Hypercholesterolaemia

Numerical Definition

• Dyslipidaemia is typically defined by serum concentrations above the 90th percentile for TC, LDL-C, triglycerides, apolipoprotein B, or lipoprotein(a), and below the 10th percentile for HDL-C or apolipoprotein A-I within the general population.
• Traditional percentile cut-offs, however, should not be applied too rigidly. For instance, lipoprotein(a) levels at or above the 80th percentile have been associated with an increased risk of cardiovascular disease.
• Clinically, hypercholesterolaemia is also defined by LDL-C thresholds: values greater than 190 mg/dL, above 160 mg/dL with one cardiovascular risk factor, or above 130 mg/dL with two risk factors are considered abnormal.

Primary Causes

Familial Hypercholesterolaemia (FH)

• The most recognised primary cause, inherited in an autosomal co-dominant fashion.
• Caused predominantly by mutations in the LDL receptor gene, accounting for ~85% of cases.
• Over 1600 mutations identified, resulting in reduced LDL receptor activity and delayed clearance of LDL and IDL.
• Heterozygotes typically have LDL-C >190 mg/dL; homozygotes may exceed 450 mg/dL.
• Associated with xanthomas, corneal arcus, and strong family history of premature coronary artery disease.
• Cascade screening of first-degree relatives is recommended.

Apolipoprotein B Mutations

• Mutation at position 3500 of the apoB gene leads to defective binding of LDL to its receptor.
• Results in elevated plasma LDL-C despite normal LDL receptor function.

PCSK9 Gain-of-Function Mutations

• Mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene increase receptor degradation.
• Leads to fewer hepatic LDL receptors and increased circulating LDL-C.

Autosomal Recessive Hypercholesterolaemia

• Rare cause due to mutations in LDL receptor adaptor protein, impairing endocytosis of LDL receptors.
• Presents with markedly elevated LDL-C, similar to homozygous FH but with different inheritance pattern.

Polygenic Hypercholesterolaemia

• Arises from multiple minor genetic variants combined with environmental and lifestyle factors.
• More common than monogenic FH and often linked to unhealthy diet, obesity, and physical inactivity.

Secondary Causes

• More frequent than primary forms and typically develop later in life.
• Major contributors include:
  • Lifestyle: sedentary behaviour, diets rich in saturated and trans fats, obesity.
  • Endocrine/metabolic disorders: diabetes mellitus, hypothyroidism, metabolic syndrome, abdominal obesity.
  • Renal/hepatic disease: nephrotic syndrome, chronic renal insufficiency, cholestatic liver disease.
  • Physiological states: pregnancy.
  • Alcohol dependence: linked particularly to hypertriglyceridaemia.
  • Medications: high-dose thiazide diuretics, oral oestrogens, glucocorticoids, anabolic steroids, ciclosporin, antiretroviral therapy, and atypical antipsychotics (e.g., olanzapine, clozapine). Beta-blockers lacking intrinsic sympathomimetic or alpha-blocking activity can also lower HDL-C.

Risk Factors

• LDL-C >190 mg/dL, >160 mg/dL with one cardiovascular risk factor, or >130 mg/dL with two risk factors.
• Additional independent risk factors:
  • Male ≥45 years, female ≥55 years.
  • Family history of premature ASCVD (before 55 years in men, 65 years in women).
  • Hypertension.
  • Diabetes mellitus.
  • Cigarette smoking.
  • Low HDL-C (<40 mg/dL in men, <55 mg/dL in women).

Lipoprotein Retention and Oxidation

• A central theory of atherogenesis proposes that apolipoprotein B-100–containing lipoproteins (predominantly LDL) are retained in the subendothelial space via charge-mediated interactions with extracellular matrix proteoglycans.
• Once retained, LDL undergoes oxidative modification by reactive oxygen species, altering surface phospholipids and cholesterol.
• Circulating LDL can also be engulfed by macrophages through scavenger receptors, leading to lipid accumulation within these cells.
• Oxidised LDL (oxLDL) plays a pivotal role in vascular injury, stimulating inflammatory pathways, inducing growth factors, damaging endothelium, and recruiting monocytes and macrophages.
• Isoprostanes, stable free radical–derived products of arachidonic acid, are formed during LDL oxidation. These can be detected in atherosclerotic plaques and in the urine of asymptomatic hypercholesterolaemic individuals.

