Hyperlipidaemias

1. Introduction
2. Lipid Physiology Recap
   • Lipoproteins
   • Atherogenesis
3. When to Treat: NICE and QRISK
4. Statins
   • Mechanism
   • Pleiotropic Effects
   • Adverse Effects
   • Choice of Statin
5. Ezetimibe
6. PCSK9 Inhibitors
7. Fibrates
8. Bile Acid Sequestrants
9. Nicotinic Acid (Niacin)
10. Familial Hypercholesterolaemia
11. Non-Pharmacological Treatment
12. Summary
13. Drug Summary Table
14. Quiz

• Lipids are transported in blood as lipoproteins. LDL ("bad cholesterol") deposits cholesterol in arterial walls and drives atherosclerosis; HDL ("good cholesterol") returns cholesterol to the liver.
• Statins are first-line lipid-lowering drugs. They competitively inhibit HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase), the enzyme that sets the pace of cholesterol synthesis (the rate-limiting enzyme). This indirectly increases the number of LDL receptors on liver cells, so more LDL is cleared from the blood.
• Other classes are ezetimibe (blocks NPC1L1, a cholesterol transporter in the gut wall, so less cholesterol is absorbed), bempedoic acid (blocks ATP-citrate lyase, an enzyme that works earlier in the cholesterol-making pathway than HMG-CoA reductase), PCSK9 inhibitors (monoclonal antibodies, which are lab-made antibodies; very expensive), fibrates (PPAR-α agonists, mainly for hypertriglyceridaemia, meaning high triglycerides), bile acid sequestrants and niacin (rarely used).
• UK practice: NICE recommends atorvastatin 20 mg for primary prevention (preventing a first event) if the 10-year cardiovascular risk on QRISK (a calculator that estimates the chance of a heart attack or stroke over the next 10 years) is ≥ 10%. For secondary prevention (people who already have cardiovascular disease), NICE recommends atorvastatin 80 mg, with a lower dose for some people (for example, those with chronic kidney disease).

Introduction

Cardiovascular disease is one of the main causes of death in the UK, and a high blood cholesterol concentration is one of its strongest modifiable risk factors. Large trials show that each 1 mmol/L fall in LDL cholesterol reduces the yearly rate of major vascular events by just over a fifth. Major vascular events are heart attack, ischaemic stroke (stroke caused by a blocked artery) and the need for revascularisation (a procedure to restore blood flow).

This article covers the principal classes of lipid-lowering drug. The underlying biochemistry is covered in Lipid Metabolism and Transport and the disease processes in Artery and Vein Disease.

Lipid Physiology Recap

Lipoproteins

Cholesterol and triglycerides are insoluble in plasma and are carried by lipoprotein particles, named by their density:

• Chylomicrons: carry dietary lipid from gut to peripheral tissues.
• Very low density lipoprotein (VLDL): secreted by the liver, carries endogenous triglyceride (triglyceride made in the body, not taken in from the diet) to the peripheral tissues.
• Low density lipoprotein (LDL): the principal carrier of cholesterol from liver to peripheral tissues. The "bad cholesterol". Oxidised LDL is taken up by macrophages in the arterial intima (the inner layer of the artery wall). These then become foam cells, the seed of atheroma (the fatty plaque in an artery wall).
• High density lipoprotein (HDL): carries cholesterol from peripheral tissues back to the liver for excretion. The "good cholesterol".

Atherogenesis

The simplified pre-clinical sequence:

1. LDL accumulates in the arterial intima, the layer under the endothelium (the cell lining of the artery).
2. LDL is oxidised by reactive oxygen species (unstable, highly reactive oxygen-containing molecules) generated by the endothelium.
3. Monocytes are recruited and migrate into the intima, where they take up oxidised LDL via scavenger receptors (cell-surface receptors that bind damaged lipoproteins) and become foam cells.
4. Foam cells form fatty streaks, the earliest visible lesion.
5. Smooth muscle cells migrate from the media (the muscular middle layer of the artery wall) and proliferate (multiply), producing collagen and forming a fibrous cap.
6. The mature plaque has a lipid-rich core and a fibrous cap. If the cap ruptures, the lipid core is exposed to circulating platelets. This produces the white arterial thrombus (a platelet-rich clot) that causes acute coronary syndromes (heart attack and unstable angina, which is chest pain that comes on at rest or is getting worse) and ischaemic stroke.

