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Review| Volume 129, ISSUE 1, P26-29, January 2016

Grapefruit Juice and Statins

  • Jonathan W. Lee
    Affiliations
    Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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  • Joan K. Morris
    Affiliations
    Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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  • Nicholas J. Wald
    Correspondence
    Requests for reprints should be addressed to Nicholas J. Wald, FRS, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M6BQ, UK.
    Affiliations
    Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
    Search for articles by this author

      Abstract

      We determined the validity of current medical advice to avoid grapefruit juice consumption while taking 3 widely used statins. A daily glass of grapefruit juice increases blood levels of simvastatin and lovastatin by about 260% if taken at the same time (about 90% if taken 12 hours apart), and atorvastatin by about 80% (whenever taken). Simvastatin 40 mg, lovastatin 40 mg, and atorvastatin 10 mg daily reduce low-density lipoprotein (LDL) cholesterol levels in a 60-year-old man with an LDL cholesterol of 4.8 mmol/L by 37%, reducing ischemic heart disease risk by 61%. When simvastatin or lovastatin are taken at the same time as grapefruit juice, the estimated reduction in LDL cholesterol is 48%, and in heart disease is 70%. If the juice is taken 12 hours before these statins, the reductions are, respectively, 43% and 66%, and for atorvastatin, 42% and 66%. The increased rhabdomyolysis risk from grapefruit juice consumption due to the increased effective statin dose is minimal compared with the greater effect in preventing heart disease. Grapefruit juice should not be contraindicated in people taking statins.

      Keywords

      Clinical Significance
      • Grapefruit juice enhances the efficacy of certain statins in reducing low-density lipoprotein cholesterol and heart disease.
      • Recognizing the grapefruit juice effect as an effect enhancer and therapeutic benefit is already seen in cancer treatment.
      • Moderate grapefruit juice consumption should not be regarded as contraindicated in people taking statins.
      • The focus on the risk of rhabdomyolysis from grapefruit juice consumption with statins ignores the greater benefits for the higher effective statin dose.
      Current medical advice is to avoid grapefruit juice consumption while taking a statin.

      Simvastatin: updated advice on drug interactions: Medicines and Healthcare Products Regulatory Agency; 2012. Available at: https://www.gov.uk/drug-safety-update/simvastatin-updated-advice-on-drug-interactions. Accessed June 12, 2015.

      U.S. Food and Drug Administration. Grapefruit juice and medicine may not mix [updated January 20th 2015]. Available at: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm292276.htm. Accessed June 12, 2015.

      • Pirmohamed M.
      Drug-grapefruit juice interactions: two mechanisms are clear but individual responses vary.
      The action of grapefruit juice on the effect of drugs was discovered by accident in 1989 in an experiment designed to examine the effect of ethanol on the action of felodipine, a calcium channel blocker.
      • Bailey D.G.
      • Spence J.D.
      • Edgar B.
      • Bayliff C.D.
      • Arnold J.M.
      Ethanol enhances the hemodynamic effects of felodipine.
      Grapefruit juice was used to mask the taste of alcohol but the results showed several-fold higher felodipine concentration in blood plasma than had been expected. Grapefruit juice has since been shown to interact with over 85 drugs, including statins,
      • Bailey D.G.
      • Dresser G.
      • Arnold J.M.
      Grapefruit-medication interactions: forbidden fruit or avoidable consequences?.
      which are widely used to reduce low-density lipoprotein (LDL) cholesterol to help prevent cardiovascular disease.
      • Bellosta S.
      • Paoletti R.
      • Corsini A.
      Safety of statins: focus on clinical pharmacokinetics and drug interactions.
      The adverse effects of statins on muscles can range from mild discomfort (myalgia) to the more serious rhabdomyolysis, which requires hospitalization and, in extremely rare cases, causes death. Statins increase the risk of hyperglycemia, but the much greater cardiovascular benefits of statins outweigh this small increased risk, and statins are recommended in patients with diabetes. We here focus on rhabdomyolysis as the dominant adverse event of concern.
      This review summarizes the pharmacokinetics of grapefruit juice–statin interactions, specifically, atorvastatin, simvastatin, and lovastatin, and quantifies how this interaction affects LDL cholesterol and ischemic heart disease risk and the risk of rhabdomyolysis, presenting results on which clinical advice can be based.

