LOOKING BACK
Virchow (1821 – 1902), the German pathologist and one of the 19th century's foremost
leaders in medicine and pathology, observed that the artery walls of patients dying
of occlusive vascular disease, such as myocardial infarction, were often thickened
and irregular, and contained a yellowish fatty substance. This pathological condition
was termed atheroma, the Greek word for porridge, and subsequently identified as cholesterol.
Anitschkow and Chalatow in 1913 showed that feeding cholesterol to rabbits rapidly
produces atheromatous disease similar to that found in man.
However, at that time, physicians were not convinced of any causal link between cholesterol
and coronary heart disease (CHD) because most patients with the disease have plasma
cholesterol levels not much different from that of the general population average.[1]
The Framingham study, led by Dawber, was initiated in the 1950s to prospectively study
the relationship between blood cholesterol and other potential risk factors and death
from coronary disease. This work established an increasingly strong correlation between
high plasma cholesterol and CHD mortality,[2] which was confirmed by many other population-based
studies. Moreover, the Seven Countries Study, which was initiated in the 1950s, showed
that northern European countries and the United States had both high plasma cholesterol
and high CHD mortality rates. By contrast, plasma cholesterol and CHD mortality were
both substantially lower in southern Europe, and even more so in Japan.[3] Later investigations
established that the association with CHD mortality was attributable mainly to low-density
lipoprotein (LDL) cholesterol. Subsequent studies showed that LDL cholesterol comprises
about 70% of total cholesterol and that high-density lipoprotein (HDL) cholesterol
is inversely correlated with CHD mortality.
The above findings lead to the Lipid Hypothesis, which proposed that elevated total,
or more accurately LDL, cholesterol was causally related to coronary disease and that
reducing it would reduce the risk of myocardial infarction and other coronary events.
This hypothesis remained controversial for many years because of the lack of clear
evidence that lowering cholesterol provided any clinical benefits.
Before the discovery of statins (HMG-CoA reductase inhibitors), a number of dietary
intervention studies and a few drug studies had reported a reduction in CHD events
in patients with and without CHD. No individual study was compelling enough but taken
together, there seemed to be a trend that lowering cholesterol reduced the risk of
coronary events.[4] On the basis of those studies and the National Institutes of Health
(NIH) Coronary Primary Prevention Trial (USA), an NIH Consensus Conference convened
in 1984 concluded that lowering elevated LDL cholesterol with diet and drugs would
reduce the risk of CHD.[5] The NIH (USA) accepted the findings of the Consensus Conference
and the following year initiated a massive program to educate physicians and the public
about the importance of treating hypercholesterolemia.
CHOLESTEROL SYNTHESIS
“Cholesterol is the most highly decorated small molecule in biology. Thirteen Nobel
Prizes have been awarded to scientists who devoted major parts of their careers to
cholesterol. Ever since it was isolated from gallstones in 1784, cholesterol has exerted
an almost hypnotic fascination for scientists from the most diverse areas of science
and medicine…. Cholesterol is a Janus-faced molecule. The very property that makes
it useful in cell membranes, namely its absolute insolubility in water, also makes
it lethal”.
Michael Brown and Joseph Goldstein
Nobel Lectures (1985)
Most mammalian cells can produce cholesterol. Cholesterol biosynthesis is a complex
process involving more than 30 enzymes, and the details of the biosynthetic pathway
were worked out in many institutions in the 1950s and 1960s. In the hope that lowering
cholesterol would reduce the risk of CHD, the simplified pathway in [Figure 1] was
a natural target in the search for drugs to reduce plasma cholesterol concentrations.
However, early attempts to reduce cholesterol biosynthesis were disastrous. Triparanol,
which inhibits a late step in the pathway, was introduced into clinical use in the
mid-1960s, but was withdrawn from the market shortly after because of the development
of cataracts and various cutaneous adverse effects.[6] These side effects were attributable
to tissue accumulation of desmosterol, the substrate for the inhibited enzyme.
Figure 1
The cholesterol biosynthesis pathway. Cholesterol biosynthesis is a complex process
involving more than 30 enzymes. A simplified version is shown here,which highlights
the step inhibited by statins, and shown the chemical structures of the starting material
(HMG-CoA)and product (mevaonate) of this step.