Lowering LDL slows every step of this sequence. The clinical consequence is fewer first events (primary prevention) and fewer recurrent events (secondary prevention).

When to Treat: NICE and QRISK

UK practice is based on cardiovascular risk, not on cholesterol level alone. The QRISK calculator (now QRISK3) estimates the 10-year risk of a cardiovascular event. It uses age, sex, ethnicity, smoking status, blood pressure, total/HDL cholesterol ratio, comorbidities (other medical conditions) and family history.

NICE thresholds for prescribing a statin in adults without established cardiovascular disease (primary prevention):

• 10-year QRISK ≥ 10%: offer atorvastatin 20 mg once daily (after lifestyle advice and shared decision-making).
• Type 1 diabetes: offer a statin, starting with atorvastatin 20 mg, to adults who are older than 40, or who have had diabetes for more than 10 years, or who have established nephropathy (kidney damage caused by diabetes), or who have other cardiovascular risk factors. Consider a statin for people aged 18 to 40.
• Type 2 diabetes: offer if QRISK ≥ 10%.
• Chronic kidney disease (CKD: eGFR, the estimated glomerular filtration rate, below 60, or albuminuria, meaning albumin protein in the urine): offer atorvastatin 20 mg for both primary and secondary prevention (this is the exception to atorvastatin 80 mg for secondary prevention, below).

For secondary prevention (people who already have cardiovascular disease): offer atorvastatin 80 mg, regardless of the baseline cholesterol level. Secondary prevention applies to anyone with a previous heart attack (myocardial infarction, MI), stroke, TIA (transient ischaemic attack, a brief episode of stroke symptoms), peripheral arterial disease, stable angina (chest pain on exertion), or a previous coronary stent (percutaneous coronary intervention, PCI) or bypass operation (coronary artery bypass graft, CABG). Two exceptions apply. People with chronic kidney disease are offered atorvastatin 20 mg (see above). For anyone else, a lower dose of atorvastatin is offered if the person takes a drug that interacts with it, has a high risk of adverse effects, or would prefer a lower dose.

NICE sets lipid targets, checked 2 to 3 months after starting or changing treatment. For primary prevention, aim for a reduction of more than 40% in non-HDL cholesterol (total cholesterol minus HDL cholesterol). For secondary prevention, aim for LDL cholesterol of 2.0 mmol/L or less, or non-HDL cholesterol of 2.6 mmol/L or less. If the target is not met, first discuss adherence (whether the person is taking the tablets as prescribed) and the timing of the dose, and encourage further lifestyle changes. Then consider a higher dose if the person is not already taking the maximum tolerated dose of a high-intensity statin. High intensity means a dose that lowers LDL cholesterol by a large amount: NICE counts atorvastatin 20 to 80 mg and rosuvastatin 10 to 40 mg as high intensity. After that, consider adding other lipid-lowering drugs, such as ezetimibe (see below).

Statins

Mechanism

Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway (the chain of reactions that makes cholesterol) and therefore of cholesterol synthesis. Reduced intracellular cholesterol triggers two compensatory responses in hepatocytes (liver cells):

• Upregulation of LDL receptors (more receptors are made) on the hepatocyte surface, accelerating clearance of circulating LDL.
• Reduced VLDL secretion.

The net effect is reduced LDL (typically 30-55% depending on dose and statin), modestly reduced triglycerides (~15%), and a small increase in HDL.

Pleiotropic Effects

Statins have a number of beneficial effects beyond LDL reduction, collectively called pleiotropic effects, but their clinical importance is uncertain. In a large meta-analysis (a study that pools the results of many trials), each 1 mmol/L fall in LDL cholesterol lowered the risk of major vascular events by a similar amount with statins and with non-statin treatments that also work by increasing LDL receptors (diet, bile acid sequestrants, ileal bypass surgery and ezetimibe). So there is no clear evidence that statins give extra benefit beyond their LDL lowering. The proposed effects are:

• Improved vascular endothelial function (more nitric oxide, a vasodilator; less endothelin-1, a vasoconstrictor).
• Stabilisation of atherosclerotic plaque.
• Anti-inflammatory effects (reduced C-reactive protein, a blood marker of inflammation; fewer adhesion molecules, which help white cells stick to the vessel wall).
• Antithrombotic effects (reduced platelet aggregation, meaning less clumping of platelets; increased fibrinolysis, meaning faster breakdown of clots).
• Antioxidant effects.

