By Mignon Fogarty
This article originally appeared in The Scientist, Novebmer 17, 2003
The 25 million people who take cholesterol-lowering drugs like Lipitor
may be in for a nice surprise. New research reported at the American
Society of Clinical Oncology (ASCO) annual meeting in New Orleans, LA
shows that people who take these "statin" drugs are less likely to get
colon cancer, supporting the idea that statins are providing more bang
for their buck than previously thought. In a questionnaire-based study
including thousands of people researchers found that those who took
statins had a 51% lower risk of developing colorectal cancer than
people who didn’t take statins.
Furthermore, a growing mountain of research suggests that statins could
also prevent or treat diseases ranging from Alzheimer's to osteoporosis
to multiple sclerosis. With promising results in a wide variety of
studies, statins are poised to become the next aspirin. Just as aspirin
has expanded its repertoire beyond headaches, statins may expand their
already nearly $20 billion (U.S.) market.
Nevertheless, dangerous side effects temper this enthusiasm; a few
patients have experienced rare muscle degeneration. And while some quip
that drinking water should be statinated, researchers remain dubious.
"No one should ever consider putting [a statin] in the water. It's
still a drug. It still causes adverse effects, and its use must be
monitored by a physician," says Larry Sparks, senior scientist at
Arizona's Sun Health Research Institute.
Statins are designed to target just one enzyme, HMG coA reductase, that
makes cholesterol. But that same enzyme also influences vitamin
D, vitamin E, vitamin D, coenzyme Q, and steroid hormones like
estrogen. Researchers are starting to think statins could have
far-reach effects. "All of the intermediate compounds between HMG coA
reductase and cholesterol are being reduced, and this offers a gold
mine for looking at other things," says David Kritchevsky, of the
Wistar Institute in Philadelphia.
Just as a greater understanding of aspirin's mechanisms of action has
inspired the development of more specific COX inhibitors like
Celebrex(TM) and Vioxx (TM), Kritchevsky says that a better
understanding of statins' roles in divergent and downstream pathways
will aid in developing more specific drugs that directly harness
statins' off-target effects. "We never paid attention to these
compounds ... but they just offer fantastic potential for discovering
new compounds that act on many diseases other than atherosclerosis," he
says.
CAN STATINS STOP CANCER?
The new research presented by Dr. Stephen Gruber of the University of
Michigan at the ASCO meeting confirms what scientists have been
studying for a while now. "Statins may have unexpected activity in
cancer, because the same pathways that are at work in the immune system
are also in play in neoplastic cells," says Lawrence Steinman,
professor of neurology and neurological science at Stanford University.
Jane Cauley, professor of epidemiology at the University of Pittsburgh
has also conducted a large study looking at statins and cancer where
she reviewing the long-term cancer follow-up results from the
Scandinavian simvastatin survival study (4S). People in the study had a
lower risk of dying of cancer.
Cauley cautions that the results were not statistically significant,
but says they were, "hypothesis generating," particularly when viewed
in light of animal data showing that statins inhibit tumor growth. And
indeed, her study found a reduction in breast cancer in women who take
both statins and other cholesterol-lowering drugs.
A PILE OF EVIDENCE ON
DEMENTIA
"Statins definitely reduce your incidence of stroke ... so from that
standpoint, statins will reduce the risk of dementia," says Len
Kritharides, an associate professor at the University of Sydney in
Australia. Researchers also are hopeful that statins can combat
dementia caused by Alzheimer disease . After all, high cholesterol is a
risk factor for Alzheimer's.
Sparks first glimpsed the relationship between cholesterol and
Alzheimer's as a forensic scientist sorting through old brain slides.
"All the demented people were in the heart disease pile," he says. With
this clue in hand, he looked for the tell-tale signs of Alzheimer's in
the brains of rabbits that has gorged on cholesterol -- a great model
for heart disease that had been ignored by Alzheimer's researchers.
