Cancer and lipid lowering drugs

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    Special Communication to the American Medical Assn;
    Published in the January 3, 1996 Volume of the Journal of
    the American Medical Association

    Carcinogenicity of Lipid-Lowering Drugs

    Thomas B. Newman, MD, MPH, Stephan B. Hulley, MD, MPH

    Objective – To review the findings and implications of
    studies of rodent carcinogenicity of lipid-lowering 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.

    The past decade has seen a more than 10-fold increase in
    prescriptions for lipid-lowering drugs, with more than 26
    million prescriptions in 1992 in the United States. The
    number of prescriptions for these drugs is likely to
    continue to increase because they are being aggressively
    promoted by their manufacturers and because many patients
    who are eligible for lipid-lowering treatment according to
    the most widely publicized US guidelines are still not
    receiving them.

    The duration and impact of such treatment in any one patient
    may extend for 30 years or more. Yet the drugs have been
    approved by the Food and Drug Administration (FDA) based on
    the findings of full-scale clinical trials lasting less than
    a decade - far less in the case of the
    hydroxymethylglutaryl.C0A reductase inhibitors (the
    statins). Thus, millions of asymptomatic people are being
    treated with medications, the ultimate effects of which are
    not yet known. This situation has become more controversial
    recently, particularly for primary prevention, because meta-
    analyses of randomized clinical trials have suggested that
    cholesterol-lowering drugs may increase noncardiovasular
    mortality. In this article we turn to less direct evidence.
    As part of the new drug approval process, pharmaceutical
    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) and in
    the prescribing information that accompanies advertisements
    and the medications themselves. We examine this evidence
    herein, comparing results of carcinogenicity studies of lipid-
    lowering agents with those of antihypertensive agents,
    another class of drugs often prescribed for decades in
    asymptomatic people with the goal of preventing
    cardiovascular disease.

    Methods

    Rodent toxicity date were abstracted from the product
    information in the 1992 and 1994 editions of the PDR for all
    drugs listed in the ?Product Category Index? as
    ?hypolipidemics.? For each drug, we abstracted data on all
    the studies of carcinogenesis in animals. The relative
    exposures listed in Tables 1 through 3 represent the lowest
    exposures at which statistically significant increase in the
    incidence of tumors was reported in treated animals when
    compared with control animals.

    For comparison, we drew a sample of oral drugs listed in
    the ?Product Category Index? as cardiovascular agents with
    hypertension s an inedication, after stratifying these
    adrenergic blockers, adregenic stimulants, a/b adrenergic
    blockers, angiotensin-converting enzyme inhibitors, B-
    blockers, calcium channel blockers, diuretics, rauwolfia
    derivatives, and vasodilators. After excluding combination
    and duplicate preparations, we randomly sampled one third
    of the drugs in each category, increasing the sample by
    one if the number of drugs in the category was not
    divisible by three.

    Specific methods for conducting rodent carcinogenicity
    studies are at the discretion of pharmaceutical companies
    rather than being explicitly regulated by the FDA. The most
    common approach is to use Sprague-Dawley rats and CD1 mice,
    with groups of 50 animals of each

    for 2 years. Tumor incidence in these groups is compared
    with the incidence in one or two control groups at each dose
    separately and in a test of trend.

    Results

    The product information for lipid-lowering drugs indicates
    that all the fibric acid derivatives and statins caused
    cancer in rodents (Table 1). 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. Cholestyramine resin and
    probucol were not found to be carcinogens themselves, but
    cholestyramine enhanced the effects of other carcinogens.
    Niacin,.like many older drugs, was not tested for
    carcinogenicity in rodents.