STATIN BREAKTHROUGHS
HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA) is the rate-limiting enzyme in
the cholesterol biosynthetic pathway and was an attractive target in the search for
drugs to reduce plasma cholesterol concentrations.
In the 1970s, the Japanese microbiologist Akira Endo, during a search for antimicrobial
agents, first discovered natural products with a powerful inhibitory effect on HMG-CoA
reductase, including ML236B (compactin) in a fermentation broth of Penicillium citrinum.[4
5] Although no HMG-CoA reductase inhibitor has been shown to have useful antimicrobial
activity, the possibility that an agent that inhibited the rate-limiting step in the
cholesterol biosynthesis pathway could have useful lipid-lowering properties was quickly
appreciated by Endo and others.
In the rabbit, monkey, and dog, compactin was shown to lower plasma cholesterol.[6]
The prototype compound compactin was developed by Sankyo, and was shown to be highly
effective in reducing concentrations of total and LDL cholesterol in the plasma of
patients with heterozygous familial hypercholesterolaemia.[7
8] In 1978, Alberts, Chen and others at Merck Research Laboratories found a potent
inhibitor of HMG-CoA reductase in a fermentation broth of Aspergillus terreus.[9]
They named their discovery mevinolin and later named officially as lovastatin.
LOVASTATIN – THE FIRST STATIN
Merck began clinical trials of lovastatin in healthy volunteers in 1980. Lovastatin
was shown to be dramatically effective for lowering LDL cholesterol in healthy volunteers,
with no obvious adverse effects.[10
11] However, clinical trials of compactin were stopped because of concerns with serious
animal toxicity. Compactin and lovastatin have close structural similarity; hence
Merck suspended clinical trials with lovastatin and initiated additional animal safety
studies. The future of lovastatin was uncertain. However in 1982, small-scale clinical
investigations asked Merck for lovastatin to test its effect in selected small groups
of patients with severe heterozygous familial hypercholesterolaemia (FH) refractory
to existing therapy. The investigators found dramatic reductions in LDL cholesterol.[12
13] with very few adverse effects. Later, Thompson in London found that lovastatin
considerably enhanced the hypolipidemic effect of apheresis in patients with heterozygous
FH.[14]
In 1984, in randomized, double-blind Phase IIb placebo-controlled studies, lovastatin
was found to be as effective in patients with heterozygous FH[15] and patients with
CHD and non-familial hypercholesterolaemia[16] as it had been in healthy volunteers.[11]
These effects were confirmed in larger Phase III studies, in which lovastatin produced
much greater reductions in LDL cholesterol than the control agents cholestyramine[17]
and probucol,[18] with very few adverse effects.
Lovastatin produced a profound reduction of apolipoprotein-B-containing lipoproteins,
especially LDL cholesterol and, to a lesser extent, plasma triglycerides, and a small
increase in HDL cholesterol. Observed tolerability continued to be excellent, with
very few patients withdrawing from treatment due to adverse effects. In November 1986,
Merck applied for regulatory approval of lovastatin, and the US FDA advisory panel
voted unanimously for the approval of the drug, with approval given in 1987.
When lovastatin became available for prescription use, physicians were able to obtain
large reductions in plasma cholesterol – for the first time. Lovastatin at its maximal
recommended dose of 80 mg daily produced a mean reduction in LDL cholesterol of 40%,[15–18]
a far greater reduction than could be obtained with any of the treatments available
at the time. The drug produced very few adverse effects, and with once- or twice-daily
dosing, was easy for patients to take. Lovastatin, went on to revolutionize the treatment
of hypercholesterolaemia, achieving peak annual sales of more than US $1 billion initially.
Statins generated $35.3 billion worldwide in 2009. So, lovastatin became a success
story despite initial skepticism from the medical community.
STATINS AND CLINICAL USE
Before the commercial availability of lovastatin in 1987, lipid lowering was limited
to dietary changes, bile acid sequestrants such as cholestyramine and colestipol,
nicotinic acid, the fibrates, and probucol. However, these treatments have limited
efficacy or tolerability, or both. Dietary changes acceptable to patients produced
only small changes in total and LDL cholesterol.[19]
On the other hand, lovastatin, the first statin developed, produced a significant
mean reduction in LDL cholesterol, had few adverse effects, and was easy for patients
to take, requiring only once- or twice-daily dosing. For these reasons, lovastatin
was rapidly accepted by patients.
