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 creatinine 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]
  • Patients with a clinical atherosclerotic cardiovascular disease (includes coronary artery disease, stroke, and peripheral arterial disease)
  • Patients with LDL cholesterol elevated ≥ 190 mg/dL (first-line treatment)
  • Patients with diabetes and multiple risk factors
• Low- to moderate-intensity statins: primary prevention of ASCVD ^[5][6]
  • Patients aged 40–75 with no history of CVD, ≥ 1 CVD risk factors (dyslipidemia, diabetes, hypertension, smoking), and calculated 10-year ASCVD risk ≥ 10%
  • Consider in patients aged 40–75 with no history of CVD, ≥ 1 CVD risk factors, and calculated 10-year ASCVD risk 7.5–10%

For details, see therapy of atherosclerotic disease and guidelines for lipid-lowering therapy (ATP III guidelines)

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)