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Cholesterol Levels -

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Norman Swan: Hello and welcome to the Health Report with me, Norman Swan.

Today: a new way of looking after people with chronic pain which has slashed waiting lists for specialist care from two years to six weeks in Western Australia.

Did you know that if India were to provide doctor-centred medical care to the same level as we do, they'd need every medical graduate produced by every developed nation for ten years? So what's the alternative, and can we learn from new ways of doing business in emerging nations?

Exciting findings in schizophrenia.

And a new way of lowering cholesterol levels. An Australian led trial into cholesterol reduction published last week found that a specially made antibody could lower the bad form of cholesterol, LDL, very significantly, even if someone was already on a cholesterol lowering medication.

This is a hot area of research. It originated in the discovery of families with high cholesterol levels where, according to Associate Professor David Sullivan, a blood fat expert at Royal Prince Alfred Hospital in Sydney, the usual genetic defects were not the culprits.

David Sullivan: We couldn't find one when we looked for one. And by studying the families in greater detail we found a new entity which was being produced in larger amounts than usual. It was destroying the usual removal pathway and causing high cholesterols with the resultant risk of heart attack and stroke.

Norman Swan: So it was a gene where the amplification, the volume, was turned up.

David Sullivan: That's exactly right, it was called over-expression.

Norman Swan: And what was it doing, or what is it doing?

David Sullivan: It’s gobbling up the removal pathway for cholesterol, which depends on a cell receptor called the LDL receptor.

Norman Swan: The LDL, low-density lipoprotein, takes cholesterol to the artery and deposits it, but there is also a waste disposal mechanism as well, so it was getting to the waste disposal mechanism.

David Sullivan: That's right. The LDL cholesterol actually needs to be used, and the usual usage pathway involves removal to cells which need it via the LDL receptor. If that's not happening it hangs around in the blood and builds up in the artery wall.

Norman Swan: So in a sense this gene was toxic to this receptor.

David Sullivan: That's right. It's actually designed to remove the receptor after an appropriate amount of time, but it was removing it too quickly and leading to low levels.

Norman Swan: And then people, once they'd identified this gene, they actually flew to people who had under-activity of this gene.

David Sullivan: Well, the logic was if too much is a problem, maybe too little is an advantage, and they did find naturally occurring families in whom the entity was at a low level. These people had cholesterol levels that were about 20% to 40% lower than you would expect, and because they'd had that prevailing their whole lives, they actually had a reduction in their heart attack rate of about 90% and they were completely well from all other aspects.

Norman Swan: And what about the cancer risk? Because people have said low cholesterol means higher cancer risk.

David Sullivan: Look, we've got a number of these genetic examples of people living with low cholesterol and there is absolutely no suggestion of that. If you look at the animal kingdom, most animals run at cholesterol levels of about 1 to 2, and it's adult humans that are the exception of the rule.

Norman Swan: So somebody developed a blocker for this gene.

David Sullivan: Yes, they found a way of taking it out of the blood via an antibody.

Norman Swan: And you just completed a trial, not a definitive trial but an intermediate trial to see whether or not it works.

David Sullivan: Yes, there's a lot of development work going on for this particular idea, and we've been one of a number of groups who contributed to information about its effectiveness.

Norman Swan: What did you do in the trial and what did you find?

David Sullivan: We looked for people who were having trouble taking their usual statin medication, particularly people who'd complained of muscle problems, and we invited them to have an injection once every four weeks...

Norman Swan: So because it's an antibody, you can't take it by mouth because it gets destroyed in the stomach.

David Sullivan: That's right.

Norman Swan: So you give them one injection a month. And what happened?

David Sullivan: Remarkably their cholesterol levels went down by 40% to 50% for the lower doses, and 50% to 60% for the higher doses, and they remained completely free of their previous muscle problems.

Norman Swan: And what side-effects did they get?

David Sullivan: Look, there were patchy complaints and so forth, but none that made sense as a serious problem coming from the treatment. These were people who were selected for muscle problems and there was the occasional complaint of a bit of muscle pain. No one stopped their treatment for that particular reason, and the actual distribution of those people didn't suggest that the drug was causing it.

Norman Swan: And how does that compare, that sort of level of reduction compare to if you took an average statin these days?

David Sullivan: That's as good as you get with the highest dose of the most active statins we've got.

Norman Swan: And of course you don't know whether it prevents heart attacks, you're just going to assume that it does.

David Sullivan: They've started a program to try and look at this, and the expectation would be that it's only when that proof is available that this medicine will be approved.

Norman Swan: This trial that you were involved with was called a phase two, which means that you're finding the right dose to give rather than a very large trial to prove effectiveness. When is the really large trial going to occur, because that will take a while?

David Sullivan: It's recruiting at the moment, and I think because of the power of the medication we can look forward to results within four or five years, which is actually quite quick within this sort of timeframe.

Norman Swan: How long would somebody have to be followed up for to be sure that it isn't causing serious side-effects? Because you are knocking out a gene that pervades the whole body and could have effects on other parts of the body that you don't know about.

David Sullivan: That's true. This study that we did lasted for 12 weeks, but all of the patients who participated have been invited to continue their therapy, so that I think is helpful from both the patient and the study point of view. The experience is rapidly growing worldwide without any indication of a problem. To be really informed about safety we probably need to monitor drugs well after they've been introduced into the marketplace, and so that is really going to be the next 10 to 15 years.

Norman Swan: So there are a few pharmaceutical companies playing in the sandpit?

David Sullivan: At least four I know about.

Norman Swan: And cost...because these biologicals, at least in cancer and rheumatoid arthritis and other areas, cost a bloody fortune, and you wonder whether the pharmaceutical companies are gouging with them, you know, $60,000, $70,000 a year. How much is it going to cost to put this on the market?

David Sullivan: That's a very interesting question and I don't know the answer. Certainly there are increased cost structures just with the fact that these products are going to have to be refrigerated, distributed in a different way et cetera.

Norman Swan: But you don't know the end price here?

David Sullivan: No. As I said, I think it's going to be substantial, I think there will be a very strong incentive for both the current manufacturers to improve the usage of statins and for government to really try to encourage people to use them to their maximum benefit.

Norman Swan: So in other words, the use of this new form of medication will be in the people who are really hard to treat.

David Sullivan: Exactly, people who are inadequately responsive to standard statin treatment or those who require additional treatment because of side-effects.

Norman Swan: Associate Professor David Sullivan is a lipidologist at the University of Sydney.