      Chemistry of the Grapefruit Juice Effect

      Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Different statins vary in their bioavailability, half-life, and method of metabolic degradation (see Table 1).
      • Bellosta S.
      • Paoletti R.
      • Corsini A.
      Safety of statins: focus on clinical pharmacokinetics and drug interactions.
      For example, as a consequence of their different half-lives, atorvastatin can be taken at any time during the day with a consistent efficacy, whereas simvastatin should be taken at night. Cytochrome P450 (CYP)3A4 is the major enzyme involved in the metabolic degradation of many statins, including atorvastatin, simvastatin, and lovastatin.
      • Ando H.
      • Tsuruoka S.
      • Yanagihara H.
      • et al.
      Effects of grapefruit juice on the pharmacokinetics of pitavastatin and atorvastatin.
      • Dahan A.
      • Altman H.
      Food-drug interaction: grapefruit juice augments drug bioavailability—mechanism, extent and relevance.
      • Guo L.Q.
      • Fukuda K.
      • Ohta T.
      • Yamazoe Y.
      Role of furanocoumarin derivatives on grapefruit juice-mediated inhibition of human CYP3A activity.
      • Lilja J.J.
      • Kivisto K.T.
      • Neuvonen P.J.
      Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors.
      • Lilja J.J.
      • Kivisto K.T.
      • Neuvonen P.J.
      Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin.
      • Rogers J.D.
      • Zhao J.
      • Liu L.
      • et al.
      Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.
      Table 1Time to Maximum Concentration, Half Life, and Method of Metabolic Degradation According to Statin
      Adapted from Bellosta et al.6
      StatinApprox. Time to Maximum Concentration (Hours)Half Life (Hours)Metabolic Degradation
      Atorvastatin223CYP3A4
      Lovastatin33CYP3A4
      Simvastatin22CYP3A4
      Fluvastatin11CYP2C9
      Rosuvastatin321CYP2C9
      Pravastatin12Sulphation
      Adapted from Bellosta et al.
      • Bellosta S.
      • Paoletti R.
      • Corsini A.
      Safety of statins: focus on clinical pharmacokinetics and drug interactions.
      The main agents responsible for the grapefruit juice effect on statins are bergamottin in fresh grapefruit and its derivative, 6′,7′-dihydroxybergamottin (DHB) in juice concentrate, which are furanocoumarins.
      • He K.
      • Iyer K.R.
      • Hayes R.N.
      • Sinz M.W.
      • Woolf T.F.
      • Hollenberg P.F.
      Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit juice.
      Furanocoumarins are also found in other fruit (eg, pomegranates), and in vegetables (eg, parsnips and celery), however, they are especially concentrated in grapefruit juice and fresh grapefruits.
      • Lombaert G.A.
      • Siemens K.H.
      • Pellaers P.
      • Mankotia M.
      • Ng W.
      Furanocoumarins in celery and parsnips: method and multiyear Canadian survey.
      • Schmiedlin-Ren P.
      • Edwards D.J.
      • Fitzsimmons M.E.
      • et al.
      Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins.
      • Sorokin A.V.
      • Duncan B.
      • Panetta R.
      • Thompson P.D.
      Rhabdomyolysis associated with pomegranate juice consumption.
      Kinetic studies reveal that both bergamottin and DHB inactivate CYP3A4. Studies have shown a 50% reduction in intestinal CYP3A4 concentration within 4 hours of drinking one serving of grapefruit juice (equivalent to the juice in one whole grapefruit).
      • Schmiedlin-Ren P.
      • Edwards D.J.
      • Fitzsimmons M.E.
      • et al.
      Mechanisms of enhanced oral availability of CYP3A4 substrates by grapefruit constituents. Decreased enterocyte CYP3A4 concentration and mechanism-based inactivation by furanocoumarins.
      • Lown K.S.
      • Bailey D.G.
      • Fontana R.J.
      • et al.
      Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A protein expression.
      Inhibiting the activity of CYP3A4 in the intestines presumably inhibits the presystemic degradation of statins and so increases their systemic bioavailability. Lovastatin, simvastatin, and atorvastatin are all metabolized by CYP3A4, while statins such as fluvastatin and rosuvastatin are metabolized by CYP2C9 (Table 1) and pravastatin is metabolized enzymatically in the liver.
      • Bellosta S.
      • Paoletti R.
      • Corsini A.
      Safety of statins: focus on clinical pharmacokinetics and drug interactions.
      This explains why grapefruit juice interacts with atorvastatin, simvastatin, and lovastatin, but not with fluvastatin, rosuvastatin, or pravastatin.
      • Lilja J.J.
      • Kivisto K.T.
      • Neuvonen P.J.
      Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin.
      Removal of furanocoumarins from grapefruit juice eliminates the grapefruit juice effect.
      • Paine M.F.
      • Widmer W.W.
      • Hart H.L.
      • et al.
      A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction.