Endothelial Dysfunction and Vascular Effects

• Elevated oxLDL concentrations impair endothelial nitric oxide production, reducing vasodilatation and promoting vasoconstriction.
• OxLDL also promotes platelet aggregation and thromboxane release, contributing to a pro-thrombotic vascular environment.
• Activated platelets release cytokines, stimulating vascular smooth muscle proliferation, a hallmark of progressive atherosclerotic lesions.
• Macrophages overloaded with oxLDL transform into foam cells, which are central to fatty streak formation. Their rupture releases free radicals, oxLDL, and enzymes, further damaging the vascular wall.

Familial Hypercholesterolaemia

• In familial hypercholesterolaemia, LDL receptor defects or absence prevent hepatic uptake of circulating LDL. Normally, the liver clears around two-thirds of plasma LDL, but mutations in the LDL receptor gene (over 1600 described) markedly impair this process.
• The accumulation of LDL in plasma drives premature and severe atherogenesis, often presenting clinically in early life.

Phenotypic Classification (WHO/Fredrickson)

Type I: Elevated chylomicrons 

• linked to lipoprotein lipase or apolipoprotein C-II deficiency.

Type IIa: Elevated LDL

• Associated with familial hypercholesterolaemia, polygenic hypercholesterolaemia, nephrosis, hypothyroidism, and familial combined hyperlipidaemia.

Type IIb: Elevated LDL and VLDL

• Typical of familial combined hyperlipidaemia.

Type III: Elevated intermediate-density lipoprotein (IDL)

• Associated with dysbetalipoproteinaemia.

Type IV: Elevated VLDL

• Seen in familial hypertriglyceridaemia, familial combined hyperlipidaemia, sporadic hypertriglyceridaemia, abdominal obesity, and diabetes.

Type V: Elevated chylomicrons and VLDL

• Usually secondary to diabetes.

General Population Prevalence

• In the United States, an estimated 24.7 million adults (10% of the adult population) have total cholesterol concentrations ≥6.2 mmol/L (≥240 mg/dL).
• Data from 2007 to 2018 demonstrated a modest decline in mean age-adjusted total cholesterol levels across racial and ethnic groups (from 5.1 mmol/L [197 mg/dL] to 4.9 mmol/L [189 mg/dL]), with the notable exception of non-Hispanic Asian adults, who did not exhibit this improvement.
• According to the CDC, approximately 73.5 million adults (31.7%) in the US have elevated LDL-C, placing them at double the risk of cardiovascular disease compared with those with normal LDL-C. Alarmingly, only about half (48.1%) of these individuals receive treatment.

Coronary Heart Disease and Population Risk

• In patients with coronary heart disease (CHD), dyslipidaemia prevalence ranges from 80–88%, significantly higher than the 40–48% observed in age-matched controls.
• The INTERHEART study identified dyslipidaemia, particularly elevated apoB/apoA1 ratio, as one of the most important risk factors for myocardial infarction, with a population attributable risk of 49%.
• Hypercholesterolaemia has a strong correlation with body mass index (BMI), underscoring the interaction between obesity and lipid disorders.

Global and Socioeconomic Patterns

• A worrying trend is the rising prevalence of cardiovascular risk factors such as hypercholesterolaemia in low- and middle-income countries, contrasting with decreasing prevalence in high-income nations.
• While mortality from heart disease declined steadily in the United States from the 1960s onwards, this trend slowed and reversed after 2010, highlighting persistent challenges in prevention and treatment.
• Disparities in treatment remain evident: studies show that black and Hispanic populations in the US are less likely to receive statins for primary prevention compared with white individuals.

Familial Hypercholesterolaemia

• Familial hypercholesterolaemia (FH) occurs in approximately 1 in 250 individuals in the heterozygous form and 1 in 300,000 in the homozygous form.
• Prevalence is higher in certain founder populations, including French Canadians, Lebanese, and Afrikaners, where it may be as high as 1 in 100.
• FH represents one of the most common genetic disorders contributing to markedly elevated LDL-C levels and premature cardiovascular disease.

