Hyperlipidaemia
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"hyperlipidemia"[MeSH Terms] AND "treatment"[MeSH Terms]
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"dyslipidem*" AND "cardiovascular risk"
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Hyperlipidaemia
Definition
Hyperlipidaemia (dyslipidaemia) refers to elevated levels of lipids - cholesterol, triglycerides, or both - in the blood, or low levels of HDL cholesterol. It is one of the most important modifiable risk factors for atherosclerotic cardiovascular disease (ASCVD), which includes coronary heart disease (CHD), ischaemic stroke, and peripheral artery disease.
Lipoprotein Physiology
Lipids are transported in plasma as lipoprotein particles. The major classes are:
| Lipoprotein | Primary Lipid | Function |
|---|---|---|
| Chylomicrons | Triglycerides (dietary) | Exogenous fat transport |
| VLDL | Triglycerides (endogenous) | Hepatic TG export |
| IDL | Mixed | VLDL remnant |
| LDL | Cholesterol | Deliver cholesterol to tissues |
| HDL | Cholesterol (reverse) | Reverse cholesterol transport |
LDL is atherogenic - it accumulates in arterial walls and drives plaque formation. HDL is cardioprotective. Elevated triglycerides (especially >500 mg/dL) carry risk of acute pancreatitis.
Classification: Fredrickson/WHO System
| Phenotype | Diagnosis | Elevated Lipid | Elevated Lipoprotein | Genetics |
|---|---|---|---|---|
| Type I | Familial hyperchylomicronaemia | ↑ TG | Chylomicrons | Autosomal recessive (LPL deficiency) |
| Type IIA | Familial hypercholesterolaemia | ↑ TC | ↑ LDL | Autosomal codominant / polygenic |
| Type IIB | Familial combined hyperlipidaemia | ↑ TC, ↑ TG | ↑ LDL, ↑ VLDL | Polygenic |
| Type III | Dysbetalipoproteinaemia | ↑ TC, ↑ TG | ↑ IDL | ApoE2/E2 homozygosity |
| Type IV | Primary hypertriglyceridaemia | ↑ TG | ↑ VLDL | Polygenic |
| Type V | Mixed hypertriglyceridaemia | ↑ TC, ↑ TG | ↑ VLDL + chylomicrons | Polygenic |
- Firestein & Kelley's Textbook of Rheumatology
Causes
Primary (genetic):
- Familial hypercholesterolaemia (FH) - LDL receptor mutations (heterozygous: LDL 190-400 mg/dL; homozygous: >400 mg/dL)
- Familial combined hyperlipidaemia
- Familial hypertriglyceridaemia
- Polygenic hypercholesterolaemia (commonest)
Secondary:
- Hypothyroidism, diabetes mellitus, nephrotic syndrome, chronic kidney disease
- Obesity, sedentary lifestyle, high saturated-fat diet
- Drugs: corticosteroids (↑ VLDL, ↑ LDL), cyclosporine (↑ LDL), sirolimus (↑ TG), thiazides, beta-blockers, retinoids, antiretrovirals
- Alcohol excess (↑ TG), liver disease, pregnancy
Clinical Features
Most patients are asymptomatic - hyperlipidaemia is detected on routine screening.
