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BRITISH BROADCASTING CORPORATION
RADIO SCIENCE UNIT
CASE NOTES
Programme no. 7 - Statins
RADIO 4
TUESDAY 16/10/07 2100-2130
PRESENTER:
MARK PORTER
CONTRIBUTORS:
SARAH JARVIS
BARBARA HUTTON
TOM SANDERS
DEVAKI NAIR
PRODUCER:
NOT CHECKED AS BROADCAST
PORTER
Hello and welcome to a Case Notes special on statins - the family of cholesterol lowering drugs. Around three million people in the UK are currently thought to be taking a statin to reduce their risk of heart attack and stroke. And according to the latest guidelines, at least as many again should be on one, but aren't.
But how do doctors decide who might benefit from a statin - and when?
Does it make a difference which statin you take?
What about rumblings from some quarters that statins are not the wonder drugs they are made out to be - that their benefits have been overblown, and the downsides, particularly side effects, glossed over?
And are there alternatives for people who can't, or don't want to take a statin?
All questions I hope to answer over the next half hour with the help of a group of experts including my guest today, Dr Sarah Jarvis. Sarah's a GP with a special interest in cardiovascular disease, and spokesperson for the Royal College of General Practitioners.
Sarah, start with some basics - what are statins?
JARVIS
Well effectively they're a group of drugs that change the way our body makes cholesterol. It's interesting how we always tend to think that cholesterol is what we eat but actually on the whole if you eat food that's high in cholesterol it doesn't make that much difference to your cholesterol - this is where the anxieties about eggs and egg yolks came from. In fact some cholesterol we take in but most of it our body makes and they change the way our body makes cholesterol, so it makes less of the bad cholesterol and more of the good.
PORTER
And remind us why reducing cholesterol levels in the blood might be helpful.
JARVIS
Well we're naturally born with a cholesterol level of about 3.8 and the World Health Organisation reckons that half the heart disease in the world - and don't forget about 40% of people in the UK die of heart disease - half the heart disease in the world is due to raised cholesterol.
PORTER
How do you respond to the sceptics - and there are a vocal minority out there - who say that the link between cholesterol and cardiovascular disease - that link you were referring to there - is in fact unproven?
JARVIS
Well I would suggest there are still some people out there who believe the world is flat.
PORTER
Okay that's pretty clear. It's obvious which side of the fence you're on. But most people in the UK have higher than ideal levels of cholesterol so how do we decide who might benefit from a statin and who won't?
JARVIS
That's really difficult because it is a completely arbitrary cut off. What we're recommending at the moment - and it's quite interesting that both the bodies of doctors and the government have agreed that this should be the level - is if your risk of a heart attack or a stroke is more than one in five - 20% - over the next 10 years we think that you would benefit from having a statin.
PORTER
And to put that into perspective, I mean I'm a fairly clean living chap, I'm in my mid-40s, but I've got an unusually abnormal cholesterol level that means that I fall into that group so that I would benefit from a statin medically. Now I'm sitting here thinking I don't really want to take a pill for the rest of my life unless I have to, how would you sell it to me or somebody like me?
JARVIS
Well the first thing to say is have we got any risk factors that you could look at? There was a big study which showed that 90% of your risk of having heart attack can be predicted on the basis of risk factors and they're risk factors you can something about. So that includes whether you've got diabetes, whether you're an apple or a pear - have you got abnormal obesity - do you smoke - bit of a no brainer that one - do you exercise regularly, do you eat fruit and vegetables daily. If you're already doing all of those and you haven't got the other risk factors we can't try and reduce your risk through lifestyle so for you I would be saying, look let's look, let's see if there is anything else we can do ...
PORTER
But if there's not give me the bottom line - how much is it going to reduce my risk of having a heart attack?
JARVIS
If we can reduce your bad cholesterol by 1 millimole per litre, that's about by say a third, that's what a statin will very commonly do. We can cut your risk of having a heart attack by about a quarter.
PORTER
So that's the upside but what about the downside, what sort of side effects do you see in your surgery?