Sex and Ethnic Differences

• Within the United States:
  • Hispanic males exhibit the highest mean LDL-C levels, followed by African American and white males.
  • Overall, females are more likely than males to have elevated LDL-C.

Family History

• Document premature atherosclerotic cardiovascular disease (ASCVD) in first-degree relatives (before 55 years in men, before 60–65 years in women).
• Constructing a family tree can assist in identifying inherited conditions such as familial hypercholesterolaemia.
• Enquire about early-onset dyslipidaemia or coronary heart disease in relatives.

Cardiovascular History

• Many patients are first identified after premature cardiovascular events: angina, myocardial infarction, stroke, or peripheral vascular disease.
• Explore prior hospitalisations or interventions for cardiovascular disease.
• Ask about symptoms of angina, intermittent claudication, and transient ischaemic attacks.

Lifestyle and Dietary History

• Dietary intake: excess saturated fats, trans-fatty acids, and overall calorie load.
• Physical activity: sedentary lifestyle is a strong risk factor.
• Alcohol: dependency increases lipid disturbances.
• Smoking: reduces HDL-C, increases insulin resistance, and alters lipoprotein particle size and number.

Metabolic and Anthropometric Risk

• Excess body weight: particularly abdominal obesity, associated with insulin resistance and unfavourable lipid profiles.
  • Waist circumference thresholds:
    • 94 cm in white/black men
    • 80 cm in white/black women
    • 90 cm in Asian men
    • 80 cm in Asian women

Comorbid Conditions

Hypothyroidism

• Up to 56% of patients may present with isolated hypercholesterolaemia, and others with combined lipid abnormalities.
• Both overt and subclinical hypothyroidism can contribute, with severity of lipid disturbance correlating with thyroid dysfunction.
• Always assess thyroid function in patients with unexplained dyslipidaemia.

Cholestatic Liver Disease

• Abnormal lipoprotein-X particles accumulate in cholestatic conditions such as primary biliary cholangitis.
• Serum cholesterol may exceed 12.95 mmol/L (500 mg/dL), and patients may develop xanthomas.

Nephrotic Syndrome

• Dyslipidaemia occurs due to reduced lipid catabolism and increased hepatic lipoprotein synthesis from low plasma oncotic pressure.

Insulin Resistance and Type 2 Diabetes Mellitus

• Characterised by increased VLDL and apolipoprotein B particles, reduced HDL-C, and smaller LDL/HDL particle size.
• Lipid abnormalities worsen with greater degrees of insulin resistance.

Medication History

• Important drug classes include:
  • High-dose thiazide diuretics.
  • Oral oestrogens and glucocorticoids.
  • Anabolic steroids (also reduce HDL-C).
  • Atypical antipsychotics (olanzapine, clozapine).
  • Protease inhibitors in HIV, associated with lipodystrophy and severe metabolic changes.
  • Isotretinoin, linked to hypercholesterolaemia and hypertriglyceridaemia.

Cutaneous and Ocular Features (Historical Clues)

Xanthelasma

• Yellow periorbital plaques often noted by patients.
• Around half of cases are associated with elevated lipid levels.

Tendinous Xanthomas

• Slowly enlarging nodules on extensor tendons (hands, feet, Achilles tendon).
• Strongly associated with familial hypercholesterolaemia.

Tuberous Xanthomas

• Firm, red-yellow nodules on pressure areas (knees, elbows, buttocks).
• May occur in familial dysbetalipoproteinaemia and severe hypercholesterolaemia.

Arcus Cornealis (before age 45)

• Grey-white ring at the corneal margin due to cholesterol deposition.
• In young patients, strongly suggests a familial lipid disorder.

General Examination

• Assess body mass index (BMI) and waist circumference, as excess weight and abdominal obesity are closely linked with lipid abnormalities.
• Palpate all peripheral pulses and listen for carotid and femoral bruits, suggestive of established atherosclerotic disease.
• In suspected familial hypercholesterolaemia, evaluate the heart carefully for signs of supra-valvar aortic stenosis from atheroma deposition.

Cutaneous and Ocular Manifestations

Xanthelasma

• Yellow plaques, most often located at the inner canthus of the eyelids.
• Present in up to half of patients with lipid abnormalities, though they may also occur in normolipidaemic individuals.
• Frequently seen in type II and type IV hyperlipidaemia.

