DrG's Medisense Feature Article
120201-Statins-Side_Effects
Cholesterol-Lowering
Statins: Diabetes and Other Side Effects
March 2012
Print Version
Statins, the cholesterol-lowering drugs that have saved innumerable
lives from heart attacks, have a dark side. Currently
available statins include pravastatin (Pravachol), lovastatin
(Mevacor), atorvastatin (Lipitor), rosuvastatin (Crestor) and
simvastatin (Zocor).
Scientists probing statin study results for ancillary information have
found possible associations of statins with
diabetes and hemorrhagic
stroke. The goal
and design of most of these studies was to assess statins’
effect on heart and vascular disease and death. The new
concerns make you wonder how drugs proven to reduce vascular disease
could also cause conditions that usually make vascular disease worse.
First,
some background.
Statins inhibit an enzyme in the metabolic pathway that the body uses
to make cholesterol (yes, we do make cholesterol, since we need it for
cell walls, neurologic function and hormones like adrenaline, cortisol,
estrogen and testosterone).
Normally the liver clears the body of excess cholesterol.
People who can’t maintain a healthy balance of incoming and
out-going cholesterol tend to have more vascular disease.
Doctors strongly recommend taking a statin after experiencing a heart
attack, stroke or other acute vascular event. These drugs
dramatically reduce subsequent heart attacks, strokes and deaths from
cardiovascular causes.
Some doctors suggest that anyone at risk of ever having vascular
disease should take a statin. That would just about be
everyone, since, if you live long enough, your arteries will stiffen
and clog with plaque. Some even joke that we should put the
drugs in our water supply.
The
problem with statin enthusiasm is that they don’t reduce
all-cause mortality.
So deaths from other maladies make up for those saved from vascular
disease. Hence the ongoing furor over side-effects.
One study hinted that statin users risked more hemorrhagic strokes
(strokes that result from bleeding into the brain). That
study, called Stroke Prevention by Aggressive Reduction in Cholesterol
Levels (SPARCL), compared 80 mg of atorvastatin to
placebo. You can forget this potential problem,
since subsequent analyses discounted that association.
The
Women’s Health Initiative (WHI) recently dropped the
statins-cause-diabetes bombshell.
Retrospective analysis of 153,840 post-menopausal women (age 50-79)
found that taking a statin increased the risk of new diabetes diagnoses
by 48%, after adjustment for some of the most obvious variables.
Like most WHI bombshells, the devil’s in the
details. The WHI trial was not a direct comparison of women
randomly assigned to statin or placebo. The women’s
doctors, in 40 different geographic centers, had made independent
clinical decisions, prior to the study, to use or not use statins.
It’s easy to see that the
women
taking stains in the
WHI were likely skewed to those at risk for diabetes.
Doctors are more likely to prescribe a statin for people with diabetes
or at risk of diabetes, because those patients are more likely to
develop vascular disease. Doctors also prescribe statins for
those who have high cholesterol, other risk factors or a strong family
history of heart attack. Those risk factors often overlap
with Metabolic Syndrome, the precursor for adult-onset diabetes.
There is a more practical reason that WHI statin-users might have been
diagnosed with more diabetes - they have more lab testing done for
monitoring. If you don’t do the testing, you
won’t identify diabetes. Remember, WHI
was not a study of statins and diabetes: The investigators took what
information was available to them from the patients’ usual
care.
Another skewed trial was the JUPITER trial (Justification for the Use
of Statins in Prevention: an Intervention Trial Evaluating
Rosuvastatin). In this trial physicians reported a
25% higher risk of new diabetes cases, compared to the risk with
placebo. The striking finding is that rosuvastatin reduced
cardiovascular disease so much that, in spite of increased diabetes,
the study was terminated after only 1.9 years.
Though the patients in JUPITER were randomly assigned to rosuvastatin
or placebo, the whole study group was at higher than normal risk for
diabetes. This study included only men with high CRP levels,
a blood test that is often elevated in Metabolic Syndrome.
The vast majority (78%) of new diabetes cases had had abnormal glucose
levels at the start of the trial.
