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Carcinogenicity of Lipid-lowering Drugs

Carcinogenicity of Lipid-lowering Drugs

Journal of the American Medical Association

January 3, 1996;275(1):55-60 Newman TB, Hulley SB.Department of Laboratory Medicine, School of Medicine, University of California, San Francisco, USA. 

  

1) "Drug companies are required to submit data from rodent carcinogenicity studies to the FDA. These studies are not generally published in scientific journals but are summarized in the Physicians' Desk Reference (PDR)." These authors evaluated the results of these carcinogenicity rodent studies in the PDR and compared them to other classes of drugs.

2) "The results of experiments in animals and humans suggest that lipidlowering drug treatment, especially with the fibrates and statins, should be avoided except in patients at high short-term risk of coronary heart disease."

3) Lipid-lowering drugs may be taken for 30 years or more, yet the FDA approved these drugs based upon clinical trials that lasted only a fraction of this time.
4) "Millions of asymptomatic people are being treated with medications [lipidlowering
drugs], the ultimate effects of which are not yet known."
5) "Meta-analyses of randomized clinical trials have suggested that cholesterol lowering drugs may increase noncardiovascular mortality."
6) "The product information for lipid-lowering drugs indicates that all the fibric acid derivatives and statins caused cancer in rodents."
7) "In most cases the rodent exposure at which carcinogenicity was observed was of the same order of magnitude as that observed with the maximum dose recommended for humans."
8) "Almost all known human carcinogens have been found to be carcinogenic in mice and rats."
9) "For patients not at high short-term risk of CHD death, especially patients
with life expectancies of more than 10 to 20 years, pharmacologic treatment [with
lipid-lowering drugs] probably should be avoided."
10) It is possible that these drugs are not carcinogenic, but rather that it is the lower cholesterol levels they cause being responsible for the adverse effects. "Persons with low cholesterol levels have higher cancer death rates in cohort studies."
11) "It seems prudent to reserve the statins for people at high short-term risk of heart disease and to be wary about their long-term use."
12) "Most cholesterol-lowering drugs cause or promote cancer."
13) "All members of the two most popular classes of lipid-lowering drugs (the fibrates and the statins) cause cancer in rodents, in some cases at levels of animal exposure close to those prescribed to humans."
14) "Patients to whom these drugs are prescribed are exposed throughout many years to doses approaching those shown to be carcinogenic in animals."
15) Use of cholesterol-lowering drugs should be restricted to those at high risk of short-term CHD death, such as those with prior CHD, in whom the short-term benefits of treatment are most likely to justify the long-term risks.

  

 (This is the abstract from this article)

 

Carcinogenicity of Lipid-lowering Drugs

Journal of the American Medical Association

January 3, 1996;275(1):55-60

Newman TB, Hulley SB.

Department of Laboratory Medicine, School of Medicine, University of California,

San Francisco, USA.

BACKGROUND INFORMATION:

Fibrates:

Bezafibrate (e.g. Bezalip)

Ciprofibrate (e.g. Modalim)

Gemfibrozil (e.g. Lopid)

Fenofibrate (e.g. TriCor)

Statin Brand name Derivation

Atorvastatin Lipitor, Torvast Synthetic

Fluvastatin Lescol Synthetic

Lovastatin Mevacor, Altocor, Altoprev Fermentation-derived

Mevastatin Naturally-occurring, found in

red yeast rice

Pitavastatin Livalo, Pitava Synthetic

Pravastatin Pravachol, Selektine, Lipostat Fermentation-derived

Rosuvastatin Crestor Synthetic

Simvastatin Zocor, Lipex Fermentation-derived

Simvastatin+Ezetimibe Vytorin Combination therapy

Lovastatin+Niacin Advicor Combination therapy

Simvastatin+Niacin Simcor Combination therapy

OBJECTIVE

To review the findings and implications of studies of rodent carcinogenicity of lipidlowering

drugs.

DATA SOURCES

Summaries of carcinogenicity studies published in the 1992 and 1994 Physicians'

Desk Reference (PDR), additional information obtained from the US Food and Drug

Administration, and published articles identified by computer searching,

bibliographies, and consultation with experts.

