Jay S. Cohen M.D. http://medicationsense.com      1337 Camino Del Mar   Suite C Del Mar, CA 92014 Phone: 858.345.1760 Fax: 858.509.8944


Drugs, Liver Injury, and Cancer: Is there a Connection?

A New Study Provides Additional Reasons to Avoid High Doses of Statin Medications

In articles posted at MedicationSense.com in recent months, I discussed the findings of two major studies of maximum-dose 80-mg Lipitor (atorvastatin).  Despite the authors' claims that these studies proved the benefit of maximum-dose Lipitor for preventing heart attacks and strokes, the MedicationSense.com articles revealed that maximum-dose Lipitor caused far more liver injuries than placebo or low-dose Lipitor.  Even worse, despite a reduction in heart attacks and a slight reduction in strokes, there was no improvement in overall mortality because more subjects on maximum-dose Lipitor died of other causes including cancer.1,2

Now comes a study in which the authors examined the relationship of LDL lowering by statins with the occurrence of liver injury and cancer.  The study, a meta-analysis titled "Effect of the Magnitude of Lipid Lowering on Risk of Elevated Liver Enzymes, Rhabdomyolysis, and Cancer," derived its results from 23 large clinical trials involving statin drugs.3  Unlike the maximum-dose Lipitor studies, which were authored entirely by consultants to and employees of Pfizer, most of the authors of the new article had no financial ties to drug companies.

Liver Injury Caused by Statins

When liver cells die, enzymes are released.These enzymes can be measured in the blood.  Liver injury is usually defined as liver enzyme levels more than three times greater than normal.  In the new meta-analysis, higher doses of statins were associated with higher numbers of subjects with liver injury.  Per 100,000 subjects, 271 cases of liver injury were associated with high-dose statins.  Low-dose statins were linked to 114 cases of liver injury per 100,000 subjects.  This meant that high-dose statins were linked with 2.4 times more cases of liver injury than low-dose statins.

This trend was also seen with individual statin drugs. For example, the rate of liver injury with high-dose Zocor (simvastatin) was 1.6 times greater than with low-dose Zocor.  The rate of liver injury with high-dose Lipitor (atorvastatin) was 4.0 times greater than with low-dose Lipitor.

These findings are consistent with the results seen previously in the maximum-dose Lipitor studies.  In the heart attack study, the number of subjects developing liver injury with maximum-dose Lipitor was 5.5 times greater than with low-dose Lipitor.1  In the stroke study, the rate was 4.5 times greater with maximum-dose Lipitor than with placebo.2  Thus, if 10 million patients are prescribed maximum-dose Lipitor, between 400,000 and 550,000 patients will sustain liver injuries.  Most of these injuries will be minor and reversible with discontinuation of the drug.  However, it is also likely that some of these liver injuries will be serious or life-threatening.  Statin medications have been linked on occasion with liver failure.

Statins and Muscle Pain

Statins are well known to cause muscle pain and muscle weakness.  Rhabdomyolysis is the term for severe muscle injury that can cause kidney injury, kidney failure and death.  Data on rhabdomyolysis in the new study was sparse.  Nevertheless, some data was obtained on statin dosage and the risk of rhabdomyolysis.  For example, in one clinical trial, the reported rate of rhabdomyolysis was more than 7-fold greater with high-dose Zocor (simvastatin) than with a moderate dose.3

Statins and Cancer

Dr. Alsheikh-Ali et al. also examined data from thirteen clinical trials for associations between LDL reduction with statins and the risk of cancer.  The authors noted, "there was a highly significant inverse relationship between achieved LDL levels and rates of newly diagnosed cancer."3  This meant that as subjects achieved lower LDL and cholesterol levels from their use of statins, their frequency of developing cancer increased.  Similarly, there was a trend toward more new cancer cases with increasing statin dosage.4

The authors also pointed out that epidemiological studies have consistently shown an increased incidence of cancer with low cholesterol levels.  On the other hand, most of the large clinical trials did not demonstrate an increase in the occurrence of cancer with statins in comparison with placebo.  So the evidence remains mixed.