    The carcinogenicity data for most drugs listed in Table 1,
    from the 1994 PDR, present relative exposure in terms of
    blood levels. Before 1993, relative exposures were3
    presented in terms of milligrams per kilogram of body
    weight. The information in the PDR changed in 1993 for the
    two most popular cholesterol-lowering drugs, lovostatin and
    gemfibrozil (Table 2). The 1992 PDR reported that lovastatin
    causes liver cancer in mice at 312 times the maximum
    recommended human dose when relative exposure is based on
    the dose administered in milligrams per kilogram of body
    weight, but the 1994 PDR reported carcinogenicity at three
    to four times the human exposure when relative exposure is
    based on blood levels. Similarly, gemfibrozil is listed as
    causing cancer at 10 times the human dose in the 1992 PDR
    when expressed as milligrams per kilogram of body weight but
    at 1.3 times the human dose in the 1994 PDR based on blood
    levels achieved.

    For comparison, we examined whether rodent carcinogenicity
    is also reported for antihypertensive drugs (Table 3). (Note
    that for antihypertensive drugs most of the relative
    exposures are based on milligrams per kilogram administered;
    these are higher than the values when expressed as
    milligrams per meter squared of body surface area, or as
    blood levels.) unlike the lipid-lowering drugs, most drugs
    for lowering blood pressure do not cause cancer in rodents.
    Of the 20 hypertensive drugs sampled for Table 3, only three
    (15%) caused cancer and three (15%) caused benign tumors.
    Among all 41 antihypertensive drugs for which results were
    reported in the PDR, six (15%) caused cancer and seven (17%)
    caused benign tumors. For 28 (68%), results of
    carcinogenicity studies were entirely negative.

    COMMENT Extrapolating From Rodent Studies

    In this article we call attention to evidence of
    experimental carcinogenicity of lipid-lowering medications.
    This class of drugs has come into widespread use in people
    who are currently healthy, but who have laboratory findings
    – high blood cholesterol levels – that place them at above-
    average risk for their age for the development of coronary
    heart disease (CHD) in the future. Because the latent period
    between exposure to a carcinogen and the incidence of
    clinical cancer in humans may be 20 years or more, the
    absence of any controlled trials of this duration means that
    we do not know whether current drug treatment of
    hypercholesterolemia will lead to an increased rate of
    cancer in coming decades.

    What are the implications of this uncertainty for clinicians
    and patients trying to decide whether to prescribe or take
    cholesterol-lowering drugs? The answer depends on how we
    extrapolate the risk of cancer from rodents to humans and
    how the risk compares with the benefit of preventing CHD by
    lowering blood cholesterol levels.

    The extrapolation of cancer risk from rodents to humans is
    controversial, particularly for agents such as those
    mentioned in this article that test negative on the Ames
    test or other tests for mutagenicity. Mechanisms of
    carcinogenicity in such drugs are incompletely understood,
    and sufficient empiric data to estimate what proportion
    represents a clear risk to humans are lacking. Most all
    known human carcinogens have been found to be carcinogenic
    in mice or rats, ie, the sensitivity of rodent studies is
    reasonably high. Unfortunately, what we need to know is not
    sensitivity, but relative predictive value, and the positive-
    predictive value of rodent carcinogenicity assays is not
    known. There are several examples of rodent carcinogenicity
    that were subsequently proven to be carcinogenic in humans,
    but for the carcinogenicity of such chemicals, data .re not
    adequate to establish human carcinogenicity or lack thereof.

    Matushak/Pinsky et al have argued that the concordance
    rate between rats and mice, 0% to 75%, provides an upper
    end of the concordance to be expected between rodents and
    humans. However, these are diverse species, probably with
    varying susceptibility to carcinogens. In some cases,
    differences in carcinogenic metabolism with the human
    species is larger than average differences between humans
    and rats. Thus, drugs that are carcinogenic in rodents may
    be carcinogenic in humans in general or in subsets of the
    human population but not others, or they may not be
    carcinogenic in humans at all.

    Extrapolation from rodents to humans deserves special
    comment for the record. These drugs belong to a group of
    mutagenic carcinogens in which heightened carcinogenicity
    is associated with proliferation of peroxisomes (an
    organelle in liver cells involved in oxidative metabolism).
    Because humans and other primates are much less susceptible
    to this peroxisomal proliferation than rodents, some
    authors have questioned the relevance of the rodent
    carcinogenicity of these drugs. However, some peroxisome
    proliferation has been reported in humans on therapeutic
    doses of fibrates, and other histologic and biochemical
    changes in the liver are common, especially with long-term
    use. Thus, while it is unlikely that the fibrates are as
    carcinogenic in people as in rodents, it would be unwise to
    dismiss the rodent studies entirely.

