Lipid lowering therapy in the prevention / treatment of atherosclerosis (Guidelines)

Always consider secondary causes for raised lipids and address these if possible before considering whether lipid lowering therapy is required e.g. hypothyroidism, uncontrolled diabetes, excess alcohol, medications, proteinuria, liver disease.

Lipid lowering therapy should be considered for all patients who meet any of the following criteria:

• have a high predicted cardiovascular disease risk; ASSIGN score ≥ 20
• have chronic kidney disease stages 3 to 5
  • NB lipids for patients on dialysis or post renal transplant managed by renal team
• have micro or macroalbuminuria
• have diabetes and aged >40, or >20 years duration of diabetes, or proliferative retinopathy
  • NB if aged 18 to 30 with microalbuminuria advised only to treat if additional risk factor e.g. smoking, hypertension, obesity
• living with HIV aged 40 years or older, irrespective of lipid profile or estimated CVD risk
  • BHIVA-rapid-guidance-on-the-use-of-statins.pdf

Recommended first line lipid lowering therapy is atorvastatin 20mg. Please see BNF for details on interactions and cautions. When considering starting a patient on lipid lowering therapy consider potential benefits from lifestyle changes, their preferences, other comorbidities / medications and life expectancy.

Monitoring

Ensure lipid profile, U&Es, ALT, TSH (if not measured within last 3 years), HbA1c (if not measured within last 3 years) and urine ACR, are measured prior to starting lipid lowering therapy.

If ALT level >3 x upper limit of normal (ULN): do not start lipid lowering medication; identify cause of raised ALT before deciding on lipid lowering therapy.

Hypothyroidism causes hyperlipidaemia and increases chance of muscular side-effects. If patient identified to have hypothyroidism: treat before deciding on lipid lowering therapy.

NICE NG238 advises remeasure ALT 3 and 12 months after starting or changing the dose of lipid lowering medication.

If ALT level 1 to 3 x ULN and patient already on statin: remeasure ALT at 1 month.

• If remeasured ALT remains 1 to 3 x ULN: continue.
• If ALT level >3 x ULN: stop statin for 4 weeks and then remeasure ALT.
• If remeasured ALT returns to <3 x ULN: move to next step on statin intolerance pathway.
• If ALT remains >3 x ULN: identify cause of raised ALT before deciding on lipid lowering therapy.

Only measure CK if patient has muscle symptoms.

• If CK level >5 x ULN do not start a statin and re-measure CK after 7 days. If CK level still >5 x ULN, do not start a statin and identify cause of raised CK before deciding on lipid lowering therapy. If CK level raised but <5 x ULN, start statin treatment at atorvastatin 10mg.
• If CK level >5 x ULN and already on a statin, stop statin for 4 weeks and then remeasure CK. If remeasured CK returns to <5 x ULN move to next step on statin intolerance pathway, if CK remains >5 x ULN identify cause of raised CK before deciding on lipid lowering therapy.
• If CK >10 x ULN urgent assessment for rhabdomyolysis recommended.

NICE NG238 advises remeasure lipid profile at 3 months after starting or changing the dose of lipid lowering medication, and aim for reduction in nonHDL cholesterol >40%.

Non-HDL cholesterol (calculated as total cholesterol minus HDL cholesterol) can be measured on a non-fasting sample and represents all the cholesterol capable of causing atherosclerosis.
If >40% reduction target not reached: consider adherence, other factors e.g. diet, alcohol, medications and consider increasing dose to atorvastatin 40mg or 80mg, if required.

Further ongoing measurements of lipid profile may be considered to inform discussion with the patient, if required.

Clinical practice guidelines for management of lipids in adults with diabetic kidney disease advise treat individuals with diabetes requiring primary prevention to achieve non-HDL cholesterol ≤2.5 mmol/L. This may not be possible on maximally tolerated medication for which the patient is eligible, and aim should be to achieve as close to target as possible.

If patient is not able to tolerate atorvastatin: stop statin for 4 to 6 weeks to allow full washout. Measure CK if muscle symptoms.

