Origin of drugs in current use: the
story of statins
by Mark Gilson
Abstract
The story of the statin based drugs provides an interesting insight into the discovery and development of
modern Pharmaceuticals. As well as looking at the complexity of the technology and science involved,
this Special Studies Module also looks at the time and resources that must be devoted to developing a
marketable drug from an initial concept. Whilst the pharmacology of a specific family of drugs might be
similar, small differences in molecular composition, and human physiology can substantially alter the
overall effectiveness of the drug, and even classes of patient in which the drug might be of use.
Given the cost of development, many drugs will become unaffordable to a large proportion of the
world population, even if the cost seems reasonable in terms of suffering and the palliative care that
might have to be offered in their place. The problem of cost may also be exasperated as the
development and marketing of new drugs often seems to be in the control of a handful of large
multinational companies.
Discovery of the Statins
Various cholesterol-lowering agents had been discovered during the 1950s and 1960s. However, the
majority had unwanted side effects. In 1971 Dr Akira Endo and Dr Masao Kuroda began the search for
a cleaner drug to treat hypercholesterolemia [1]. The starting point for their research was work that had
previously been carried out during the 1960's.
Various experiments on animals and humans had shown that cholesterol could either be absorbed from
the diet, or if the diet was lacking sufficient cholesterol to meet the body's needs, then it could be
synthesized - mainly in the liver (82%) and the intestine (11%) [2]. However, if the diet was rich in
cholesterol then synthesis within the body virtually stopped. Previous work had shown that cholesterol
production within the body was controlled by a feedback mechanism in which cholesterol inhibited the
enzyme -hydroxy--methylglutaryl-CoA reductase (HMG Co-A reductase). By inhibiting this
enzyme, the conversion of HMG-CoA to mevalonic acid was stopped [3] - this step being crucial to
the body in creating cholesterol.
Fig.l. Pathway of cholesterol synthesis [from reference 4]
The aim of Drs Kuroda and Endo was therefore to find a substance that would inhibit the action of
HMG-CoA reductase. In looking to the microbial world, researchers were hoping to find a
microorganism that produced an HMG-CoA reductase inhibitor as a defence mechanism against attack
by other microbes which relied on sterols as part of their biochemical make up.
The search for a suitable compound took two years and involved more than 6,000 microbes. Initially,
researchers were looking for microbial broths that would inhibit the incorporation of carbon-14 acetate
into lipids. In a second set of experiments, broths that had acted as inhibitors between acetate and lipid
were tested to see whether they would inhibit the production of lipids from tritium-labelled
mevalonate. Broths that acted as inhibitors in the first set of experiments, but not in the second set of
experiments, were deemed to be inhibitors in the early part of cholesterol synthesis.
In the early stages, two moulds were found to meet the above requirements. Firstly Pythium ultimum
was found to produce a substance called Citrinin. Citrinin, also an anti-fungal, was shown to
irreversibly inhibit HMG Co-A reductase. The second mould shown to inhibit lipid synthesis was
Penicillium citrinum. The active compound from P. citrinum was isolated by silica gel
chromatography and crystallization. Further investigation of the inhibiting compound by spectroscopy,
X-ray crystallography and chemical means showed the new compound, ML-236B (now known as
Mevastatin) to have the following structure:
Mevastatin
Fig. 2. Structure of Mevastatin [redrawn after reference 1]
Research into mevastatin showed that the compound was capable of inhibiting lipid synthesis from
either carbon-14 HMG Co-A, or carbon-14 acetate. However, there was no inhibitory effect on lipid
production from tritium-labeled mevalonate. From this, it was possible to deduce that mevastatin did in
fact inhibit the enzyme HMG Co-A reductase.
By 1976 the drug company Merck & Co. had become involved in the development of the statins.
Having successfully repeated the experiments of Endo and Kuroda, they proceeded to isolate a similar
molecule, Lovastatin, from Aspergillus terreus. The new compound was slightly more effective as an
HMG Co-A reductase inhibitor than mevastatin. The time periods involved in getting new drugs to the
market are also well demonstrated by Lovastatin. Although Merck isolated the new compound in 1978,
it did not receive approval from the US Food and Drug Administration until 1987.
Lovastatin
Fig. 3. Structure of Lovastatin [redrawn after reference 1]
Development of other drugs based on mevastatin and lovastatin has continued all over the world. Three
main approaches have been utilized. Firstly, synthetic compounds, such as Fluvastatin, were produced.
