Statins

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis, lowering intracellular cholesterol, raising hepatic LDL receptor numbers and clearing LDL from plasma. They reduce LDL cholesterol by 20% to 60%, lower triglycerides modestly, and reduce major vascular events, stroke and mortality in primary and secondary prevention. They are the foundation of lipid lowering.

Members. Atorvastatin, rosuvastatin, simvastatin, pravastatin, fluvastatin, pitavastatin. Lovastatin is rarely used.

Mechanism. Competitive inhibition of HMG-CoA reductase lowers hepatic cholesterol. Pleiotropic effects include plaque stabilisation, less inflammation and improved endothelial function, which contribute to benefit.

Intensity. High intensity (about 50% or greater LDL reduction): atorvastatin 40 to 80 mg, rosuvastatin 20 to 40 mg. Moderate intensity (30% to 49%): atorvastatin 10 to 20 mg, rosuvastatin 5 to 10 mg, simvastatin 20 to 40 mg, pravastatin 40 to 80 mg, pitavastatin 1 to 4 mg, fluvastatin XL 80 mg.

Pharmacokinetics. Atorvastatin and rosuvastatin have long half-lives (14 hours and 19 hours) and can be taken at any time. Simvastatin, pravastatin and fluvastatin are short acting and are better taken in the evening. Simvastatin, atorvastatin and lovastatin use CYP3A4. Fluvastatin uses CYP2C9. Rosuvastatin, pravastatin and pitavastatin have little CYP metabolism. Hepatic uptake depends on OATP1B1. Rosuvastatin and pravastatin are cleared in part by the kidney.

• Atorvastatin: high potency; no renal dose adjustment; CYP3A4 interactions.
• Rosuvastatin: most potent; renal dose limits; start 5 mg in patients of Asian ancestry; hydrophilic.
• Simvastatin: low cost; dose caps with interacting drugs; 80 mg not used.
• Pravastatin: fewest interactions; suited to polypharmacy, transplant and HIV.
• Fluvastatin: modest potency; fewer interactions.
• Pitavastatin: low interaction; little effect on glucose.

• Secondary prevention: atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg daily.
• Primary prevention: atorvastatin 10 to 20 mg or rosuvastatin 5 to 10 mg for adults at moderate or high risk, titrated to the LDL cholesterol target.
• Diabetes: moderate-intensity statin aged 40 to 75 years, high intensity with multiple risk factors.
• Chronic kidney disease: atorvastatin 20 mg or simvastatin 20 mg with ezetimibe 10 mg; not initiated in dialysis.
• Acute coronary syndrome and stroke: high-intensity atorvastatin started early.
• Familial hypercholesterolaemia: high-intensity statin, from age 8 to 10 years in children with specialist care.
• Statin intolerance: try another statin, lower dose, alternate-day rosuvastatin or atorvastatin, then ezetimibe, bempedoic acid or a PCSK9 inhibitor.
• Selection: choose atorvastatin or rosuvastatin for potency, pravastatin or pitavastatin when interactions are a concern.

Contraindications. Pregnancy and breastfeeding, active liver disease or unexplained persistent liver enzyme elevation over 3 times the upper limit, and hypersensitivity.

Adverse effects. Muscle symptoms (myalgia in 5% to 10%, many not caused by the drug), myopathy with creatine kinase over 10 times the upper limit, rhabdomyolysis (rare, under 0.1%), raised liver enzymes (1%), new-onset diabetes (small absolute rise, benefit outweighs risk), headache, gastrointestinal upset, and rarely immune-mediated necrotising myopathy. Haemorrhagic stroke risk is not meaningfully increased.

Interactions. Simvastatin: maximum 20 mg with amlodipine and amiodarone, 10 mg with verapamil and diltiazem, and avoid with clarithromycin, erythromycin, itraconazole, ketoconazole, ritonavir-boosted regimens, gemfibrozil and ciclosporin. Atorvastatin: limit to 20 mg with clarithromycin, avoid with ciclosporin, and use the lowest effective dose with protease inhibitors. Rosuvastatin: avoid with ciclosporin, limit to 5 mg with gemfibrozil.

Rifampicin lowers levels. Grapefruit juice raises simvastatin and atorvastatin levels. Daptomycin and fusidic acid add muscle toxicity, so stop the statin during systemic fusidic acid.

Monitoring. Lipid profile at 4 to 12 weeks and yearly. Liver enzymes at baseline and if symptoms arise. Creatine kinase if muscle pain, weakness or dark urine. Stop the statin if creatine kinase is over 10 times the upper limit or rhabdomyolysis is suspected, and restart after recovery with a lower dose or another statin.

Referral and escalation. Severe weakness with dark urine, acute kidney injury or jaundice needs same-day care.

Special groups. Pregnancy: stop when planning or discovering pregnancy. Older adults: benefit continues, with lower starting doses if frail. Kidney disease: reduce rosuvastatin (maximum 10 mg if creatinine clearance under 30 mL/min). Liver disease: compensated chronic liver disease is not a bar, decompensated disease is. Hypothyroidism: treat first, because it raises muscle risk.