Adverse Effects

Statins are remarkably well tolerated by most patients. The principal adverse effects are:

• Myalgia (muscle pain): commonly reported by people taking statins. In large double-blind trials (in which neither the participants nor the researchers knew who had the statin), about 27% of people given a statin and about 27% of those given a placebo reported muscle pain or weakness. In the first year, only about one in 15 of the reports in the statin group was actually due to the statin.
• Rhabdomyolysis (breakdown of muscle that can damage the kidneys): rare but serious. Risk increased by combination with fibrates (especially gemfibrozil), ciclosporin, or by drugs that inhibit CYP3A4 (cytochrome P450 3A4, an enzyme in the liver and gut wall that breaks down some statins). Measure creatine kinase (CK, a muscle enzyme that rises when muscle is damaged) if the person develops unexplained muscle pain, tenderness or weakness. Do not measure it in people without symptoms.
• Transient transaminase elevation (a temporary rise in liver enzymes): liver function tests (LFTs) are often mildly raised; this usually resolves and rarely requires stopping. NICE advises measuring liver transaminase 2 to 3 months after starting treatment and again at 12 months, but not again unless clinically indicated.
• New-onset diabetes: small absolute increase, more common with higher-potency statins. The cardiovascular benefit outweighs this.
• Gastrointestinal (GI) disturbance, headache, sleep disturbance: minor.

Drug interactions: simvastatin and atorvastatin are CYP3A4 substrates. CYP3A4 inhibitors, such as the macrolide antibiotic clarithromycin, azole antifungals such as itraconazole, and ritonavir, increase plasma levels and the risk of rhabdomyolysis. Ciclosporin also markedly increases exposure to both statins. For simvastatin, the BNF (British National Formulary, the UK drug reference book) advises avoiding clarithromycin, itraconazole, ritonavir and ciclosporin. For atorvastatin, the BNF advises avoiding those drugs or adjusting the dose. Grapefruit juice also raises statin levels. The interaction matters most for simvastatin, where the BNF advises avoiding grapefruit juice. For atorvastatin, it advises caution.

Choice of Statin

The five statins available in the UK differ in potency, half-life (the time taken for the blood level to fall by half) and metabolism:

• Atorvastatin: high-intensity, long half-life (~14 hours), once daily at any time of day. UK first-line in NICE guidance.
• Rosuvastatin: high-intensity, longest half-life (~19 hours), not metabolised by CYP3A4 (fewer interactions).
• Simvastatin: medium-intensity at the usual doses of 20 to 40 mg (10 mg is low intensity), short half-life (~2 hours); given at night because cholesterol synthesis peaks overnight. CYP3A4 substrate: substantial grapefruit interaction.
• Pravastatin: low-intensity at its usual doses (5 to 40 mg), hydrophilic (water-soluble), fewer drug interactions.
• Fluvastatin: lower-intensity, occasionally used in patients with statin intolerance.

Ezetimibe

Ezetimibe blocks the NPC1L1 transporter on the brush border (the fringe of tiny projections on the cell surface) of small intestinal enterocytes (gut-lining cells). This reduces dietary and biliary (from the bile) cholesterol absorption by around 50%. Used alone, it produces a modest LDL reduction (~15-20%). It is most useful added to a statin in patients who do not reach their lipid target on a statin alone.

Indications:

• Add-on to the maximum tolerated statin if the lipid target (LDL or non-HDL cholesterol) is not achieved. NICE also says to consider it in people with cardiovascular disease even when the target is met.
• Statin intolerance, no dose tolerated: ezetimibe alone, if statins are contraindicated or cannot be tolerated at any dose.
• Statin intolerance, only a low dose tolerated: ezetimibe with the maximum tolerated statin dose.
• Familial hypercholesterolaemia (an inherited condition that causes very high LDL cholesterol, described below).

Pharmacokinetics (what the body does to the drug): ezetimibe itself is active. It is glucuronidated (joined to glucuronic acid) in the liver to a still-active metabolite. This metabolite undergoes enterohepatic circulation (it is secreted in bile, reabsorbed from the gut and returned to the liver). The half-life is long (~22 hours).

