10/16/2020 Statins - AMBOSS

Statins
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Summary

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.

Overview

Statin Half-life in hours CYP-450 Bioavailability

Atorvastatin 15–30 CYP3A4 ∼ 10%

Simvastatin 2–3 CYP3A4, CYP3A5 ∼ 5%

Pravastatin ∼2 - ∼ 20%

Lovastatin 3 CYP3A4 ∼ 5%

Fluvastatin 0.5–2.5 CYP2C9 ∼20–30%

Pitavastatin 12 Limited CYP2C9 ∼ 50%

Rosuvastatin 19 Limited CYP2C9 ∼ 20%

Potency (and cost) increases in the following order: fluvastatin → lovastatin and
pravastatin → simvastatin and atorvastatin!
References:[1][2]

Pharmacodynamics

Competitive inhibition of HMG-CoA reductase

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→ reduced intrahepatic cholesterol biosynthesis → upregulation of expression of LDL

receptor gene via sterol regulatory element-binding protein (SREBP) →
↓↓ LDL cholesterol (by ∼ 21–63%)

↑ HDL cholesterol (by ∼ 5–10%)

↓ triglyceride level (by ∼ 10–20%)
Pleiotropic effect: ↓ C-reactive protein, ↑ plaque stabilization, ↑ anti-inflammatory
effect, antioxidant effect and improved endothelial function of coronary arteries

Treatment of hyperlipidemia with statins significantly reduces the risk of mortality!

References:[3][4][2]

Adverse effects

General (common): headache and gastrointestinal symptoms (e.g., constipation,

diarrhea, flatulence)
Hepatic: (up to 3% of patients) ↑ LFTs due to the involvement of cytochrome P450
systems (CYP3A4 and CYP2C9) in the breakdown of statins

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 (< 0.5%): ↑ CK

May progress to rhabdomyolysis: rare but severe side-effect that may

lead to myoglobulinuria → 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!
References:[4][5][6]
We list the most important adverse effects. The selection is not exhaustive.

Indications

Patients with LDL cholesterol elevated ≥ 190 mg/dL

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Patients with a clinical atherosclerotic cardiovascular disease (includes coronary

artery disease (CAD), stroke, and peripheral arterial disease)
Patients aged 40–75 with diabetes and LDL levels of 70–189 mg/dL
Patients aged 40–75 with an estimated 10-year ASCVD risk ≥ 7.5% and LDL levels
70–189 mg/dL

→ For details see therapy of atherosclerotic disease and Guidelines for lipid-lowering
therapy (ATP III guidelines)
Statins are the first-line therapy for hypercholesterolemia!
References:[7]

Contraindications

Hypersensitivity
Active liver disease
Muscle disorder
Pregnancy, breastfeeding

References:[2]

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

Interactions

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!

References:[4][5][2][6][8]

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Additional considerations

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)

References:[2]

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