and repeat again in 6 months.
  • Do not routinely exclude from therapy if ALT or AST are elevated but are <3x ULN

Creatine kinase (CK)

Measure CK if patient has new onset or worsening muscle symptoms which are typical of statin-related muscle toxicity – See 'Statin Intolerance below

Annual review

• Patients receiving ORAL lipid-lowering therapy: measure non-fasting lipid profile.
• Patients receiving INJECTABLE lipid-lowering therapy: measure fasting full lipid profile (total cholesterol, LDL-C, HDL-C and triglyceride).
• All patients, discuss:
  • Effectiveness of therapy
  • Medicines adherence
  • Lifestyle modification
  • Address CVD risk factors

Offer statin to:

• Age ≤84 and QRISK ≥10% over next 10 years*
• Type 2 diabetes and QRISK ≥10% over next 10 years*
• Type 1 diabetes, if they have one or more of the following:
  • Over 40 years
  • Had diabetes for >10 years
  • Have established nephropathy
  • Have other CVD risk factors
• CKD: eGFR <60 mL/min/1.73m² and/or albuminuria

Consider statin for:

• All patients with type 1 diabetes
• Age ≥85 years. Consider people aged ≥85 years at increased risk of CVD because of age alone particularly people who smoke or have raised BP. If appropriate, consider comorbidities, whether they are on multiple medications, frailty and life expectancy.

*These are the only circumstances when the QRISK tool should be used to assess CVD risk.

Do not use the QRISK tool for those who are at high risk of developing CVD because of familial hypercholesterolaemia or other inherited disorders of lipid metabolism. 

If QRISK <10% over the next 10 years - give lifestyle advice and ensure regular review of CVD risk in line with guidance.

• Do not rule out treatment if there is an informed preference for taking a statin or a concern that risk may be underestimated.

Use QRISK3 version of the calculator (or QRISK2 if not available).

QRISK2 may underestimate 10-year CVD risk in the following patient populations. Use QRISK3 (online version, if necessary) to estimate CVD risk:

• people taking corticosteroids or atypical antipsychotics or people with systemic lupus erythematosus, migraine, severe mental illness (schizophrenia, bipolar disorder or other psychoses), or erectile dysfunction

Additional risk factors

Standard CVD risk scores including QRISK may underestimate risk in people who have additional risk because of underlying medical conditions or treatments, including the following groups of people:

• obesity
• treated for HIV
• severe mental illness (schizophrenia, bipolar disorder or other psychoses), even when using QRISK3
• taking medicines that can cause dyslipidaemia such as immunosuppressant drugs
• autoimmune disorders and other systemic inflammatory disorders
• significant hypertriglyceridaemia (fasting triglycerides ≥4.5mmol/L)
• recent risk factor changes e.g. quit smoking, antihypertensive or lipid treatment

Consider socio-economic status as an additional factor contributing to CVD risk.

Discuss benefits of lifestyle changes and optimise management of all other modifiable CVD risk factors if possible. Offer people the opportunity to have their risk of CVD assessed again after they have tried to change their lifestyle.

Before starting statins, treat comorbidities and secondary causes of dyslipidaemia.

Advice for patient on statins:

• Seek medical advice if they develop unexplained muscle symptoms (pain, tenderness or weakness)
• The risk of muscle pain, tenderness or weakness associated with statin use is small and the rate of severe muscle adverse effects (rhabdomyolysis) because of statins is extremely low.

Treatment target: Non-HDL-C reduction >40% from baseline.

Starting treatment: statins

If lifestyle modification is ineffective or inappropriate:

• Offer Atorvastatin 20mg once daily (see 2.12 Lipid-regulating drugs)

If statin contraindicated: see below for options.

Measure non-fasting lipid profile again within 2 to 3 months.

High intensity statin treatment should achieve >40% reduction in non-HDL-C. If not achieved within 2 to 3 months:

• Discuss treatment adherence, timing of dose, diet and lifestyle
• Consider increasing daily dose of atorvastatin every 2-3 months up to a maximum dose of 80mg once daily
  • CKD: Agree the use of doses higher than 20mg/day with a renal specialist if eGFR <30 mL/min/1.73m². Maximum dose 80mg once daily.

If ≤40% reduction in non-HDL-C on maximum tolerated statin dose:

• add Ezetimibe 10mg once daily to statin (see 2.12 Lipid-regulating drugs)
• Measure non-fasting lipid profile again within 2 to 3 months, if target reduction in non-HDL-C is not achieved, consider seeking specialist advice.

