Dyslipidaemia and familial hypercholesterolaemia

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Lipid treatment is risk-based as well as concentration-based. Primary prevention combines QRISK3 with comorbidity and informed preference; prior atherosclerotic CVD, CKD, type 1 diabetes and FH have dedicated recommendations that should not be diluted by a low calculated score.

Non-HDL cholesterol is practical for routine follow-up because it captures cholesterol in all atherogenic particles and does not require fasting. A fasting sample is mainly useful when triglycerides are very high or the laboratory cannot calculate LDL reliably.

FH is an autosomal dominant lifelong exposure state, not simply a high result. Clinical criteria, exclusion of secondary causes, specialist phenotyping/genetic testing and cascade testing can prevent events across an entire family.

Key points

Offer atorvastatin 20 mg for primary prevention when QRISK3 10-year CVD risk is at least 10%; do not deny treatment solely because risk is below 10% when informed preference or underestimated risk supports it.
For established CVD, offer atorvastatin 80 mg unless interactions, adverse-effect risk or patient preference justify a lower dose.
Aim for more than a 40% reduction in non-HDL cholesterol in primary prevention and LDL cholesterol 2.0 mmol/L or less or non-HDL cholesterol 2.6 mmol/L or less in secondary prevention.
Measure a full lipid profile and ALT/AST at baseline; recheck lipids and transaminases 2–3 months after starting or changing lipid-lowering treatment.
Do not measure CK routinely: check it before treatment only with unexplained muscle symptoms and measure it if such symptoms develop on therapy.
Suspect familial hypercholesterolaemia from marked untreated cholesterol, premature coronary disease, tendon xanthomata or family history; do not use QRISK to decide treatment in FH.
Adults with FH need a high-intensity statin aiming for at least a 50% LDL reduction from baseline, specialist assessment when criteria are met and DNA-based cascade testing of relatives after an index mutation is found.
Severe triglycerides need a separate pathway: triglycerides above 20 mmol/L require urgent specialist review because pancreatitis risk is substantial.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Familial hypercholesterolaemia

Usually autosomal dominant impairment of LDL clearance produces high LDL from birth and prolonged arterial exposure. Premature coronary disease, tendon xanthomata and similarly affected relatives strengthen the clinical suspicion.

Polygenic and lifestyle-related dyslipidaemia

Multiple common variants interact with excess weight, dietary pattern, inactivity and insulin resistance. The result may be raised LDL, triglycerides or both, often without the striking family pattern of monogenic FH.

Secondary medical causes

Hypothyroidism, diabetes, nephrotic or chronic kidney disease and cholestatic liver disease can alter lipoprotein production or clearance. Treating the underlying disorder may materially improve the lipid profile.

Alcohol and medicine effects

Excess alcohol and several prescribed medicines can particularly raise triglycerides, sometimes alongside uncontrolled diabetes. A temporal exposure review helps avoid mistaking a secondary pattern for a primary inherited disorder.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Atherogenic particle excess
Reduced receptor-mediated clearance or increased hepatic production raises circulating LDL and other apolipoprotein-B-containing particles. FH creates especially prolonged exposure because the abnormality is present from early life.
2
Arterial retention
Atherogenic particles enter and become retained within the arterial intima. Modification of these lipoproteins activates endothelial cells and recruits inflammatory monocytes into the vessel wall.
3
Plaque formation
Macrophages ingest modified lipid and become foam cells. Smooth-muscle migration, extracellular lipid and fibrous tissue then form an enlarging atherosclerotic plaque that may restrict arterial flow.
4
Plaque disruption and thrombosis
Inflammation may weaken the plaque surface, allowing rupture or erosion. Platelet activation and thrombus can then abruptly occlude coronary, cerebral or peripheral arteries and cause acute ischaemia.
5
Severe triglyceride excess
With very marked accumulation of triglyceride-rich particles, pancreatic capillary lipolysis may release locally injurious fatty acids. This separate pathway helps explain the increased acute-pancreatitis risk in severe hypertriglyceridaemia.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Primary-prevention candidate

No established CVD and QRISK3 at least 10%, or a lower calculated risk that may be underestimated because of comorbidity, medicines, family history or patient preference.