      Effects of Grapefruit Juice on the Pharmacokinetics of Statins

      A study
      • Lilja J.J.
      • Kivisto K.T.
      • Neuvonen P.J.
      Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin.
      showed that when 40 mg simvastatin was taken with unusually large intakes of grapefruit juice (equivalent to 6 whole grapefruits a day), the blood levels of the statin (expressed as the area under the curve [AUC] in a pharmacokinetic study) increased by about 13.5-fold. However, another study
      • Lilja J.J.
      • Neuvonen M.
      • Nevonen P.J.
      Effect of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin.
      examined the effect of a typical grapefruit juice intake (equivalent to an 8-oz [240-mL] glass or 1 grapefruit per day) consumed at breakfast, and 40 mg simvastatin was taken at the same time, as there was only a 3.6-fold increase in the AUC.
      The grapefruit juice effect with statins has been shown to decrease to 10% of its maximum 24 hours after intake of grapefruit juice, suggesting that the half-life of the grapefruit juice effect is between 7 and 8 hours, similar to that of CYP3A4.
      • Lilja J.J.
      • Kivisto K.T.
      • Neuvonen P.J.
      Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin.
      Therefore, it can be deduced that for statins that have relatively short half-lives (eg, simvastatin or lovastatin), grapefruit juice taken in the evening will have approximately half the effect of grapefruit juice taken in the morning. The results from a study
      • Rogers J.D.
      • Zhao J.
      • Liu L.
      • et al.
      Grapefruit juice has minimal effects on plasma concentrations of lovastatin-derived 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.
      that observed a 1.9-fold increase in the AUC of lovastatin when grapefruit juice was taken at breakfast and 40 mg of lovastatin in the evening are consistent with this; they were approximately 50% lower than the study that observed a 3.6-fold increase with simvastatin and grapefruit juice both taken in the morning.
      Another study
      • Lilja J.J.
      • Kivisto K.T.
      • Neuvonen P.J.
      Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin.
      observed a 1.8-fold increase in the blood levels of 10 mg of atorvastatin when taken with grapefruit juice. This effect would be expected to be unaffected by the time of taking the grapefruit juice because the half-life of atorvastatin is relatively long.