Research in this area concentrated on replacing the decalin ring of the fungal compounds with an
aromatic ring. Secondly, chemical alteration of fungal products created drugs such as Simvastatin. In
this drug, modifications were made to the acyl group at C1. Finally, microbial alteration of fungal
compounds has lead to drugs such as Pravastatin.
By altering the basic chemical composition of the mevastatin molecule, potency of the drug can be
increased. Simvastatin is approximately twice as potent as Pravastatin and Lovastatin, whilst
Mevastatin is the least powerful. However, in changing the shape of the active molecule, the chances
and severity of side effects is also altered. For example there is an increased risk of muscle toxicity with
Lovastatin, in comparison to Pravastatin.
Simvastatin
Pravastatin
Fluvastatin
Fig. 4. Chemical structures of three statins, including the synthetic structural
analogue, Fluvastatin [redrawn after reference 1].
Pharmacology & Clinical Aspects of the Statins
The production of mevalonic acid (a precursor to cholesterol) is brought about when HMG Co-A binds
to the enzyme HMG Go-A reductase. After this has occurred, NADPH binds to the enzyme/substrate
combination. A reaction then occurs in which NADPH is oxidized to NADP-CoA, and HMG Co-A is
reduced to mevalonic acid. As the affinity of HMG Co-A reductase is substantially higher for the
statins (in the case of mevastatin 10,000 times higher) than it is for HMG Co-A, mevastatin acts as a
reversible competitive inhibitor to the enzyme reaction and less mevalonic acid is produced in its
presence. Thus the cholesterol production pathway is broken.
The introduction of a competitive inhibitor for HMG Co-A reductase results in two physiological
responses. In compensation for the inhibition, cells begin to produce more HMG Co-A. The direct
reduction in circulating cholesterol is therefore only small. However, the number of low-density
lipoprotein (LDL) receptors on hepatocytes increases markedly[5]. As the liver is responsible for
removing LDL's (of which cholesterol is a component) from plasma via the LDL receptor
mechanism, blood cholesterol levels also fall dramatically.
As LDL receptors are critical to the effectiveness of the statins in reducing plasma cholesterol, it is
worth noting their ineffectiveness in treating patients with homozygous familial
hypercholesterolaemia. In this disease, the patient will have inherited recessive and ineffective alleles
for LDL receptor production from both parents. The lack of LDL receptors means that cholesterol
clearance from blood plasma cannot be increased by this method. Therefore the statins are of little use.
One exception to this rule is Atorvastatin. Atorvastatin has been shown to be of use in patients with
homozygous familial hypercholesterolaemia as it a much longer inhibitory effect on the HMG
Co-A reductase enzymes with which it comes into contact [6]. Refinement of the mevastatin molecule
has therefore increased the range of patients for whom the statins are useful.
Although some early research carried out in rodents indicated that the statins would only work in the
very short term, more positive trials in dogs, monkeys and man have shown them to be potent
cholesterol lowering drugs. One such trial was the Scandinavian Simvastatin Survival Study [6]. In the
study 4444 patients who had recovered from heart attacks, or who suffered from angina and had
plasma cholesterol levels of between 5.5 and 8 mmol/litre were split into two groups. One of the
groups was given Simvastatin, and the other group a placebo. Treatment was continued for a median
5.4 years. In the group treated with Simvastatin, cholesterol levels were lowered by 35%, and death
from coronary disease was reduced by 42%.
Side effects resulting from treatment with the statins are uncommon, although concerns were raised as a
result of trials carried out in Japan during the 1980's. In this trial toxic effects were reported to have
occurred in dogs [1]. However, the research was largely discredited as the dogs had been given a dose
of mevastatin 1000 times greater than that shown to be effective in man. Further research involving
Pravastatin and a placebo showed that only 1.7% of patients receiving Pravastatin were withdrawn
from therapy during a four month trial, in comparison to 1.2% of patients who were receiving the
placebo[7]. Known side effects of the statins include gastrointestinal upset, insomnia and rashes.
However, more serious side effects may include myositis, hepatitis and renal failure [6].
Whilst the statins are of use in treating hypercholesterolaemia caused by LDLs, they are of less use in
treating other hyperlipoproteinaemias. The effect of statins on very low-density lipoproteins (VLDL)
and plasma triglycerides is limited, and they may even cause a slight increase in plasma concentrations
of high-density lipoproteins (HDL). However, given that high plasma concentrations of LDLcholesterol is a greater risk factor in the development of atherosclerosis, and therefore coronary heart
disease (CHD), their importance in the fight to reduce deaths should not be underestimated[8].
