Contents

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

Abstract

• 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, the rate-limiting enzyme of cholesterol synthesis, and indirectly upregulate hepatic LDL receptors.
• Other classes are ezetimibe (NPC1L1 inhibitor, blocks gut absorption), bempedoic acid (ATP-citrate lyase inhibitor), PCSK9 inhibitors (monoclonal antibodies, very expensive), fibrates (PPAR-α agonists, mainly for hypertriglyceridaemia), bile acid sequestrants and niacin (rarely used).
• UK practice: NICE recommends atorvastatin 20 mg for primary prevention if 10-year cardiovascular risk on QRISK is ≥ 10%, and atorvastatin 80 mg for secondary prevention after any atherosclerotic event.

Core

Introduction

Cardiovascular disease is the largest single cause of death in the UK, and a high blood cholesterol concentration is one of its strongest modifiable risk factors. Even a 10% reduction in total cholesterol produces a roughly 15% reduction in coronary heart disease mortality; a benefit no other cardiovascular drug class quite matches.

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 liver, carries endogenous triglyceride to the periphery.
• Low density lipoprotein (LDL): the principal carrier of cholesterol from liver to peripheral tissues. The "bad cholesterol": oxidised LDL is the substance taken up by macrophages in the arterial intima to form foam cells, the seed of atheroma.
• 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 (sub-endothelial space).
2. LDL is oxidised by reactive oxygen species generated by the endothelium.
3. Monocytes are recruited and migrate into the intima, where they take up oxidised LDL via scavenger receptors and become foam cells.
4. Foam cells form fatty streaks, the earliest visible lesion.
5. Smooth muscle cells migrate from the media and proliferate, 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; producing the white arterial thrombus that causes acute coronary syndromes 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) uses age, sex, ethnicity, smoking status, blood pressure, total/HDL cholesterol ratio, comorbidities and family history to estimate the 10-year risk of a cardiovascular event.

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 to most adults aged 40 or over, or with longer disease duration or established nephropathy.
• Type 2 diabetes: offer if QRISK ≥ 10%.
• CKD (eGFR < 60 or albuminuria): offer atorvastatin 20 mg.

For secondary prevention (any patient with established atherosclerotic vascular disease: previous MI, stroke, TIA, peripheral arterial disease, stable angina, prior PCI or CABG): offer atorvastatin 80 mg, regardless of baseline cholesterol level.

The therapeutic target is a ≥ 40% reduction in non-HDL cholesterol at three months. If this is not achieved, options are increasing the dose, switching statin, or adding ezetimibe.

Statins

Mechanism

Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway and therefore of cholesterol synthesis. Reduced intracellular cholesterol triggers two compensatory responses in hepatocytes:

• Upregulation of LDL receptors 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, which may explain why their cardiovascular benefit is greater than LDL reduction alone would predict:

• Improved vascular endothelial function (more nitric oxide, less endothelin-1).
• Stabilisation of atherosclerotic plaque.
• Anti-inflammatory effects (reduced CRP, fewer adhesion molecules).
• Antithrombotic effects (reduced platelet aggregation, increased fibrinolysis).
• Antioxidant effects.

Adverse Effects

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

• Myalgia: muscle aches, present in around 5-10% of patients in real-world studies, although the placebo-controlled rate is much lower (most "statin myalgia" is not actually drug-related).
• Rhabdomyolysis: rare but serious. Risk increased by combination with fibrates (especially gemfibrozil), ciclosporin, or by drugs that inhibit CYP3A4. Check creatine kinase if muscle symptoms are suggestive.
• Transient transaminase elevation: LFTs are often mildly raised; usually resolves and rarely requires stopping. Routine LFT monitoring at 3 and 12 months.
• New-onset diabetes: small absolute increase, more common with higher-potency statins. The cardiovascular benefit outweighs this.
• GI disturbance, headache, sleep disturbance: minor.

Drug interactions: simvastatin and atorvastatin are CYP3A4 substrates. Strong CYP3A4 inhibitors (macrolides, azole antifungals, ciclosporin, ritonavir, grapefruit juice) increase plasma levels and the risk of rhabdomyolysis. The grapefruit interaction is most important with simvastatin and is the reason the BNF advises avoiding it.

Choice of Statin

The five statins available in the UK differ in potency, half-life 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: moderate-intensity, short half-life (~2 hours); given at night because cholesterol synthesis peaks overnight. CYP3A4 substrate: substantial grapefruit interaction.
• Pravastatin: moderate-intensity, hydrophilic, fewer drug interactions.
• Fluvastatin: lower-intensity, occasionally used in patients with statin intolerance.

