Grapefruit Juice And Statins: A Potential Hazard?

Statistically significant doesn’t necessarily mean clinically significant.

Grapefruits are known for being nutritionally dense, especially with vitamins and minerals believed to help with weight management, boost the immune system, and reduce the risk of kidney stones.

But while well-known for its health-promoting effects, grapefruit is also notorious for interacting with certain medications. For example, statin, a drug that helps lower the LDL or ‘bad’ cholesterol, which I have detailed here.

So, this brings us to the important question. Should you avoid consuming grapefruit or grapefruit juice when taking statins?

But first, let’s understand how orally administered drugs — such as statins — are processed in the body.

What You Take ≠ What You Have

Drugs can be administered in many ways — through the mouth (oral), nose (nasal), muscle (intramuscular injection), etc.

In the body, the drugs undergo four processes, they are

• absorbed into the systemic (blood) circulation.
• distributed through the circulation to the targetted site to carry out their intended effect.
• metabolized (converted or broken down) into metabolites that can be cleared off easily.
• excreted from the body either through the kidney (urine) or feces.

However, before that, medications taken orally need to go through an extra process before entering the circulation. Because, unlike intravenous administration — where medications are directly inserted into the blood circulation — swallowed medications need to go through the stomach, the small intestine, and then the liver before finally reaching the circulation and traveling to where they are needed.

And because the liver is the major site of metabolism, a portion of the drug will be booted out as it passes through the liver, leaving a smaller fraction to enter the circulation. This process is referred to as the first-pass effect.

Now, many of the metabolizing effects are carried out by enzymes called cytochrome P450 (hereafter referred to as CYP). These CYPs are present in abundance in liver cells and small intestinal cells.

One of the many enzymes belonging in this class is called the CYP3A4, which is known to metabolize most clinically prescribed drugs. This includes statins like lovastatin, simvastatin, and atorvastatin.

Other statins like pravastatin, rosuvastatin, or fluvastatin are not mainly metabolized by CYP3A4. Hence, they are less or not affected by grapefruit juice.

So, what is the concern behind grapefruit and some statins?

Grapefruit And Statins

Apparently, grapefruits — specifically a bioactive compound within the fruit called furanocoumarin — are inhibitors of CYP3A4. Meaning that it interferes with CYP3A4 metabolizing or breaking down substrates.

As a result, more of that medication (i.e., statins) slip through unscathed into the circulation, thus increasing the risk of overdose or dose-dependent adverse effects such as myopathy [muscle disorders], diabetes, and hemorrhagic stroke.

But how significant is the increase resulting from grapefruit juice and statins?

Controlled Clinical Pharmacokinetic Studies

In a 2004 Finnish study, “Effects of regular consumption of grapefruit juice on the pharmacokinetics of simvastatin,” researchers gave 10 healthy men (aged 20–24 years) 200 mL of commercial regular-strength grapefruit juice (GFJ) or water (control) at breakfast for 3 consecutive days. On day 3, a single dose of 40 mg simvastatin was administered with GFJ or water.

The concentration of simvastatin and its metabolites (e.g., simvastatin acid) in their blood [plasma concentration] was measured before and up to 24 hours after drug administration.

By 24 hours, relative to the control group, the concentration of simvastatin and its metabolites increased by 1.8- to 6.0-fold in the GFJ group. Results were statistically significant.

Regular-strength GFJ (GFJ) refers to the reconstitution of frozen concentrated grapefruit juice with 3 equal parts of water.
(e.g., 200 mL GFJ prepared from 1 can of frozen concentrated grapefruit juice with 3 cans of water.)

Double-strength GFJ (DS-GFJ) means the reconstitution of frozen concentrated grapefruit juice with equal parts of water.
(e.g., 200 mL GFJ prepared from 1 can of frozen concentrated grapefruit juice with 3 cans of water.)