If symptoms remain unchanged, ALT <3 x ULN and CK <5 x ULN: then unlikely patient is intolerant and consider a rechallenge with the same statin. Look for alternative cause for muscle symptoms e.g. vitamin D deficiency, arthritis, polymyalgia rheumatica.

If patient symptoms resolved after 6 weeks washout: rechallenge with rosuvastatin 5mg daily. Please see BNF for details on interactions and cautions.

• If tolerated: increase to 10mg.
• If not tolerated: trial rosuvastatin 5mg once a week and build up to as many days of the week as tolerated.

If patient not able to tolerate any statin: consider ezetimibe 10mg. Please see BNF for details on interactions and cautions.

Refer to lipid clinic for consideration of Nustendi (ezetimibe 10mg + bempedoic acid 180mg):

• If patient intolerant of all statins, tolerates ezetimibe 10mg and non-HDL cholesterol not reduced by 40%.
• Nustendi is currently for specialist initiation only due to being new drug and need to confirm statin intolerance. Trial data for Nustendi beneficial outcomes was in patients with LDL ≥2.6 mmol/L.

All secondary prevention patients should be considered for lipid lowering therapy i.e. those who have evidence of atherosclerosis such as myocardial infarction, acute coronary syndrome, ischaemic stroke, transient ischaemic attack, peripheral artery disease.

Recommended first line lipid lowering therapy is atorvastatin 80mg. Please see BNF for details on interactions and cautions. Offer a lower dose of atorvastatin if there is a high risk of adverse effects, after a full explanation and discussion the patient would prefer to take a lower dose, or it could react with other drugs (also consider rosuvastatin first line as less drug interactions).

Monitoring

Do not delay lipid lowering medication starting but aim to measure U&Es, ALT, TSH (if not measured within last 3 years) and HbA1c (if not measured within last 3 years) as soon as possible to starting lipid lowering therapy.

If ALT level >3 x upper limit of normal (ULN): identify cause of raised ALT and urgently consider whether you need to stop lipid lowering therapy.

Hypothyroidism increases chance of muscular side-effects. If patient identified to have hypothyroidism: treat and consider impact on lipid lowering therapy.

NICE NG238 advises remeasure ALT 3 and 12 months after starting or changing the dose of lipid lowering medication.

If ALT level 1 to 3 x ULN and patient already on statin: remeasure ALT at 1 month.

• If remeasured ALT remains 1 to 3 x ULN: continue.
• If ALT level >3 x ULN: stop statin for 4 weeks and then remeasure ALT.
• If remeasured ALT returns to <3 x ULN: move to next step on statin intolerance pathway
• If ALT remains >3 x ULN: identify cause of raised ALT before deciding on lipid lowering therapy.

Only measure CK if patient has muscle symptoms.

• If CK level >5 x ULN do not start a statin and re-measure CK after 7 days. If CK level still >5 x ULN, do not start a statin and identify cause of raised CK before deciding on lipid lowering therapy. If CK level raised but <5 x ULN, start statin treatment at a lower dose.
• If CK level >5 x ULN and already on a statin, stop statin for 4 weeks and then remeasure CK. If remeasured CK returns to <5 x ULN move to next step on statin intolerance pathway, if CK remains >5 x ULN identify cause of raised CK before deciding on lipid lowering therapy.
• If CK >10 x ULN: urgent assessment for rhabdomyolysis recommended.

Measure lipid profile at 3 months after starting or changing the dose of lipid lowering medication, and aim for non-HDL cholesterol ≤2.5 mmol/L.

If this is not achieved on maximal tolerated statin: add ezetimibe 10mg. Please see BNF for details on interactions and cautions.

Lipid profile measurement is particularly recommended for patients <60 years (consider whether patient could have a genetic hyperlipidaemia), patients intolerant to statins (to assess what lipid lowering agents patient suitable for) and where recurrent / polyvascular disease (consider eligibility for PCSK9 inhibitor).

Atorvastatin 80mg is expected to reduce cholesterol by 55%, so patients with baseline non-HDL cholesterol >5.5 mmol/L should be prioritised for repeat lipid profile measurement, as likely not to meet target on statin alone. The target may not be possible on maximally tolerated medication for which the patient is eligible, and aim should be to achieve as close to target as possible.