Tendinous Xanthomas

• Firm, slowly enlarging subcutaneous nodules over tendons or ligaments.
• Common sites include the Achilles tendon and extensor tendons of the hands and feet.
• Strongly associated with familial hypercholesterolaemia and occasionally with secondary causes such as cholestasis.

Tuberous Xanthomas

• Firm, painless, red-yellow nodules, often multilobulated when confluent.
• Usually arise over pressure areas (knees, elbows, buttocks).
• Associated with familial dysbetalipoproteinaemia, familial hypercholesterolaemia, and some secondary lipid disorders.

Arcus Cornealis (before age 45 years)

• White or grey opaque ring at the corneal margin caused by cholesterol deposition.
• Presence before age 45 is strongly suggestive of an inherited lipid disorder.

Systemic Signs of Underlying Conditions

Hypothyroidism

• Clinical features such as bradycardia, dry skin, and delayed reflexes may accompany lipid abnormalities.

Cholestatic Liver Disease

• May present with jaundice and hepatomegaly, in addition to xanthomas.

Nephrotic Syndrome

• Signs include oedema and ascites, with hyperlipidaemia developing due to increased hepatic lipoprotein synthesis.

Initial Laboratory Investigations

Lipid Profile

• Core test, consisting of total cholesterol (TC), triglycerides (TG), LDL-C, HDL-C, and non-HDL-C.
• Can be measured in non-fasting states; however, fasting is preferred when triglycerides are expected to be elevated.
• Non-HDL-C (TC minus HDL-C) is an independent marker of cardiovascular risk and valid in non-fasting samples.
• Formulas for LDL-C:
  • Friedewald equation:
     LDL-C = TC – HDL-C – (TG/5).
    Accurate if TG <200 mg/dL; invalid if TG >400 mg/dL.
  • Martin-Hopkins formula: more accurate across a range of TG levels, including non-fasting samples.
• Biological variability exists: TC may vary by ~10% and TG by up to 25% day-to-day, even without disease.
• Acute illnesses, particularly myocardial infarction, can lower cholesterol and raise TG within 24 hours; lipid testing should be performed acutely or deferred until recovery.

Serum Thyroid-Stimulating Hormone (TSH)

• Used to exclude hypothyroidism as a secondary cause of dyslipidaemia.
• Elevated in primary hypothyroidism; reduced or normal in secondary hypothyroidism.

Lipoprotein(a) [Lp(a)]

• An LDL particle bound to apolipoprotein(a).
• Levels >50 mg/dL or >125 nmol/L (above 80th percentile) are considered high.
• Associated with increased cardiovascular risk independent of LDL-C.

Confirmatory and Additional Testing

Repeat Lipid Profile

• Abnormal results should be repeated within 2 weeks to confirm persistent dyslipidaemia before initiating lifelong therapy.

Genetic Testing

• Can confirm familial hypercholesterolaemia (FH) by identifying pathogenic variants, though detection rates range between 30% and 80% in clinically diagnosed FH.
• Facilitates cascade screening of family members.
• Provides prognostic information: patients with severe hypercholesterolaemia plus a pathogenic FH mutation have a 22-fold higher risk of coronary artery disease, compared to a 6-fold higher risk in those without mutations at similar LDL-C levels.

Screening Recommendations

• Men >35 years.
• Women >45 years.
• Patients with diabetes mellitus, hypertension, obesity (BMI >30), smoking history, or family history of premature cardiovascular disease.
• Individuals with established cardiovascular or peripheral vascular disease.

Endocrine and Metabolic Causes

Hypothyroidism

• Clinical features: lethargy, cold intolerance, constipation, dry skin or hair, goitre, delayed relaxation of reflexes.
• Association: present in approximately 4% of patients evaluated for hyperlipidaemia.
• Investigations: elevated TSH confirms the diagnosis. A significant reduction in serum cholesterol is most evident when TSH >10 mU/L following thyroid hormone replacement.

