One of the first duties of the physician is to educate the masses not to take medicine.
Sir William Osler, MD (1849–1919)
There are a number of different statins:
• Lovastatin
• Fluvastatin
• Pravastatin
• Simvastatin
• Cerivastatin
• Atorvastatin
• Rosuvastatin
Why so many? Actually, as mentioned before, cerivastatin was voluntarily withdrawn after killing rather to many people. Somewhat inconveniently, it was said to cause muscle disintegration, followed by death. (In fact, all statins can cause muscle disintegration and death, although the risk seems to be greatest with cerivastatin.) So at least you can cross cerivastatin off your list. Which leaves a mere six in active service. In my opinion, that’s six too many.
Statins all come under different brand names in different countries. In the UK, the only one that is available over the counter (OTC) – thus not requiring a doctor’s prescription – is simvastatin. This is also known as Zocor, or Zocor Heart Pro. Which should be said in a kind of awestruck American/Hollywood film announcer-type accent. You know the sort of thing:
‘He was a man with heart disease.
‘She was a doctor with a passion for saving lives.
‘Together, they discovered Zocor Heart Pro… and nothing would ever be the same again… ‘
Atorvastatin (Lipitor), and simvastatin (Zocor), are among the most widely prescribed of the statins. Lipitor sits proudly at the top of the sales pyramid with over £6 billion per year in sales worldwide. Rosuvastatin (Crestor) was the latest to hit the market. It was discovered in Japan, and the marketing rights were sold to AstraZeneca. It has not done as well as was hoped.
All statins are also known as HMG-CoA Reductase Inhibitors – because inhibiting the actions of the enzyme known as HMG-CoA reductase is what they actually do. If you remember my horribly complicated diagram of cholesterol synthesis from earlier on, one of the steps is the following:
Fig. 15 Where statins work
I think that this diagram (Fig. 15) represents about step four in the long and winding road from HMG-CoA Statins converting Acetyl CoA to cholesterol.
And why, you might ask, have HMG CoA Reductase scientists not found ways to inhibit other steps in cholesterol Mevalonate synthesis? Why this particular one? It is not for a want of trying, that’s for sure. However, problems ensued with drugs that acted elsewhere in cholesterol synthesis – problems such as the death of the surrounding organism, for example. This was a fairly common problem and tended to negate the huge health benefits gained from reduced cholesterol production…
Now, those who were paying attention earlier on may just have spotted a problem with how statins work. If not, I will point it out to you anyway:
• Statins reduce the synthesis of cholesterol.(Yes.)
• By reducing cholesterol synthesis, they should in turn reduce the production of VLDL in the liver.(Yes.)
• VLDLs shrink to form LDLs.(Yes.)
• So, if you have fewer VLDLs, the level of LDL will drop. (Ah. No.)
As explained in the last chapter, there is no association between the VLDL level and the LDL level, so that’s not the answer. Or, at least, that’s far from the whole answer. In fact, the LDL level is controlled by the number of LDL receptors in the body. The more LDL receptors you have, the more LDL will be removed from the circulation.
Unlike VLDL, or IDL, LDLs do not shrink, thereby changing into other types of lipoprotein. LDLs wander about in the circulation, essentially unaltered, until they lock on to an LDL receptor. At this point, the LDL and all of its contents are pulled into cells and then broken down, along with the receptor itself. So if you have a million LDL receptors waving about trying to attract some passing LDL, a million LDLs will be removed from the circulation. And if you want to remove more LDLs, more receptors must be manufactured, then transported to the surface of the cell – wherever in the body those cells may be.
At this point, I think it would be timely to mention a condition by the name of Familial Hypercholesterolaemia (FH), in which LDL levels are extremely high. In some cases, levels are more than five times ‘normal’. The underlying problem in FH is a lack of LDL receptors. With very few receptors available, LDL is stuck in the circulation and consequently its level skyrockets. The LDL receptor – or lack of it in FH – was discovered by two scientists called Brown and Goldstein in 1973. For their work in this area they were awarded the Nobel prize.
* * * * *
OK, time out for a second. By now you may well find that your head is swimming with facts and stats. I did say that this stuff was a bit complicated. I also realise that you may be thinking to yourself: ‘Boring! who needs to know this? ‘You need to know this, I believe, because you need to know that the entire cholesterol/diet-heart hypothesis is nothing like you thought it was. Nor are statins super-simple things that lower so-called ‘cholesterol levels’ through the simple mechanism of reducing cholesterol production in the liver.
