hyperlipidaemia

see also:

• cardiology;
• atherosclerosis - risk factors and molecular genetics
• acute severe hypertriglyceridaemia (SHTG)
• xanthelasma

• Hypercholesterolaemia is a major risk factor along with smoking, hypertension and diabetes for developing atherosclerosis and primary prevention.
• Coronary heart disease is almost entirely due to atherosclerosis in the coronary arteries.
• atherosclerosis in the carotid arteries also plays a major role in stroke (CVA).
• acute severe hypertriglyceridaemia (SHTG) may cause pancreatitis

• the serum lipids are cholesterol and triglycerides which transported in the blood as large molecules known as lipoproteins.
• There are five major classes of lipoprotein:
  • triglyceride-rich and atherogenic:
    • chylomicrons
    • very low density (VLDL)
    • intermediate density lipoprotein (IDL)
  • cholesterol-rich and atherogenic:
    • low density lipoprotein (LDL)
  • cholesterol-rich and anti-atherogenic:
    • high density lipoprotein (HDL)

• A meta-analysis of randomised trials of statins showed that for each 1 mmol/L reduction of LDL cholesterol (which generally equates to a 20% reduction of LDL cholesterol) there is a 20–30% relative risk reduction of coronary heart disease events.
• Lowering the LDL a further 30% or so, or an extra 1 mmol/L, reduces coronary heart disease events by a further 20–30%.
• Reducing LDL cholesterol to below appropriate targets is more important than the method or specific drug used to achieve the reduction.

• LDL cholesterol < 4 mM
• triglycerides < 2 mM
• HDL > 1 mM
• total cholesterol < 5.5 mM

• LDL cholesterol < 2.5 mM (< 2mM if very high risk of future cardiovascular event)
• triglycerides < 2 mM
• HDL > 1 mM
• total cholesterol < 5.5 mM

• replacing saturated fat with either carbohydrate or foods rich in mono- or polyunsaturated fats and high fibre foods is effective in lowering LDL cholesterol.
• avoid baked foods containing trans fatty acids, such as pies, pastries, cakes and biscuits.
• response to diet can vary considerably and is usually seen in 4−6 weeks
• some patients are very responsive and can have up to 30% lowering of LDL cholesterol
• diets to consider:
  • Mediterranean-type diets, as found in Greece, Italy and Spain.
    • vegetarian-like, high in nuts and olive oil, vegetables and pasta which was cooked al dente. Fruit was eaten frequently along with some cheese, wine and nuts.
    • after a myocardial infarction, a Mediterranean-type diet compared to a usual low fat diet is associated with a 50% relative reduction in mortality. This is independent of any change in serum cholesterol.
  • low in total fat such as in Japanese cuisine
  • high intake of fish, particularly fish rich in marine omega-3 fatty acids
  • 48g/d bran-enriched corn flour lowers LDL cholesterol by ~5% in adults with elevated levels ¹⁾

• For every kilogram decrease in body weight, LDL cholesterol decreases by 0.02 mmol/L, triglycerides decrease by 0.015 mmol/L and HDL cholesterol increases by 0.14 mmol/L.
• losing 5–10 kg is achievable and can make a difference to the risk profile.

• regular aerobic exercise (moderate effort of half an hour of intentional exercise most days of the week) improves the lipid profile independent of diet and drugs, and decreases LDL cholesterol by 10% and increases HDL cholesterol by 5%.

• On average plant sterols reduce LDL cholesterol by 10%, but this may vary from 0 to 30%. They have an additive effect to drug therapy.
• A dose of 2–4 g of plant sterols is needed, which equates to at least four teaspoons of plant-enriched margarine per day.

• A tablespoon or two of soluble fibre (eg. psyllium) each day, lowers LDL cholesterol by approximately 5%.

• in 2018, the Cochrane review found that there is little evidence to support these supplements as benefiting reducing cardiovascular disease

• If diet and nutraceuticals do not adequately reduce the LDL cholesterol and the patient remains at high risk of a cardiovascular event, drug therapy is indicated.