Diabetes Mellitus

• Clinical features: polyuria, polydipsia, polyphagia, recurrent infections.
• Association: insulin resistance is linked with increased VLDL and apolipoprotein B particles, reduced HDL-C, and smaller LDL/HDL particle size.
• Investigations: fasting plasma glucose, HbA1c.

Chronic Renal Insufficiency / Chronic Kidney Disease

• Clinical features: may present with features of uraemia or chronic illness; patients on peritoneal dialysis often show a more atherogenic lipid profile than those on haemodialysis.
• Lipid pattern: hypertriglyceridaemia (TG >2.7 mmol/L in ~50%), reduced HDL-C, with variable total cholesterol (sometimes low due to malnutrition).
• Investigations: serum creatinine, urea, albumin, eGFR, 24-hour urinary protein.

Renal Syndromes

Nephrotic Syndrome

• Clinical features: oedema, frothy urine, ascites.
• Mechanism: reduced plasma oncotic pressure stimulates hepatic lipoprotein synthesis.
• Lipid pattern: marked cholesterol elevation, variably increased TG and lipoprotein(a), normal or reduced HDL-C.
• Investigations: serum creatinine, albumin, urea; 24-hour urinary protein markedly elevated.

Hepatic Causes

Obstructive Liver Disease

• Clinical features: jaundice, abdominal pain or tenderness, pruritus.
• Lipid pattern: raised cholesterol, with abnormal lipoprotein-X particles.
• Investigations:
  • Elevated ALP, GGT, ALT, AST, bilirubin.
  • Imaging (ultrasound, CT, MRI) often demonstrates dilated bile ducts and underlying obstruction.

Lifestyle and Substance-Related

Smoking

• Clinical features: may not be directly symptomatic but contributes to endothelial dysfunction.
• Association: reduces HDL-C; may also increase VLDL and LDL particle number and size.
• Additional impact: combined smoking and alcohol use further worsens lipid metabolism

Alcoholism

• Clinical features: history of excessive alcohol use, hepatomegaly, or symptoms of liver disease.
• Association: linked mainly to hypertriglyceridaemia, but may also contribute to elevated cholesterol depending on hepatic injury.
• Investigations: liver function tests, carbohydrate-deficient transferrin, lipid panel.

Risk Stratification

Who is “High Risk”?

• Clinical ASCVD: prior myocardial infarction, unstable angina/revascularisation, ischaemic stroke/TIA of atherosclerotic origin, symptomatic peripheral arterial disease, abdominal aortic aneurysm, or carotid stenosis.
• Very High Risk within ASCVD: recent ACS (≤12 months), recurrent major events, or one major event plus multiple high-risk conditions (e.g., age ≥65, diabetes, CKD, persistent LDL-C ≥2.6 mmol/L despite therapy).
• Severe primary hypercholesterolaemia: LDL-C ≥4.9 mmol/L (≥190 mg/dL), often indicating FH.

Risk Estimation in Primary Prevention

• Use population-appropriate tools (e.g., QRISK, SCORE2/SCORE2-OP, Framingham/PROCAM, Pooled Cohort Equations, PREVENT).
• In borderline/intermediate risk, apply risk enhancers (family history of premature ASCVD, LDL-C ≥4.1 mmol/L, CKD, metabolic syndrome, inflammatory disease, South Asian ancestry, elevated hs-CRP, Lp(a) >50 mg/dL [>125 nmol/L], apoB ≥1.3 g/L, ABI <0.9).
• Coronary artery calcium (CAC) can guide decisions when uncertainty remains (CAC 0 may defer therapy unless strong enhancers; CAC ≥100 or ≥75th percentile favours statin initiation/intensification).

Lifestyle Modification (for all patients)

Diet & Weight

• Reduce saturated and trans-fat, dietary cholesterol; emphasise Mediterranean-style or plant-forward patterns, soluble fibre, and nuts.
• Plant stanols/sterols can further lower LDL-C.
• Aim for weight loss in overweight/obese patients; even modest reductions improve lipids.

Physical Activity & Habits

• Aerobic exercise augments LDL-C reduction and raises HDL-C when combined with diet.
• Smoking cessation and moderation/avoidance of alcohol (especially if hypertriglyceridaemia).
• In lower-risk individuals, a 3–6-month intensive lifestyle trial is reasonable before pharmacotherapy; in high-risk or LDL-C ≥4.9 mmol/L, start drugs alongside lifestyle.
  
