ISCHEMIC STROKE / PREVENTION

Statins and their interactions

David Goldemund M.D.
Updated on 18/03/2024, published on 19/10/2023

  • statins are competitive HMG-CoA reductase inhibitors  that are effective in stroke prevention
  • interactions of statins with other drugs affect their metabolism and can be clinically serious; they may be responsible for up to nearly 60% of statin-related myopathy/rhabdomyolysis cases

Classification of drug interactions

  • interactions are, in general, divided into:
    • pharmacodynamic (usually the interaction at the target receptor site)
      • less likely mechanism in statins because HMG-CoA reductase is a highly selective enzyme. There are no other known receptors for this enzyme, and statins inhibit this enzyme very selectively
    • pharmacokinetic (the reaction between drugs during their pathway to the target site of action and elimination)
      • the vast majority of statin interactions are pharmacokinetic interactions at the level of metabolism (because statins are substrates of cytochrome P450 isoenzymes)

Pharmacokinetic interactions of statins

  • drugs that may interact with statins at the level of metabolism are either inhibitors or inducers of CYP450 enzymes
    • statins are predominantly metabolized by two different P450 isoforms, CYP3A4 and CYP2C9
      • lipophilic statins lovastatin, simvastatin, and atorvastatin – isoenzyme 3A4
      • fluvastatin and partially rosuvastatin (10%) – isoenzyme 2C9
    • pravastatin and rosuvastatin are mainly excreted unchanged in feces and urine
  • the pharmacokinetic interactions of statins may also involve interactions at the level of glucuronidation and membrane transporters
    • OATP1B1*5, OATP2B1 – organic anion transporting polypeptide
    • MDR1 – multidrug resistance protein 1
    • P-glycoprotein
    • MRP2 – multidrug resistance-associated protein 2
CYP2C9 CYP3A4 Pgp OATP1B1 OATP1B3
atorvastatin + + +
fluvastatin + +
lovastatin + +
pravastatin + +
rosuvastatin + + +
simvastatin + + +
OATP – organic anion-transporting polypeptide, Pgp – P-glycoprotein
The potency of P450 inhibitors taking part in statin metabolism
3A4 (3A5,3A7) 2C9 2C8
indinavir, nelfinavir, ritonavir, saquinavir

clarithromycin, erythromycin

cetoconasole, itraconasole

cyclosporin

erythromycin

fluconazole

verapamil

diltiazem

amiodaron

 fluconazole

amiodaron

fenofibrate

fluvoxamine

sertraline

sulfamethoxazole

 gemfibrozil

trimethoprim
  • strong inhibitor  ~ 5-fold increase in plasma AUC  or > 80% decrease in clearance
  • moderate inhibitor  ~ 2-fold increase in plasma AUC or 50-80% decrease in clearance

