Key Facts

Hyperlipidaemia refers to elevated levels of lipids in the blood, primarily total cholesterol, LDL cholesterol, and triglycerides. It is a major modifiable risk factor for atherosclerotic cardiovascular disease.

Epidemiology

• ~60% of UK adults have total cholesterol >5 mmol/L
• ~1 in 250 people have heterozygous FH (under-diagnosed)
• CVD accounts for ~25% of deaths in the UK

Aetiology

Primary (genetic):

• Familial hypercholesterolaemia (FH): LDLR, ApoB100, PCSK9 mutations
• Familial combined hyperlipidaemia
• Familial hypertriglyceridaemia
• Polygenic hypercholesterolaemia (most common)

Secondary:

• Hypothyroidism, diabetes, nephrotic syndrome, CKD, cholestasis
• Drugs: thiazides, beta-blockers, corticosteroids, retinoids, protease inhibitors
• Diet: high saturated fat, excess alcohol (hypertriglyceridaemia)
• Obesity, sedentary lifestyle

Pathophysiology

• Elevated LDL-C → penetration of arterial intima → oxidation → foam cell formation → atherosclerotic plaque
• Plaque progression → stenosis, plaque rupture → thrombosis → MI, stroke
• High TG associated with pancreatitis risk (>10 mmol/L)
• Low HDL-C is an independent CVD risk factor

Typical Presentation

• Usually asymptomatic: detected on routine blood tests
• May present with complications of CVD (angina, MI, stroke, PAD)

Physical Signs of FH

• Tendon xanthomata: pathognomonic; especially Achilles tendon and extensor tendons of hands
• Xanthelasma: yellow deposits around eyelids (non-specific; can occur without FH)
• Corneal arcus: grey-white ring around corneal margin (significant if <45 years)
• Tuberous xanthomata: over elbows, knees
• Xanthomata of palmar creases: suggest familial dysbetalipoproteinaemia (type III)

Red Flags

• Total cholesterol >7.5 mmol/L or LDL >4.9 mmol/L: suspect FH
• Premature CVD (MI <55 in men, <60 in women)
• Family history of premature CVD or very high cholesterol
• Tendon xanthomata
• TG >10 mmol/L: risk of acute pancreatitis

Bloods

• Full lipid profile (fasting or non-fasting): total cholesterol, LDL-C, HDL-C, triglycerides, non-HDL-C
• QRISK3 assessment: 10-year cardiovascular risk calculation
• Exclude secondary causes: TFTs, fasting glucose/HbA1c, U&Es, LFTs, urine ACR
• LFTs: baseline before statin initiation, at 3 months, then annually
• CK: if myalgia develops on statin

Lipid Targets (NICE CG181)

• Primary prevention: achieve >40% reduction in non-HDL-C from baseline
• Secondary prevention: atorvastatin 80mg OD; aim >40% reduction in non-HDL-C
• ESC targets: LDL <1.4 mmol/L for very high risk; <1.8 mmol/L for high risk; <2.6 mmol/L for moderate risk

FH Diagnosis (Simon Broome Criteria)

Definite FH:

• TC >7.5 mmol/L or LDL >4.9 mmol/L PLUS tendon xanthomata, or
• Genetic confirmation of LDLR/ApoB/PCSK9 mutation

Possible FH:

• TC >7.5 mmol/L or LDL >4.9 mmol/L PLUS family history of premature MI (<60 in 1st degree) or TC >7.5 mmol/L in 1st/2nd degree relative

Non-pharmacological

• Dietary modification: reduce saturated fat, replace with unsaturated fats; increase fibre, fruit, vegetables; Mediterranean diet
• Exercise: ≥150 minutes moderate aerobic activity per week
• Weight management: target BMI <25 kg/m²
• Smoking cessation
• Limit alcohol: reduces TG
• Plant stanols/sterols (2g/day): reduce LDL by ~10%

Pharmacological

Statins (first-line):

• Primary prevention (QRISK3 ≥10%): atorvastatin 20mg OD
• Secondary prevention: atorvastatin 80mg OD
• FH: high-intensity statin (atorvastatin 40-80mg or rosuvastatin 20-40mg)
• Statin intolerance: try alternative statin, lower dose, alternate-day dosing

Second-line (add to statin if target not met):

• Ezetimibe 10mg OD: cholesterol absorption inhibitor; reduces LDL by ~15-20% (IMPROVE-IT trial)

Third-line:

• PCSK9 inhibitors (NICE TA394/TA393): alirocumab or evolocumab SC every 2-4 weeks
  • For FH with very high LDL despite max statin + ezetimibe
  • Secondary prevention with recurrent events despite max statin + ezetimibe
  • FOURIER trial: evolocumab reduced LDL by 59% and CV events by 15%
• Inclisiran (NICE TA733): siRNA targeting PCSK9 mRNA; SC injection every 6 months
  • For primary hypercholesterolaemia or mixed dyslipidaemia inadequately controlled on max statin ± ezetimibe

Severe hypertriglyceridaemia (>10 mmol/L):

• Fibrates (bezafibrate, fenofibrate)
• Omega-3 fatty acids (prescription icosapent ethyl — REDUCE-IT trial)
• Urgent if TG >20 mmol/L (pancreatitis risk)

Referral Criteria

• Suspected FH: lipid specialist or FH service (NICE CG71)
• Statin intolerance: specialist lipid clinic
• Very high LDL despite max therapy: PCSK9 inhibitor eligibility assessment
• Severe hypertriglyceridaemia: urgent lipid clinic referral

• Statin therapy reduces major vascular events by ~25-35% per mmol/L reduction in LDL-C
• Heterozygous FH: without treatment, 50% of men develop coronary events by age 50
• With early statin therapy: FH patients can achieve near-normal life expectancy
• Homozygous FH: severe CVD in childhood without aggressive treatment
• Every 1 mmol/L reduction in LDL-C → ~22% reduction in major vascular events (CTT Collaboration meta-analysis)
• PCSK9 inhibitors provide additional 15-20% CV risk reduction when added to statin

Statin Intensity Classification

Key Landmark Lipid Trials