Simvastatin was the second statin used clinically. Simvastatin which differs from
lovastatin in an additional side chain methyl group was approved for marketing in
Sweden in 1988, and then worldwide. Pravastatin followed in 1991, fluvastatin in 1994,
atorvastatin in 1997, cerivastatin in 1998 (of which more below), and rosuvastatin
in 2003.
Lovastatin is a fermentation product. Simvastatin is a semisynthetic derivative of
lovastatin, and pravastatin is derived from the natural product compactin by biotransformation.
All other HMG-CoA reductase inhibitors are totally synthetic products. The mean reduction
in LDL cholesterol attainable with the maximal recommended dose of different statins
ranges from 35 to 55%.
STATIN ADVERSE EFFECTS
In animals, statins produce significant toxicity at high doses: increases in hepatic
transaminases, atypical focal hyperplasia of the liver, squamous epithelial hyperplasia
of the rat fore stomach (an organ not present in man), cataracts, vascular lesions
in the central nervous system (CNS), skeletal muscle toxicity, testicular degeneration
and, although the statins are clearly not genotoxic, tumours of the liver and other
sites (details can be found in the product circulars of the individual statins). Fortunately,
except for rare cases of myopathy and marked but asymptomatic increases in hepatic
transaminases, none of the adverse effects found in animals occur at human therapeutic
doses.
Establishment of the safety of statins required considerable effort in large long-term
clinical trials and shorter specialized studies. Five-year trials have been published
with simvastatin,[20–22] pravastatin[23–25] and lovastatin.[26] A smaller four-year
trial with fluvastatin has also been reported,[27] as has a recent large trial with
atorvastatin with 3.3 years follow-up.[28]
Of particular concern was the observation of cataracts in animal toxicology studies.
When lovastatin and simvastatin were first marketed, slit-lamp examination was required
to detect possible lens opacities at an early stage. Several studies using either
specialized techniques in relatively small patient populations,[29–31] or routine
slit-lamp examination in large populations,[21
32] showed that lens opacities occurred with similar frequencies in the active and
placebo groups. However, in 2010, the British Medical Journal published a study that
statins may raise cataract and kidney risk. Researchers estimated that for every 10,000
people taking a statin, there were about 271 fewer cases of heart disease, 8 fewer
cases of esophageal cancer, 307 extra patients with cataracts, 23 additional patients
with acute kidney failure, and 74 extra patients with liver dysfunction.[33]
There has been no good evidence of any increase in the risk of cancer at any particular
site.[22
34] In the Scandinavian Simvastatin Survival Study (4S), there was a trend towards
fewer cancers among the patients originally randomized to simvastatin[35] after seven
years (an additional two years after the end of the study). Researchers have been
unable to find a link between statins and cancer – neither an increase nor reduction
in cancer in risk.
On March 3, 2012, the FDA announced changes to the safety information on the labels
of statins: there is a small increased risk of higher blood sugar levels and of being
diagnosed with type 2 diabetes. In addition, the statin labels will also now reflect
reports of certain cognitive effects such as memory loss and confusion experienced
by some patients taking the drugs. The announcement said the risk was “small” and
should not materially affect the use of these medications.
It seems that the risk of diabetes is real only with the more potent statins such
as simvastatin (Zocor), atorvastatin (Lipitor), and rosuvastatin (crestor), and particularly
at higher doses.
The latest FDA change to the safety information is that patients taking statins will
no longer need routine periodic monitoring of liver enzymes. FDA has concluded that
serious liver injury with statins is rare and unpredictable in individual patients,
and that routine periodic monitoring of liver enzymes does not appear to be effective
in detecting or preventing this rare side effect.
STATIN-INDUCED MYOPATHY
Muscle complaints are common in statin users, occurring in more than 10% of this population.[36]
Myalgia or muscle pain occurs in about 7% of statin users. Interestingly, myopathy
was not among the numerous abnormalities detected in the original animal safety studies
with statins.