Rosuvastatin
  • CYP2C9 Inhibitors (e.g., fluconazole, ketoconazole) –  ↑ rosuvastatin plasma levels (⇒ myopathy)
  • fibrates (e.g., fenofibrate) – elevated risk of myopathy or rhabdomyolysis; avoid gemfibrozil
  • anticoagulants (e.g., warfarin) –  increased bleeding risk
  • cyclosporine – avoid  (↑ rosuvastatin plasma levels and risk of myopathy)
  • niacin – increased risk of myopathy
  • HIV protease inhibitors – altered rosuvastatin pharmacokinetics with increased risk of myopathy; max 10 mg or avoid
  • digoxin – increased digoxin levels
  • oral contraceptives – co-administration may increase ethinyl estradiol and norgestrel levels
  • alcohol – additive hepatotoxicity risk
  • macrolides – no significant interaction
Atorvastatin
  • CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) – ↑ atorvastatin plasma levels (⇒ myopathy) – avoid (or dose < 40mg)
  • CYP3A4 inducers (e.g., rifampin) – ↓ atorvastatin efficacy due to decreased plasma levels
  • anticoagulants (e.g., warfarin) – increased bleeding risk
  • fibrates (e.g., fenofibrate) – elevated risk of myopathy or rhabdomyolysis; avoid gemfibrozil
  • digoxin – elevated digoxin plasma levels when co-administered
  • calcium channel blockers (e.g., amlodipine) – potential for increased atorvastatin levels (⇒ myopathy), but may be used
  • amiodarone – ↑ atorvastatin levels (⇒ myopathy), low risk
  • HIV protease inhibitors – increased atorvastatin levels (⇒ myopathy); max 10 mg
  • macrolides – interaction with clarithromycin/erythromycin/telithromycin; atorvastatin is not contraindicated but should be used with caution
Simvastatin
  • CYP3A4 Inhibitors (e.g., itraconazole, ketoconazole, grapefruit juice) – ↑ simvastatin plasma levels (⇒ myopathy/rhabdomyolysis) – avoid
  • CYP3A4 Inducers (e.g., rifampin) – ↓ simvastatin efficacy due to decreased simvastatin levels
  • fibrates (e.g., gemfibrozil, fenofibrate) – ↑ risk of myopathy/rhabdomyolysis; avoid gemfibrozil
  • anticoagulants (e.g., warfarin) – ↑ bleeding risk
  • amiodarone – ↑ simvastatin plasma levels (⇒ myopathy/rhabdomyolysis); max dose 10 mg
  • calcium channel blockers (e.g., verapamil, amlodipine) – ↑ simvastatin levels (⇒ myopathy/rhabdomyolysis); max dose 10 mg or switch to atorvastatin
  • digoxin – slight elevation of digoxin plasma levels
  • HIV protease inhibitors – ↑ simvastatin plasma levels (⇒ myopathy/rhabdomyolysis) – contraindicated
  • alcohol – ↑ hepatotoxicity risk,
  • macrolides – significant interaction with clarithromycin/erythromycin/telithromycin ⇒ avoid

Statins and macrolide antibiotics

  • probably the most common statin interaction
  • the most serious interactions are with simvastatin/lovastatin + clarithromycin/erythromycin/telithromycin  ⇒ avoid
    • interaction with roxithromycin is less significant
  • the combination of atorvastatin+clarithromycin/erythromycin is not contraindicated; increased caution is advised; the interaction with azithromycin is clinically unlikely to be serious
  • drug interactions between macrolides and fluvastatin, rosuvastatin and pravastatin are not expected; patients should be monitored for symptoms of myopathy
  • a physician prescribing a macrolide antibiotic should actively seek to determine whether the patient is taking a statin
  • if the patient is taking simvastatin/lovastatin:
    • prescribe a macrolide other than clarithromycin (azithromycin)
    • indicate a completely different antibiotic
    • replace or temporarily discontinue statin

Statins and calcium blockers

  • calcium blockers like diltiazem and verapamil inhibit CYP3A4 and P-glycoprotein, which can increase the availability of statins
    • simvastatin and lovastatin can have their AUC increased by 3-8 fold 
  • verapamil or diltiazem: maximal dose of simvastatin 10 mg or switch to fluvastatin, rosuvastatin, or atorvastatin
  • amlodipine: maximal dose of simvastatin 20 mg or switch to a statin with lower interaction potential
  • when combining atorvastatin with diltiazem, close monitoring for signs of rhabdomyolysis is advised

Statins and HIV protease inhibitors

  • HIV protease inhibitors (such as saquinavir, indinavir, ritonavir, nelfinavir, lopinavir, fosamprenavir, atazanavir, darunavir) are potent inhibitors of CYP3A4
    •  a 30-fold increase in simvastatin AUC has been demonstrated with ritonavir potentiated by saquinavir 
  • fluvastatin and pravastatin (except in combination with darunavir) can be used without dose changes
  • atorvastatin can be given only in low doses (≤ 10 mg); careful monitoring and appropriate patient education are required
  • rosuvastatin therapy should start with low doses while monitoring the patient; some manufacturers recommend taking no more than 10 mg of rosuvastatin in combination with protease inhibitors
  • simvastatin and lovastatin are contraindicated when protease inhibitors are used

Statins and azole antifungal drugs

  • azole antifungal drugs (ketoconazole, itraconazole, fluconazole) are potent inhibitors of CYP3A4, increasing plasmatic levels of statins
  • avoid a combination of simvastatin/lovastatin/atorvastatin together with ketoconazole or itraconazole; their levels increase up to 20-fold); avoid such combination
    • some manufacturers allow the use of atorvastatin ≤ 40 mg
  • fluvastatin, pravastatin, and rosuvastatin levels are not affected, or very little (up to 1.5-fold) ⇒ no clinical intervention is required

