Statins

Statins are the lipid-lowering drugs of choice. Statins reduce hepatic cholesterol synthesis by inhibiting enzyme HMG-CoA reductase. This leads to a consequent upregulation of LDL receptors on hepatocytes, which, in turn, lowers LDL cholesterol levels and triglycerides while raising HDL cholesterol. Headache and gastrointestinal side-effects are common. Statins carry a risk of hepatic and muscle toxicity. Muscle toxicity may rarely manifest with rhabdomyolysis.

For a comparison of statins with other lipid-lowering agents, see “Overview of lipid metabolism and lipid-lowering agents.”

“Flo Loves Prague Since A Tour of Russia.” Lipid-lowering potency increases in the following order: Fluvastatin → Lovastatin → Pravastatin → Simvastatin → Atorvastatin → Rosuvastatin

• Competitive inhibition of HMG-CoA reductase renders this enzyme unable to convert HMG-CoA to mevalonate (the rate-limiting step of cholesterol synthesis) → reduced intrahepatic cholesterol biosynthesis → upregulation of expression of LDL receptor gene via sterol regulatory element-binding protein (SREBP) → increased LDL recycling and: ^[2]
  • ↓↓ LDL cholesterol
  • ↑ HDL cholesterol
  • ↓ Triglyceride level
  • See the article on second-line lipid-lowering agents to see the comparison of lipid-lowering potency of different lipid-lowering agents.
• Pleiotropic effect:
  • ↓ C-reactive protein
  • ↑ Plaque stabilization
  • ↑ Anti-inflammatory effect
  • Antioxidant effect and improved endothelial function of coronary arteries

• General (common): headache and gastrointestinal symptoms (e.g., constipation, diarrhea)
• Hepatic: : (up to 3% of patients) ↑ LFTs due to the involvement of cytochrome P450 systems (CYP3A4 and CYP2C9) in the breakdown of statins ^[3][4]
• Muscular: Statins decrease the synthesis of coenzyme Q₁₀ and impair energy production within the muscle.
  • Myalgia: (muscle pain): continue treatment as long as creatine phosphokinase (CK) remain normal
  • Statin-associated myopathy
    • Muscle pain and weakness, especially when used alongside fibrates or niacin
    • Myositis: ↑ CK
    • May progress to rhabdomyolysis; : rare but severe side-effect that may lead to myoglobinuria → AKI (↑ BUN and ↑ creatinine)
    • Management: discontinue statin therapy for 2–4 weeks; start treatment with a low-dose statin (e.g., pravastatin or fluvastatin) once symptoms have resolved

Treatment must be discontinued if myopathy/rhabdomyolysis occurs.

Interaction with certain drugs can increase the risk of myopathy (see “Interactions” section below).

We list the most important adverse effects. The selection is not exhaustive.

• High-intensity statins ^[5][6][7]
  • Patients < 75 years of age with clinical atherosclerotic cardiovascular disease (includes coronary artery disease, stroke, and peripheral arterial disease)
  • Patients 20–75 years of age with LDL cholesterol ≥ 190 mg/dL (first-line treatment)
  • Adult patients with diabetes mellitus and multiple ASCVD risk factors
• Low- to moderate-intensity statins: primary prevention of ASCVD (see “Indications for statins for primary ASCVD prevention”)

For details on treatment of very high LDL cholesterol, see the treatment section in Lipid disorders.

Statins are the first-line therapy for hypercholesterolemia.

Treatment of hyperlipidemia with statins significantly reduces the risk of mortality in patients suffering from CAD.

• Hypersensitivity
• Active liver disease
• Muscle disorder
• Pregnancy, breastfeeding

We list the most important contraindications. The selection is not exhaustive.

• Other lipid-lowering agents
  • Fibrates
  • Nicotinic acid
  • Both agents may also cause myopathy → concomitant use with statins further increases the risk of myopathy!
• CYP3A4 inhibitors
  • HIV/HCV protease inhibitors
  • Macrolides (especially erythromycin and clarithromycin)
  • Azole antifungals
  • Cyclosporine
• Warfarin

Maintain a high index of suspicion for rhabdomyolysis if muscle pain occurs after administering statins.

• Ideally administered in the evenings (especially simvastatin)
• Combination therapy with bile acid resins has a stronger hypolipidemic effect compared to treatment with statins alone (both groups of drugs increase LDL receptor expression)