It was first reported in a cardiac transplant patient receiving the immunosuppressive
cyclosporine, in addition to gemfibrozil.[37] Both of these drugs were later found
to substantially increase the risk of myopathy with statins.[38
39] The mechanism of statin-associated myotoxicity has not been satisfactorily defined
and is likely due to multiple factors, including membrane instability, mitochondrial
dysfunction, and defects in myocyte duplication.
Cerivastatin was introduced in 1998 but was withdrawn in August 2001 by the manufacturer
because of a large number of reports of rhabdomyolysis, of which more than 50 cases
were fatal.[40
41] The risk of rhabdomyolysis was much higher with cerivastatin than with the other
statins.[40–42]
Some of the reported cases of rhabdomyolysis occurred during concomitant use of gemfibrozil
and cerivastatin.[42] Gemfibrozil increases the risk of myopathy with all statins;
the mechanism is probably partly pharmacodynamic, as gemfibrozil can cause myopathy
alone,[43] and partly pharmacokinetic. In the case of cerivastatin, the pharmacokinetic
interaction is particularly marked; gemfibrozil was recently reported to increase
the plasma concentration of cerivastatin approximately fivefold.[44]
It is not known why cerivastatin is more myotoxic than other statins. Its withdrawal
shook the confidence of some physicians in the safety of statins in general.[40] Prescription
growth rates for the class, which had approached 20% annually in many countries, fell
dramatically.
HOW STATINS LOWER CHOLESTEROL
The Nobel Prize in Physiology or Medicine 1985 was awarded jointly to Michael S. Brown
and Joseph L. Goldstein “for their discoveries concerning the regulation of cholesterol
metabolism.”
They found that cells on their surfaces have receptors which mediate the uptake of
the cholesterol-containing particles called low-density lipoprotein (LDL) that circulate
in the blood stream. They discovered that the underlying mechanism to the severe hereditary
familial hypercholesterolemia is a complete, or partial, lack of functional LDL-receptors.
In normal individuals the uptake of dietary cholesterol inhibits the cells own synthesis
of cholesterol. As a consequence the number of LDL-receptors on the cell surface is
reduced. This leads to increased levels of cholesterol in the blood which subsequently
may accumulate in the wall of arteries, causing atherosclerosis and eventually a heart
attack or a stroke.
Statins lower human plasma cholesterol by increasing the uptake of LDL via the LDL
receptor. Although LDL receptor upregulation is clearly the primary mechanism of action,
these drugs also decrease the production of apolipoprotein-B-containing lipoproteins
by the liver.[44] Consistent with this mechanism is the fact that high doses of atorvastatin[43]
and simvastatin[45] produce moderate reductions of LDL cholesterol in patients with
homozygous FH, who lack the LDL receptor.
THE CHOLESTEROL CONTROVERSY
For many years, the role of cholesterol in the pathogenesis of atherosclerosis was
controversial.[46] There was skepticism in the medical community that elevated cholesterol
is an important cause of atherosclerosis and coronary heart disease even though there
was growing body of supportive evidence from experimental studies in animals, striking
findings in humans with familial hypercholesterolemia, consistent epidemiologic correlations,
and several small but impressive clinical trials.[47] Many leaders in the field of
lipoprotein and atherosclerosis research however, were convinced that the accumulated
evidence justified intervention to lower blood cholesterol levels.[47]
The American Heart Association began recommending dietary changes to control blood
cholesterol levels as early as 1960. Diet alone, however, was insufficient, and the
drugs available at that time had limited effectiveness. Cholestyramine, an inhibitor
of bile acid reabsorption, was among the more effective drugs in use, but it was unpleasant
to take, and compliance was poor.
The results of the Coronary Primary Prevention Trial,[48] a 7-year, double-blind,
randomized clinical trial of cholestyramine among 3800 men with hypercholesterolemia
was a turning point in medical thinking. That study showed a significant 20% decrease
in the rate of fatal coronary heart disease or nonfatal myocardial infarction. The
American National Institute of Health, after a panel review of the findings, declared
in 1985 that lowering blood cholesterol should be a major national health goal.