This suggests that, yes, rosuvastatin increases diabetes risk over that
of placebo, but predominantly does so in people already predisposed to
diabetes. (Metabolic Syndrome criteria include large
waistlines, high triglycerides, low HDL-cholesterol, high blood
pressure, gout and insulin resistance.) BUT, in spite of
pushing these Metabolic Syndrome people into overt diabetes, the drug
still lowered vascular risk.
There have been some studies not biased towards diabetes.
These randomly assigned people to statin or no statin, and generated
less striking diabetes results. Simvastatin, cerivastatin,
atorvastatin and rosuvastatin all increased diabetes risk, but only by
1-20%. These are the more fat-soluble statins, the ones that
also cause more statin-induced muscle aches. My cursory
comparison of disparate studies puts pravastatin at the low and
simvastatin at the high ends of the risk continuum.
It’s interesting
that increasing
statin
dose does not seem to bring more diabetes doom.
Comparing data from three atorvastatin trials, (TNT, IDEAL and SPARCL)
80 mg of atorvastatin bumps up diabetes risk by ~2% over placebo, but
only ~ 1% over 10 mg atorvastatin or 20 mg simvastatin.
This is all very disconcerting to cardiologists, who originally thought
statins might decrease diabetes, based on the West of Scotland Coronary
Prevention Study (WOSCOPS). The men in this study who took
pravastatin (a more water-soluble statin) had 30% lower risk of new
diabetes than those who took placebo. The study enrolled a
different patient type – men with high cholesterol and no
history of heart attack. Few had diabetes or significant risk
factors for diabetes and the criteria for diabetes diagnosis were more
strict than usual, so, overall, there were fewer diabetes diagnoses.
The LIPID trial of pravastatin more closely mimicked other statin
trials. In it, elderly patients who had known coronary
disease prior to the trial took pravastatin and had no increased
incidence of diabetes.
Pravastatin
is the most
water-soluble statin, confirming the notion that a continuum within the
statin drug class relates their fat-solubility to their likelihood of
inducing diabetes in susceptible individuals.
Mechanisms: Statins inhibit an enzyme that not only blocks
cholesterol synthesis, but also blocks the body’s ability to
make other things, like isoprenoids. These compounds regulate
many enzymes in the body and may be involved in glucose
regulation. We know that statins reduce cells’
production in test tubes of the glucose transporters used to take up
glucose. Less transport means more insulin resistance, which
can lead to metabolic syndrome and diabetes. Adding back
mevalonate, blocked by statins but normally converted into either
cholesterol or isoprenoids, can reverse this effect.
Scientists postulate that isoprenoids, or some other downstream product
of mavalonate, may mediate the effect on glucose transport.
Another possible mechanism related to the pancreas’ ability
to make insulin. Pancreatic cells bathed in a solution
containing statins make less insulin. This only occurs with
fat-soluble, not water-soluble statins.
Other
statin adverse effects:
We’ve known about possible liver damage, especially with high
doses of statins, since the drugs came out. This is uncommon.
Statins may also cause muscle inflammation, called statin
myopathy. The user may feel an array of symptoms, ranging
from insidious, deep aches, to near paralysis from severe muscle
wasting.
Normally these side effects occur in people taking high doses, but
sometimes that is not the case. Statins are broken down in
the body by liver enzymes - Taking a medicine that blocks these enzymes
may raise statin blood levels enough to cause damage even on lower
doses. One statin, cerivastatin (Baycol) was removed from the
market because of 52 deaths from severe enough muscle damage to kill
the kidneys.
Like all drugs, and most substances we put in our bodies, statins have
potential side effects. Statins may push you into overt
diabetes, especially if you have metabolic syndrome, but even then they
reduce the risks of vascular disease and deaths from heart attack and
stroke. So we shouldn’t put them in the water
supply, but instead take them as recommended – for prevention
of recurrence
after
vascular disease or diabetes is diagnosed. Choosing a more water-soluble
statin should minimize the diabetes risk, and adopting a prudent diet
and regular exercise routine would help even more.╣