    Interpretation of rodent findings commonly involves
    extrapolating not only from rodents to humans, but also from
    high dose to low dose. However, the dose extrapolation is
    less problematic for cholesterol-lowering drugs because
    humans are exposed to doses similar to those that cause
    cancer in rodents. Gold et al have emphasized the importance
    of relating concentrations of chemicals that cause cancer in
    rodents to the concentrations to which humans are typically
    exposed. In their ranked list of 80 possible carcinogenic
    hazards to humans, the average daily dose of the cholesterol-
    lowering drug clofibrate was ranked second, exceeded only by
    high levels of daily occupational exposure to the fumigant
    ethylene dibromide.

    In sum, rodent carcinogenicity studies can provide only a
    suggestion of carcinogenic risk to humans. However, the
    consistent carcinogenicity of the cholesterol-lowering
    drugs, coupled with their intended pattern of long-term use
    in healthy people, sets them apart from the
    antihypertensives and other drugs and is a matter of
    concern. If this were not so, there would be no point in
    requiring that drugs be tested for carcinogenicity in
    rodents. As stated by the World Health Organization?s
    International Agency for Research on Cancer, ?.
    . . in the absence of adequate data on humans, it is
    biologically plausible and prudent to regard agents and
    mixtures for which there is sufficient evidence of
    carcinogenicity in experimental animals as if they
    presented carcinogenic risk to humans?.

    Estimating Relative Exposure

    As shown in Table 2, the apparent riskiness of a drug
    depends on how relative exposure is measured. Because the
    patterns of drug absorption, metabolism, and exretion are
    different in rodents and humans, comparisons of drug
    exposures based on blood levels over time are now considered
    more valid thatn comparisons based on dose administrere per
    unit of body weight. The FDA policy on how to express dose
    equivalency has changed accordingly. When doses are compared
    using blood levels rather than dose administered, the animal
    dose that causes cancer appears closer to the dose
    prescribed to humans. For hepatic carcinogens the blood
    levels may underestimate exposure, both in rodents and in
    humans, because the liver may be exposed through portal
    circulation to much higher levels of drugs given orally than
    measurements in the peripheral blood would indicate.

    A draft guideline recently issued by the FDA, developed as
    part of an international effort to harmonize drug testing
    requirements, suggests testing drugs at systemic exposures
    (based on the area under the curve of blood levels vs time)
    at least 25 times those observed at the maximum dose
    recommended for humans. Table 1 shows that most of the lipid-
    lowering drugs cause cancer at exposures well below this
    suggested margin of safety.

    Why Were These Drugs Approved?

    How did it happen that cholesterol-lowering agents were
    approved by the FDA for long-term use in spite of their
    animal carcinogenicity? To address this question, we
    obtained minutes of the Endocrinologic and Metabolic Drugs
    Advisory Committee meetings (under the Freedom of
    Information Act) at which lovastatin and gemfibrozil were
    discussed. For lovastatin, part of the answer may be that
    the doses for the carcinogenicity data were presented in
    milligrams per kilogram of body weight. As shown in Table 2,
    this presentation gives the impression that carcinogenicity
    occurred only at very high doses. In any case, the only
    reported discussion of animal carcinogenicity studies at the
    FDA advisory committee meeting on lovastatin (February 19
    and 20, 1987) was by the representative of Merck Sharp &
    Dohme (makers of Mevacor brand of lovastatin), who
    downplayed the importance of the studies.

    In contrast, carcinogen city appears to have been a greater
    concern to participants of the meeting on gemfibrozil
    (October 17, 1988). The minutes state, ?Dr. Gloria Troendle
    (deputy director, Division of Metabolism and Endocrine Drug
    Products for the FDA) noted that gemfibrozil belongs to a
    class of drugs that has been shown to increase total
    mortality. It has been shown to have animal carcinogenicity
    and she does not believe the FDA has ever approved a drug
    for long-term prophylactic use that was carcinogenic at such
    low multiples of the human dose as gemfibrozil.?