JARVIS
Muscle aches are undoubtedly the most common side effect and the figures I've seen are about 1 in 20, which probably tallies with what I see in the surgery. Don't forget though that a lot of people will read the patient information leaflet and get some muscle ache because they've been doing some exercise when they haven't done it for a while and put it down to the statin. So I think probably about 1 in 20 people.
PORTER
But generally that's the main side effect that you see?
JARVIS
That's the main side effect. I think if you start off at very high doses of statins we know you're going to have far more in the way of side effects and particularly tummy side effects - diarrhoea, bloating, tummy pain. I start all my patients on 20 milligrams of Simvastatin and then move them up to the 40 milligram dose to keep that side effect at bay.
PORTER
And have you ever seen a serious reaction because they can happen?
JARVIS
They can happen and no I've absolutely never seen one and I think of all the doctors I've spoken to I've only ever met one who has.
PORTER
Well Billie Marchant took a statin for years without a problem - until she was switched to a different type.
MARCHANT
In 2005 I started suffering from muscle weakness in my calves and my thighs, put it down to old age and thought no more about it. After about two months, it was in July - July 2005, I started having extreme pain in my calves and my thighs to the point that I couldn't sort of really get my knickers on and off basically. And I couldn't get upstairs, in fact I couldn't even lift my foot sort of my than half an inch, an inch, off the ground and that with extreme pain. I couldn't walk. I couldn't move my legs without pain. It was extremely limiting to everyday life. Now fortunately my doctor was really on the ball and when I presented with these symptoms she immediately said stop taking the statins and it took a very, very, very long time before I regained normal use and could actually get upstairs and simple things like that and getting out of a chair even without being helped.
PORTER
Billie Marchant. Sarah, that was a fairly extreme case, but the fact that it came on after changing to a different statin is interesting. Are all statins equal?
JARVIS
No they're not. For instance some statins have to be taken at night, some statins, in order to get the same benefit from the point of view of lowering your cholesterol, you have to take a higher dose. Some statins also have drug interactions, so they'll interact with drugs that actually we take quite commonly ...
PORTER
GPs at the moment are actively encouraged to swap patients to cheaper older statins because the NHS spends a fortune on them and the cheapest currently available being generic Simvastatin but is that as effective and as safe as the more modern drugs?
JARVIS
The answer is yes it's as safe and yes it's as effective if you give it at the right dose but you do have to give a slightly higher dose, so for instance 40 milligrams of Simvastatin is about the same as 10 milligrams of some of the others. Now in terms of safety that doesn't make a difference, it may mean that you're slightly more likely to get side effects. But I think what we need to remember is that the vast majority of people are going to be absolutely fine. So they'll be just as well cared for, will have cut their risks by just as much and we're not spending nearly as much money.
PORTER
And if they're not happy on the new drug you can always go back to the old one. Sarah, what are your thoughts on the recent move to de-restrict Simvastatin, you can get it over-the-counter now, it's been available for three or four years?
JARVIS
It's interesting that that move came in when we were much more cautious about prescribing statins. It's only in the last couple of years that the 10 years, where we recommend you get prescribed a statin, has gone down to 20%...
PORTER
Because we were talking about the threshold being one in five for GPs, of course that's 20%.
JARVIS
That's 20% but don't forget that has got to be to an extent a financial thing. And I think that for people whose risk is pretty moderate I would say on the whole I'd really like it if you could look at your lifestyle first and not take a statin as an excuse so that you can carry on smoking and eating your pie and chips.
PORTER
Because the pharmacists I mean they can sell this drug to people who've got a risk as low as 10-15% if that's the case for the over-the-counter why are prescription only drugs limited to this 20% - is that an economic decision?
JARVIS
It's an economic decision, I don't think there's any question about it. If we look at the research data it suggests that there might be a benefit in terms of cost effectiveness down as low as 8 or 10% but we need to bear in mind that that's going to cost the government an awful lot of money and it's a long term investment because in these people the heart attacks that we're preventing are going to be years and years in the future. So it's a lot of money to lay out now to cut heart attacks a long time away.
PORTER
Well, not surprisingly, the risk of a heart attack and stroke rises inexorably with age, but why wait until it becomes significant? Should statins be started earlier in people with very high cholesterol levels, like the 1 in 500 children born with familial hypercholesterolaemia? A condition that now affects 10 million people worldwide and, which left untreated, can lead to someone dying from a heart attack in their 30s or 40s. Dr Barbara Hutton is a clinical epidemiologist at the University of Amsterdam where she has been investigating the use of statins in childhood.