Side effects are common. The BNF lists asthenia (weakness or tiredness), diarrhoea, abdominal (gastrointestinal) discomfort, headache and muscle complaints as common or very common.

PCSK9 Inhibitors

Alirocumab and evolocumab are monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 normally targets the LDL receptor for degradation after the receptor has taken up (internalised) LDL; blocking PCSK9 allows the receptor to be recycled, increasing LDL clearance.

The effect on LDL is large: reductions of 50-60% on top of a statin (59% with evolocumab in the FOURIER trial). Cardiovascular events fall too, but by less. In FOURIER, evolocumab reduced the combined outcome of cardiovascular death, heart attack, stroke, hospital admission for unstable angina or coronary revascularisation by 15% (hazard ratio 0.85: the rate of events on treatment divided by the rate on placebo, so a value below 1 means fewer events) over a median follow-up of 2.2 years.

The story behind these drugs is one of the best examples of human-genetics-driven drug development. PCSK9 was first linked to disease in 2003, when mutations in the gene were found to cause a dominantly inherited form of high LDL cholesterol. These are thought to be gain-of-function mutations, meaning the gene is overactive. In 2005, sequencing PCSK9 in 128 people with low LDL found two nonsense mutations, which switch the gene off so that it makes no working protein (loss-of-function mutations). A later large study found that people carrying such mutations had lower LDL and a much lower risk of coronary heart disease. The monoclonal antibodies (lab-made antibodies) copy the effect of those loss-of-function mutations.

The drawback is cost. At NHS indicative prices, four weeks of alirocumab 75 mg every 2 weeks costs £336 (two pens at £168 each), whereas 28 tablets of generic atorvastatin 20 mg cost £0.72. PCSK9 inhibitors are therefore hundreds of times more expensive than generic atorvastatin. NICE restricts alirocumab and evolocumab to people whose LDL cholesterol stays persistently above set thresholds despite the maximum tolerated lipid-lowering treatment. The thresholds are between 3.5 and 5.0 mmol/L, depending on the person's cardiovascular risk and whether they have familial hypercholesterolaemia. People without cardiovascular disease qualify only if they have familial hypercholesterolaemia.

Inclisiran is a more recent agent, a small interfering RNA (siRNA) that silences the PCSK9 gene in the liver, so less PCSK9 protein is made. It is given by subcutaneous injection: a first dose, a second dose after 3 months, then one dose every 6 months. NICE recommends it only for people with a history of cardiovascular events whose LDL cholesterol stays at 2.6 mmol/L or more despite maximum tolerated lipid-lowering treatment.

Fibrates

Fenofibrate, bezafibrate, ciprofibrate and gemfibrozil activate the nuclear transcription factor (a protein in the cell nucleus that switches genes on) peroxisome proliferator-activated receptor α (PPARα). PPARα upregulates (increases) lipoprotein lipase, the enzyme that breaks down triglycerides in the blood, and increases hepatic fatty acid uptake. The major effect is a reduction in triglycerides (~30-50%). HDL often rises, but the LDL response depends on the lipid phenotype: LDL may rise in type IV hypertriglyceridaemia (raised VLDL, a pattern from an older classification of lipid disorders).

Indications:

• Severe hypertriglyceridaemia (especially > 10 mmol/L, where there is a risk of acute pancreatitis, which is inflammation of the pancreas).
• Mixed dyslipidaemia (raised LDL and triglycerides together) when a statin is contraindicated or not tolerated. Fenofibrate can also be added to a statin in people at high cardiovascular risk whose triglycerides and HDL are inadequately controlled.
• Generally specialist initiation. NICE advises against routinely offering fibrates to prevent cardiovascular disease.

Side effects: GI upset, gallstones (cholelithiasis: fibrates increase biliary cholesterol), myositis (inflammation of muscle), abnormal LFTs, and an increased effect of warfarin. Combination with a statin increases the risk of rhabdomyolysis. The BNF advises avoiding gemfibrozil with simvastatin or atorvastatin, avoiding it or adjusting the dose with rosuvastatin, avoiding it or monitoring closely with pravastatin, and taking caution with fluvastatin.

Contraindications: gallbladder disease. The BNF also advises avoiding fibrates in significant hepatic impairment and in severe renal impairment (for fenofibrate and gemfibrozil, eGFR below 30). In milder renal impairment, use with caution because of the risk of muscle toxicity.

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