Physical signs (when present):
- Xanthelasma - yellowish plaques on eyelids (type II)
- Corneal arcus - grey-white ring around cornea (significant <45 years)
- Tendon xanthomata - Achilles tendon and extensor tendons of hands (type II); associated with 3.2x higher cardiovascular risk
- Eruptive xanthomata - small papules on buttocks/elbows (type IV, V - severe hypertriglyceridaemia)
- Tubero-eruptive and palmar crease xanthomata - type III (dysbetalipoproteinaemia)
- Lipaemia retinalis - type I and V (TG >2000 mg/dL)
- Acute pancreatitis - type I, IV, V (severe hypertriglyceridaemia)
- Transient migratory polyarthritis has been reported in type II
Diagnosis & Targets
A fasting lipid panel measures:
- Total cholesterol (TC)
- LDL cholesterol (LDL-C) - calculated via Friedewald equation or measured directly
- HDL cholesterol (HDL-C)
- Triglycerides (TG)
- Non-HDL cholesterol = TC minus HDL (includes all atherogenic particles)
LDL-C targets (ESC/ACC/AHA guidelines):
| Risk Category | LDL-C Target |
|---|---|
| Very high (prior ASCVD) | <55 mg/dL (<1.4 mmol/L) |
| High (10-year CVD risk ≥10%) | <70 mg/dL (<1.8 mmol/L) |
| Moderate | <100 mg/dL (<2.6 mmol/L) |
| Low | <116 mg/dL (<3.0 mmol/L) |
Management
1. Lifestyle Modification (First-line for all)
- Reduce saturated fats (<7% of total calories) and trans fats
- Increase soluble fibre, plant sterols, omega-3 fatty acids
- Regular aerobic exercise (30+ min, 5 days/week)
- Weight loss, smoking cessation, reduce alcohol
- Dietary changes can lower LDL by 10-15%
2. Drug Therapy
A. Statins (HMG-CoA Reductase Inhibitors) - First-line
Drugs: Atorvastatin, rosuvastatin (high-intensity), simvastatin, pravastatin, lovastatin, pitavastatin, fluvastatin
Mechanism: Block HMG-CoA reductase (rate-limiting step of cholesterol synthesis in liver) → ↓ intracellular cholesterol → upregulate LDL receptors → ↑ LDL clearance from plasma
Effect: Lower LDL-C 30-60% depending on agent and dose; modest ↑ HDL; modest ↓ TG
Adverse effects:
- Myopathy/myalgia (dose-dependent; most important - risk ↑ with CYP3A4 inhibitors, fibrates, cyclosporine)
- Rhabdomyolysis (rare but serious)
- Hepatotoxicity (transaminase elevation; routine monitoring not required)
- New-onset diabetes (small but real risk)
Contraindications: Pregnancy, active liver disease
B. Ezetimibe - Second-line add-on
Mechanism: Inhibits NPC1L1 (Niemann-Pick C1-like 1) transporter in intestinal brush border → blocks dietary and biliary cholesterol absorption
Effect: ↓ LDL-C ~15-20%; well tolerated
Use: Add to maximally tolerated statin when LDL target not achieved; shown to further reduce ASCVD events (IMPROVE-IT trial)
C. PCSK9 Inhibitors - Powerful add-on / FH
Drugs: Alirocumab (Praluent), evolocumab (Repatha) - subcutaneous injection every 2-4 weeks; inclisiran (small interfering RNA, twice yearly)
Mechanism: PCSK9 normally degrades LDL receptors after internalisation. Inhibiting PCSK9 → LDL receptors recycled back to hepatocyte surface → markedly ↑ LDL clearance
Effect: ↓ LDL-C by 50-60% on top of statins
Use: Very high-risk ASCVD patients, heterozygous/homozygous FH, statin intolerance
D. Bile Acid Sequestrants (Resins)
Drugs: Cholestyramine, colestipol, colesevelam
Mechanism: Anion-exchange resins bind bile acids in small intestine → excreted in faeces → liver upregulates bile acid synthesis from cholesterol → ↓ intracellular cholesterol → upregulate LDL receptors
Effect: ↓ LDL-C 15-30%
Adverse effects: GI disturbance (constipation, flatulence), impair absorption of fat-soluble vitamins (A, D, E, K) and drugs (warfarin, digoxin, thyroid hormone - give 1-2 hours before or 4-6 hours after resin). May raise TG - contraindicated if TG >400 mg/dL
Special: Colesevelam also lowers blood glucose (useful in type 2 diabetes); in homozygous FH with absent LDL receptors, these drugs have minimal effect
E. Bempedoic Acid (ACL Inhibitor)
Mechanism: Inhibits ATP-citrate lyase (ACL), upstream of HMG-CoA reductase → ↓ hepatic cholesterol synthesis; pro-drug activated only in liver (not muscle) → less myopathy risk