HUTTON
Familial hypercholesterolaemia is an inherited disorder which leads to severely elevated levels of the bad cholesterol from birth onwards. And this causes a hardening and narrowing of the arteries, we call it arterial sclerosis. And consequently the chance of having a heart attack early in life is greatly enhanced.
PORTER
But how much earlier might these people run into trouble?
HUTTON
If patients are untreated the risk for cardiovascular events is about 5% in [indistinct word] patients by the age of 30 and 50% by the age of 50 years.
PORTER
So they're 10 times more likely to develop premature heart disease?
HUTTON
Yeah, familial hypercholesterolaemia is really a devastating disease and most children you don't see any symptoms, sometimes they have some outward lumps and bumps but in general you don't see any symptoms.
PORTER
So the only way of making the diagnosis is to do a blood test and look for the cholesterol level?
HUTTON
Yeah.
PORTER
If we find that elevated level I mean there's good evidence now that intervening with statins or cholesterol lowering drugs in adults is a very effective intervention do we have that same level of evidence for children?
HUTTON
We performed a study and we followed children for almost five years, they all were on statin treatment and this allowed us to explore the relationship between the age of statin initiation and the progression of arterial sclerosis. And our findings demonstrated that the age when treatment started was linked to the artery wall thickness and artery wall thickness is a reliable marker for the risk of cardiovascular events. And this data we found strongly indicates that early statin treatment reduces arterial sclerotic burden more strongly, which supports the concept that statin treatment should be initiated already in childhood.
PORTER
What about the other effects - I mean obviously statins are useful for lowering cholesterol and looking at your study that - and other studies - that would suggest that that reduces the damage to arteries - but is cholesterol important for other things in growing children, were there any side effects that you've seen in children that hadn't been seen in adults?
HUTTON
Now during our study period no serious clinical or laboratory adverse events were reported. And as well there's no untoward effects on sexual maturation or growth.
PORTER
Barbara Hutton talking to me from Amsterdam.
Although Dr Hutton's study reassuringly found no evidence of impact on growth and development, there has been concern that inhibiting one of the key enzymes in cholesterol production may have a knock on effect on other systems in the body. Something I put to Tom Sanders, Professor of Nutrition and Dietetics at King's College, London.
SANDERS
We need some cholesterol to make up membranes and to make some of the steroid hormones. Most of the drugs that inhibit cholesterol synthesis actually act by reducing the amount of cholesterol that's made in the liver, not in the gonads or tissues that make the steroid hormones, so it doesn't effect levels of steroid hormones. They do also interfere with the production of a compound called Q10.
PORTER
And Q10 does what?
SANDERS
Q10 has a role in the respiratory chain in producing energy and it's been used as a medication in Japan for heart failure. It's not used as a medication in any European country. And some years ago when the statins first came about there was a bit of concern that the muscle pains that people got might be due to a lack of Q10. I think this has now pretty well discounted, the most severe form of muscle pain, that's called rhabdomyalosis, very rare, there's about three per 100,000 people treated, is more complicated than probably is caused by mixing drugs that don't get on or it may be a genetic defect. But there are more common muscle cramps and pains and some people have claimed that taking supplements of Q10 help relieve these but there are other trials that don't show any benefit at all. And we can make Q10 in the body normally from other dietary components and we can get it in diet, it's in a lot of foods naturally, so even if we have a reduced capacity to make this Q10 we're getting quite a lot in dietary seeds and grains and things. So the view at the moment, there's no benefit from taking Q10 if you're on a statin.
PORTER
What about other dietary considerations - one of the other things that you often read about is the interaction or potential interaction with grapefruit juice?
SANDERS
Grapefruit juice is a bit of a problem with a lot of drugs, it first came up about 10 years ago with a hay fever drug called terfenadine and it caused cardiac arrhythmias if you consumed grapefruit with it and it does if you interfere with some statins, not all of them, if you eat large amounts. So if you have the odd glass of grapefruit it's fine but it's probably not a good idea to be drinking litres of grapefruit if you're taking a statin.