Statins and cyclosporine

  • interactions may increase statin levels (↑ risk of myalgia) and reduce the effect of cyclosporine
    • these interactions are likely to occur through several mechanisms – inhibition of CYP3A4 (intestinal and hepatic), P-glycoprotein, and membrane transporters (OATP1B1, OATP2B1, MRP2)
  • cyclosporine increases up to 7-fold the AUC of rosuvastatin ⇒ co-administration of rosuvastatin and cyclosporine should be avoided
  • cyclosporine also increases plasma levels of other statins; concomitant use should be well-monitored
    • simvastatin max 10 mg (or avoid according to some experts)
    • atorvastatin/lovastatin/pravastin max 10 mg
  • simvastatin and atorvastatin decrease affect cyclosporine plasma levels (no effect on levels was observed with fluvastatin, lovastatin, and pravastatin)
  • closer monitoring of cyclosporine levels is recommended for statins

Statins and amiodarone

  • amiodarone is an inhibitor of both CYP3A4 and the CYP2C9 form and, therefore, interacts with statins metabolized by these cytochrome P450 isoforms
  • the most clinically relevant interactions with amiodarone are with simvastatin/lovastatin
    • a maximum of 10 mg simvastatin and 40 mg lovastatin is recommended
  • when higher doses are indicated, it is recommended to switch to a “safer” statin (rosuvastatin, fluvastatin, pravastatin)
  • interaction with atorvastatin is not clinically significant

Statins and warfarin

  • statins can interact with warfarin via
    • competition for metabolism on CYP3A4 (simvastatin)
    • inhibition of S-warfarin metabolism on CYP2C9  (fluvastatin)
    • unknown mechanism (rosuvastatin)
  • this interaction (not very serious) may result in an increase in INR as well as an increased risk of myopathy
  • it is recommended that INR, creatine kinase (CK), and myopathy symptoms be carefully monitored when starting, stopping, or changing any treatment with warfarin + simvastatin (or other statins)

Statins and other hypolipidemics

  • fibrates are increasingly used in combination with statins
  • this combination increases the risk of myopathy, which has mostly been observed in the first 12 weeks of co-administration; interactions with gemfibrozil are the most frequent and serious
  • multiple mechanisms are probably involved (pharmacodynamic and pharmacokinetic
  • cases of rhabdomyolysis have also been described with the use of bezafibrate, clofibrate, and fenofibrate alone

Statins and grapefruit

  • grapefruit and grapefruit juice are potent inhibitors of CYP3A4
  • one glass (200 ml) of juice and/or one-half of grapefruit is sufficient to reduce CYP3A4 activity by half (and increase simvastatin AUC 3-4 times)
  • the effect persists for at least 24 hours
  • patients taking simvastatin, lovastatin, or atorvastatin, which are preferentially metabolized by CYP3A4, should avoid consuming grapefruit, pomelo, or their juices (and replace it with orange juice)
  • patients may switch to fluvastatin, rosuvastatin, pitavastatin, pravastatin

Enzyme inducers and statins

  • enzyme inducers (rifampicin, carbamazepine, phenytoin, St. John’s wort, barbiturates) may decrease the AUC of statins;  the highest reductions were observed with simvastatin, lovastatin, and atorvastatin
  • if statins and enzyme inducers are used together, it is recommended to monitor the efficacy of statins and increase their dose if necessary
  • therapeutic options can also be considered to avoid the use of an inducer

Contraindicated and harmful combinations

Contraindicated combinations
simvastatin, lovastatin ketoconazole, itraconazole, HIV protease inhibitors, clarithromycin (cyclosporine)
atorvastatin HIV protease inhibitors
rosuvastatin
 (cyclosporine)
Potentially harmful combinations
simvastatin, lovastatin cyclosporine, erythromycin, roxithromycin, diltiazem, verapamil, fluconazole, voriconazole, amiodarone, fibrates (except for gemfibrozil), grapefruit
rosuvastatin fluconazole, ciclosporine, fibrates, HIV protease inhibitors
atorvastatin cyclosporine, fibrates, grapefruit
fluvastatin fibrates (except for gemfibrozil)

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Statins and their interactions
link: https://www.stroke-manual.com/statins-and-their-interactions/