In fact, I often think that if those who started the whole cholesterol shebang had any idea how damn complicated it would all turn out to be, once they started thinking it through, they would have realised that it couldn’t possibly work. But they didn’t. They kept clinging to cholesterol while all else crumbled around them. I think it’s a kind of quasi-religious thing: ‘We cannot lose faith…’
What I do find somewhat ironic is that statins were designed to reduce cholesterol production in the liver, thus lowering cholesterol levels. And this is exactly what they do! This is despite the fact that you don’t actually have a cholesterol level in the blood in the first place. How strange is that? Very, actually. It’s so strange that I can’t even think of a suitable analogy.
In a nutshell, statins work (to lower cholesterol levels) in the following way:
1: They lower cholesterol synthesis in the liver.
2: The liver starts running out of the cholesterol needed to make VLDLs.
3: The liver then has to increase the number of LDL receptors to pull cholesterol back in to make more VLDLs.
4: More LDL is dragged back into the liver, as a result of which…
5: The LDL level in the blood falls. So now you know. Very simple really.
Other actions of statins
But if you think that the only action of statins is to reduce the synthesis of cholesterol in the liver, then you are very much mistaken. Statins do many other things. Drugs are very rarely like Koch’s ‘magic bullets’ of yore, designed to pick off one precise bacterium, or enzyme, or biochemical action, in the body.
With most drugs, putting them into the body is a bit like handing a five-year-old an Uzi 9mm machine gun in a hostage situation, then hoping that when the ammo runs out the net result will be that more bad guys got killed than good guys. Sometimes yes, sometimes no. Take steroids, for example. This is a class of drugs that act just about everywhere in the body, and they can be used to treat a huge range of different conditions. For example:
• Eczema
• Organ transplantation – to prevent rejection
• Rheumatoid arthritis
• Ulcerative colitis
• Asthma
• Injection into tennis elbow
• Inability to win a gold medal at the Olympics
How precise is that? Not very.
And how about thalidomide – designed initially to treat morning sickness, but found to create terrible limb deformities in babies? However, the very action that stops limbs from forming properly in unborn children also stops tumours growing by preventing the formation of new blood vessels. Currently, thalidomide is the hottest new thing in cancer treatment.
Or Viagra. Developed to treat angina, found to create long-lasting erections by the students enrolled in clinical studies. And no, they didn’t get many unused Viagra tablets back. Interestingly, Viagra may now have come full circle as it is increasingly being used to treat pulmonary hypertension (high blood pressure in the lungs).
Finally, and perhaps most pertinent to this discussion, is the drug aspirin. Aspirin started life as a painkiller – mainly. About 40 years ago, it was found to ‘thin’ the blood by stopping platelets sticking together. Consequently, aspirin is now used to prevent heart attacks. Who would ever have guessed?
In short, drugs almost always have a wide range of different actions. Some expected, some completely unexpected. And statins are no exception to this rule. Thus, it is fully possible that statins may have ‘coincidental’ effects on preventing heart disease that have nothing whatsoever to do with lowering LDL levels.
You think I am stretching things a bit here? Then read this:
There is increasing evidence, however, that statins may also exert effects beyond cholesterol lowering. Indeed, many of these cholesterol-independent or ‘pleiotropic’ vascular effects of statins appear to involve restoring or improving endothelial function through increasing the bioavailability of nitric oxide, promoting reendothelialization, reducing oxidative stress, and inhibiting inflammatory responses. Thus, the endothelium-dependent effects of statins are thought to contribute to many of the beneficial effects of statin therapy in cardiovascular disease.
Too much scientific gobbledegook? Sorry, but it does make the point that statins have a whole series of effects on blood vessels that could be protective against heart disease. At the last count I got together 35 ‘non-cholesterol-lowering’ actions of statins.
You’re still doubtful? Well, I hope to convince you later on that the ‘non-cholesterol-lowering’ actions of statins are – in fact – the only possible explanation as to how they work. After all, there were plenty of drugs around that lowered cholesterol before statins were discovered. But only statins showed any significant benefit in treating cardiovascular disease. And why would this be, I wonder?