Cancer, Longevity and Statins
http://www.hoptechno.com/statinsheets.htm
Do statins cause cancer or affect longevity?
Editor's note: The following are a sample of results of a search on the
safety of statins (Cholesterol lowering drugs; e.g. Lipitor, Mevacor,
Pravachol, Zocor).
It appears that:
1. there is a danger that statins cause cancer in humans
2. death rates in the population have not been reduced as a result
of statin use
3. prescribing sheets show that statins cause liver cancer in
animals.
Cancer: Source - Journal of the American Medical Association (JAMA)
January 1996 The following is an extract.
Carcinogenicity of lipid-lowering drugs.
Newman TB, Hulley SB.
Department of Laboratory Medicine, School of Medicine, University of
California, San Francisco, USA.
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 cl***** 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 postmarketing 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.
Death Rate. Source:
http://www.drugintel.com/drugs/statins/statins_critical_review.htm
Besides cancer, the other side effects of statins listed were
incomplete, and should have included constipation, myalgia, myopathy,
polyneuropathy, liver and kidney damage, congestive heart failure and
amnesia. Side-effects are usually said to affect 2-6% of patients. In
fact, a recent meta-analysis noted side-effects in 20% of patients
above the placebo rate (65% vs. 45%), and no change whatever in the
all-cause death rate for atorvastatin (Lipitor). [8] The PROSPER trial
on pravastatin (Pravachol) showed no change in the all-cause death
rate, and increased cancer and stroke rates. [9] Statins are commonly
used at a dose to lower TC to <160 mg/dL, a level noted in the re****t
of a NHLBI conference to be associated with higher cancer rates.[10]
Footnotes:
[8] Newman CB, Palmer G, Silbershatz H, Szarek M. Safety of
Atorvastatin Derived from Analysis of 44 Completed Trials in 9,416
Patients. Am J Cardiol 2003;92:670-6.
[9] Shepherd J, Blauw GJ, Murphy MB et al. Pravastatin in elderly
individuals at risk of vascular disease (PROSPER): a randomised
controlled trial. Lancet 2002;360(9346):1623-30.
[10] Jacobs D, Blackburn H, Higgins M et al. Re****t of the Conference
on Low Blood Cholesterol: Mortality Associations. Circulation
1992:86:1046-60.
Death Rate: Source: Archives of Internal Medicine Vol. 153 No. 9, May
10, 1993 Total serum cholesterol levels and mortality risk as a
function of age. A re****t based on the Framingham data
http://archinte.ama-assn.org/cgi/content/abstract/153/9/1065
The relation****p between total cholesterol level and all-cause
mortality was positive (ie, higher cholesterol level associated with
higher mortality) at age 40 years, negative at age 80 years, and
negligible at ages 50 to 70 years. The relation****p with CHD mortality
was significantly positive at ages 40, 50, and 60 years but attenuated
with age until the relation****p was positive, but not significant, at
age 70 years and negative, but not significant, at age 80 years.
Results for the relation****p between low-density lipoprotein
cholesterol and high-density lipoprotein cholesterol and mortality help
explain these findings. Non-CHD mortality was significantly negatively
related to cholesterol level for ages 50 years and above. [Ed: - low
cholesterol =3D higher non-chd mortality; high cholesterol =3D lower; CHD
=
=3D
Coronary Heart Disease]
Prescribing sheets published by manufacturers of statin drugs (Oct
2005):
Lipitor: In a 2-year carcinogenicity study in rats at dose levels of
10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in
high-dose females: in one, there was a rhabdomyosarcoma and, in
another, there was a fibrosarcoma. This dose represents a plasma AUC
(0-24) value of approximately 16 times the mean human plasma drug
exposure after an 80 mg oral dose. A 2-year carcinogenicity study in
mice given 100, 200, or 400 mg/kg/day resulted in a significant
increase in liver adenomas in high-dose males and liver carcinomas in
highdose females. These findings occurred at plasma AUC (0-24) values
of approximately 6 times the mean human plasma drug exposure after an
80 mg oral dose.
Mevacor: In a 24-month carcinogenicity study in rats, there was a
positive dose response relation****p for hepatocellular carcinogenicity
in males at drug exposures between 2-7 times that of human exposure at
80 mg/day (doses in rats were 5, 30 and 180 mg/kg/day).