STUDY SAMPLE

We tabulated rodent carcinogenicity data from the 1994 PDR for all drugs listed as

"hypolipidemics." For comparison, we selected a stratified random sample of

antihypertensive drugs. We also reviewed methods and interpretation of

carcinogenicity studies in rodents and results of clinical trials in humans.

DATA SYNTHESIS

All members of the two most popular classes of lipid-lowering drugs (the fibrates

and the statins) cause cancer in rodents, in some cases at levels of animal exposure

close to those prescribed to humans.

In contrast, few of the antihypertensive drugs have been found to be carcinogenic

in rodents.

Evidence of carcinogenicity of lipid-lowering drugs from clinical trials in humans is

inconclusive because of inconsistent results and insufficient duration of follow-up.

CONCLUSIONS

Extrapolation of this evidence of carcinogenesis from rodents to humans is an

uncertain process. Longer-term clinical trials and careful post-marketing

surveillance during the next several decades are needed to determine whether

cholesterol-lowering drugs cause cancer in humans.

In the meantime, the results of experiments in animals and humans suggest that

lipid-lowering drug treatment, especially with the fibrates and statins, should be

avoided except in patients at high short-term risk of coronary heart disease.

THESE AUTHORS ALSO NOTE:

In the past decade (1985 - 1995) there has been a greater than 10-fold

increase in the prescription of lipid-lowering drugs because they are being

aggressively promoted by their manufacturers.

Lipid-lowering drugs may be taken for 30 years or more, yet the FDA

approved these drugs based upon clinical trial that lasted only a fraction of this

time.

"Thus, millions of asymptomatic people are being treated with medications,

the ultimate effects of which are not yet known."

"Meta-analyses of randomized clinical trials have suggested that cholesterollowering

drugs may increase noncardiovascular mortality."

"Drug companies are required to submit data from rodent carcinogenicity

studies to the FDA. These studies are not generally published in scientific journals

but are summarized in the Physicians' Desk Reference (PDR)." These authors

evaluated the results of these carcinogenicity rodent studies in the PDR and

compared them to other classes of drugs.

RESULTS

"The product information for lipid-lowering drugs indicates that all the fibric

acid derivatives and statins caused cancer in rodents."

"In most cases the rodent exposure at which carcinogenicity was observed

was of the same order of magnitude as that observed with the maximum dose

recommended for humans."

"Unlike the lipid-lowering drugs, most drugs for lowering blood pressure do

not cause cancer."

"Almost all known human carcinogens have been found to be carcinogenic in

mice and rats."

"Why Were These Drugs Approved?"

These authors reviewed the minutes of the approval committee meeting, and

found that representatives of the makers of these drugs downplayed the importance

of the rodent carcinogenicity studies. Additionally, for gemfibrozil, "only three of the

nine members of the advisory committee believed that the potential benefit of using

gemfibrozil, for the prevention of coronary heart disease outweighed the potential

risks associated with such use."

Sadly, such votes are only advisory, and the FDA approved gemfibrozil, when

all of the following criteria are met:

1) Low high-density lipoprotein cholesterol.

2) Elevated low-density lipoprotein cholesterol.

3) Elevated triglycerides.

4) Inadequate response to weight loss, diet, and exercise.

"Unfortunately, the subsequent popularity of gemfibrozil suggests that its use has

not been restricted to this small group."

"For patients not at high short-term risk of CHD death, especially patients

with life expectancies of more than 10 to 20 years, pharmacologic treatment

probably should be avoided."

It is possible that these drugs are not carcinogenic, but rather that it is the

lower cholesterol levels they cause being responsible for the adverse effects.

"Persons with low cholesterol levels have higher cancer death rates in cohort

studies."

"It seems prudent to reserve the statins for people at high short-term risk of

heart disease and to be wary about their long-term use."

CONCLUSION

"Most cholesterol-lowering drugs cause or promote cancer."

"Patients to whom these drugs are prescribed are exposed throughout many

years to doses approaching those shown to be carcinogenic in animals."

Use of cholesterol-lowering drugs should be restricted to those at high risk of

short-term CHD death, such as those with prior CHD, in whom the short-term

benefits of treatment are most likely to justify the long-term risks.