If side effects with initial statin

See ‘Statin Intolerance’ below for advice on adverse effects. Therapy with a low dose statin is preferred to no statin.

Side effects on a high-intensity statin: offer a lower dose or an alternative statin:

• High intensity statin: Rosuvastatin 5mg once daily starting dose for a statin intolerant patient to be increased to a high intensity dose (10mg and above).
  • See 2.12 Lipid-regulating drugs for other patient groups who require a starting dose of 5mg once daily.
• Medium intensity statins should only be used if high intensity statin is not tolerated or not appropriate: atorvastatin 10mg once daily, or rosuvastatin 5mg once daily. See  2.12 Lipid-regulating drugs

If ≤40% reduction in non-HDL-C on maximum tolerated statin dose:

• add Ezetimibe 10mg once daily to statin (see 2.12 Lipid-regulating drugs)
• Measure non-fasting lipid profile again within 2 to 3 months, if target reduction in non-HDL-C is not achieved, consider seeking specialist advice.

If statin treatment contraindicated or not tolerated

See ‘Statin Intolerance’ below for advice on adverse effects. Therapy with a low dose statin is preferred to no statin.

Consider ezetimibe 10mg once daily as monotherapy (see 2.12 Lipid-regulating drugs)

Measure non-fasting lipid profile again within 2 to 3 months.

If ≤40% reduction in non-HDL-C on ezetimibe, consider bempedoic acid 180mg (with ezetimibe 10mg) once daily.

• These are available as single constituents or a combination product (see 2.12 Lipid-regulating drugs).

Assess response within 2 to 3 months, if ≤40% reduction in non-HDL-C despite maximum tolerated lipid-lowering therapy, consider seeking specialist advice.

Offer statin therapy to adults with CVD:

• this includes angina, previous MI, revascularisation, stroke or TIA or symptomatic peripheral arterial disease.

Do not delay starting statin treatment for secondary prevention while optimising management of modifiable CVD risk factors. Treat comorbidities and secondary causes of dyslipidaemia at the same time as starting statin treatment.

Do not delay statin treatment if a person has acute coronary syndrome. Measure full lipid profile on admission (within 24 hours).

Advice for patient on statins:

• Seek medical advice if they develop unexplained muscle symptoms (pain, tenderness or weakness).
• The risk of muscle pain, tenderness or weakness associated with statin use is small and the rate of severe muscle adverse effects (rhabdomyolysis) because of statins is extremely low.

Treatment target: LDL-C 2.0 mmol/L or less, or non-HDL-C 2.6 mmol/L or less.

Starting treatment: statins

Offer Atorvastatin 80mg once daily (see 2.12 Lipid-regulating drugs)

• Use a lower dose of atorvastatin if there is a potential drug interaction, high risk of or experiencing adverse effects, or patient preference.
  CKD: offer atorvastatin 20mg once daily if eGFR less than 60mL/min/1.73m² and/or albuminuria.
  

If statin contraindicated, see below for options.

Measure full lipid profile again within 2 to 3 months. If target lipid level not achieved:

• Discuss treatment adherence, timing of dose, diet and lifestyle
• Review atorvastatin daily dose
  • If started on less than atorvastatin 80mg once daily, consider increasing the dose every 2-3 months up to a maximum dose of 80mg once daily.
  • CKD: Agree the use of doses higher than 20mg/day with a renal specialist if eGFR <30 mL/min/1.73m². Maximum dose 80mg once daily.

Measure lipid profile within 2 to 3 months:

• If target lipid level is met, consider ezetimibe 10mg once daily in addition to maximum tolerated intensity and dose of statin to reduce CVD risk further.
  • Take into account patient preference, comorbidities, whether they are on multiple medicines, frailty and life expectancy.
• If target lipid level not achieved on maximum tolerated statin dose, see below for further options 

If side effects with initial statin 

See ‘Statin Intolerance’ below for advice on adverse effects. Therapy with a low dose statin is preferred to no statin.

Side effects on a high-intensity statin, offer a lower dose or an alternative statin:

• High intensity statin: Rosuvastatin 5mg once daily starting dose for a statin intolerant patient to be increased to a high intensity dose (10mg and above). 
  • See 2.12 Lipid-regulating drugs for other patient groups who require a starting dose of 5mg once daily.
• Medium intensity statins, should only be used if high intensity statin is not tolerated or not appropriate: atorvastatin 10mg once daily, or rosuvastatin 5mg once daily. See 2.12 Lipid-regulating drugs.

