The
information in this column is intended for informational
purposes only, and does not constitute medical advice or
recommendations by the author. Please consult with your
physician before making any lifestyle or medication changes, or if you
have any other concerns regarding your health.
STATINS
CUT HEART ATTACK RISK EVEN WITH NORMAL
CHOLESTEROL LEVELS
The
cholesterol-lowering statin drugs have become one of the most commonly
prescribed classes of medications in the world, and nearly 20 million
patients
have been prescribed statins in the United States
alone. The statins
block a critical enzyme (HMGCoA
reductase) that is required for the manufacture of cholesterol in our
bodies. An
extensive body of clinical research has
shown that statins can significantly reduce the risk of heart attack
and stroke
in patients with high levels of the “bad cholesterol,” LDL. There is also some
research evidence that
patients with LDL levels in the high-normal range may benefit from
statin
medications as well (it should be remembered that nearly half of all
heart
attacks and strokes occur in patients who have normal LDL cholesterol
levels). Now, a new
study, published online in the New England
Journal of Medicine,
strongly suggests that statin drugs may also significantly decrease the
risk of
coronary artery disease, heart attack, stroke, and death from all of
these
diseases, in at least some patients with completely normal LDL
cholesterol
levels.
This
newly
published prospective, randomized, placebo-controlled research study,
and referred
to as the JUPITER study, enrolled nearly 18,000 adults in the United States
and in other countries, and was supposed to have lasted for 5 years. Because the study’s
researchers noted such
striking benefits during a recent interim analysis of the study’s data,
the
JUPITER study was prematurely terminated in March of this year, only 2
years
after the study was initiated.
There
are several
unique and clinically important aspects of this clinical study to be
considered. First
unlike many of the previously published
clinical studies looking at statins, the JUPITER study included large
numbers
of women, African-Americans and Hispanics, and the study confirmed that
all of
these groups appeared to benefit from treatment with statin drugs. The other important
difference in this study
is that the volunteer patients participating in this clinical study all
had
normal total cholesterol and LDL cholesterol levels in their blood. However, these patients
also had abnormally
high levels of C-reactive protein (CRP) in their blood.
CRP
is a protein
that is manufactured primarily in the liver, and is a marker of both
acute and
chronic inflammation. Many
cardiovascular disease experts believe that coronary artery disease,
peripheral
vascular disease and some types of stroke are all associated with
chronic inflammation
occurring within diseased blood vessels.
CRP has been shown, in some research studies, to act as a
marker for
cardiovascular disease, especially in patients with elevated
cholesterol levels
(although elevated LDL cholesterol levels are thought to be more
predictive of
cardiovascular disease risk than elevated CRP levels).
In
the JUPITER
study, volunteer patients were randomized to receive either Crestor, a
relatively new statin drug, or a placebo (sugar pill). Neither the patient
volunteers nor the researchers
knew which pill each patient was randomized to receive. (Randomized “double-blinded”
prospective studies,
such as this one, are generally accepted as the most accurate way of
validating
the effects of new treatments.)
At
the point when
this study was prematurely halted, the collected data revealed that the
patients receiving the statin drug Crestor, when compared to the
patients receiving
a placebo, experienced a 55 percent reduction in the risk of heart
attack and a
48 percent decrease in the risk of stroke.
Overall, the risk of experiencing a major heart attack,
stroke, or death
from any cardiovascular disease was reduced by 47 percent in the group
of
volunteer patients who received Crestor.
The patients who were randomized to receive Crestor
experienced, on
average, a 50 percent reduction in LDL cholesterol blood levels and a
37
percent reduction in CRP blood levels. It
is very important to point out that the JUPITER study’s patient
volunteers better
represented the general population in terms of age, gender and race
than most of
the previously published statin studies, and all of these various
subgroups of
patients appeared to benefit equally from statin therapy.
The
results of
this study are likely to significantly change the existing guidelines
for the
use of statins in cardiovascular disease prevention, as many of the
patients in
the JUPITER trial who appeared to benefit from statin therapy would be
considered, by current guidelines, to be at relatively low risk for
cardiovascular disease (e.g., based upon their age, weight, smoking
history, family
history, cholesterol levels, and the presence or absence of high blood
pressure). Indeed,
many of the JUPITER study patients
would not be candidates for statin medications under the current
clinical
guidelines for the use of these potent drugs.