Such increases were also observed in other studies using various amounts or doses of GFJ and statins:

• In a 1998 Finnish study, 10 healthy individuals (aged 18–30 years; 50% male) consumed DS-GFJ 3 times/day for 2 days. On the third day, they were given a total of 600 mL DS-GFJ and 60 mg of simvastatin in the morning. Their plasma concentration of simvastatin and its metabolites increased by 1.8- to 37.7-fold in the GFJ group compared to the control group. Results were statistically significant.
• A follow-up study attempted to see how long the effect of repeated consumption of high doses of GFJ will last after the cessation of GFJ. Here, 10 healthy individuals (20–34 years; 90% male) consumed DS-GFJ 3 times/day for 2 days. Then, they took 40 mg simvastatin concomitantly, 3 and 7 days after the last dose of DS-GFJ. The increase was 4.5- to 13.5-fold for concomitant administration, 1.7- to 2.1-fold at 24 hours, 1.4-fold at 3 days, and no differences with control at 7 days. Results were statistically significant for concomitant administration and 24 hours but not for 3 and 7 days.

For lovastatin,

• A 1998 Finnish study with 10 healthy individuals (21–35 years; 40% male) showed that DS-GFJ 3 times/day for 2 days and 80 mg of lovastatin with a total of 600 mL DS-GFJ taken in the morning on the third day increased the plasma concentration of lovastatin and its metabolites by 2.4- to 23.3-fold at 12 hours. Results were statistically significant.
• In a 1999 U.S.A study involving sixteen healthy male subjects (18–39 years), a single daily glass of regular-strength GFJ in the morning for three days and a single dose of 40 mg lovastatin were taken in the evening. The increase was 1.6- to 1.9-fold. Results were statistically significant for lovastatin but not lovastatin acid (metabolite).

For atorvastatin,

• In a 1999 Finnish study involving 12 healthy individuals (19–27 years, 50% male), 40 mg of atorvastatin with a total of 600 mL DS-GFJ taken in the morning on the third day increased the plasma concentration of atorvastatin and its metabolites by 1.7- to 5.7-fold. Results were statistically significant.
• In a 2004 Japanese study, 10 healthy males (20–33 years) who took 250 mL GFJ 3 times/day for 3 days with a single dose of 10 mg of atorvastatin in the morning of the third day saw an increase in bloodstream atorvastatin metabolites by 1.4- to 1.6-fold.

So yes, grapefruit juice does increase the plasma concentration of statins, specifically simvastatin, lovastatin, and atorvastatin in the blood. In fact, the effect seems to be most prominent for simvastatin.

Nevertheless, controlled clinical studies for drug interactions are often designed to document the ‘worst case’ scenario. Hence, the GFJ doses used in most of these studies were much higher than what is normally consumed, especially in studies reporting an increase in plasma concentration of the drugs exceeding 10-fold.

As Dr. Darrell Abernethy, a former American Associate Director for Drug Safety in the Office of Clinical Pharmacology at the Food and Drug Administration (FDA), and who, sadly, has passed on in 2017, pointed out, “the findings are best demonstrated when 240 ml (8 oz) of double-strength reconstituted grapefruit concentrate is ingested simultaneously with the drug substrate or 8 oz [240 mL] of regular strength grapefruit juice ingested three times daily,” he wrote in 1997. “It is fair to say this is a substantial grapefruit juice exposure that would occur only during unusual dietary circumstances.”

Is Statistically Significant Clinically Significant?

In 2011, the GREAT (GRapefruit Effect on Atorvastatin Therapy) Trial was initiated to assess the long-term effects of a daily single 300 mL glass of GFJ among atorvastatin users.

The 130 participants (mean age: 63 and 66 years; 59% male) who took part in this study were daily atorvastatin (10 mg, 20 mg, 40 mg) users for at least 3 months before the study. They were randomized into two groups:

• Group A: participants take a 300 mL glass of commercially available 100% GFJ in the morning every day with their usual daily dose of atorvastatin in the evening.
• Group B: participants take a 300 mL glass of commercially available 100% GFJ in the morning every day with half their usual daily dose of atorvastatin in the evening.

