FUNGI AND THEIR STATINS: The Latest about Statins

by Chee-Peng Lydia Pavey

(2003)

Abstract

Statins have only really been recognised as a treatment for hyperlipidaemia within the last twenty years. They are fast progressing as one of the most interesting and useful drugs. There have been a number of clinically important trials performed on statins within the last ten years each allowing a greater understanding of CHD, its causes and risk factors. Not only can they be used to effective treat those at high risk of CHD, they have also been investigated in conjunction with the treatment of osteoporosis, multiple sclerosis, Alzheimer’s disease and in reducing the unwanted increased incidence in CHD in women on HRT treatment. Not everything is such a rosy picture however, as recently one of the major statins has been removed from the market followed reports of muscle wasting and deaths.

A Brief Introduction to Statins

Coronary heart disease (CHD) is the leading cause of death in the world today and unfortunately this is a trend that looks set to stay as we become an aging population. In fact, one million Americans die from cardiac disease every year. Who, then, would have suspected then that the humble fungi would be the answer to the physicians prayer with respect to tackling the epidemic of cardiovascular disease. From CHD(encompassing myocardial infarction (M.I) and angina pectoris)  to cerebrovascular disease to peripheral vascular disease, statins have proven to be the most effective and consistent treatment¹.

Aspergillus griseus is a soil-borne fungus. It produces secondary metabolites from which statins originate². Strangely enough fungal metabolites were initially looked at with respect to producing an antifungal agent but in fact were found to be far more adept at lowering cholesterol levels³.

            In the liver, cholesterol is synthesis from acyl coenzyme A (ACoA). ACoA relies on hydroxyl-β-methylglutaryl-coenzyme A (HMG-CoA) reductase to convert it to mevalonate and in turn this is converted to cholesterol. This step is the rate limiting step in the synthesis of cholesterol. Thus, if a HMG-CoA reductase inhibitor is introduced (which these fungal metabolites were found to be), then the amount of mevalonate will fall leading to a decrease in cholesterol which is needed for bile synthesis. This causes a compensatory upregulation in the number of LDL receptors on the cell surface and therefore a decrease in the amount of circulating LDL.

Statins are also able to reduce the hepatic production of VLDL and the amount of triglycerides circuiting in the blood, but the mechanism by which statins achieve this is unknown. There are also non-lipid effects of statins that are extremely important in the recent advancements in statin therapy that I shall be looking at later.

Little active compound reaches the circulation as statins are activated by first pass metabolism by the cytochrome P450 system yet deactivated by further metabolism. This is an important factor in drug interactions which I shall be looking at later.

Statins are well absorbed from the gut, yet have only a short half life and are mainly eliminated by the kidneys⁴. There are five main statins. Even though statins function via the same mechanism of action they are different in a number of ways⁵.

The structure of the statins [Reference 6].

Important Statin Trials

The first major study investigating the treatment of hyperlipidaemia was the Scandinavian Simvastatin Survival Study (4s study). In effect, it acted as the catalyst for the following trials that I will also be looking at. Therefore it is with the aid of this study that we can realise what a disconcerting thought it is that barely ten years ago, we knew only a fraction of that which we know today; even the validity of hypolipidemic therapy was under question!

            The 4S study took 4444 patients suffering from Ischemic Heart Disease (IHD) and elevated cholesterol levels (between 5.5-8mmol/L) and gave them either simvastatin or a placebo. The patients were then closely monitored for a median of 5.4 years. During this period, a 25% decrease in the total cholesterol serum and a 35% decrease in the LDL cholesterol was observed⁷. Not only this, but the probability of a major coronary event occurring was reduced by 35%, that of coronary mortality by 30% and the need for coronary revascularisation with bypass surgery or an angiography was reduced by 37%. 8 This trail was important in the respect that it gave evidence highlighting that effective treatment of hyperlipidaemia with statins has a strong protective effect on people with IHD.

A year later, in 1995, the conclusions of the West of Scotland Coronary Prevention Study (WOSCOPS) were released. Now the emphasis was placed on primary prevention of CHD.