At
the present
time, CRP is not routinely used to screen for cardiovascular disease in
the asymptomatic
population. Thus,
this study raises the additional
question as to whether or not CRP levels should be regularly measured,
in
addition to cholesterol and triglyceride levels, as part of routine
cardiovascular disease screening. Certainly,
the results of this study would suggest that CRP levels should probably
be
checked more frequently, particularly in patients who do not have other
apparent
risk factors for cardiovascular disease, such as advanced age, a
history of
smoking, obesity, diabetes, hypertension, sedentary lifestyle or
elevated
levels of total and LDL cholesterol.
Based
upon the entry criteria for the JUPITER study, men at or above the age
of 50
and women at or above the age of 60 who have a CRP blood level greater
than 2.0
milligrams per liter should at least be considered for statin therapy,
even if
their cholesterol levels are within the normal range. (It
should also be noted that CRP levels can become
elevated at any single point in time for a variety of reasons,
including periods
of acute illness and infection, and so single measurements of CRP may
therefore
not accurately reflect an individual’s risk of cardiovascular disease
over the
long-term.)
Whether
or not everyone should be
considered for statin
therapy is unclear at this time, and another large scale prospective,
randomized, placebo-controlled, double-blinded study, like the JUPITER
study, will
be necessary to answer this question. It
should also be remembered that statins, like most drugs, are associated
with a
small but significant risk of potentially serious side effects. In a small percentage of
patients, statin
drugs have been associated with serious liver, muscle and kidney
toxicity, and
all patients who are started on statin drugs must be carefully followed
by
their physicians for any evidence of these potential complications of
statin
therapy.
Finally,
it is
important to note that this study was funded by the manufacturer of
Crestor
(AstraZeneca). As I
have previously
warned, clinical research studies that are conducted with funding from
“interested
parties” must always be viewed with a critical eye. As
this is an increasingly more common
phenomenon, however, as government sources of research funding continue
to
shrink, it has become impossible to simply reject the findings of all
“industry-sponsored”
research studies. In
the case of the JUPITER
study, the authors have filed disclosures indicating that AstraZeneca
was
completely excluded from all data collection and data analysis, and
from the
writing of the study’s soon-to-be published manuscript.
In
this study,
more than 1200 male veterans, all of whom were taking statin drugs for
elevated
LDL cholesterol, were followed between 1990 and 2006 at the Durham,
North Carolina, Veterans
Affairs Medical Center. At the time of their entry
into this study,
none of these men, with an average age of 60 years, had a history of
any previous
prostate gland diseases, including prostate cancer. All
of the men underwent testing of their
blood prostate-specific antigen (PSA) levels both prior to and
following the
initiation of statin therapy.
On
average, LDL
cholesterol levels decreased by 28 percent after beginning treatment
with
statin drugs. Interestingly,
PSA levels
also declined after these men began taking statins and, moreover, the
greatest
reductions in PSA levels were observed in the men who also had the
largest
reductions in their LDL cholesterol levels. Among
the men who experienced the largest
reduction in LDL cholesterol levels, after initiating statin therapy, a
17
percent reduction in blood PSA levels was observed.
Currently,
the
measurement of blood PSA levels is an important part of routine
screening for prostate
cancer, and elevated levels of this protein generally indicate the need
to
perform biopsies of the prostate gland to rule-out cancer. The results of this study,
therefore, raise the
concern that early cases of prostate cancer might conceivably be missed
in men
who are taking statins, as mildly-to-moderately elevated levels of PSA
might be
suppressed by long-term statin use. Whether
or not statin-associated reductions in PSA levels might actually be
associated
with a lower risk of prostate
cancer
was beyond the scope of this study, and so further prospective
randomized
clinical trials with statin drugs and placebos must be completed before
any claims
can be made that statins reduce the risk of prostate cancer. For now, however, the
results of this limited
observational research study suggest the need for caution when
interpreting PSA
results in men who are taking statins. Certainly,
men with a family history of prostate cancer (and at an early age, in
particular), and African-American men, should advise their physicians
about the
results of this research study if they are currently taking statin
drugs, and
these high-risk men should be carefully monitored for other signs and
symptoms
of prostate cancer, in addition to PSA levels. In
such cases, a low threshold to perform
biopsies of the prostate gland should at least be considered.
Disclaimer:
As always, my advice to readers is to seek the advice of your physician
before making any significant changes in
medications, diet, or level of physical activity.