    Elizabeth Barbehenn, PhD, a pharmacologist with the FDA,
    expressed similar concerns at the same meeting. After
    summarizing animal carcinogenicity studies and reviewing the
    hypothesis that liver carcinogenicity is related to (missing
    text in original copy of report), she pointed out that
    ?peroxisomal proliferation has been found in the liver of
    all species studied? and that in any case peroxisomal
    proliferation in the liver would not explain tumors in other
    tissues. She concluded that ?fibrates must be considered as
    potential human carcinogens and their carcinogenic potential
    should be part of the risk-benefit-equation for evaluating
    gemfibrozil.? The rebuttal to these comments came from
    representatives of Parke-Davis (makers of the Lopid brand of
    gemfibrozil), who ?noted that peroxisomes in man are not the
    same as peroxisomes in rodents,? peroxisomal proliferation
    although florid in rodents ?has not been proven
    unequivocally in man? and that ?unlike the vast majority
    (85% to 90%) is not mutagenic and not genotoxic.?

    When asked to vote at the end of the meeting, the minutes
    state that only ?three of the nine members (of the advisory
    committee) believed that the potential benefit of using
    gemfibrozil for prevention of coronary heart disease out
    weighed the potential risk associated with such use.?
    However, such votes are only advisory to the FDA, which
    decided to approve the re-labeling of gemfibrozil for
    prevention of CHD, although only for the narrow group of
    patients in whom the Helsinki Heart Study suggested the
    greatest likelihood of benefit ?(Type IIb) patients with low
    HDL-C (high-density lipoprotein cholesterol), elevated LDL-C
    (low-density lipoprotein cholesterol) and triglycerides who
    have had an inadequate response to weight loss, diet,
    exercise, and other pharmacologic agents such as bile acid
    sequestrants and nicotinic acid? (Lopid advertisement in the
    New England Journal of Medicine, June 15, 1989).
    Unfortunately, the subsequent popularity of gemfibrozil
    suggests that its use has not been restricted to this small
    groiup; it was the second most popular lipid-lowering drug
    in the United States in 1992, the most recent year for which
    data are available.

    Risks and Benefits of Lipid-Lowering Drug Treatment

    How should the worrisome but uncertain risk of cancer be
    weighted against demonstrated benefits of cholesterol
    lowering? The answer depends on both the patient and the
    class of drug being considered. For patients with known CHD,
    the recent Scandinavian Simvastin Survival Study strongly
    suggests that the benefits of cholesterol lowing exceed the
    risks, at least6 in men an din the short term (5 years).
    This result is consistent with earlier meta-analyses of
    trials of other classes of cholesterol-lowering drugs, which
    also suggested a mortality benefit in those at high short-
    term risk of CHD. Given the strength of this evidence, it is
    reasonable to treat high blood cholesterol with drugs in
    patients with coronary or other atherosclerotic disease.

    On the other hand, for patients not at high (>1% per year)
    short-term risk of CHD death, especially patients with life
    expectancies of more than 10 to 20 years, pharmacologic
    treatment probably should be avoided. For this group, the
    benefits of treatment are smaller and the potential risk of
    increased cancer in the decades after treatment is of
    greater concern. More significantly, meta-analysis of cholesterol-
    lowering trials have suggested that in this large group the
    risks of cholesterol lowering may exceed the benefits.