National Clinical Guideline for Stroke for the UK and Ireland advises treat people with ischaemic stroke or TIA and evidence of atherosclerosis to achieve non-HDL cholesterol <2.5 mmol/L. This may not be possible on maximally tolerated medication for which the patient is eligible, and aim should be to achieve as close to target as possible.

NICE NG238 advises to offer an annual lipid measurement to inform the discussion about secondary prevention with the patient.

If patient is unable to tolerate atorvastatin: stop statin for 4 to 6 weeks to allow full washout. Measure CK if muscle symptoms.

If symptoms remain unchanged, ALT <3 x ULN and CK <5 x ULN: then unlikely patient is intolerant and consider a rechallenge with the same statin. Look for alternative cause for muscle symptoms e.g. vitamin D deficiency, arthritis, polymyalgia rheumatica.

If patient symptoms resolved after 6 weeks washout: rechallenge with atorvastatin 20mg daily. If can tolerate increase to atorvastatin 40mg.

• If atorvastatin 20mg not tolerated: trial rosuvastatin 5mg daily. Please see BNF for details on interactions and cautions. If can tolerate increase up to rosuvastatin 20mg. If not tolerated, trial rosuvastatin 5mg once a week and build up to as many days of the week as tolerated.
• If patient unable to tolerate any statin: use ezetimibe 10mg to reduce cholesterol further. Please see BNF for details on interactions and cautions.

Refer to lipid clinic for consideration for PCSK9 inhibitor, if despite maximal tolerated lipid lowering therapy (statins and ezetimibe):

• LDL ≥4 mmol/L and one previous cardiovascular event or
• LDL ≥3.5 mmol/L and recurrent / polyvascular disease.

Refer to lipid clinic for consideration of Nustendi (ezetimibe 10 mg + bempedoic acid 180 mg):

• If patient not eligible for PCSK9 inhibitor, intolerant of all statins, tolerates ezetimibe 10mg and non-HDL cholesterol not at target.
• Nustendi is currently for specialist initiation only due to being new drug and need to confirm statin intolerance. Trial data for Nustendi beneficial outcomes was in patients with LDL ≥2.6 mmol/L.

When triglycerides >10 mmol/L the main risk is acute pancreatitis.

If triglycerides 4.5 to 10 mmol/L:

• This is most likely caused by oral intake prior to the test, diabetes, alcohol intake, elevated BMI, medications or liver disease.
• Aim to treat triglycerides via cause.
• If ALT also raised: consider liver screen as per TAM liver guidance and assessment for metabolic-dysfunction associated steatotic liver disease (MASLD).
• Treat cholesterol as per appropriate primary or secondary prevention guidance.

If triglycerides 10 to 20 mmol/L:

• Assess patient for pancreatitis and hyperglycaemia, and consider alcohol intake.
• Most raised triglycerides at this level are caused by uncontrolled diet, diabetes or alcohol intake.
• Promptly aim to treat triglycerides via cause.
• Repeat lipid profile within 6-14 days, preferably on fasting sample, if safe to do so.
• If no clear reversible cause or unable to remove cause: consider use of bezafibrate and referral to lipid clinic.
• If ALT also raised: consider liver screen as per TAM liver guidance and assessment for metabolic-dysfunction associated steatotic liver disease (MASLD).
• Lipid consultant available via Clinical Dialogue, if required, but note single handed consultant and reply only guaranteed within 15 days.

If triglycerides >20 mmol/L:

• Urgently assess patient for pancreatitis and hyperglycaemia, and consider alcohol intake.
• Discuss with acute medical or surgical team, as required.
• Advise urgent lifestyle intervention: stop all alcohol (ensure safe to do so), no fat intake for 48 hours (removes dietary source, ensure safe to do so), and if hyperglycaemia, insulin infusion should be considered.
• Also consider medications and liver disease.
• Aim to treat triglycerides via cause if possible.
• If no clear reversible cause or unable to remove cause: consider use of bezafibrate.
• Lipid consultant available via Clinical Dialogue if required but note single handed consultant and reply only guaranteed within 15 days. Phone Duty Biochemist 01463 705931, available Monday to Friday 09:00 to 18:00, to prompt if more urgent reply required.