  

Pharmacotherapy: Statins (first-line)

Rationale & Expected Benefit

• Each 1.0 mmol/L (39 mg/dL) LDL-C reduction yields ~10% relative reduction in all-cause mortality and ~20–27% reductions in major vascular events.
• Moderate-intensity lowers LDL-C ~30–49%; high-intensity ≥50%.

When to Start

• ASCVD: high-intensity (or maximally tolerated) statin; consider very high-risk goals below.
• Severe primary hypercholesterolaemia (LDL-C ≥4.9 mmol/L): high-intensity statin without risk calculation.
• Diabetes (40–75 years): at least moderate-intensity; high-intensity if multiple risk factors.
• Primary prevention (no diabetes/ASCVD, LDL-C 1.8–4.9 mmol/L): use risk calculators + enhancers; escalate based on estimated 10-year risk and CAC.

Targets / Goals (illustrative from major guidelines)

• Established ASCVD: aim LDL-C <1.8 mmol/L (<70 mg/dL); some recommend <1.4 mmol/L (<55 mg/dL) with ≥50% reduction in very high risk.
• Primary prevention (high risk): ≥50% LDL-C reduction and <2.6 mmol/L (<100 mg/dL) where goals are used; non-HDL-C thresholds may complement LDL-C.
• UK practice (NICE): high-dose atorvastatin first-line; reassess lipids at ~3 months and aim for >40% non-HDL-C reduction; intensify if not achieved and safe.

Safety & Interactions

• Common: myalgia, transaminase rise; rare myopathy/rhabdomyolysis.
• Drug interactions: CYP3A4 inhibitors (macrolides, azoles, protease inhibitors, ciclosporin), gemfibrozil; review warfarin/digoxin effects with certain statins.
• Diabetes risk: small increase in new-onset diabetes, outweighed by CV benefit.
• Consider dose adjustments/agent switches in intolerance; avoid initiating high-dose simvastatin de novo.

Non-Statin Therapies (add-on or alternative)

Ezetimibe

• LDL-C reduction: ~15–20% alone; additional ~14–20% on top of statins.
• Outcomes: improved CV outcomes when added to statin in high-risk CHD; benefit tracks with LDL-C lowering.
• Role: first add-on when targets unmet or in partial statin intolerance.

PCSK9 Inhibitors (alirocumab, evolocumab)

• LDL-C reduction: ~50–60% additional lowering on background therapy.
• Outcomes: reduced major CV events in high-risk/ASCVD populations; useful in heterozygous FH or when aggressive targets are required.
• Tolerability: generally well tolerated; injection-site reactions most common.

Bile Acid Sequestrants (colestyramine, colesevelam)

• LDL-C reduction: ~10–24%; useful adjunct, including in sitosterolaemia.
• Constraints: GI side-effects, drug–drug interactions; avoid if TG >5.65 mmol/L (>500 mg/dL).

Other/Emerging Options

• Bempedoic acid, inclisiran (where available/locally approved) for patients not at goal despite statin±ezetimibe or with documented intolerance—follow local protocols.

Special Populations & Situations

Chronic Kidney Disease

• Lipid lowering (statin ± ezetimibe) reduces CV events; titrate to goals with renal-appropriate dosing.

Chronic Inflammatory Disorders / HIV

• Check fasting lipids and ASCVD risk before and 4–12 weeks after starting disease-modifying or antiretroviral therapy; initiate/intensify lipid therapy as indicated.

Older Adults (≥75 years)

• Secondary prevention: recommend statins; primary prevention: consider after shared decision-making—benefit similar per mmol/L LDL-C reduction, but monitor for polypharmacy and adverse effects.

Follow-Up, Monitoring, and Adherence

After Initiation or Change

• Re-check lipids 4–12 weeks after starting/intensifying therapy; thereafter every 3–12 months to confirm maintenance of % reduction and absolute target (where used).
• If suboptimal response: review adherence, timing (evening dosing for short-half-life statins), lifestyle, interactions, and secondary causes; then up-titrate or add ezetimibe/PCSK9 inhibitor.