Pravachol: Carcinogenesis, Mutagenesis, Impairment of Fertility In a
2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg
body weight, there was an increased incidence of hepatocellular
carcinomas in males at the highest dose (p<0.01). These effects in rats
were observed at approximately 12 times the human dose (HD) of 80 mg,
based on body surface area mg/m2 and at approximately 4 times the human
dose, based on AUC. In a 2-year study in mice fed pravastatin at doses
of 250 and 500 mg/kg/day, there was an increased incidence of
hepatocellular carcinomas in males and females at both 250 and 500
mg/kg/day (p<0.0001). At these doses, lung adenomas in females were
increased (p=3D0.013). These effects in mice were observed at
approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the
human dose of 80 mg, based on AUC. In another 2-year study in mice with
doses up to 100 mg/kg/day (producing drug exposures approximately 2
times the human dose of 80 mg, based on AUC), there were no
drug-induced tumors. No evidence of mutagenicity was observed in vitro,
with or without rat-liver metabolic activation, in the following
studies: microbial mutagen tests, using mutant strains of Salmonella
typhimurium or Escherichia coli ; a forward mutation assay in L5178Y TK
+/- mouse lymphoma cells; a chromosomal aberration test in hamster
cells; and a gene conversion assay using Saccharomyces cerevisiae. In
addition, there was no evidence of mutagenicity in either a dominant
lethal test in mice or a micronucleus test in mice.
Zocor: In a 72-week carcinogenicity study, mice were administered daily
doses of simvastatin of 25, 100, and 400 mg/kg body weight, which
resulted in mean plasma drug levels approximately 1, 4, and 8 times
higher than the mean human plasma drug level, respectively (as total
inhibitory activity based on AUC) after an 80-mg oral dose. Liver
carcinomas were significantly increased in high-dose females and midand
high-dose males with a maximum incidence of 90% in males. The incidence
of adenomas of the liver was significantly increased in mid- and
high-dose females. Drug treatment also significantly increased the
incidence of lung adenomas in mid- and high-dose males and females.
Adenomas of the Harderian gland (a gland of the eye of rodents) were
significantly higher in high-dose mice than in controls. No evidence of
a tumorigenic effect was observed at 25 mg/kg/day. In a separate
92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no
evidence of a tumorigenic effect was observed (mean plasma drug levels
were 1 times higher than humans given 80 mg simvastatin as measured by
AUC). In a two-year study in rats at 25 mg/kg/day, there was a
statistically significant increase in the incidence of thyroid
follicular adenomas in female rats exposed to approximately 11 times
higher levels of simvastatin than in humans given 80 mg simvastatin (as
measured by AUC). A second two-year rat carcinogenicity study with
doses of 50 and 100 mg/kg/day produced hepatocellular adenomas and
carcinomas (in female rats at both doses and in males at 100
mg/kg/day). Thyroid follicular cell adenomas were increased in males
and females at both doses; thyroid follicular cell carcinomas were
increased in females at 100 mg/kg/day. The increased incidence of
thyroid neoplasms appears to be consistent with findings from other
HMG-CoA reductase inhibitors. These treatment levels represented plasma
drug levels (AUC) of approximately 7 and 15 times (males) and 22 and 25
times (females) the mean human plasma drug exposure after an 80
milligram daily dose. No evidence of mutagenicity was observed in a
microbial mutagenicity (Ames) test with or without rat or mouse liver
metabolic activation. In addition, no evidence of damage to genetic
material was noted in ZOCOR=AE (simvastatin) 9556649 14 an in vitro
alkaline elution assay using rat hepatocytes, a V-79 mammalian cell
forward mutation study, an in vitro chromosome aberration study in CHO
cells, or an in vivo chromosomal aberration assay in mouse bone marrow.
Crestor: (Jan 2006) In a 104-week carcinogenicity study in rats at dose
levels of 2, 20, 60, or 80 mg/kg/day by oral gavage, the incidence of
uterine stromal polyps was significantly increased in females at 80
mg/kg/day at systemic exposure 20 times the human exposure at 40 mg/day
based on AUC. Increased incidence of polyps was not seen at lower
doses. In a 107-week carcinogenicity study in mice given 10, 60, 200
mg/kg/day by oral gavage, an increased incidence of hepatocellular
adenoma/carcinoma was observed at 200 mg/kg/day at systemic exposures
20 times human exposure at 40 mg/day based on AUC. An increased
incidence of hepatocellular tumors was not seen at lower doses.
Rosuvastatin was not mutagenic or clastogenic with or without me.
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