The WOSCOPS study took 6595 men aged between 35 and 64 year s of age. They were then given either 40 mg of pravastatin or a placebo and monitored for a mean of 4.9 years. Even though patients were chosen with no previous history of myocardial infarction⁷ the fact that West Scotland has one of the highest IHD death rates in the world it was therefore unsurprising that the men (that itself being a risk category for CHD) picked for this study were all in a high risk group⁵: the mean cholesterol of the men was 7.03mmol/L (+/- 0.57), the mean BMI was 26 (+/- 3.1kg/m² [ref. 7], 44% were current smokers, 13% were hypertensive, 5% had experienced angina and 8% had abnormal ECG tracings⁵. Results showed a 32% decrease in cardiovascular mortality, 37% decrease in revascularisation procedures⁷ and a 31% reduction in myocardial infarction-caused or coronary artery disease (CAD)-caused death⁵. Even though the reduction in total mortality was 22% this only qualified as borderline significance. Even so, the results in general were indicative of the fact that people at high risk of CHD and who had not ‘yet’ become afflicted were suitable candidates for statin therapy.

Attention returned to that of secondary prevention of CHD and the year 1996 saw the publication of the ‘Cholesterol and Recurrent Events (CARE) Trial’.

This trial constituted 4159 patients who had previously experienced a myocardial infarction yet had average cholesterol levels i.e. 5.4mmol/L (+/- 0.4mmol/L). There was a median follow period of 5 years which yielded promising results: there was a 20% decrease in the level of total cholesterol, a 28% decrease in LDL cholesterol⁷, 31% reduction in the incident of stroke⁸ (although this was only in cases where there was no previous history of stroke)⁵ and most importantly a reduction of MI by 37%. 8 Thus, even though these post-MI patients had healthy cholesterol levels they still demonstrated the benefits of statin prescription⁷. That said, it must be noted that  percentage reductions of 24% for coronary death and non fatal MI were relatively low compared to the 4S trial and consequently it appeared that patients with higher cholesterol levels reaped the benefits more⁸.

The results of the CARE trial were verified by a further study conducted in 1998 called the ‘Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study. Here, patients with history of M.I but with varying cholesterol levels were given⁷ 40mg of pravastatin. A greater number of participants (9014) took part and the follow up period was longer (a mean of 6.1 years) than the CARE study, but conclusions were the same⁸, all patients benefited but those with higher cholesterol levels benefited the most.

Now that secondary prevention in CHD had been thoroughly investigated for the time being, primary prevention became the focus point of discussion and in 2001 results of the Air Force/ Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) were uncovered. This was a randomised trial on 5608 men and 999 women in which they took⁷ 20-40mg of Lovaststin⁸ for a mean of 5.2 years. The participants were all at average risk of CHD and had normal total cholesterol levels with the mean being 5.7mmol/L (+/- 0.54)⁷. Again, the results showed dramatic decreases: primary end point (which represented fatal and non fatal MI, unstable angina and Sudden Cardiac Arrest) decreased by 37%, and the need for revascularisation was down by 33%⁸ But, total mortality was virtually the same in both groups, of which, two thirds were from noncardiovascular causes. Therefore one can conclude that statins although capable of reducing the number of deaths from coronary causes, do not affect overall mortality rates as these average risk participants are just as likely to die from other causes. This is an important lesson in the considering the cost-effectiveness of statins and factors influencing prescription. This shall be addressed later⁷

The HPS Study

It can undoubtedly be said that the Heart Protection Study (HPS) was one of the most ground-breaking trials concerning statins. Released in 2001 at the American Heart Scientific Session it is so far the largest and most far-reaching statin trial. 20,536 people at 69 different British Medical centres took part for a duration of 5 years. 10 Patients used were those who were at high risk of atheromatous disease because of previous coronary disease (i.e. these participant catered for the secondary prevention sector of the trial), those who had non-coronary atheromatous disease and those with diabetes.⁷ Concerning other categories, e.g. serum cholesterol level and LDL cholesterol level and age etc, there were many variables thus adding to the multi-faceted nature of this trial.⁹

The findings of the study are shown below:

Heart Protection Study: Primary Outcomes

[Reference 9]

            Most importantly was the fact that the benefits, shown in the table above were present in to the same extent in all categories of people regardless of their LDL cholesterol level. This may appear at odds with the results of the CARE and LIPID studies, but we must remember that here all participants were high risk candidates for CHD although their high risk may not have been due to LDL level but other possible risk factors for CHD shown below:

            Therefore the medical profession was presented with information that needed to be incorporated into new statin prescribing guidelines to best target those people who will benefit, even if their LDL cholesterol is not above the current mandatory ‘healthy’ level. Indeed, this will greatly increase the number of people who will be prescribed statins, but as things stand, the current guidelines are not being followed as it is, thus statins are greatly underutilised. But why is this?