Effect: ↓ LDL-C ~18%; useful in statin-intolerant patients
F. Fibrates
Drugs: Gemfibrozil, fenofibrate
Mechanism: PPAR-alpha agonists → ↑ lipoprotein lipase activity → ↑ TG catabolism; ↑ HDL synthesis
Effect: ↓ TG 40-60%; modest ↑ HDL; minimal LDL effect
Use: Primary indication = severe hypertriglyceridaemia (especially to prevent pancreatitis); fenofibrate preferred if combining with a statin (gemfibrozil significantly ↑ risk of statin myopathy via CYP2C8/glucuronidation interaction)
Adverse effects: Myopathy (especially with statins + gemfibrozil), cholelithiasis (↑ biliary cholesterol secretion), elevated creatinine
G. Niacin (Nicotinic Acid)
Mechanism: Inhibits lipolysis in adipose tissue → ↓ free fatty acid delivery to liver → ↓ VLDL synthesis → ↓ TG and LDL; most potent agent for raising HDL
Effect: ↓ TG 30-50%, ↓ LDL 15-30%, ↑ HDL 15-35%
Adverse effects: Flushing (prostaglandin-mediated; reduced by aspirin pretreatment), hyperglycaemia, hyperuricaemia, hepatotoxicity at high doses
Current status: Clinical use has declined significantly - trials (AIM-HIGH, HPS2-THRIVE) showed no additional CV benefit when added to statin therapy despite improving lipids
H. Omega-3 Fatty Acids
Drugs: EPA + DHA (Lovaza), icosapent ethyl/EPA only (Vascepa/Omacor)
Mechanism: ↓ hepatic TG synthesis and ↑ clearance
Effect: ↓ TG 30-50% at high doses (4 g/day)
Special: Icosapent ethyl (pure EPA) showed significant reduction in ASCVD events in the REDUCE-IT trial (PMID 30145934) at 4 g/day, beyond TG lowering
I. Lomitapide (MTP Inhibitor)
Mechanism: Inhibits microsomal triglyceride transfer protein (MTP) → blocks assembly of VLDL and chylomicrons in liver and intestine
Use: Homozygous FH only (orphan drug)
Adverse effects: Severe hepatic steatosis, GI effects; teratogenic
Combination Drug Therapy
Combination therapy to achieve LDL targets:
-
Statin + ezetimibe - first-line combination; additive LDL lowering
-
Statin + PCSK9 inhibitor - for very high-risk patients or FH
-
Statin + bempedoic acid - statin-intolerant patients
-
For hypertriglyceridaemia: add fibrate, omega-3 fatty acids, or niacin
-
Icosapent ethyl, PCSK9 inhibitors, and ezetimibe can all be considered as add-on therapy for patients already on maximally tolerated statin with evidence of further ASCVD event reduction
-
Lippincott Illustrated Reviews: Pharmacology
Special Populations
Post-renal transplant: Corticosteroids, cyclosporine, sirolimus all worsen lipids. Statin use is advised in all transplant recipients regardless of lipid level (associated with improved survival and reduced coronary allograft vasculopathy). - Braunwald's Heart Disease
Familial Hypercholesterolaemia (FH): High-intensity statin + ezetimibe is standard; PCSK9 inhibitors often required. Treatment should start early in life. Homozygous FH may need lomitapide or LDL apheresis.
Chronic Kidney Disease: Statin ± ezetimibe recommended; fibrates with caution (↑ creatinine).
Pregnancy: All statins are contraindicated (teratogenic). Bile acid sequestrants and omega-3 may be used.
Key Points Summary
- CHD is the leading cause of death worldwide; hyperlipidaemia is its major modifiable risk factor
- Elevated LDL-C and TG, and low HDL-C all contribute to ASCVD risk
- Treatment begins with lifestyle changes for all patients
- Statins are the cornerstone of pharmacotherapy, reducing LDL-C 30-60%
- Ezetimibe and PCSK9 inhibitors provide additional LDL lowering and proven cardiovascular outcome benefits
- Fibrates and omega-3 fatty acids are first-line for severe hypertriglyceridaemia
- Niacin is no longer routinely recommended due to lack of incremental CV benefit on statin therapy
- Combination therapy is the norm for high-risk patients and FH
Sources: Lippincott Illustrated Reviews: Pharmacology; Firestein & Kelley's Textbook of Rheumatology; Braunwald's Heart Disease; Comprehensive Clinical Nephrology
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