    Although, as discussed herein, the risk of causing or
    promoting cancer probably needs to be considered separately
    for the different classes of cholesterol-lowering drugs (and
    possibly for different members within a class), it is worth
    addressing the possibility that it is the cholesterol
    lowering itself, rather than an adverse effect of the drugs,
    that might be carcinogenic. Persons with low cholesterol
    levels have higher cancer death rates in cohort studies, but
    evidence for causality for this association is weak. At
    least for some cancer sites there is good evidence that
    preexisting cancer or confounding may be responsible.
    Clinical trial evidence on this question is also
    inconclusive. In a recent meta-analysis of primary and
    secondary prevention trials, Law et al found an odds ration
    for cancer death of
    1.07(95% confidence interval (CI). 0.90 to 1.26), decreasing
    to 0.85% (95% CI, 0.74 to 1.05) when cancer deaths from
    six clinical trials with extended follow-up were pooled.
    This finding occurred because increased cancer deaths
    during or soon after cholesterol lowering in some
    randomized trials tend to be balanced by fewer cancer
    deaths than expected later. This occurrence may be due to
    chance or a tendency of cholesterol lowering to promote
    rather than cause cancer. While trials with extended follow-
    up are in some ways reassuring, we must remember that what
    happens after cholesterol-lowering interventions have been
    discontinued may not reflect what will happen if
    medications are continued for many more years.

    What can be said specifically about the likely risks and
    benefits of different classes of drugs? The greatest concern
    is with the fibrates, because in the two largest primary
    prevention trials of these drugs, there was a higher total
    mortality in the intervention group. Current labeling for
    gemfibrozil also cautions against using it for secondary
    prevention because of the trend toward increased CHD and
    total mortality in the Helsinki Hart Study secondary
    prevention arm. Thus, quite apart from their animal
    carcinogenicity, the fibrates should have limited use for
    either primary or secondary prevention of CHD.

    Risks and benefits are much less clear for the statins,
    currently the most popular group of cholesterol-lowering
    drugs, because for this class of drugs clinical trial
    experience, while more favorable, has involved too few
    people for too short a time. There were only 68 cancer
    deaths in the 5.4 years of the Scandinavian Simvastatin
    Survival Study, evenly divided between the simvastatin and
    placebo groups (relative risk=0.94%;95%CI, 0.6 to 1.5). If
    drugs from this class caused a rapid increase in a
    particular cancer (especially an otherwise uncommon cancer),
    this adverse effect could be discovered from post marketing
    surveillance or tumor registries. On the other hand, if (as
    is the case for smoking) an increase in cancer was delayed
    for decades, or if (as discussed herein) there was a more
    subtle or more diffuse increase in overall risk of cancer,
    the statins? carcinogenicity could have important public
    health consequences, but would be difficult to detect. Thus,
    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.

    Niacin and cholestyramine, although harder to take than
    other hypolipidemic drugs because of frequent side effects,
    may be safer. (Colestipol hydrochloride may e similar to
    cholestyramine, but data on it are much more limited.)
    although the PDR provides little data on rodent
    carcinogenicity of either of these drugs, they are older,
    and long-term (12 to 15 years) follow-up of clinical trials
    in which they were used reveals more favorable results than
    were seen with the fibrates. In the Coronary Drug Project, a
    secondary prevention trial, niacin decreased all-cause
    mortality, although this did not occur until after the
    participants had stopped taking the drug. Cholestyramine has
    not been shown to decrease all-cause mortality and may be a
    cancer promoter, but the follow-up of the large Lipid
    Research Clinics trial did not show any trend toward
    increased cancer deaths or total mortality.

    Conclusion

    Most cholesterol-lowering drugs cause or promote cancer in
    rodents. Patents to whom these drugs are prescribed, either
    singly or in combination, are exposed throughout many years
    to doses approaching those shown to be carcinogenic in
    animals. Although consideratlbe uncertainty is involved in
    extrapolating results of carcinogenicity studies fropm
    rodents to humans, the implication of these findings matches
    that of meta-analyses of clinical trials in humans. 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.

    Table 1

    Drug Animal Relative Exposure Method Neoplasia Observed
    Bile acid binders Cholestyrame resin Rat NG NG Enhanced
    intestinal carcinogenesis Colestipol hydrochloride Rat NG
    NG No increase in intestinal tumors Fibric acid derivatives
    Clofibrate Rat 5 NG Benign and malignant liver tumors Rat
    10 NG Benign Leydig cell tumors Mouse 8 NG Benign and
    malignant liver tumors Gemfibrozil Rat 1.3 AUC Benign liver
    nodules and liver cancer Rat 1-2 AUC Stomach papillomas
    Moeuse .7 AUC No
     
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