            One of the factors that may be discouraging the prescription of statins is the relatively recent withdrawal of Bayer’s statin drug ‘Baycol’ (Cerivastatin) in August 2001 by the manufacturer in agreement with the FDA⁹. This action was due to the increasing reports of serious myopathy and the reports of the serious, yet normally rare rhabdomyolysis¹¹ (a muscle wasting condition that can cause death). At the time the drug was withdrawn, more than 30 deaths had been reported.⁹

There was an increased number of reports in conjunction with higher doses¹¹ (Baycol released a new high dose formulation i.e. 0.8mg of Cerivastatin in 2000),⁹  in fact 60% of the cases fell under this parameter and many reported deaths were due to the co-prescription of Cerivastatin with gemfibrozil. Indeed the FDA enquiry confirmed that the incidence of fatal rhabdomyolysis was 16 to 80 time more frequent for Bayer’s Baycol than for any other statin and even when the those incidences where the co-prescription of gemfibrozil were removed, the frequency was still 10 to 50 times higher.

            All in all there have been more than 50,000 individuals taking part in statin trials, of which there have been no serious morbidity or increase in mortality. Statins are drugs with live saving properties, they are the most effective drug for combating every aspect of atherosclerosis, are far more easy for the patient to cope with than a dramatic change in lifestyle and offer  very few side effects (and we must remember that every drug has complications).¹¹

Statins in Postmenopausal Women

The Women’s Health Initiative (WHI) had to halt a HRT trial after 5.2.years because the study was providing alarming results which highly suggested that HRT increased the incidence of many cardiovascular diseases: The overall cardiovascular disease incidence was increased by 22% , while the probability of stroke was increase by 41% and heart attacks by 29%. These findings were in keeping with those of the Heart and Eostrogen/progestin Replacement Study (HERS II) whose were published only a week earlier.

It would not be viable to take women off their HRT treatment and it was decided that statin therapy would be ideal in reducing these increases cardiovascular related risks. Thus, after looking again at the HERS study but this time isolating those who were on a statin at the time procured the much needed results showing that these drugs reduced the risk of heart attack by 21%, the risk of all-cause mortality by 33% and the risk of venous thromboembolism by 55%. In fact, the incidence of a coronary event occurring within the first year of HRT prescription was reduced by 75% in those women co-prescribed with statins. Thus, the apparent major flaw of HRT had been successful and effectively removed.⁹

Statins and Bone Health

In 1999, Mundy et al¹² tested more than 30,000 drugs in the hope of finding one that would stimulate the production of a certain protein that is essential to bone formation (as it stimulates osteoblast differentiation),¹³ called Bone Morphogenetic protein-2. Not all statins appear to have an effect on bone marrow the main factor appearing to be the uptake of the statin into the bone marrow. Lovastatin is proving particularly significant in its anabolic effects in the bone marrow¹² increasing the expression of BMP-2 RNA and more than doubling the amount of BMP-2 protein whereas  Fluvastatin, Simvastatin and Mevastatin showed less noticeable results.

            Osteoporosis occurs when ‘the amount of bone removed from the

skeleton by bone-reabsorbing osteoclasts exceeds that laid down by osteoblasts, the cells responsible for new bone formation’. Thus not only is the production of new bone increased but depressing the activity of the bone dissolving osteoclasts is also important. Therefore, statins have also attracted attention in conjunction with their mechanism in controlling hyperlipidaemia: As they are HMG-Co A inhibitors they inhibit the mevalonate pathway.¹³ G proteins which are essential in certain functions of osteoclasts require 20C and 15C side chains¹² (isoprenoids) which are added to them via a process known as prenylation. These side chains are produced through the very same mevalonate pathways that statins inhibit!  Thus inhibition of these isoprenoids decrease the production of small GTPases, for example¹³ Rho (involved in apoptosis and cytoskeletal organisation) and Rac (needed for endocytosis and membrane ruffling).

Six months after the publication of Mundy’s research, Wang et al looked at more than 1,200 patients in New Jersey aged 65 years and over and found that there was a 70% decrease in the probability of a hip fracture in those currently using stains, a 50% decrease in those who had stopped using statins 6 months ago and a 45% reduction in those who had not used a statin for the past three years! Interestingly, oestrogen deemed to have no protective effect from hip fractures.