Table 1 - Fredrickson classification of hyperlipoproteinaemia [6]:
Typ Lipoprotein elevated
Cholester Triglycerid Atherosclerosis Drug treatment
e
ol
es
risk
I Chylomicrons
+
+++
not elevated none
IIa low density lipoprotein
++
not
high
HMG-CoA reductase ±
lIb low density and very low density
lipoproteins
++
elevated
++
III beta-VLDL (electrophoretically
abnormal very low density
lipoprotein)
IV VLDL
V Chylomicrons + VLDL
++
++
resins
fibrates, HMG-CoA
reductase inhibitor,
nicotinic acid
moderate fibrates
+
+
++
++
moderate fibrates (± fish oil)
not elevated none (± fish oil)
high
Social Aspects, the Cost of Coronary Heart Disease, and New Drugs
In the UK, coronary heart disease (CHD) is responsible for 28% of all deaths, and 33% of deaths in
men under 65 years old, making it the leading cause of death [9]. Globally, CHD is also set to become a
much larger threat. Whilst in 1990 pneumonia, diarrheal disease and perinatal conditions were the
leading causes of death, it is predicted that by 2020 ischemic heart disease, depression and road traffic
accidents will be the three greatest killers world wide [10].
The link between increased LDL-cholesterol levels and the chances of developing coronary heart
disease has long been acknowledged. Given the high cost of CHD to the NHS (in 1985-86 it is
estimated to have cost £390 million [9]), ways of reducing the burden are likely to become more and
more necessary. However, whilst the development of new drugs such as the statins might provide part
of the answer, other solutions are also going to have to be found as new drugs are often prohibitively
expensive.
According to research carried out by the Committee of the West of Scotland Coronary Prevention
Study, the cost of treating a patient in the UK with Pravastatin is approximately £6,000 per life year
gained (interestingly this research was funded by Bristol-Myers Squibb, the US and European license
holder for pravastatin!) [11]. Whilst new drugs might be in reach of those in the developed world, most
developing countries will not be able to afford them.
Various schemes have been put forward to try and break the monopoly position of the large drug
companies, especially in the third world. Some African countries will allow domestic companies to
produce generic substitutes for branded drugs, in breach of patent laws, in an attempt to make new
advances in drug technology available to their citizens. However, with the massive costs involved in
the design of new drugs this might have a detrimental effect on future developments. Other solutions
have been put forward by organizations such as the World Heart Federation. In the case of CHD, they
feel a lot can be achieved in poorer parts of the world through education on issues such as diet and
exercise [10].
Patent Holders
The drug industry seems to be dominated by a few very large players. This is well illustrated by the
development of the statins. Pravastatin, which is marketed under the trade name Pravachol, is owned
by the second largest Japanese pharmaceutical company, Sankyo Co. Ltd.
Sankyo, which has a work force of nearly 7,000 people, had sales of $4.7 billion in 1998, with a $500
million research and development budget (according to figures released in 2000, Pravachol alone
accounted for sales of $3 billion in comparison to $1.9 billion in 1995) [12]. Many of the large
pharmaceutical companies seem to work together, as is illustrated by the US and European licencing
agreement between Bristol-Myers Squibb and Sankyo for Pravachol [13].
Whilst the patents for other statins are held by different companies, all are large global players. For
example the patent for lovastatin (trade name, Mevacor) is held by Merck, as is the patent for
Simvastatin (trade name, Zocor). The patent for atorvastatin (trade name, Lipitor) is held by Warner
Lambert [13]. An interesting degree of'collusion' can also be seen between Sankyo and Parke Davis (a
subsidiary of Warner Lambert) in setting up a joint venture for the marketing of Colesevelam - a new
cholesterol lowering drug, in direct competition with Lipitor and Pravachol [13]!
Conclusion
As can be seen from the discovery and development of the statins, many new drugs take vast amounts
of time and resources to bring to the market place. Given the ever increasing advances in drug design
(and associated cost!), political and social questions are going to have to be asked about availability,
funding and licensing of the drugs. With life expectancy increasing and resources limited, questions
regarding new drug design are set to become as much political (e.g. Relenza) as scientific.
References
l.Endo, A., The discovery and development of HMG-CoA reductase inhibitors. Journal of Lipid Research, 33, 1992, 1569-1582.
2. Dietschy, J. M. and Wilson, J.D. Regulation of cholesterol metabolism. New England Journal of Medicine, 282, 1970, 1128-1138,
1179-1183,1241-1249.