• HMGCoA reductase inhibitors, 'statins', are the first drugs to use. They are extremely efficacious and more than 90% of patients can tolerate them with negligible or no adverse effects.
• see statins
• In approximately 75% of the patients who cannot tolerate even half the usual dose of statins, ezetimibe can be effective.
  • Ezetimibe 10mg/d inhibits the absorption of dietary cholesterol.
  • in patients on maximal statins without adequate effect, adding ezetimibe can often lead to a synergistic lowering of LDL cholesterol by an extra 20–25%.

• Proprotein Convertase Subtilisin/Kexin Type 9 was discovered in 2003 when studying a cohort of French individuals with autosomal dominant hypercholesterolaemia
• these inhibits the PCSK9 enzyme, which plays a major role in the breakdown of hepatic LDL receptors and is typically upregulated in the presence of statins
• inhibition of this enzyme enables more efficient hepatic uptake of LDL, decreasing serum LDL levels by >50% in most cases
• “The majority of PCSK9 is secreted by the liver and impacts plasma LDL-C concentration by interfering with LDL receptor (LDLR) recycling
• LDL binds to its receptor through the interaction of APOB on LDL with the LDLR on the hepatocyte surface, this binding leads to internalisation of LDL particles into the cell via a process known as receptor-mediated endocytosis. Once internalised, the LDL–LDLR complex is transported to an early endosome, which becomes increasingly acidic due to proton pumping by the voltage-dependent ATPase pump on the endosomal surface. The acidification of the late endosome leads to a conformation change in the receptor, which allows for the receptor to release the LDL particle. The endosome containing the LDL particle then fuses with the lysosome for degradation and repurposing of its lipid cargo, depending on cellular needs. The LDLR is recycled back to the surface of the cell to engage in further rounds of LDL clearance. The rapid recycling of LDLR during its 20-hour lifespan allows for clearance of approximately 100–150 LDL particles.
• PCSK9 interferes with the normal LDLR recycling loop and reduces the quantity of LDLRs at the hepatocyte surface. This action ultimately decreases the capacity of the hepatocytes to clear LDL from the circulation. The strong binding of PCSK9 prevents the conformational change of LDLR, and thus, decoupling of LDL and LDLR does not occur and instead, the endosome with its ternary complex (LDL–PCSK9–LDLR) fuses with the lysosome, and the LDLR is destroyed. Gain-of-function mutations in PCSK9 reduce the density of LDLR on the cell surface and decrease the capacity to clear LDL from the plasma. Conversely, LOF mutations in PCSK9 lead to lower plasma LDL-C and profound cardiovascular protection. Those with homozygous LOF PCSK9 mutations have been shown to have lifelong severely low plasma LDL-C (<15 mg/dl), without health consequences. The absence of circulating PCSK9 does not appear to impact cognition, physical development or reproductive capacity.”²⁾

• given every 2 or 4 weeks
• examples:
  • alirocumab (FDA approval 2015)
  • evolocumab (FDA approval 2015)

• inclisiran
  • It is conjugated to GalNAc which binds to the asialoglycoprotein receptor, exclusively expressed on the sinusoidal surface of the liver and thus is only taken up by the liver reducing dosage needs and unwanted effects in other cell types.
  • Once inside the hepatic cell cytoplasm, the antisense strand of inclisiran is loaded into an RNA-induced silencing complex. The loaded RNA-induced silencing complex then binds to PCSK9 messenger RNA (mRNA), leading to its degradation and preventing protein translation. ³⁾
  • Dosing:
    • two initial doses given at days 1 and 90
  • further research on efficacy is in progress.

• currently in development eg. IV infusion of VERVE-101 - in a study of cynomolgus monkeys, a single dose of VERVE-101 was able to reduce PCSK9 levels by 90% and LDL-C by 60%, with stable values over the next 8 months. 1st human dose was given in 2022.

• currently in development
• oral PCSK9 inhibitors
• oral antisense oligonucleotide (ASO)

• diet rich in mono- and polyunsaturated fat and low glycaemic index carbohydrate food
• caloric restriction (leading to weight reduction) and exercise.
• consideration of marine omega-3 fatty acids (fish oil) and fibrates.

• Aust Prescr 2008; 31:119-22; How to treat hypercholesterolaemia; David Colquhoun
• Aust. Heart Foundation - Reducing risk in coronary heart disease
• Aust. Heart Foundation - Prevention of heart disease