A second study carried out by the ‘United Kingdom General Practice Research Database researching over 90,000 individuals found the same trend with respect to the fact that statins reduced the incidence of fractures, but concluded that those who had not taken a statin for more than three months were not protected.

Of course, things are never so straight forward. Reid et al, conducted a double-blind study of Pravastatin for atherosclerosis. Those who developed fractures were noted and patients were grouped (unlike the UK General Practice research) according to a number of variables, among which were, body mass index, height, sex, age etc…This study failed to provide a beneficial link between statins and reduction in fracture incidence, but, it must be noted that Pravastatin is water soluble and therefore is one of the least likely statins to be taken up by the bone in such quantities as to have an anabolic effect.

So far, these trials have failed to establish or discredit the protective effect of statins on bone and indeed have bestowed upon us more questions; what are the different effects between different statins, if statins are protective, to what extent is this so and could they ever replace the existing osteoporosis drugs.¹²

Statins Benefit the Elderly

When looking at lipid lowering drugs prescription with respect to age a clear trend can be observed: the Odds Raito (OR) for receiving a statin if one if between the ages of 55-64 is 1, this falls to 0.64 at ages 65-74 and to 0.16 at 75-84. But do these trends correlate with data on the effectiveness of statins in the elderly?¹⁴

The findings of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial was published online November 19^th 2002 in The Lancet. This trial consisted of 2804 men and 3000 women aged between 70 to 82 years¹⁵ who were at risk of vascular disease and of which some were randomly prescribed Pravastatin at 40mg/d.  ⁸ After an average follow up of 3.2 years¹⁵ results showed that the LDL Cholesterol level had dropped by 34% and  the primary end point (which was composed of coronary death, non-fatal MI and nonfatal/fatal cerebrovascular accident) decreased by 15%. Although the CAD attributed mortality rate was reduced by 24% there was no effect on all-cause mortality.⁸ In a similar fashion as statin trials on the middle aged, the statins had a protective effect on CAD in as little as three years. These results were surprising in that the link between plasma cholesterol level and CAD decreases with age, yet these result show a definite benefit in the use of statins in the elderly, thus guidelines for vascular risk management should perhaps consider extending it’s focus beyond the middle aged to those in their 60 and 70’s.

An important initial anomaly brought up by the PROSPER study was an increased incidence in cancer diagnosis in patients taking pravastatin. But, after a meta-analysis, there appeared to be no overall increased risk.¹⁵

C-Reactive Protein and Statins

            For a long period of time now, it has been suggested but never really proven that inflammation has a key role in atherosclerosis. Also, that HDL –cholesterol has a protective effect on the risk of vascular disease, but yet again we are unsure as to how¹⁶. The important molecule at the centre of the inflammation quandary is C-reactive protein (CRP), it activates monocytes and is responsible for an increase in the production of cytokines.¹⁷

            Studies have shown that high levels of CRP increase the incidence of CHD, peripheral vascular disease, type 2 diabetes mellitus and stroke. Some of these trials even go no to suggest that CRP should be used as the primary measure of risk factor in CHD as not only is it an independent factor but it is also superior to other factors currently assessed (e.g. LDL cholesterol)!

In 2001 Jialal et al reported a random cross-over comparison they had conducted on 22 people. They had compared the efficacy of three different stains in reducing CRP levels. Participants took either 40mg of pravastatin, 20mg of simvastatin or 10mg of Atorvastatin. After six weeks the reductions were 20.3%, 22.8% and 28.3% respectively. Coincidentally, these reductions were not related to changes in LDL cholesterol.

            This study has since been followed up with the recent publication of the ‘hsCRP and HDL Effects of Stain Trial’ (i.e. CHEST) in February 2003. This trial looked at the ability of a statin to reduce CRP levels and HDL levels and the time course and magnitude in which this occurs. Chest referred to the results from jialal et al as inconclusive as the study was adversely affected by the small number of participants, the fact that people with diabetes were excluded and the actual cross-over design itself which did not allow for cRP levels to return to baseline in the washout phase.

