Management of blood lipids

Baseline measurements

• Non-fasting full lipid profile (total cholesterol, HDL-C, non-HDL-C, triglycerides).
• Renal, thyroid and liver profiles (including albumin) and HbA1c to exclude secondary causes and co-morbidities. Possible common secondary causes include excess alcohol, uncontrolled diabetes, hypothyroidism, liver disease and nephrotic syndrome.
• BMI
• 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 persistent generalised unexplained muscle pain, whether or not associated 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

Suspect familial hypercholesterolaemia (possible heterozygous FH) if:

• Total cholesterol > 7.5mmol/L, or
• LDL-C > 4.9mmol/L and /or non-HDL-C > 5.9mmol/L, or
• 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

Do not use the QRISK assessment tool, follow the guidance under “Familial Hyperlipidaemia” below.

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 the 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 3 months of starting treatment with an ORAL lipid-lowering drug, and then within 3 months of each up-titration of dose or addition of a further ORAL lipid-lowering drug.
• Measure fasting lipid profile three months after 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, frailty and life expectancy.

*These are the only circumstances when the QRISK tool should be used to assess cardiovascular 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. See 'Familial hypercholesterolaemia' below.

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:

• severe obesity (BMI > 40kg/m2) increases CVD risk
• treated for HIV
• serious mental health problems
• taking medicines that can cause dyslipidaemia such as antipsychotic medication, corticosteroids or immunosuppressant drugs
• autoimmune disorders such as SLE, and other systemic inflammatory disorders
• recent risk factor changes e.g. quit smoking, antihypertensive or lipid treatment

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

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

For all patients: Identify and address all modifiable risk factors - smoking, diet, obesity, alcohol intake, physical activity, blood pressure and HbA1c. Do not delay starting statin treatment for secondary prevention while addressing these.

Treatment target for primary and secondary prevention: Non-HDL-C reduction > 40% from baseline.

Starting treatment: statins

Primary prevention

If lifestyle modification is ineffective or inappropriate:

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

Advise people who are being treated with a statin to seek medical advice if they develop muscle symptoms (pain, tenderness or weakness).

If statin contraindicated: see 'Statin treatment contraindicated or statins not tolerated' below for further options.

Secondary prevention

Offer statin therapy to adults with CVD:

• this includes angina, previous MI, revascularisation, stroke or TIA or symptomatic peripheral arterial disease
• Do not delay statin treatment:
  • if a person has acute coronary syndrome. Take a lipid sample on admission (within 24 hours)
  • while managing modifiable risk factors (smoking, diet, obesity, alcohol intake, physical activity, blood pressure and HbA1c)

Offer Atorvastatin 80mg once daily (see section 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.
  • Advise people who are being treated with a statin to seek medical advice if they develop muscle symptoms (pain, tenderness or weakness).
• CKD: offer atorvastatin 20mg once daily if eGFR less than 60mL/min/1.73m2 and/or albuminuria.
• If statin contraindicated, see 'Statin treatment contraindicated or statins not tolerated' below for further options.

Primary and secondary prevention: next steps

Measure non-fasting lipid profile again after 3 months.

High intensity statin treatment should achieve > 40% reduction in non-HDL-C from baseline. If not achieved after 3 months:

• 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: Dose can be increased above 20mg/day if necessary. Agree the use of higher doses with a renal specialist if eGFR < 30 mL/min/1.73m2. Maximum dose 80mg once daily.
• If ≤ 40% reduction in non-HDL-C from baseline on maximum tolerated dose, see further options under 'If side effects with initial statin or statin not effective' below.

If side effects with initial statin or statin not effective

If 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 section 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 section 2.12 Lipid-regulating drugs

Therapy with a low dose statin is preferred to no statin.

If maximum tolerated dose of statin does not achieve > 40% reduction in non-HDL-C from baseline:

• Add Ezetimibe 10mg once daily to statin* (see section 2.12 Lipid-regulating drugs)
• Measure non-fasting lipid profile again after 3 months
• If ≤ 40% reduction in non-HDL-C from baseline:
  • Primary prevention: seek specialist advice if needed
  • Secondary prevention: If non-HDL-C remains > 2.5mmol/L, arrange a fasting LDL-C test 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 LDL-C test 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 section 2.12 Lipid-regulating drugs)

Measure non-fasting lipid profile again after 3 months.

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

• These are available as single constituents or a combination product (see section 2.12 Lipid-regulating drugs).
• Bempedoic acid with ezetimibe does not have evidence from a cardiovascular clinical outcome trial.

