Hypercholesterolaemia

Hypercholesterolaemia is a major contributor to cardiovascular disease. It is usually multifactorial, but there are some genetic conditions (discussed below) where more intensive therapy is warranted. The mainstays of therapy are identifying & treating reversible causes, lifestyle modification (particularly around smoking, diet and exercise), and prescription of statins. 

Sections on this page: 

• Assessment
• Drug management of hypercholesterolaemia
• Targets for lipid control
• Familial hypercholesterolaemia
• Familial combined hypercholesterolaemia

Assessment

Many cases of hypercholesterolaemia are related to lifestyle. Secondary causes include: 

• Uncontrolled diabetes mellitus
• Obesity
• Excess alcohol consumption
• Untreated hypothyroidism 
• Some medications, such as thiazide diuretics and ciclosporin.

If any of these are present, interventions to target these risk factors should be initiated. 

Assessment should focus on identifying secondary causes, evidence of end-organ damage and other risk factors for cardiovascular disease. 

After this, calculate cardiovascular risk. If the 10-year risk is >20%, offer drug therapy. If risk is 10-20%, discuss starting drug therapy with the patient. 

Note: CVD risk calculators underestimate risk up to 2-fold in those with: 

• Obesity
• Interited dysplipidaemias (e.g. Familial hypercholesterolaemia or Familial combined hypercholesterolaemia)
• Hypertriglyeridaemia
• HIV
• Systemic inflammatory conditions
• Serious mental health problems
• Those already on antihypertensive treatment 
• Certain ethnic populations, particularly south asian men

Drug Management of Hypercholesterolaemia

Statins

Statins are the mainstay of treatment. High-intensity statins (atorvastatin & rosuvastatin) are the most cost-effective, and produce the greatest reduction in LDL. Levels of LDL reductions with various statins are given in the table: 

*Simvastatin 80mg/d is no longer recommended due to significantly increased incidence of myositis, and expense when compared to atorvastatin 20mg/d, which provides a similar reduction in LDL

• For primary prevention of cardiovascular disease in patients with a 10-year risk of >20%, prescribe atorvastatin 20mg/d. This lowers LDL more than the maximal doses of moderate-intensity statins and is well tolerated. 
• For secondary prevention, we recommend atorvastatin 40-80mg/d (according to tolerability). 

If a patient is already on a moderate-intensity statin discuss switching to a high-intensity statin, unless they have previously been intolerant of such therapy. 

Choosing a statin

• First-line: High-intensity statins – atorvastatin, then rosuvastatin
• Second-line: Moderate-intensity statins – simvastatin, then pravastatin

Atorvastatin and simvastatin are both metabolised by CYP3A4 – patients taking drugs which inhibit 3A4 (e.g. Azole antifungals, HIV protease inhibitors, macrolide antibiotics, verapamil/diltiazem, amiodarone, grapefruit juice) are more likely to develop myositis/rhabdomyolysis – use alternatives instead. Rosuvastatin and pravastatin are not metabolised by CYP3A4. 

Rosuvastatin is now off-patent, and provides the most intense LDL-lowering effect per dose. 

Statin intolerance

Myalgia is commonly reported in patients starting statins, but statin myopathy (raised CK with myalgia) or rhabdomyolysis is rare. ~80% of patients reporting intolerance to statins can be successfully rechallenged. If a patient reports intolerance to statin therapy, we recommend the following: 

• Check Creatinine Kinase if the symptom is myalgia; if raised, discontinue the drug. 
• Consider reintroducing the same drug at the same dosage. 
• If symptoms recur, reduce the dosage of the same drug (atorvastatin 10mg reduces LDL by 37%); most of the benefit can be obtained with small doses of statin. 
• If symptoms persist, switch to a lower-intensity statin (e.g. simvastatin). 
• As a last resort, consider rosuvastatin 5mg 3x/week. 

If the patient is truly intolerant of statins, consider use of the alternatives below. 

Ezetimibe

Ezetimibe is a cholesterol absorption inhibitor. It has few significant side effects, and reduces LDL by 15-20%. Indications for starting Ezetimibe 10mg daily are: 

• Primary prevention in statin-intolerant patients
• Secondary prevention in patients on maximum-tolerated doses of statins where LDL targets have not been attained. 

PCSK9 Inhibitors

These are monoclonal antibodies which prevent LDL-receptor degradation, resulting in more LDL being removed from the systemic circulation and lower plasma LDL cholesterol. Two drugs are available, Evolocumab (£680/month) and Alirocumab (£340/month). Use of these drugs is restricted in Lothian. If you think a patient should be considered for PCSK9 inhibitor therapy, please refer them to the lipid clinic at RIE.

Targets for Lipid Control

Primary prevention: There is no specific LDL reduction target

Secondary prevention: Aim for a 1mmol / 40% reduction in non-HDL cholesterol. If this is not obtained: 

• Increase statin dose 
• Consider addition of other lipid-lowering therapies. 
• Revisit lifestyle modification
• Consider nonadherence

Familial Hypercholesterolaemia (FH)

Suspect FH in adults with:

• Total cholesterol >7.5 mmol/l or
• Past or family history of premature coronary heart disease (<60 years in patient or their first-degree relative).

In such patients apply the Simon Broome Criteria: 

Refer patients who meet definite or possible Simon Broome criteria for DNA testing via Refhelp.

Cardiovascular risk calculators (QRISK3/ASSIGN) should not be used in patients with confirmed FH, as they are already at markedly increased risk of cardiovascular disease. 

Familial Combined Hypercholesterolaemia (FCH)

Definition

This condition has a high prevalence (~1%), and presents as marked elevation of LDL and triglycerides. It is commonly associated with type 2 diabetes and the metabolic syndrome. The origin is polygenic, but the condition runs in families. 

Assessment

If you suspect a patient has FCH, perform a full lipid screen and obtain past medical and family history of cardiovascular disease (including age at which cardiovascular events occurred). There is no formal genetic diagnosis (though a raised serum ApoB is suggestive)

Management

Treatment should consist of lifestyle modification and medication to reduce cholesterol (statins) and triglycerides (fibrates; rarely used, and only in combination with a statin). We are able to discuss and advise on cases via refhelp.