In CHEST, 80 dyslipidemic adults without evidence of cardiovascular disease were prescribed either 10mg of Atorvastatin, 20mg of simvastatin or 40mg of pravastatin each day. After a 12 week course the reduction in CRP levels were 33%, 42% and 30% respectively and the decrease in LDL levels were 43%, 34% and 30% likewise. In this case too, statins did not significantly reduce the level of HDL-Cholesterol but the reduction in CRP levels directly correlated with that in LDL levels:

Relationship between log-transformed changes in CRP and LDL-cholesterol

with statin treatment (correlation coefficient = 0.33, P = 0.004).

[Reference 16]

On longitudinal analysis the decrease in CRP levels over time appeared to be linear. As CRP levels did not level off over the 12 week period is can be concluded that further anti-inflammatory benefits may be observed in longer trials. Also, this progressive and consistent decrease in CRP levels indicates that the mechanism by which the statin reduces CRP levels must be indirect, as CRP has a very sort half life.

In 1998 the CARE study was reanalysed and it was found that those people who developed recurrent coronary events had CRP baselines at higher levels than those who did not. Interestingly enough, Pravastatin did not conform to this statement and thus this points to its anti-inflammatory properties being the main factor for the reduction in these coronary incidents. Paradoxically, it was pravastatin that appeared to be briefly detrimental to decreasing CRP levels as in the first week of therapy, CRP levels actually increased, before conforming to the trend set by the other stains and decreasing the CRP levels steadily: ¹⁶

Sample mean (bar height) and SD (error bar) CRP levels over time

in substudy of 21 individuals receiving statin treatment.

[Reference 16]

So although CHEST did not answer many questions, as the findings differed from that of other studies it was useful in provoking more concise investigations including the mechanism by which statins reduced CRP levels and the link between CRP levels and LDL cholesterol.¹⁶

Statins and Multiple Sclerosis

Multiple Sclerosis (MS) is an autoimmune disease. The immune system initiates inflammation in the perivascular white matter of the central nervous system. The blood-brain barrier is then breached by lymphocytes and macrophages which lead to demyelination of the nerves and the formation of plaques instead. Thus inflammatory cytokines aid this process and if there is too much destruction, the ability for myelin repair will be exceeded and scar tissue will predominate.⁴

            Scott Zamvil of the university of California, Sans Francisco¹⁸ used simvastatin to treat mice with chronic and relapsing Experiment Autoimmune Encephalomyelitis (EAE). EAE is a CD4⁺  Th-1 mediated CNS demyelinating disease that is frequently used as a model of MS.¹⁹ After just a weeks treatment, which constitutes the highest does a patient would be offered,¹⁸ he histologically studied the brains and spinal chords of the mice and found a significant decrease in the number of perivascular lesions and extent of infiltration. On comparing in vitro samples taken from MS suffers treated with IFN beta-1b ²⁰ (currently prescribed to reduced the inflammation process in acute attacks)⁴ and those left untreated, statins demonstrated beneficial effects in both groups, thus suggesting that statins have a use as a co-prescriptive drug with pre-existing treatments, if not as a stand alone treatment by itself.²⁰

            Statins induce STAT 6 phosphorylation and secretion of Th-2 cytokines (IL-4, IL-5, IL-10) and transforming growth factor. Yet decrease the secretion of Th1 cytokines (il-2, IL-12, interferon –γ) and tumour necrosis factor and inhibited STAT 4 phosphorlyation.¹⁹ Thus, in all, promoting Th2 bias, which is considered protective against the disease.²⁰

Statins and Alzheimers Disease

At the 54^th Annual Meeting of the American Academy of Neurology in April 2002, Researchers from Boston University School of Medicine unveiled one of the biggest studies into the link between Alzheimer’s and statins yet performed. It consisted of 912 potential or definite patients with Alzheimer’s and 1669 family members who did not suffer from dementia. It was found that participants who took statins had a 79% decrease in the incidence of Alzheimer’s. This was the case even after factors such as age, race and apoE gene were taken into account. ⁹ (The apolipoprotein E gene is situated on chromosome 19 and affects cell activity, it has three alleles, of which, the presence of ApoE e4 is associated with an increased risk of Alzheimer’s)²¹

Conclusion

       Hypolipidemic therapy has come such a long way over the past ten years that the field is virtually unrecognisable. This credit is all to be laid at the door of ‘the statins’. In the bourgeois society in which we live today, the luxury of fine food and the excess of life often takes its toll on our cardiovascular system, hence it is vitally important that statins are utilised to as great efficacy as possible, both in this respect and as a possible opening for cures for various other diseases.

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