PORTER
And that interaction comes about how?
SANDERS
The interaction comes about because a flavonoid called Naringenin which is present in grapefruit juice is detoxified in the liver by the same mechanism that breaks down the statin drug and where you get this competition for breakdown between non-nutritive material then you can get problems. And it's quite well known - there are some other drugs that interfere with the breakdown, some of them are anti-fungal drugs, some antibiotics and they don't mix together, they form effectively a toxic cocktail.
PORTER
Professor Tom Sanders talking to me earlier. You are listening to Case Notes, I am Dr Mark Porter and I am discussing statins with my guest Dr Sarah Jarvis.
Sarah, Tom mentioned interactions there - how big a problem are they actually in clinical practice?
JARVIS
One of the big problems we've got is that a lot of the interactions are with other heart drugs. So in the past, certainly when statins were pretty much reserved for people who already had heart disease, I think it was probably more of an issue. So warfarin, three quarters of a million people in the UK take that, and other heart drugs like Verapamil and Diltiazem. These days, now that we're giving them to more and more people who perhaps are otherwise "healthy", who haven't had any medical condition diagnosed, I think it's probably likely to be less of an issue. And although people don't like the idea of taking grapefruit juice that's not a problem with all the statins.
PORTER
Okay, what sort of monitoring is required when someone's taking a statin, I mean we used to monitor people for both side effects and to check that the statin was getting their cholesterol level to what we call target? Perhaps we should start with the safety monitoring first.
JARVIS
Well interestingly I think it's an indication of quite how safe these drugs are in terms of safety and I think it's worth saying that - I mentioned before that safety is great with these drugs but a lot of people get side effects. Now side effects are not serious side effects so they don't need monitoring except that the patient will come in and say I've got muscle ache. So if you have a muscle ache you go into to see your GP and you should get a blood test done. But we no longer recommend that that blood test is done routinely because we know that actually in terms of muscles they're pretty safe.
PORTER
But you do need a blood test to check to see what's happened to your cholesterol and perhaps we should talk about the targets here, how low is good?
JARVIS
Well this is again a constantly changing target - it's always moving. Certainly across Europe and most of the rest of the world we look for a total cholesterol level below 4 and a level for bad cholesterol - that's LDL cholesterol - of below 2. Now if you're in America where they're obsessed with this sort of thing in all their measurements they also target good cholesterol and they want to get your good cholesterol up - that's your HDL cholesterol. And that's because we know that one of the biggest influences on whether you have a heart attack is the ratio of good to bad cholesterol in your system. But we don't have drugs that will increase your good cholesterol that much, we need to rely on diet and lifestyle for that.
PORTER
To put that very simply: good cholesterol doesn't get deposited in the walls of your arteries, in fact can slow deposition, whereas bad cholesterol is the stuff that clogs it up. That's put very simply but ...
JARVIS
That's right, yeah absolutely, the good cholesterol actually picks up the bad cholesterol and carries it back to the liver, so we can get rid of it.
PORTER
So that target of 4 and 2 is the one that you work to. Well not everyone can take high enough doses of statins to get to ideal cholesterol levels. Others have very high cholesterol levels that can't be reduced by statins alone, whatever the dose. And some people simply can't tolerate a statin at all.
Ezetimibe is another drug that can be used alongside a statin to drop cholesterol levels further. I went to the Royal Free Hospital in North London to meet John who is on the drug and consultant lipidologist Dr Devaki Nair, to see how the drug's being used.
NAIR
One of the problems we have with statins is that as you increase the dose you don't get a proportionate reduction in LDL cholesterol. With doubling the dose you only get around 6% reduction in LDL cholesterol. So you get the most benefit at the lowest dose. The new drug works in a different way - it blocks the absorption of cholesterol in the gut by blocking a protein that helps you to absorb the cholesterol, thereby giving you a bigger reduction than you would get by doubling the dose of statin.
JOHN
I had a stroke a year ago and I'm on the highest value of statin that I was on, which is Pravastatin. And my cholesterol was moving about a bit and not constant, slightly up, so Dr Nair put me on Ezetimibe as a supplementary to the statin that I was on. And my cholesterol has been fairly constant - about 3.6 mils - ever since then.