Secondary prevention

Previous acute coronary syndrome, angina/coronary disease, coronary or other arterial revascularisation, ischaemic stroke/TIA or peripheral arterial disease warrants treatment without recalculating whether risk crosses 10%.

Possible familial hypercholesterolaemia

Untreated total cholesterol above 7.5 mmol/L in an adult, especially with tendon xanthomata or premature coronary disease in the patient or a first-/second-degree relative; apply Simon Broome or Dutch Lipid Clinic Network criteria.

Very high cholesterol

Total cholesterol above 9.0 mmol/L or non-HDL cholesterol above 7.5 mmol/L should prompt specialist assessment even without a clear family history after secondary causes are considered.

Severe hypertriglyceridaemiaRed flag

Triglycerides above 20 mmol/L, or 10–20 mmol/L persisting on a fasting repeat, may reflect uncontrolled diabetes, alcohol, medicines or a genetic disorder and carries pancreatitis risk.

Statin-associated symptoms

Symmetrical proximal muscle pain or weakness temporally related to treatment requires CK assessment and review of exercise, hypothyroidism, vitamin D status and interacting medicines; causality is not automatic.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Full lipid profileFirst step
Why
Quantify total, HDL, non-HDL and triglycerides and calculate LDL where valid.
Interpretation and limitations
A non-fasting sample is usually acceptable. Repeat fasting when triglycerides are 10–20 mmol/L and seek urgent specialist advice if they exceed 20 mmol/L.
02
QRISK3 assessment
Why
Estimate 10-year risk for primary prevention in people for whom a risk tool is appropriate.
Interpretation and limitations
Offer atorvastatin 20 mg at 10% or more after discussion. Do not use the score to withhold treatment in established CVD or FH, or as the sole decision tool in dedicated high-risk groups.
03
Baseline safety and secondary-cause screen
Why
Identify modifiable causes and treatment risk.
Interpretation and limitations
Record BP, BMI, smoking/alcohol and diabetes status; check ALT/AST and consider HbA1c/glucose, TSH, renal function and urine protein according to the phenotype.
04
CK when indicated
Why
Assess unexplained muscle symptoms before or during statin therapy.
Interpretation and limitations
Do not check routinely in an asymptomatic person. A value more than 5 times the laboratory upper limit before treatment warrants repeat after 7 days and deferral if still elevated.
05
Simon Broome or DLCN assessment
Why
Structure the clinical probability of FH.
Interpretation and limitations
Use untreated/pre-treatment lipids where possible, document tendon xanthomata and a three-generation pedigree; refer for specialist/DNA testing when criteria indicate possible or definite FH.
06
DNA testing and cascade testing
Why
Confirm monogenic FH and identify affected relatives early.
Interpretation and limitations
A pathogenic familial variant confirms the index diagnosis and enables systematic DNA testing of first-degree and then wider relatives through an FH service.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Polygenic hypercholesterolaemia

Common genetic and lifestyle influences can raise LDL without a single causal variant. Less marked untreated cholesterol, absent tendon xanthomata and a weaker pattern of premature family disease may favour this explanation, but none excludes FH.

Hypothyroidism

Reduced thyroid hormone lowers LDL clearance and can mimic primary hypercholesterolaemia. Fatigue, weight gain or other thyroid features and an abnormal thyroid profile identify a treatable secondary cause.

Nephrotic or chronic kidney disease

Protein loss and altered hepatic lipoprotein handling can produce substantial cholesterol or triglyceride elevation. Proteinuria, oedema or impaired renal function supports a renal contribution, although kidney disease and familial dyslipidaemia can coexist.

Diabetes or alcohol-related hypertriglyceridaemia

Poor glycaemic control and heavy alcohol exposure often raise triglycerides more than LDL. Glucose results, alcohol history and improvement after correcting the driver help distinguish a secondary pattern.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01primary preventionNo established CVDFirst stepA lipid profile and cardiovascular risk review identify a prevention opportunity.