Managing Statin Intolerance

• Verify symptoms and CK; switch statin, lower dose, or alternate-day dosing (especially with long half-life agents); add ezetimibe and consider PCSK9 inhibitor in complete intolerance (rare). Shared decision-making is essential.

Impact of Statin Therapy

• Statins have transformed outcomes, with large-scale randomised trials consistently demonstrating significant reductions in all-cause mortality, coronary heart disease (CHD) events, and stroke in both primary and secondary prevention settings.
• The vast majority of patients tolerate statins well, and adverse effects such as myopathy or muscle-related symptoms are uncommon and usually reversible upon discontinuation or switching therapy.
• Statin-associated risk of new-onset diabetes mellitus exists but is outweighed by cardiovascular benefits, especially in patients at moderate to high baseline risk.

Prognostic Modifiers

• Prognosis is strongly influenced by the presence and management of additional risk factors, including:
  • Hypertension
  • Type 2 diabetes mellitus
  • Cigarette smoking
  • Obesity and metabolic syndrome
• Comprehensive risk factor control significantly enhances long-term outcomes beyond lipid lowering alone.

Primary and Secondary Prevention

Primary prevention

• Cholesterol reduction reduces CHD risk in individuals without established ASCVD but with risk factors such as diabetes, elevated LDL-C, or family history of premature CHD.

Secondary prevention

•  Patients with established ASCVD derive even greater absolute benefit, with statins and other lipid-lowering therapies reducing recurrent events and mortality.

Long-Term Outlook

• With effective treatment and adherence to lifestyle modification, most patients with hypercholesterolaemia can achieve favourable long-term outcomes.
• Persistent undertreatment or untreated familial hypercholesterolaemia remains associated with substantial lifetime risk of early ASCVD, underscoring the importance of early detection, cascade screening, and intensive therapy.

Cardiovascular Complications

Chronic Coronary Disease

• Long-term exposure to elevated LDL-C fosters coronary atherosclerosis, leading to chronic coronary disease and, in some cases, progression to ischaemic cardiomyopathy.
• Prognosis is influenced by co-existing vascular risk factors (e.g., hypertension, diabetes, smoking).
• Aggressive lipid-lowering therapy, combined with control of modifiable risks, is essential to reduce progression.

Acute Coronary Syndrome (ACS)

• Plaque rupture or erosion in hypercholesterolaemic coronary arteries precipitates ACS (unstable angina, myocardial infarction).
• Statins play a critical role in plaque stabilisation, and high-intensity regimens are indicated in the acute setting.
• Guideline targets:
  • LDL-C <1.8 mmol/L (<70 mg/dL); ESC/EAS guidelines recommend <1.4 mmol/L (<55 mg/dL).
  • Non-HDL-C <2.6 mmol/L (<100 mg/dL).
• Evidence from the ODYSSEY OUTCOMES trial demonstrated that adding alirocumab to high-intensity statin therapy reduced recurrent ischaemic cardiovascular events, including all-cause mortality.

Cerebrovascular Complications

Stroke

• Hypercholesterolaemia is a major risk factor for ischaemic stroke and transient ischaemic attack (TIA).
• Secondary prevention requires intensive lipid lowering, as these patients are at very high ASCVD risk.
• NCEP goals: LDL-C <2.6 mmol/L (<100 mg/dL); non-HDL-C <3.4 mmol/L (<130 mg/dL).
• Many patients hospitalised with ischaemic stroke have LDL-C levels above recommended targets, and those at greatest risk are paradoxically least likely to meet guideline goals.
• Statins provide modest benefit in preventing stroke recurrence but significantly reduce overall cardiovascular events.

Peripheral Vascular Complications

Peripheral Arterial Disease (PAD)

• Long-term consequence of systemic atherosclerosis, manifesting as claudication or critical limb ischaemia.
• PAD reflects diffuse vascular disease and carries risks of limb loss and cardiovascular mortality.
• Management centres on lipid lowering and aggressive modification of all co-existing risk factors.

Other Complications

Erectile Dysfunction

• Endothelial dysfunction underlies erectile dysfunction and is aggravated by oxidative stress and elevated LDL-C.
• Lifestyle interventions (weight reduction, diet quality, physical activity) can improve erectile function and vascular health in affected men.

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