It Was Never “An Apple a Day”: Grapefruit Juice and Statins

Gregory W. Rutecki, MD

It began as serendipity. In an experiment designed to determine the effect of ethanol on felodipine levels,1 researchers used grapefruit juice to mask the taste of alcohol. Felodipine concentrations in the patients’ blood increased. Later, grapefruit products were found to increase levels of many other drugs, including statins. Furanocoumarins in grapefruit juice inactivate CYP3A4, the enzyme responsible for metabolizing lovastatin, simvastatin, and atorvastatin (but not fluvastatin, rosuvastatin, or pravastatin).2 Taking atorvastatin with grapefruit juice, for example, increases this statin’s blood level 1.8 times.2 Drinking grapefruit juice with lovastatin, simvastatin, or atorvastatin also may induce rhabdomyolysis, a complication related to statin use in certain individuals (incidence of 4 per 100,000 person-years with these 3 statins).2

Despite the fact that the studies examining possible cause-and-effect relationships between statins and muscle necrosis were characterized by large doses of grapefruit juice,2 a universal prohibition followed nonetheless: No grapefruits or grapefruit juice for users of atorvastatin, simvastatin, or lovastatin!

Fast-forward to 2016, where a Top Paper by Lee, Morris, and Wald reframes the grapefruit-statin interaction.2 They note that a meta-analysis3 in 2003 estimated that 40 mg of simvastatin reduces low-density lipoprotein (LDL) cholesterol by 37%, but double this dosage and LDL drops by 43%. The authors also note that a standard serving of grapefruit juice, taken at the same time as simvastatin, increases the effective dose of the drug 3.6-fold; this increase would be 1.9-fold were the grapefruit product consumed 12 hours earlier.2 Using these calculations, and knowing that 10 mg of simvastatin reduces the ischemic heart disease risk by 61%, the authors conclude that adding grapefruit juice 12 hours before dosing would further reduce risk by 66%.2

What about the potential negative corollary, rhabdomyolysis? A recent study enrolling 313,552 simvastatin users identified 29 individuals who developed rhabdomyolysis.4 Comparing 2 doses of simvastatin, 40 and 20 mg, demonstrated that the rate of muscle injury with higher doses of statin was unlikely to be greater than 1 or 2 per 100,000 person-years.2

The authors’ conclusions:

  1. Grapefruit juice enhances the efficacy of certain statins by raising blood levels; in so doing, it reduces LDL levels further and, as a result, reduces the risk of ischemic heart disease more.
  2. Contraindicating grapefruits or their juice in statin users may not be necessary.
  3. Although the risk of rhabdomyolysis may increase with grapefruit products, that risk does not increase substantially; withholding grapefruits may obviate the positive effects of statin concentration increases and the benefits derived from these increases.

You may want to weigh these facts at your next breakfast, or even with your next margarita (moderation please!). 

Gregory W. Rutecki, MD, is a physician at the National Consult Service at the Cleveland Clinic. He is also a member of the editorial board of Consultant. He reports that he has no relevant financial relationships to disclose.


  1. Bailey DG, Spence JD, Edgar B, Bayliff CD, Arnold JM. Ethanol enhances the hemodynamic effects of felodipine. Clin Invest Med. 1989;12(6):357-362.
  2. Lee JW, Morris JK, Wald NJ. Grapefruit juice and statins. Am J Med. 2016; 129(1):26-29.
  3. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ. 2003;326(7404):1423.
  4. Parkin L, Paul C, Herbison GP. Simvastatin dose and risk of rhabdomyolysis: nested case-control study based on national health and drug dispensing data. Int J Cardiol. 2014;174(1):83-89.