1First: optimise smoking, diet, activity, weight, alcohol and blood pressure, and correct major secondary causes; do not make lifestyle change a prerequisite for statin discussion.
2Next: calculate QRISK3 where appropriate and offer atorvastatin 20 mg when risk is at least 10%, also considering treatment below 10% when risk may be underestimated or the informed patient prefers it.
3Next: repeat full lipids and ALT/AST after 2–3 months; seek more than a 40% non-HDL reduction and check adherence/timing/secondary causes before increasing intensity.
4EscalationEscalation: use a higher dose/intensity if needed and tolerated, or add ezetimibe when the goal is not achieved on maximum tolerated statin treatment.

02secondary preventionEstablished cardiovascular diseaseCoronary disease, ischaemic stroke/TIA or peripheral arterial disease is present.

1First: start atorvastatin 80 mg without delaying for a fasting sample unless interactions, frailty/adverse-effect risk or preference justify a lower dose.
2Next: review lipids and ALT/AST at 2–3 months and aim for LDL 2.0 mmol/L or less or non-HDL 2.6 mmol/L or less.
3Next: verify adherence and maximise tolerated statin; add ezetimibe if either secondary-prevention target is not met.
4EscalationEscalation: assess eligibility for injectable or additional therapy such as inclisiran through the NICE technology-appraisal criteria and specialist pathway.

03FHSuspected familial hypercholesterolaemiaMarked untreated cholesterol, tendon xanthomata or premature coronary/family history suggests inherited disease.

1First: exclude secondary causes, retrieve the highest untreated lipid values and construct a three-generation pedigree including age and type of vascular events.
2Next: apply Simon Broome or DLCN criteria and refer for FH specialist assessment and DNA testing when indicated.
3Next: offer a high-intensity statin aiming for at least a 50% LDL reduction from baseline; add ezetimibe and specialist agents if this is not reached.
4EscalationEscalation: when a pathogenic variant is found, initiate systematic DNA cascade testing of relatives rather than cholesterol testing alone.

04intolerance or non-responseSymptoms or target not achievedMuscle symptoms, biochemical abnormality or insufficient lipid reduction limits treatment.

1First: assess symptom timing, CK if symptomatic, ALT/AST, adherence, interacting drugs and secondary causes such as hypothyroidism; urgently stop and assess severe weakness, dark urine or marked CK elevation.
2Next: after symptoms settle, rechallenge with the same statin at a lower dose or a different statin/intensity; any tolerated statin is generally preferable to none.
3Next: add ezetimibe 10 mg daily when the statin is contraindicated/not tolerated or the target remains unmet on maximum tolerated statin.
4EscalationEscalation: consider bempedoic acid with ezetimibe when TA694 criteria are met, or an injectable pathway when the relevant NICE criteria and lipid thresholds are satisfied.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

First-line high-intensity statin for primary and secondary prevention; in FH use an intensity sufficient to aim for at least a 50% LDL reduction.

Atorvastatin

Primary prevention: 20 mg orally once daily. Secondary prevention: 80 mg orally once daily; use a lower dose when interactions, high adverse-effect risk or patient preference require it.

Contraindicated in active liver disease and during pregnancy/breastfeeding. Review CYP3A4 interactions including some macrolides, azoles, antivirals and ciclosporin; muscle risk rises with interacting drugs. Stop and urgently assess suspected rhabdomyolysis.

Add to maximum tolerated statin when the prevention target is not met, or use alone when statins are contraindicated or not tolerated.

Ezetimibe

10 mg orally once daily, with or without food.

Check liver tests when combined with a statin according to the statin regimen. Review unexplained muscle symptoms and avoid in pregnancy when given with a statin; ciclosporin can increase exposure.

NICE TA694 option for primary hypercholesterolaemia or mixed dyslipidaemia when statins are contraindicated/not tolerated and ezetimibe alone has not controlled LDL sufficiently.

Bempedoic acid

180 mg orally once daily; when used as separate tablets with ezetimibe, also give ezetimibe 10 mg once daily.