      Clinical Implications of Consuming Grapefruit Juice with Statins

      Effect on LDL Cholesterol and Heart Disease Risk

      A meta-analysis by Law et al
      • Law M.R.
      • Wald N.J.
      • Rudnicka A.R.
      Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.
      estimated that 10 mg atorvastatin, 40 mg simvastatin, or 40 mg lovastatin reduce LDL cholesterol by 37%, and double these doses reduces LDL cholesterol by 43%, an extra 6 percentage points. For someone with a baseline LDL cholesterol of 4.8 mmol/L, these are equivalent to a 1.8-mmol/L reduction (0.37 × 4.8) and a 2.1 mmol/L reduction, respectively.
      The effect of a standard serving of grapefruit juice is to increase the effective dose of simvastatin or lovastatin by about 3.6-fold when given at the same time as the statin, and by 1.9-fold when given 12 hours earlier. Therefore, the effect of grapefruit juice if consumed at the same time as taking simvastatin or lovastatin is to reduce LDL cholesterol by an additional 11.1% [log(3.6)/log(2) × 6%], equivalent to a 0.53 mmol/L (11.1% × 4.8 mmol/L) reduction (see Table 2). The effect of grapefruit juice if consumed 12 hours before taking simvastatin or lovastatin is to reduce LDL cholesterol by an additional 5.6% [log(1.9)/log(2) × 6%], equivalent to a 0.27-mmol/L (5.6% × 4.8 mmol/L) reduction (see Table 2).
      Table 2Estimated Reduction in Serum LDL Cholesterol and Risk of Heart Attack According to Typical Grapefruit Juice Consumption and Time of Consumption in Relation to Taking the Statin
      Estimated reductions for a 60-year-old man with a baseline serum LDL cholesterol of 4.8 mmol/L.
      [Grapefruit Juice Has No Effect on Pravastatin or Rosuvastatin]
      Consumption of Grapefruit Juice in Relation to Taking the StatinEffective Standard Dose of Statin

      (a)
      % Reduction in Serum LDL Cholesterol

      37% +[log(a)/log(2) × 6%]

      (b)
      Absolute Reduction in Serum LDL Cholesterol (mmol/L)

      b × 4.8

      (c)
      Estimated Reduction in Ischemic Heart Disease Risk

      1−(1−0.41)c

      (d)
      Not consumed137%1.861%
      12 hours before simvastatin (40 mg) or lovastatin (40 mg)1.943%2.066%
      At same time as simvastatin (40 mg) or lovastatin (40 mg)3.648%2.370%
      Any time with atorvastatin (10 mg)1.842%2.066%
      LDL = low-density lipoprotein.
      Estimated reductions for a 60-year-old man with a baseline serum LDL cholesterol of 4.8 mmol/L.
      A 1-mmol/L reduction in serum LDL cholesterol reduces the risk of ischemic heart disease (IHD) in a 60-year-old by 41%.
      • Law M.R.
      • Wald N.J.
      • Rudnicka A.R.
      Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.
      Using this, together with the absolute reduction in LDL shown in Table 2, 10 mg atorvastatin, 40 mg simvastatin, or 40 mg lovastatin reduces IHD risk by 61% (1-[1-0.41]1.8). Grapefruit juice + 40 mg simvastatin or 40 mg lovastatin reduces IHD risk by 70% (1-[1-0.41]2.3), and grapefruit juice 12 hours before 40 mg simvastatin or 40 mg lovastatin reduces IHD risk by 66% (1-[1-0.41]2.0). This is summarized in Table 2.

      Risk of Rhabdomyolysis in Statin Users

      The single serious and potentially fatal side effect of statin use is rhabdomyolysis. A study published in 2006 examined this risk using data from cohort studies, randomized trials, voluntary notifications to health agencies, and case reports.
      • Law M.
      • Rudnicka A.R.
      Statin safety: a systematic review.
      The incidence of rhabdomyolysis for individuals on lovastatin, simvastatin, and atorvastatin was about 4 per 100,000 person-years, compared with a 1 per 100,000 person-years risk for fluvastatin or pravastatin, which are less effective in lowering LDL cholesterol. A nested case-control study on 29 cases of rhabdomyolysis from a cohort of 315,562 simvastatin users compared simvastatin 40 mg and 20 mg daily and reported rates of rhabdomyolysis to be 11.5 (95% confidence interval, 7.1-17.5) and 2 (0.7-4.8) per 100,000 person-years, respectively.
      • Parkin L.
      • Paul C.
      • Herbison G.P.
      Simvastatin dose and risk of rhabdomyolysis: nested case-control study based on national health and drug dispensing data.
      The incidence of statin-induced rhabdomyolysis is so rare that the increase in effective statin dose with concomitant use of grapefruit juice would increase the risk by a small amount – the magnitude of the increased risk is uncertain, but on the basis of the increase in blood levels of the statin on its metabolite, is unlikely to exceed 1-2 per 100,000 person years.