Assess response after 3 months:

• Primary prevention: If ≤ 40% reduction in non-HDL-C from baseline despite maximal-tolerated lipid-lowering therapy, seek specialist advice.
• Secondary prevention: if non-HDL-C remains > 2.5mmol/L, arrange a fasting LDL-C test 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 section 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 hyperlipidaemia' 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 PCSK9 inhibitors, there is no evidence from a cardiovascular clinical outcome trial 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.

This guidance is based on the NHSE AAC Statin Intolerance Pathway.

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.

Assessment

Criteria for familial hypercholesterolaemia

Clinicians may use either the old Simon-Broome criteria or the latest Dutch Lipid Clinical Network (DLCN) criteria which are evidence-based and more accurate than the Simon-Broome criteria to assess patients.

The DLCN criteria are used to diagnose Familial Hypercholesterolaemia based on work from the Netherlands. It relies on a points system, where a set number of points are given to lipid stigmata, personal or family history of premature CVD and LDL-cholesterol levels. A score more than 5 makes the patient probable or definite Familial Hypercholesterolaemia and eligible for genetic testing which is commissioned by NHS England. A score of 5 or less means Familial Hypercholesterolaemia is still possible but less likely and those patients are generally not eligible for genetic testing unless in exceptional circumstance.

Severe hyperlipidaemia

Suspect familial hypercholesterolaemia (possible heterozygous FH) if:

• Total cholesterol > 7.5mmol/L, or
• LDL-C > 4.9mmol/L and /or non-HDL-C > 5.9mmol/L, or
• 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

Take fasting blood for repeat full lipid profile to measure LDL-C.

Use the Simon Broome criteria or Dutch Lipid Clinic Network (DLCN) criteria to make a clinical diagnosis of FH.

Referral

Refer the person to a lipid clinic if:

• they either meet the Simon Broome criteria for possible or definite FH, or ideally they have a DLCN score greater than 5, or
• they meet any of the following criteria (regardless of family history):
  • Total cholesterol > 9.0mmol/L, or
  • LDL-C > 6.5mmol/L and / or non-HDL-C > 7.5mmol/L

Management

Primary and secondary prevention

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

Treatment target: Aim to achieve at least a 50% reduction of LDL-C (or non-fasting non-HDL-C) from baseline for primary and secondary prevention

Consider referral to a specialist for further treatment and/or consideration of PCSK9 inhibitor therapy (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 section 2.12 Lipid-regulating drugs

Do not offer nicotinic acid or omega-3 fatty acids* alone or combination with a statin for:

• Primary or secondary prevention of cardiovascular disease
• CKD or Type 1 or type 2 diabetes

*There is no evidence that omega-3 fatty acids help 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 section 2.12 Lipid-regulating drugs for fibrates and section 1.9.2 Bile acid sequestrants.

Seek advice or refer in the following circumstances:

Baseline assessment

Triglyceride > 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.

Triglyceride 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/litre. At risk of acute pancreatitis

Triglyceride 4.5 - 9.9mmol/L

• Triglyceride > 4.5mmol/L, repeat with a fasting triglyceride measurement.
• Be aware that the 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/litre.

Primary prevention

Agree the use of atorvastatin at doses higher than 20mg/day with a renal specialist if eGFR is less than 30 mL/min/1.73m2

Consider seeking advice from a specialist if:

• the maximum tolerated dose of statin plus ezetimibe is not effective (≤ 40% reduction in non-HDL-C from baseline)
• a statin is contraindicated or not tolerated and ezetimibe with bempedoic acid is not effective (≤ 40% reduction in non-HDL-C from baseline)

Secondary prevention

Agree the use of atorvastatin at doses higher than 20mg/day with a renal specialist if eGFR is less than 30 mL/min/1.73m2

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 > 1 vascular bed

Consider seeking advice from a specialist if following inclisiran treatment, the patient’s LDL-C remains persistently above 2.6 mmol/L.

Statin intolerance

Possible rhabdomyolysis

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

• Symptoms typical for statin-related muscle toxicity and CK ≥ 50 x 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

Where statin treatment is stopped and CK ≥ 5x and < 10x ULN or intolerable symptoms or clinical concern:

• If CK has not normalised 4-6 weeks after stopping statin: consider statin-induced necrotizing autoimmune myopathy (SINAM). Seek specialist advice

Familial hyperlipidaemia

Refer the person to a lipid clinic if:

• they either meet the Simon Broome criteria for possible or definite FH, or ideally they have a DLCN score greater than 5, or
• they meet any of the following criteria (regardless of family history):
  • Total cholesterol > 9.0mmol/L, or
  • LDL-C > 6.5mmol/L and / or non-HDL-C > 7.5mmol/L

Consider referral to a specialist for further treatment and/or consideration of PCSK9 inhibitor therapy (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 > 3.5mmol/L (secondary prevention)