"They had all kinds of b-amyloid in their brains," he says. When he
stopped feeding them cholesterol the b-amyloid, a sign of Alzheimer's,
went away; and when they received cholesterol-lowering drugs it didn't
build up in the first place.
Sparks says that cholesterol doesn't necessarily cause Alzheimer's, but
instead fuels the fire once the other important players such as
b-amyloid are in place. "Cholesterol promotes the production of this
toxin, b-amyloid," he says, but then other environmental and genetic
factors cause it to build up to disease-causing levels. For example,
although the roles of inflammation and immune response in Alzheimer's
are far from dogma, a variety of studies have suggested that statins
could modulate both. They might work, for example, by reducing
C-reactive protein levels in the plasma. Thus, it is tempting to
theorize that statins could influence the development of Alzheimer's
through anti-inflammatory or immunomodulatory action.
DOWNSTREAM EVENTS:
MULTIPLE SCLEROSIS
There is little doubt that the immune system is central to the disease
process in multiple sclerosis (MS), and in a recent mouse study Lipitor
restored movement to paralyzed animals and prevented further paralysis.
"These effects [of statins] on the immune system are entirely
independent of their effects on cholesterol," says Lawrence Steinman,
professor of neurology and neurological science at Stanford University.
Statins influence the immune system and may influence MS outcomes by
blocking the production an important immune system component, and
preventing inflammation. Steinman says they're working on the mechanism
and believe it involves compounds somewhere the statin acts before it
gets to cholesterol. "Some of these [intermediate metabolites] are
unexpected and of immense importance in modulating the immune system,"
he says.
UNKNOWNS ABOUND
Cauley, too, acknowledges she doesn't know how statins cause their
effects, but because the incidence of cancer in her studies was reduced
whether patients used statins or other cholesterol-lowering drugs, she
suspects the effect is directly related to cholesterol levels. Cauley
also notes other possible statin mechanisms that could be influencing
cancer: In addition to immunomodulation and anti-inflammatory effects,
researchers have presented studies showing that statins may activate
enzymes that degrade cell-cycle proteins -- proteins important for cell
division, which could clearly have an effect on cancer cells. Even
lowering of lipids alone could lead to an indirect effect such as a
change in sex steroid levels that perturb cancer. Despite the
uncertainty, Cauley says the collection of data is promising. "[It]
suggests that this whole idea is not just a statistical fluke, but
there is some biological plausibility," she says.
A BONE TO PICK
Osteoporosis appears the least likely candidate to have a statin
connection. "Bone density doesn't seem to have any connection to
cholesterol," says Kritchevsky. Nevertheless, in 1999 Gregory Mundy
showed that statins increased the expression of an important
bone-generating molecule and enhanced new bone formation in mice.
Furthermore, bisphosphonate drugs like Evista (TM) and Fosamax(TM)
inhibit bone resorbtion and are also act in the middle of the
cholesterol pathway. As with Alzheimer's, multiple sclerosis, and
cancer, no randomized, controlled human clinical trial has been done
yet to prove a benefit. After-the-fact analysis of patients from the
cholesterol-lowering trials showed that patients got fractures at the
same rate whether they were taking statins or not.
These trials have limitations because enrollees may not have been at
high risk of osteoporosis in the first place. For example, such trials
tended to have fewer women than men enrolled as well as people who
would have been too young to show clinical signs of osteoporosis.
Despite the limitations, Kritharides is reluctant to dismiss the
studies' negative findings. "They are incredibly powerful because they
are randomized and controlled," he says. Even so, Kritharides says the
results from other observational studies warrant further research into
the effect of statins on osteoporosis.
The good news about statins is that despite concerns about rare side
effects, these drugs, which so many people already rely on to reduce
their risk of atherosclerosis, could also be reducing their risk of
diseases such as cancer and Alzheimer's. If statins are indeed found to
prevent or treat other conditions, Food and Drug Administration
approval is likely to be accelerated because of the existing data from
the millions of people already using them, says Steinman. "Instead of
taking 10 years, you could just work with the established compound."