Can raise uric acid and precipitate gout, raise liver enzymes and rarely cause tendon injury; review renal/hepatic disease and statin interactions, particularly simvastatin dose limits, against the current SmPC.

NICE TA733 option in secondary prevention when LDL remains at least 2.6 mmol/L despite maximum tolerated lipid-lowering treatment and the qualifying CVD criteria are met.

Inclisiran

284 mg by subcutaneous injection initially, again at 3 months, then every 6 months.

Administer within the commissioned pathway by a trained professional. Injection-site reactions are common; it supplements rather than replaces adherence to statin/ezetimibe when these are tolerated.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Premature coronary artery disease

Cumulative LDL exposure accelerates coronary plaque formation, particularly in untreated FH. Stable angina, acute coronary syndrome or need for early revascularisation may therefore occur decades earlier than expected.

Ischaemic stroke

Atherosclerosis in carotid, aortic and cerebral arteries can embolise or thrombose, interrupting brain perfusion. The consequence may be transient ischaemic attack, disabling stroke or vascular cognitive decline.

Peripheral arterial disease

Progressive plaque in limb arteries causes exertional claudication and impaired healing. Advanced disease can produce rest pain, ulceration or acute limb ischaemia with threat to tissue viability.

Acute pancreatitis

Severe triglyceride elevation can trigger pancreatic inflammation through toxic fatty-acid release. This may cause intense abdominal pain, systemic inflammation and organ failure, making extreme results clinically urgent.

Unrecognised familial risk

Because heterozygous FH is usually autosomal dominant, first-degree relatives may also have lifelong LDL exposure. Missed cascade assessment can delay diagnosis and preventive care across generations.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Repeat a full lipid profile and ALT/AST 2–3 months after starting or changing lipid-lowering treatment.
Measure ALT/AST again at 12 months, then only if clinically indicated; do not exclude treatment for transaminases below 3 times the upper limit of normal.
Assess primary prevention by percentage non-HDL reduction and secondary prevention against LDL 2.0 mmol/L or non-HDL 2.6 mmol/L.
Ask about adherence, new medicines and muscle symptoms at each review; measure CK only when symptoms or another clinical indication exists.
In FH, review at least annually for treatment response, adverse effects, smoking/BP/diabetes and progress with family cascade testing.
For bempedoic acid, monitor urate/gout and tendon symptoms; for inclisiran, record dose dates, LDL response and injection reactions.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Non-HDL is a treatment metric

It is total cholesterol minus HDL and remains interpretable in a non-fasting sample, making it well suited to NICE percentage-reduction monitoring.

Secondary prevention has an absolute target

NICE now uses LDL 2.0 mmol/L or less or non-HDL 2.6 mmol/L or less, rather than relying only on percentage reduction.

FH bypasses QRISK

A short-term calculator underestimates lifelong LDL exposure, so FH treatment intensity is driven by diagnosis and baseline LDL response.

Tendon xanthomata are highly informative

Examine Achilles and hand extensor tendons; xanthelasma and corneal arcus alone are not equivalent to tendon xanthomata in Simon Broome criteria.

One statin symptom episode is not permanent intolerance

Check competing causes and interactions, then use dechallenge/rechallenge, a different statin or a lower tolerated dose before concluding that the class cannot be used.

Extreme triglycerides change urgency

The immediate concern becomes pancreatitis and rapid correction of secondary drivers such as uncontrolled diabetes or alcohol, alongside specialist input.

11Common pitfallsFrequent interpretation and management errors.

01
Using QRISK3 to decide whether a patient with established CVD or FH deserves treatment.
02
Waiting for lifestyle change or a fasting lipid sample before starting secondary-prevention atorvastatin.
03
Stopping a statin permanently after uninvestigated aches without checking interactions, CK when symptomatic and a rechallenge strategy.
04
Calling xanthelasma or corneal arcus diagnostic tendon xanthomata.
05
Missing urgent referral when triglycerides exceed 20 mmol/L or specialist assessment when total cholesterol exceeds 9 mmol/L.