Ezetimibe

Ezetimibe blocks the NPC1L1 transporter on the brush border of small intestinal enterocytes, reducing dietary and biliary cholesterol absorption by around 50%. It produces a modest LDL reduction (~15-20%) when used alone, and is most useful added to a statin in patients who fail to reach target on statin alone.

Indications:

• Add-on to maximum tolerated statin if LDL target not achieved.
• Statin intolerance (combination with low-dose statin).
• Familial hypercholesterolaemia.

Pharmacokinetics: ezetimibe itself is active and is glucuronidated in the liver to a still-active metabolite that undergoes enterohepatic circulation; long half-life (~22 hours).

Side effects are rare: occasional GI upset, headache. One of the best-tolerated lipid-lowering drugs.

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 it has internalised LDL; blocking PCSK9 allows the receptor to be recycled, increasing LDL clearance.

The clinical effect is dramatic: LDL reductions of 50-60% on top of a statin, with a corresponding fall in cardiovascular events.

The story behind these drugs is one of the best examples of human-genetics-driven drug development. PCSK9 was identified by sequencing 128 individuals with unusually low LDL; many were found to have loss-of-function PCSK9 mutations and a reduced lifetime risk of coronary disease. The monoclonal antibodies copy the effect of those mutations.

The drawback is cost: PCSK9 inhibitors are around 100 times more expensive than generic atorvastatin, so NICE restricts them to patients with familial hypercholesterolaemia or established cardiovascular disease who fail to reach target on standard therapy.

Inclisiran is a more recent agent, a small interfering RNA (siRNA) that silences PCSK9 expression in the liver. It is given by subcutaneous injection twice yearly.

Fibrates

Fenofibrate, bezafibrate and ciprofibrate activate the nuclear transcription factor peroxisome proliferator-activated receptor α (PPARα), which upregulates lipoprotein lipase and increases hepatic fatty acid uptake. The major effect is a reduction in triglycerides (~30-50%); LDL falls modestly and HDL rises modestly.

Indications:

• Severe hypertriglyceridaemia (especially > 10 mmol/L, where there is a risk of acute pancreatitis).
• Mixed dyslipidaemia with low HDL and raised triglycerides.
• Generally specialist initiation.

Side effects: GI upset, gallstones (cholelithiasis: fibrates increase biliary cholesterol), myositis, abnormal LFTs, and potentiation of warfarin. Combination with a statin substantially increases the risk of rhabdomyolysis; gemfibrozil with statins is contraindicated because of fatal cases.

Contraindications: hepatic or renal impairment, gallbladder disease.

Bile Acid Sequestrants

Cholestyramine and colestipol are non-absorbed resins that bind bile acids in the gut, preventing their reabsorption. The liver then synthesises new bile acids from cholesterol, lowering hepatic cholesterol and upregulating LDL receptors. LDL falls modestly (~15-25%).

They are now rarely used because of:

• Poor palatability (gritty powder).
• GI side effects (constipation, bloating).
• Reduced absorption of fat-soluble vitamins (A, D, E, K) and other drugs (warfarin, digoxin, thyroxine, statins); other medicines should be taken at least 1 hour before, or 4-6 hours after, the bile acid sequestrant.
• Mild rise in triglycerides.

Their main remaining use is in cholestatic itch (e.g. primary biliary cholangitis), where they bind bile acids in the gut and relieve pruritus.

Nicotinic Acid (Niacin)

Nicotinic acid is vitamin B₃ at pharmacological doses. It is the most effective drug for raising HDL (around 25%), with smaller reductions in LDL and triglycerides. It has been largely abandoned in UK practice because:

• Flushing and itching are very common, mediated by prostaglandin release; can be reduced by aspirin 30 minutes before.
• Hepatotoxicity, hyperglycaemia and hyperuricaemia.
• Two large outcome trials (AIM-HIGH, HPS2-THRIVE) failed to show cardiovascular benefit when added to statins.

Familial Hypercholesterolaemia

Familial hypercholesterolaemia (FH) is an autosomal dominant condition caused by mutations in the LDL receptor (most cases), apolipoprotein B, or PCSK9 (gain of function). Heterozygotes have LDL approximately twice normal from birth and develop premature coronary disease. Homozygotes have LDL four times normal and develop coronary disease in childhood.

