Key Facts

Statins are among the most prescribed drugs globally and have the strongest evidence base of any drug class for cardiovascular prevention. For every 1 mmol/L reduction in LDL, there is a ~22% reduction in major vascular events.

Epidemiology

• ~8 million adults in UK take statins
• CVD remains leading cause of death in UK
• LDL cholesterol: causal risk factor for atherosclerotic CVD

Pharmacology

• Statins: competitively inhibit HMG-CoA reductase (rate-limiting step in cholesterol synthesis) → ↓ intrahepatic cholesterol → ↑ LDL receptor expression on hepatocytes → ↑ LDL clearance from blood
• Pleiotropic effects: anti-inflammatory (↓ CRP), endothelial function improvement, plaque stabilisation, antithrombotic
• Potency: rosuvastatin > atorvastatin > simvastatin > pravastatin
• Metabolism: simvastatin and atorvastatin via CYP3A4 (interaction risk); pravastatin NOT CYP-metabolised (fewest interactions)

Pathophysiology

• Atherosclerosis: LDL penetrates arterial wall → oxidised LDL → macrophage uptake → foam cells → fatty streak → atheromatous plaque
• Statins reduce this process by lowering circulating LDL
• Additional drugs target different pathways: ezetimibe (intestinal absorption), PCSK9 inhibitors (LDL receptor degradation), bempedoic acid (hepatic cholesterol synthesis upstream of HMG-CoA reductase)

Indications

• Primary prevention: QRISK3 ≥10% (10-year CVD risk) → atorvastatin 20 mg OD
• Secondary prevention: established CVD (ACS, stroke, PAD) → atorvastatin 80 mg OD
• Familial hypercholesterolaemia: high-intensity statin ± ezetimibe ± PCSK9 inhibitor
• CKD: atorvastatin 20 mg for CKD patients (SHARP trial)
• Type 1 diabetes >40 years or with complications: statin indicated
• Type 2 diabetes: include in QRISK assessment

Side Effects

• Myalgia (~5–10%): most common reason for discontinuation; often non-specific
• Myopathy: CK elevation >10× ULN with symptoms — rare; stop statin
• Rhabdomyolysis: very rare (~1 in 100,000); muscle breakdown → myoglobinuria → AKI; emergency
• Hepatotoxicity: transaminase elevation (rare; usually transient); check LFTs at 3 and 12 months
• New-onset diabetes: small increased risk (~9%; JUPITER trial); CV benefit outweighs this
• Drug interactions: simvastatin/atorvastatin + CYP3A4 inhibitors (clarithromycin, itraconazole, grapefruit) → rhabdomyolysis risk

Red Flags

• Severe muscle pain/weakness + dark urine → suspect rhabdomyolysis → check CK, U&Es urgently; stop statin
• Jaundice after starting statin → check LFTs; stop if ALT >3× ULN
• Drug interaction alert: simvastatin dose max 20 mg with amlodipine; avoid simvastatin with potent CYP3A4 inhibitors

Before Starting

• Fasting lipid profile: total cholesterol, LDL, HDL, triglycerides, non-HDL cholesterol
• QRISK3 score: 10-year CVD risk assessment (for primary prevention decision)
• LFTs: baseline
• TFTs: exclude hypothyroidism (secondary hyperlipidaemia)
• HbA1c/fasting glucose: diabetes screening
• Renal function: CKD screening

Monitoring

• Lipid profile at 3 months: assess response — aim >40% non-HDL reduction from baseline
• LFTs at 3 and 12 months: if ALT >3× ULN → stop
• CK: only if muscle symptoms (do NOT check routinely)
• If target not met: increase dose → add ezetimibe → consider PCSK9 inhibitor referral

Special Tests

• Familial hypercholesterolaemia screening: Simon Broome or Dutch Lipid Clinic criteria; genetic testing (LDLR, APOB, PCSK9 mutations)
• Lp(a): measure once; independent CVD risk factor; limited pharmacological options

Primary Prevention

• QRISK3 ≥10%: offer atorvastatin 20 mg OD after lifestyle discussion
• Lifestyle: diet (Mediterranean/portfolio), exercise, weight management, smoking cessation

Secondary Prevention

• Atorvastatin 80 mg OD: all patients with established CVD (unless contraindicated)
• If intolerant of atorvastatin 80 mg → try lower dose, switch to rosuvastatin, or add ezetimibe

Intensification (If Target Not Met)

1. Increase statin dose to maximum tolerated
2. Add ezetimibe 10 mg OD (IMPROVE-IT trial: additional LDL reduction + CV benefit)
3. PCSK9 inhibitor (NICE TA394): evolocumab 140 mg SC every 2 weeks or alirocumab 75–150 mg SC every 2 weeks
4. Inclisiran (NICE TA733): 284 mg SC at 0, 3 months, then 6-monthly
5. Bempedoic acid 180 mg OD: for statin-intolerant patients (CLEAR Outcomes trial)

Statin Intolerance

• True myopathy: rare (~1 in 10,000); re-challenge with different statin at low dose after washout
• Try: rosuvastatin 5 mg OD or pravastatin 20 mg OD (fewer interactions)
• If truly intolerant: ezetimibe ± bempedoic acid ± PCSK9 inhibitor

Referral Criteria

• Lipid clinic: suspected FH, severe dyslipidaemia, statin intolerance, PCSK9 inhibitor consideration
• Genetics: FH cascade screening

• Statins: 22% relative reduction in major vascular events per 1 mmol/L LDL reduction (CTT meta-analysis)
• 4S trial (simvastatin): 30% mortality reduction in patients with prior MI
• HPS trial (simvastatin 40 mg): 25% reduction in major vascular events regardless of baseline cholesterol
• PCSK9 inhibitors (FOURIER): 15% reduction in CV events when added to statin
• Number needed to treat: ~20–50 for primary prevention over 5 years; ~10–15 for secondary prevention
• Rhabdomyolysis: very rare (~1 in 100,000/year); fatal rhabdomyolysis rarer still

Key Statin Trials

Statin Intensity