Their atorvastatin concentration, lipid profile (total cholesterol, LDL, high-density lipoprotein (HDL), triglycerides), alanine transaminase and aspartate aminotransferase (biomarkers for liver function), and CPK (biomarker for muscle break-down) were measured at days 0, 30, 60, and 90 since the first intake of GFJ.

They found that on days 30, 60, and 90:

• median serum atorvastatin increased by 19% to 26% compared with day 0 in group A but decreased by 12% to 25% compared with day 0 in group B.
• there were no changes in LDL levels in group A, but there was an increase in LDL levels by 9% in group B.
• Changes in ALT, AST, and CPK were minimal and did not reach statistical significance in both groups.
• Although participants reported some myalgia [muscle ache or weakness] (20.4%-40.1% of the participants in group A and 27.3%-34.5% in group B), no cases of liver or muscle toxicity were reported.

“The findings indicate a small elevation of serum atorvastatin concentrations due to grapefruit juice, but no meaningful enhancement of lipid-lowering effects, and no evidence of adverse liver or muscle effects,” the authors concluded. “The data from [group] B patients confirm that a reduction in atorvastatin dosage is not necessary for patients who initiate daily exposure to GFJ.”

In other words, a single serving of a typical 300 mL of grapefruit juice for breakfast is not enough to create any clinical effects among atorvastatin users, even at a dose of 40 mg taken in the evening.

“Caution is by far the wisest approach.”

What The Studies Tell Us

While the results from the controlled clinical pharmacokinetic studies seemed intimidating, it should be noted that these studies were designed to present the worst-case scenario and not that of typical lifestyle circumstances.

For example, statins, especially simvastatin and lovastatin are usually taken at night instead of in the morning. And it is unlikely for someone to consume more than 600 mL of highly-concentrated grapefruit juice in a day.

The GREAT trial, which bears a closer resemblance to the usual dietary circumstances (i.e., a 300 mL glass of grapefruit juice in the morning and atorvastatin in the evening), however, has proven the lack of clinical effects worthy of concern.

Nevertheless, the exaggerated studies did point out something we should look out for.

For example, the effects of the interaction between grapefruit juice and statins may vary largely between individuals. The first 1998 Finnish study found an increase in plasma concentration of simvastatin in a range of 9- to 37.7-fold between individuals. A similar pattern was also found in all other studies.

This means that some people might be more affected by the interaction than others. Hence, there is a need to stay cautious, especially for those who are taking simvastatin, as it appears to be more sensitive toward the grapefruit juice effect. After all, an adverse event that has not been reported does not mean it has not happened or will not happen.

As Dr. Bailey, a scientist in London has stated, “That a serious adverse event has not been reported should not be interpreted to mean that it has not happened. To recognize an adverse event, there must be an awareness of the possibility of such an adverse event. Otherwise, the likelihood that it will be investigated is extremely low…Caution is by far the wisest approach. ”

Key Takeaway

To summarize from those studies, there is a concern with grapefruit juice-statin interaction if,

• ≥600 mL of regular or highly-concentrated grapefruit juice are consumed in a day with simvastatin, lovastatin, and atorvastatin.
• grapefruit juice is taken concomitantly with statins.
• your dosage of simvastatin, lovastatin, or atorvastatin is >40 mg.

In normal circumstances,

• a ≤300 mL glass of grapefruit juice in the morning and atorvastatin in the evening is safe, at least, for up to three months.
• other statins like pravastatin, rosuvastatin, pitavastatin, or fluvastatin are not or less affected by grapefruit juice.

However, the effects of the interaction may vary between individuals. Hence, one must still remain cautious, especially for those taking simvastatin, as it seems to be more affected by the interaction with grapefruit juice.

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