PORTER
So you're within the healthy range for someone who's had a stroke.
JOHN
Yes, yes, I think originally it was about 6.9, which I think is the upper end of the cholesterol level before it's very serious.
PORTER
Had anyone told you to do anything about that though?
JOHN
Yes well obviously I went on to all the correct diets - I mean I cut out the saturated foods and I cut out the yolk of eggs, butter which I think is very important, cheese - I'm on low fat cheese - and various low fat unsaturated diet as much as I possibly can. I try to do it that way but it didn't really lower the cholesterol to the optimum level that it should be.
NAIR
When you use statin with the higher dose you see more side effects. So in some patients where they experience side effects what we do is to put them on a lower dose and add Ezetimibe, which is the cholesterol absorption blocker, to get a much more bigger benefit.
PORTER
So Ezetimibe is not in most patients competing with statins as a first line choice for treating cholesterol problems, what you're saying is that rather than double up on or quadruple even the statin dose you might consider adding it in as an adjutant therapy?
NAIR
It's always an add in therapy, except in patients who cannot take any statin at all. Some patients are intolerant of statins, they complain of muscle aches and they discontinue the statin. I do use Ezetimibe on its own when patients can't take any statin.
PORTER
And how effective is it when it's used on its own, what sort of effect would it have on the cholesterol?
NAIR
Probably it depends on patients, some patients respond very well, they reduce by 30-40%, some patients only reduce by 10% and that may be the genetic difference in the protein which is involved in the cholesterol absorption. So you may have people who absorb a lot of cholesterol, you may have people who don't absorb much cholesterol and you may have people in between. So people who absorb a lot of cholesterol benefit greatly from this drug than those people who do not absorb much cholesterol.
PORTER
And is there a way of identifying people who are moderate, hyper or hypo absorbers of cholesterol?
NAIR
I think I wish could offer a laboratory test to pick these people up then we could cost effectively use Ezetimibe for those patients who are hyper absorbers and who respond well but there isn't a test as yet available to pick these patients up and so it's by trial and error.
PORTER
You say that one of its advantages is that it can be used as a drug to spare high doses of statins, therefore hopefully the patient will have fewer side effects, but what side effects does Ezetimibe have itself?
NAIR
Ezetimibe is not known to have muscle side effects which is associated with statins but I would say that it is not free of all the muscle side effects, rarely I have seen muscle side effects even with Ezetimibe, so we have to be careful that we don't think that there is no muscle problems with Ezetimibe at all.
PORTER
If it works by blocking the absorption of cholesterol from the gut, from the diet, it begs the question that presumably patients who've got a cholesterol problem should be on a low cholesterol diet in the first place, so would that suggest that if you're being good the drug's likely to be less effective in you, whereas if you're bad and cheating a bit and having a bit too much cheese and dairy products etc., it's probably going to be more effective?
NAIR
The cholesterol story's not so simple. We have cholesterol in our diet, most of us try to follow a low fat diet, however, in a normal diet it's around 200-300 milligrams per day. So we have this in our gut already. And as you may know in the normal physiology bile juice contains a lot of cholesterol which we make in the body, we empty our bile into the gut, that's the way we get rid of the cholesterol. So it comes into the gut, that is around 900 milligrams, approximately 900 milligrams, so together with the dietary cholesterol this is around 1,100-1,200 milligrams of cholesterol which is within the gut.
PORTER
So we're saying that more than 80% of the cholesterol in the gut is actually coming from bile being manufactured within our body not in the cheese and milk that we're eating?
NAIR
It's the biliary cholesterol which we absorb more than the dietary cholesterol.
PORTER
Devaki Nair talking to me in her lab at the Royal Free.
Sarah, what other alternatives are there - what about self-help measures like weight loss, exercise, fish oils, even moderate amounts of alcohol?
JARVIS
Weight loss is fantastic because not only does it make you feel better, you reduce your bad cholesterol, you increase your good cholesterol, you also reduce your blood pressure and your blood sugar if you've got diabetes. So fantastic, there's no such thing as too much weight loss as long as you don't lose - get into the aneroxics category. Now if you've had a heart attack we recommend everybody should be having a couple of portions of oily fish a week and if you can't tolerate oily fish, if you really hate it, that's one of the few groups where we recommend a supplement of omega 3 ...