Doctors Advised to Avoid Overmedication with Statins

Because of the increased risk of liver injuries and cancer that was seen in the new study was clearly linked to higher doses of statin drugs, the authors suggested that patients should not be given high statin doses unless there is a specific need to achieve target LDL levels.  Higher doses of statins that exceed the amount needed to reach target LDL levels should be avoided.  As the authors put it, "a higher dose of statin is associated with increased risk of toxicity, [so] it may be prudent not to use a statin dose beyond what is required to achieve the LDL target."3

This advice sounds familiar.  Some readers may remember that when the first maximum-dose Lipitor study was published, it was accompanied by an editorial written by an independent expert.  Dr. Bertram Pitt did not support the use of maximum-dose Lipitor for preventing heart attacks.5  Dr. Pitt noted that patients on maximum-dose Lipitor did not show an overall reduction in deaths.  Patients receiving maximum-dose Lipitor sustained fewer deaths from heart disease, but more deaths from other causes including cancer.  Until these findings were explained, Dr. Pitt advised against using maximum-dose Lipitor.  I agree with him.

Dr. Peck suggested that if the goal was a large reduction in LDL levels, this can be accomplished by combining a moderate dose statin combined with Zetia (ezetimibe), which blocks cholesterol absorption from the gastrointestinal tract.5  I will add that a similar substance, phytosterols, is a natural plant derivative that also prevents cholesterol absorption from the intestine.  Phytosterols can be taken with low or moderate dose statins.

The new study from Alsheikh-Ali et al. suggests that doctors should not try to reduce cholesterol and LDL more than necessary.  Doctors should prescribe only enough statins to reduce patients' LDL levels to reach target levels.  In an unexpected way, this approach agrees with my stance on statins for the last twenty years: excess statin medication can be harmful.  Overmedication of patients taking statins, which occurs all too frequently, should be avoided. 

My first principle of using medications wisely is: "The best dose of any medication is the lowest dose that works."  This applies to statins.  Many statin side effects are dose-related: side effects occur more frequently and severely with stronger doses of statins.  This is why so many patients quit statin treatment.  Nearly 80 percent of patients placed on statin medications discontinue treatment within one to twenty-four months.

When the first maximum-dose Lipitor study was published in 2005, the drug received a blizzard of attention from the media.  At the same time, Pfizer launched an intensive advertising campaign.  After spinning the message to consumers, doctors became the main target.  The goal was to convince doctors to prescribe more maximum-dose Lipitor to more patients.  These efforts worked handsomely.  Pfizer's profits climbed as the number of prescriptions for maximum-dose Lipitor soared.

In my upcoming book, I provide tables that you can use to define your target LDL and the percentage of LDL reduction you need.  There is also a table that recommends the right statins and doses for any LDL level.  With this information, readers will be able to define their own LDL goal and to discuss the choice of statin and the dosage with their doctors. 

This information can be extremely helpful because many doctors do not bother to define their patients' LDL goals.  Instead they prescribe the same treatment, such as maximum-dose Lipitor, for all.  Overmedication is frequently the result with increased risks of side effects.  According to the new study by Alsheikh-Ali et al., overmedication with statins may also increase your risks of liver injury and cancer.

References

1. LaRosa JC, Grundy SM, Waters DD, et al.  Intensive lipid lowering with atorvastatin in patients with stable coronary disease.  New England Journal of Medicine 2005;352:1425?]35.

2. Stroke prevention by aggressive reduction in cholesterol levels investigators.  High?]dose atorvastatin after stroke or transient ischemic hepatic.  New England Journal of Medicine 2006;355:549?]559.


3. Alsheikh-Ali AA, Maddukuri PR, Han H, et al.  Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer.  Journal of the American College of Cardiology 2007;50:409-18.

4. LaRosa JC.  Means and ends of statins and low-density lipoprotein cholesterol lowering.  Journal of the American College of Cardiology 2007;50:419-20.

5. Pitt B.  Low-density lipoprotein cholesterol in patients with stable coronary heart disease -- is it time to shift our goals?  New England Journal of Medicine 2005;352(14):1483-1484.





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