Measure lipid profile within 2 to 3 months of a change in dose or statin:

• If target lipid level is met, consider ezetimibe 10mg once daily in addition to maximum tolerated intensity and dose of statin to reduce CVD risk further
  • Take into account patient preference, comorbidities, whether they are on multiple medicines, frailty and life expectancy
• If target lipid level not achieved on maximum tolerated statin dose, see 'If statin not effective' below. 

If statin not effective

If maximum tolerated dose of statin does not achieve target lipid level:

• Add Ezetimibe 10mg once daily to statin* (see 2.12 Lipid-regulating drugs).
• Measure non-fasting lipid profile again within 2 to 3 months.
• If non-HDL-C remains >2.6mmol/L, arrange a fasting full lipid profile (including LDL-C) and consider eligibility for injectable therapies (PCSK9 inhibitors or inclisiran - see below).

*In line with NICE TA733, inclisiran may be added to maximally tolerated statin with or without another lipid-lowering therapy if LDL-C remains 2.6mmol/L or more. Local specialists recommend the addition of ezetimibe to a statin before considering inclisiran as ezetimibe is an established drug with evidence from a cardiovascular clinical outcome trial. See below for further information on injectable therapies. Fasting full lipid profile (including LDL-C) required.

Statin treatment contraindicated or statins not tolerated

See 'Statin Intolerance' below for advice on adverse effects Therapy with a low dose statin is preferred to no statin.

Consider ezetimibe 10mg once daily as monotherapy (see  2.12 Lipid-regulating drugs)

Measure non-fasting lipid profile again within 2 to 3 months.

If lipid target not achieved, consider bempedoic acid 180mg (with ezetimibe 10mg) once daily.

• These are available as single constituents or a combination product (see 2.12 Lipid-regulating drugs).

Assess response within 2 to 3 months:

• if non-HDL-C remains >2.6mmol/L, arrange a fasting full lipid profile (including LDL-C) and consider eligibility for injectable therapies (PCSK9 inhibitor or inclisiran - see below).

Injectable therapies for secondary prevention (PCSK9 inhibitors and inclisiran)

The place in therapy for injectable therapies is outlined above when statins are not effective, contra-indicated or not tolerated.

See 2.12 Lipid-regulating drugs.

Refer to specialists for consideration of a PCSK9 inhibitor (alirocumab or evolocumab) in the following circumstances:

• Fasting LDL-C > 4.0mmol/L and there is acute coronary syndrome, coronary or other arterial revascularisation procedures, coronary heart disease, ischaemic stroke or peripheral arterial disease.
• Fasting LDL-C > 3.5mmol/L and there are recurrent cardiovascular events or cardiovascular events in more than 1 vascular bed.
• Familial hypercholesterolaemia: criteria for patients with this condition are listed under 'Familial hypercholesterolaemia' below.

OR consider inclisiran if:

• Fasting LDL-C 2.6 mmol/L or more and there is acute coronary syndrome, coronary or other arterial revascularisation procedures, coronary heart disease, ischaemic stroke or peripheral arterial disease.
• Unlike the monoclonal antibody PCSK9 inhibitors, cardiovascular outcome trial evidence is not yet available for inclisiran.
• Inclisiran and PCSK9 inhibitors should not be prescribed concurrently.
• Continue treatment with oral lipid-lowering drugs if they are well tolerated.
• If following 3 months of treatment with inclisiran the patient’s LDL-C remains persistently above 2.6 mmol/L, consider seeking advice from specialist.

New onset or worsening of muscle symptoms (pain, tenderness or weakness) since starting statin

Symptoms typical for statin-related muscle toxicity: symmetrical pain and/or weakness in large proximal muscle groups, worsened by exercise. If these are present, measure CK level.

Consider other causes if:

• new onset of muscle symptoms of > 2 weeks duration in a person previously tolerant of statin therapy for > 3 months
• failure to resolve with dechallenge despite normal CK level
• muscle symptoms not typical of statin-related toxicity (e.g. asymmetric distribution)

Other possible causes may include musculoskeletal disorders, metabolic, degenerative or inflammatory (e.g. Vitamin D deficiency, polymyalgia rheumatica). Check bone profile, Vitamin D and CRP.