      Prescribing Implications

      The expected effect of grapefruit juice consumption is to increase the reduction of LDL cholesterol by up to about 6 percentage points, with a similar reduction in the incidence of IHD. It would be perverse to regard this enhanced efficacy as an adverse effect. Even with the small risk of rhabdomyolysis, there is a net health benefit. The counter argument that, if it were intended to administer an increased dose of the drug this should have been prescribed, is not persuasive because a more practical approach would be to ask whether an individual being prescribed a statin regularly drank grapefruit juice and if the prescriber felt it was necessary, to prescribe a lower dose. This is more considerate of the wishes of the individual who may enjoy drinking grapefruit juice but who requires statin therapy. In any event, doses of statins are not, in practice, carefully titrated for individual patients.
      The perception that grapefruit juice is contraindicated when taking a statin is misleading, a conclusion derived from pharmacokinetic studies that use unusually large amounts of grapefruit juice. The view that grapefruit juice can enhance the therapeutic benefit of drugs is already recognized in cancer treatment,
      • Cohen E.E.
      • Wu K.
      • Hartford C.
      • et al.
      Phase I studies of sirolimus alone or in combination with pharmacokinetic modulators in advanced cancer patients.
      where the cost of the drug is substantial and there is economic benefit in the enhancement. By contrast, for statins the economic benefit is negligible, and the utility is in accommodating the patient's dietary preferences.

      Conclusion

      There is a well-characterized interaction between grapefruit juice and certain statins. This interaction leads to the effective dose of a statin being increased, with resulting benefits in reducing LDL cholesterol and IHD. The risk of rhabdomyolysis is much less in comparison, and overall, there is no need to advise people on statins to avoid drinking grapefruit juice.

      References

      1. Simvastatin: updated advice on drug interactions: Medicines and Healthcare Products Regulatory Agency; 2012. Available at: https://www.gov.uk/drug-safety-update/simvastatin-updated-advice-on-drug-interactions. Accessed June 12, 2015.

      2. U.S. Food and Drug Administration. Grapefruit juice and medicine may not mix [updated January 20th 2015]. Available at: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm292276.htm. Accessed June 12, 2015.

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      Linked Article

      • Grapefruit with Your Statin?
        The American Journal of MedicineVol. 129Issue 8
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          We read with great interest the article by Lee et al, “Grapefruit Juice and Statins,” published in January 2016.1 The interaction between grapefruit and statins, as well as other medications, has been well described. The active component 6′,7′-dihydroxybergamottin in fresh grapefruit juice inactivates enzyme cytochrome P450 (CYP) 3A4 and subsequently decreases CYP3A4-dependent metabolism of 3 statins—atorvastatin, simvastatin, and lovastatin—but not CYP2C9-dependent and sulphation-dependent statins rosuvastatin, fluvastatin, and pravastatin.
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      • Better to Avoid Grapefruit with Certain Statins
        The American Journal of MedicineVol. 129Issue 11
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          This brief opinion piece by Lee et al1 focuses on the clinical consequences resulting from augmented systemic statin (simvastatin, lovastatin, atorvastatin) concentrations with grapefruit. The authors disagree with the long- and widely held view that the primary issue is concern for drug toxicity. Instead, they raise the hypothetical prospect for enhanced cardiovascular benefit outweighing risk of rhabdomyolysis. However, they don't seem to think that other, more frequent but less severe myopathies and hyperglycemia are pertinent considerations.
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        • PDF