PORTER
And if it's good for people with - who've had heart attacks presumably it's good for the rest of us too.
JARVIS
One portion of oily fish a week, two portions of fish - one portion of oily fish for absolutely everybody yeah.
PORTER
And the alcohol story?
JARVIS
Well alcohol you're alright, interestingly people love this story because it does suggest that a little bit of alcohol is better than no alcohol at all. But in fact a little bit of alcohol, which is sort of one unit a day, is no less good than three units a day and once you get up above there you're starting to run into problems with your liver and with the rest of your body. So I'm afraid there's not much excuse there.
PORTER
No, it won't do you any harm if you drink sensibly, that's the key message. I mean do you think we're over dependent on cholesterol lowering drugs? There's been some concern recently in the media, and just in the last week, that people on statins are seeing them as a substitute for clean living, in other words they're having their statin and then having their full cooked breakfast or their dinner.
JARVIS
I think that's absolutely right to be concerned about it because I would hate it if people used this as an alternative and I think this maybe why some people hate statins so much because they see them as an excuse for people to carry on living unhealthily. We heard earlier on about children who've got familial hypercholesterolaemia, now for them they absolutely need statins because they've had very high cholesterol since before they were born, simply because of the way their body makes cholesterol. For them I'm afraid there's no choice. For people who've had a heart attack I think there's no choice. For people who haven't I'm a great believer in trying the alternatives first and I have to say I'm not beyond giving somebody a bit of a hard time if they want to carry on eating their bad diet.
PORTER
But even if it gets to the stage where their lifestyle measures, I mean take me - a relatively clean living person, I still need to carry on being a clean living person, I can't start my statins and say right now I can have chips.
JARVIS
No absolutely not. Don't forget that if you weigh 20% more than you did then actually your cholesterol will only be back to what it was before, even if you're taking a statin.
PORTER
So just negating any of the benefits.
There's a lot of scepticism about statins out there - on either side of the consulting desk. I must say that there's a vocal minority but they are very, very vocal, whenever we cover cholesterol we often get feedback saying we have been too pro-statins. Why do you think it is that they tend to polarise opinion so much, there doesn't seem to be a lot of people in the middle ground, you're either for or agin.
JARVIS
I think one of the problems is that we do tend to forget that not taking statins has side effects as well, don't forget muscle ache is bad, stroke is much worse and of course that's often a consequence of not taking a statin. That's the first thing. The second thing is that we have got so much more fat and lazy in this country and quite frankly if we didn't have statins as an excuse then maybe not nearly as many people would need to take them, so maybe it's a kind of self-fulfilling prophesy and I think that's possibly why some people hate them so much.
PORTER
Is this why you - similar reaction that we heard with immunisation to some extent as well.
JARVIS
Absolutely. Of course we always get stories about the possible side effects from MMR and isn't it interesting how they always wheel out the same one or two people because they are a tiny minority but they are very vocal. Whereas of course we've forgotten because we're so lucky to live in an age where most people haven't experienced the side effects of measles or mumps we forget that not having the MMR can have horrible consequences too.
PORTER
We've had statins now in common usage for certainly a decade, what sort of impact have they had on the hearts of the nation?
JARVIS
Well we know that more and more people are having heart attacks and heart disease and that fewer and fewer people are dying from heart disease. So we know that our risk factors are getting worse and yet despite that last year we showed that about 40% fewer deaths from heart attacks were happening in this country compared to 15 years ago. So I think the government's got a lot to be proud of in terms of improving preventive medicine.
PORTER
Dr Sarah Jarvis, thank you very much.
If you would like to find out if you fall into the category deemed to be likely to benefit from a statin, that's anyone with a risk of 20% or above, then you will find a link to a cardiovascular risk calculator - the sort used by your GP - on our website at bbc.co.uk/radio4.
Next week's programme comes from the new burns centre at Birmingham Children's Hospital, where I'll be finding out about the latest multidisciplinary approach to managing burns and scalds.
ENDS
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