Possible rhabdomyolysis

Stop statin, urgently seek specialist advice and inpatient assessment if:

• Symptoms typical for statin-related muscle toxicity and CK ≥ 50x ULN, or
• Symptoms typical for statin-related muscle toxicity, renal impairment and CK ≥ 10x and < 50x ULN

Severe myopathy

Stop statin, refer for out-patient assessment, if stable renal function and CK ≥ 10x and < 50x ULN

Myalgia / myopathy

Continue treatment if patient happy to do so and tolerable symptoms, no clinical concern and CK < 5x ULN.

If symptoms not resolved within 6 weeks, stop the statin for 4-6 weeks and follow the guidance on 'Action to take after stopping statin' below.

Stop statin for 4-6 weeks if symptoms typical of statin-related muscle toxicity and:

• CK ≥ 5x and < 10x ULN, or
• Intolerable symptoms, or
• Clinical concern

Follow the guidance on 'Action to take after stopping statin' below.

Action to take after stopping statin (4-6 weeks later):

• If CK has not normalised: consider statin-induced necrotizing autoimmune myopathy (SINAM). Seek specialist advice
• If CK has normalised and symptoms have not resolved, consider other causes.
• If CK has normalised and patient is symptom-free for 2 weeks, reassess and restart treatment with a lower dose or alternative statin (e.g. atorvastatin 10mg once daily or 20mg once daily, OR rosuvastatin 5mg once daily
  • No recurrence of symptoms: titrate statin at 8 week intervals.
  • If statin not effective: add ezetimibe. Refer to 'Management of primary and secondary prevention' above.
  • Recurrence of symptoms: if short time to onset and symptoms intolerable, consider other options (e.g. ezetimibe as monotherapy). Refer to 'Management of primary and secondary prevention' above.

Approach to managing muscle-based symptoms

• Therapy with a lower dose statin is preferred to no statin
• For patients who do not tolerate statins on a daily basis, alternate day or twice-weekly dosing is a good option.
• Atorvastatin and rosuvastatin have longer half-lives, permitting their use on a non-daily regime.
• Adding ezetimibe to a lower dose statin may be better tolerated with robust reduction of LDL-C / non-HDL-C.

It is important to note that cardiovascular benefits have not been proven for all the above approaches but any reduction of LDL-C / non-HDL-C is beneficial.

Non-muscle related statin side effects

If symptoms appear statin-related, consider de-challenge and re-challenge or change to a different statin (e.g. hydrophilic instead of lipophilic). Atorvastatin and simvastatin are lipophilic statins. Rosuvastatin is a hydrophilic statin.

Refer to clinical referral guidance for assessment and referral criteria: South Devon; West Devon

Primary and secondary prevention

Follow the treatment management pathway for primary or secondary prevention above.

Treatment target: 

• Primary prevention: more than 50% reduction in LDL-C from baseline 
• Secondary prevention: LDL-C 2.0 mmol/L or less, or non-HDL-C 2.6 mmol/L or less

Consider referral to a specialist for further treatment and/or consideration of a PCSK9 inhibitor (alirocumab or evolocumab) if:

• they are assessed to be at very high risk of a coronary event (established coronary heart disease or two or more cardiovascular risk factors), or
• therapy is not tolerated, or
• despite maximal tolerated statin and ezetimibe, or for patients with a contraindication to statin or statin intolerance, ezetimibe with bempedoic acid:
  • LDL-C remains > 5.0 mmol/L (primary prevention)
  • LDL-C remains > 3.5 mmol/L (secondary prevention)

See 2.12 Lipid-regulating drugs

These recommendations apply to primary and secondary prevention of CVD, including people with diabetes and CKD. They do not apply to people with familial hypercholesterolaemia.

There is no evidence that omega-3 fatty acids help to prevent CVD, except use of icosapent ethyl with statin as described in NICE TA805.

Do not offer a bile acid sequestrant (anion exchange resin), nicotinic acid or omega-3 fatty acids to prevent CVD. This does not apply to icosapent ethyl with statin if used in line with NICE TA805.

Do not routinely offer fibrates to prevent CVD.

Do not offer Co-enzyme Q-10 or vitamin D to increase adherence to statin treatment.

Fibrates and bile acid sequestrants are recommended for familial hypercholesterolaemia only (NICE CG171). See 2.12 Lipid-regulating drugs for fibrates and section 1.9.2 Bile acid sequestrants.