Recognition matters because lifelong, aggressive lipid-lowering can prevent premature death:

• Total cholesterol typically > 7.5 mmol/L from young adulthood.
• Tendon xanthomata: firm cholesterol deposits within tendons (Achilles, extensor tendons of the hands).
• Corneal arcus: a pale ring at the corneal margin from cholesterol deposition; common in older adults, but suspicious for FH if seen in patients under 45.
• Xanthelasmata: soft yellow cholesterol plaques on the eyelids.
• Family history of premature MI (under 60).
• Cascade screening of first-degree relatives is the standard NICE recommendation.

Management: high-intensity statin from diagnosis, often with ezetimibe and (in many cases) a PCSK9 inhibitor. Specialist lipid clinic input.

Non-Pharmacological Treatment

Drug therapy is always combined with lifestyle measures, which alone can produce a meaningful reduction in cardiovascular risk:

• Mediterranean-style diet: replacing saturated with mono- and polyunsaturated fats, increasing fruit, vegetables, whole grains and oily fish.
• Plant sterols and stanols: structurally similar to cholesterol, compete for absorption, lower LDL by around 0.4-0.8 mmol/L. Available as enriched yoghurts and spreads.
• Soluble fibre (oats, legumes): modest LDL reduction.
• Omega-3 fatty acids: lower triglycerides; cardiovascular outcome data are mixed.
• Regular aerobic exercise: raises HDL and modestly lowers LDL and triglycerides.
• Weight loss and smoking cessation.

Summary

• LDL is the "bad" cholesterol; HDL is the "good". Atherogenesis is driven by oxidised LDL accumulating in the arterial intima.
• Statins inhibit HMG-CoA reductase and are first-line. NICE recommends atorvastatin 20 mg for primary prevention (QRISK ≥ 10%) and atorvastatin 80 mg for secondary prevention.
• Statin side effects: myalgia, transient transaminase rise, rare rhabdomyolysis. CYP3A4 interactions matter for simvastatin.
• Ezetimibe blocks NPC1L1 in the gut and is the standard add-on if statin alone fails to reach target.
• PCSK9 inhibitors (alirocumab, evolocumab) and inclisiran are highly effective but expensive; reserved for FH and high-risk secondary prevention.
• Fibrates (PPARα agonists) are mainly for severe hypertriglyceridaemia.
• Familial hypercholesterolaemia is autosomal dominant, presents with markedly elevated LDL, tendon xanthomata, corneal arcus, and premature CVD; warrants lifelong aggressive treatment and cascade family screening.
• Non-pharmacological measures (Mediterranean diet, exercise, smoking cessation) are always part of treatment.

Drug Summary Table

Class	Examples	Mechanism	Lipid effect	Key side effects
Statins	Atorvastatin, rosuvastatin, simvastatin, pravastatin	HMG-CoA reductase inhibition; ↑ LDL receptors	↓↓ LDL, ↓ TG, ↑ HDL slightly	Myalgia, ↑LFTs, rare rhabdomyolysis (esp with CYP3A4 inhibitors)
Cholesterol absorption inhibitor	Ezetimibe	Blocks NPC1L1 in gut	↓ LDL (modest)	Well tolerated; rare GI upset, headache
PCSK9 inhibitors	Alirocumab, evolocumab; inclisiran (siRNA)	Block PCSK9 → recycle LDL receptors	↓↓ LDL (50-60% on top of statin)	Injection-site reactions; very expensive (NICE-restricted)
ATP-citrate lyase inhibitor	Bempedoic acid	Blocks cholesterol synthesis upstream of HMG-CoA	↓ LDL	Statin-intolerant patients (with ezetimibe); hyperuricaemia
Fibrates	Fenofibrate, bezafibrate	PPAR-α agonists	↓↓ TG, ↓ LDL, ↑ HDL	Gallstones, myositis (esp. with statins: gemfibrozil contraindicated), LFT ↑
Bile acid sequestrants	Cholestyramine, colestipol	Bind bile acids in gut → ↑ LDL receptors	↓ LDL; ↑ TG slightly	GI upset, drug interactions (separate dosing); used for cholestatic itch
Nicotinic acid	Niacin	B3 at pharmacological dose	↑ HDL (best), ↓ LDL, ↓ TG	Flushing, hyperuricaemia, hyperglycaemia, hepatotoxicity. Rarely used.

Reviewed by: Dr. Marcus Judge

Quiz

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