The publication in 1994 of the results of the Scandinavian Simvastatin Survival Study
(4S)[20] further boosted the status of statins in preventive cardiology. A total of
4,444 patients with CHD and total plasma cholesterol 5.5–8.0 mmol l-1 on a lipid-lowering
diet were randomly allocated on a double-blind basis to simvastatin 20–40 mg once
daily or placebo for five years. There was an unequivocal 30% reduction in all-cause
mortality (P = 0.0003), due to a 42% reduction in coronary deaths. These effects on
mortality were accompanied by a 34% reduction in major coronary events (non-fatal
myocardial infarction plus CHD death) and a 37% reduction in revascularization procedures.
There was no indication of any increase in non-cardiovascular mortality, and in particular,
no increase in violent deaths or the incidence of cancer.[20
21] Only one patient in the simvastatin group developed myopathy. These results reassured
those who argued that lowering cholesterol might reduce CHD events but not total mortality.
The magnitude of the reduction in LDL cholesterol obtainable with statins is much
greater than with the earlier treatments used in previous clinical trials. Subsequent
clinical trials with simvastatin, pravastatin, lovastatin, fluvastatin, and atorvastatin
established that these staatins not only substantially reduced the risk of caardiovasccular
events but did so without any increase in non-cardiovascular mortality such as that
of cancer. The risk of CHD events was reduced both in patients who already had CHD
(secondary prevention),[20
22
27
28] and in those who did not (primary prevention).[22
23
26]
The Heart Protection Study (HPS)[22] is the largest of the placebo-controlled five-year
statin trials involving more than 20,000 patients in the United Kingdom with CHD,
or at high risk of CHD due to cerebrovascular or peripheral vessel disease, or diabetes.
Participants were randomized to simvastatin 40 mg or placebo for five years. HPS confirmed
and expanded previous evidence, including firmly establishing the benefit of simvastatin
in women, and its effectiveness for reduction of the risk not only of CHD events such
as myocardial infarction, but also of strokes. It also provided new and compelling
evidence for the beneficial effects of simvastatin on clinical outcomes in various
large patient groups that had scarcely been studied. Most importantly, significant
reductions in the risk of major vascular events were observed in patients with diabetes
but no CHD, patients with cerebrovascular or peripheral vessel disease but no CHD,
patients aged 70 or older, and patients with LDL cholesterol well below average <100
mg dl-1 (2.6 mmol l-1) at entry. These effects had not been previously reported for
any statin. The tolerability and safety of simvastatin was confirmed yet again; the
incidence of myopathy, including rhabdomyolysis, was <0.1%.
CONCLUSIONS
Coronary artery disease is still the leading cause of death in the industrialized
and developing world. Studies have shown that elevated blood cholesterol is an important
cause for atherosclerosis and large-scale trials have shown that lowering blood cholesterol
significantly reduces major coronary events and coronary heart disease deaths.
Statin drugs lower blood cholesterol levels much more effectively than any diet or
drug regimens that were available before the discovery of stains by Akira Endo in
1976. Endo's discovery opened the door to a new era in preventive cardiology. The
statins are remarkably free of serious side effects. Nevertheless, a significant number
of patients still have adverse cardiovascular events despite statin treatment. Obviously,
more need to be done. Statins can reduce blood cholesterol levels by about 30% but
this can be reduced by more than 50% if statins are combined with other drugs. The
statins are not recommended to use with other drugs such as cholestyramine and gemfibrozil
due to unwanted drug interactions. More aggressive targeting of treatable risks for
coronary artery disease in addition to lowering LDL cholesterol levels can further
lower morbidity and mortality associated with atherosclerosis.
The recent FDA warning that statins may cause diabetes is worrisome and presents a
dilemma for those taking statins for primary prevention. Unlike those with coronary
heart disease, the benefit of taking statins for primary prevention is only 2 per
100. It is estimated that about one in 200 patients treated with any of the three
most potent statins will get the side effect of diabetes. At this point in time, in
the primary prevention group, we do not know who will benefit from treatment and who
will get diabetes. Diabetes is an important and serious side effect and dose reduction
or use of a less potent statin should be considered in the primary prevention group.
For those who already have coronary heart disease, the benefit of statins is quite
clear and its use strongly recommended.
Why do statins cause diabetes? It is not known at present. Perhaps, genetic studies
might help us determine who is at risk to develop statin induced diabetes. It is a
problem in need of a solution.