3. Siperstein, M.D. and Fagan, V.M. Feedback control of mevalonate synthesis by dietary cholesterol. Journal of Biological Chemistry,
241,1966,602-609.
4. Ganong, W.F., Review of' Medical Physiology. 19th ed., Appleton & Lange, 1999, 293.
5. Page, C.P., Curtis, M.J., Sutter, M.C., Walker M.J.A. & Hoffman, B.B., Integrated Pharmacology. Mosby, 1997, 267-270.
6. Rang, H.P., Dale MM., Ritter, J.M., Pharmacology, 4" ed., Churchill Livingstone, 1999, 305-306
7.
The Parkinson List Drug Database, 1998. Pravastatin/Pravachol, Available from the URL:
http://www.ionet.net/~jcott/homepage/drugdb/106.html
8. Kumar, P., & Clark, M., Clinical Medicine. 4th ed., Saunders, 1998, 989-998.
9. Ogden, J., Health Psychology. Open University Press, 1998, 276.
10. Eckardt, L., & Breithardt, G., 1999. The Global Burden of Cardiovascular Diseases. Available from the URL:
www.medscape.com/medscape/CNO/1999/ESC/ESC-01.html
11. Adis limited, 1999. Pravastatin cost effective for prevention of coronary disorders. Available from the URL:
http:surgery.medscape.com/adis/PEON/1999/204/0204.01
12. Sankyo Parke Davies, 2000. Corporate information. Available from the URL: sankyousa.com/corporate/about.cfm
13. Sankyo Parke Davis, 2000. Corporate information. Available from the URL: sankyousa.com/corporate/headlines/111599.cfm
HOT NEWS
From the Daily Telegraph for Wednesday, November 14, 2001
Cholesterol drug 'could save 25,000 lives a year'
By Celia Hall, Medical Editor
(Filed: 14/11/2001)
© Copyright of Telegraph Group Limited 2001.
RESEARCHERS claimed yesterday that 25,000 lives a year could be saved in Britain if people at
risk from heart attacks and strokes took a new type of drug.
A seven-year study concluded that a third of heart attacks among those at risk could be avoided if
they reduced their blood cholesterol, even from normal levels, by using the drugs called statins.
Prof Collins, of the Clinical Trial Service Unit, Radcliffe Hospital, Oxford, said: "Statins are the new
aspirins. This is a stunning result with massive public health implications."
He told the American Heart Association's Scientific Session 2001 in Anaheim, California: "We now
have the first direct evidence that the therapy cuts the risk of heart attacks and strokes by at
least one third, not just in people who already have coronary disease but also in those who have
diabetes, narrowing of arteries in their legs or a previous history of stroke."
He told the conference that that 200 million people around the world would benefit from taking
statins and they would remove heart disease from its position as Britain's number one killer.
The study cost £21 million and involved 20,000 British volunteers aged 40 to 80, attending 69
hospitals. It was funded by the British Heart Foundation, the Medical Research Council and drug
manufacturers Merck & Co and Roche Vitamins.
The results were equally good for women and men and for people over 70 as well as younger
people.
After five years of treatment with statins, heart attacks, strokes or other vascular problems were
prevented in 100 out of 1,000 people who had previously had a heart attack; in 80 out of 1,000
who had angina or another heart condition; and in 70 out of 1,000 who had had a stroke, blood
clots in the leg or diabetes.
A separate component of the study found that vitamins A, C and E did not prevent deaths from
heart disease, strokes or other vascular diseases, although taking them did no harm.
Prof Sir Charles George, medical director of the British Heart Foundation, said: "This research
offers substantial evidence that statins are a key weapon in the fight against heart disease and we
are delighted to have co-funded it.
"Statins have hidden benefits that could help thousands more people, not just those with high
cholesterol levels. The results therefore are dramatic and may help to topple heart disease from
head of the league table that currently makes it the UK's biggest killer."
The foundation estimated that, at present, only about 30 per cent of people with heart disease
and high cholesterol levels are given statins. But doctors will not be able to prescribe the drugs to
at-risk patients with normal cholesterol levels immediately.
The statins cost from £12 to £50 a month per patient, so wide prescription to people at risk of
heart attacks or strokes would have serious cost implications for the NHS.
A spokesman for the Department of Health said that the drugs were licensed only for people with
raised cholesterol and companies would have to provide the Medicines Control Agency with new
data if their range of use was to be extended.
Keep watch for further developments online on the Daily Telegraph's website at
www, teleqraph.co.uk.
Go back to beginning of article