BLOG

6. The effect of the statins is not due to cholesterol-lowering

As mentioned in section 4 cholesterol-lowering by itself does not prolong your life. In the experiments, that have shown this fact beyond all doubt, cholesterol-lowering was performed by diet or by use of various older drugs such as clofibrate (Atromidin®), gemfibrozil (Lopid®), cholestyramine (Questran®), colestipol (Lestid®), and nicotinic acid (Nicangin®).
But a new type of cholesterol-lowering drugs, the so-called statins (for instance Zocor® and Pravachol®) have been succesful. For the first time cholesterol-lowering have shown significant improvement of mortality, both coronary mortality, stroke mortality and total mortality. These trials are therefore considered as strong arguments for the idea, that a high cholesterol is dangerous.

Have these trials really demonstrated that raised LDL cholesterol has importance for coronary heart disease, as the trial directors concluded in the reports?

There is reason to question that, because some of the results are not consistent with what we have learned about cholesterol.

First, old patients were protected from cardiovascular disease just as much (or as little) as young ones, although most studies have shown that a high cholesterol is a weak risk factor, or no risk factor at all, for old people. (Unfortunately, in the only trial that included old people only, the PROSPER trial, the lowering of heart mortality was smaller thanm the increse of cancer mortality).

Second, also the number of strokes was reduced after statin treatment, although no studies have shown that a high cholesterol is a risk factor for stroke.

Third, patients who had had a coronary were protected although most studies have shown that a high cholesterol is a weak risk factor, if any at all, for those who already have had a coronary. (In fact, this finding should have stopped all the previous, secondary preventive trials).

And finally, the statins protected against coronary heart disease whether the cholesterol was high or low although most studies have shown that a normal or low cholesterol is no risk factor for coronary disease.

How come that the statins are effective for old people, for patients who already have had a coronary, and even for those whose cholesterol is normal? If the cholesterol level for these people is no risk factor for coronary disease, how could a lowering of that cholesterol improve their chances to avoid a coronary? The only reasonable explanation is that the statins do more than just lower cholesterol. There is much evidence for that.

The statins inhibit the body’s production of a substance called mevalonate, which is a precursor of cholesterol. When the production of mevalonate goes down, less cholesterol is produced by the cells and thus blood cholesterol goes down as well. But mevalonate is a precursor of other substances also, substances with important biologic functions.The metabolic pathways are not known in all details, but less mevalonate may explain why simvastatin makes smooth muscle cells less active and platelets less inclined to produce thromboxane. One of the first steps in arteriosclerosis is the growth and migration of smooth muscle cells inside the artery walls; and thromboxane is a substance which promotes the clogging of blood. Thus, by blocking the function of smooth muscle cells and platelets, simvastatin may benefit cardiovascular disease by at least two mechanisms and both of these mechanisms are independent of the cholesterol level (82). In fact, up till now we have learned about eleven anti-atherosclerotic effects of statin treatment, that have been found independent on their effect on cholesterol

In one of the experiments for instance, performed by Dr. Yusuke Hidaka and his team, the inhibitory effect on the muscle cells could not be abolished by adding LDL-cholesterol to the test tubes (83); and in experiments with various cholesterol-lowering agents, thromboxane production was inhibited by statins only, indicating that the effect was not due to cholesterol lowering but to something else (82).

The protective effects of simvastatin was also demonstrated in animal experiments. In one of them, performed by Dr. B.M. Meiser and colleagues from Munich, Germany, hearts were transplanted into rats. Normally, the function of such grafts gradually deteriorates because the coronary vessels are narrowed by an increased growth of smooth muscle cells in the vascular walls, a condition called graft vessel disease. In Dr. Meiser’s experiment, however, rats that were given simvastatin had considerably less graft vessel disease than control rats not given simvastatin, and this was not due to cholesterol lowering because simvastatin does not lower cholesterol in rats. In fact, LDL cholesterol was highest in the rats treated with simvastatin (84).

In another experiment, Dr. Maurizio Soma and his colleagues from Milan, Italy placed a flexible collar around one of the carotic arteries in rabbits. After two weeks arteries with collars became narrow but less so if the rabbit had been given simvastatin. Again, the effect was unrelated to the rabbits´ cholesterol level (85).

Thus, the statins in some way protect against cardiovascular disease, but their effect is not due to cholesterol-lowering.

But why bother about pharmacological mechanisms? Isn´t it wonderful that the statins work? Shouldn´t we all take statins?

The costs:

To answer that question it is necessary to look at the figures from the trials. To be short I have chosen the figures for coronary death. According to the results from the 4S trial (86) there was a 41% reduction in the risk of coronary death. According to the results from the CARE trial (87) the reduction was 24%, and according to the WOSCOP (88) trial the reduction was 28%. These figures seem impressive, but let us look at the absolute figures also.
In the treatment group of the 4S trial five percent, or 111 individuals, died from a heart attack; in the control group 8.5 percent, or 189 individuals, died, a difference, or a risk reduction of 3.5%. To prevent these 3.5% of the patients (8.5% – 5%) or 78 individuals, from dying it was necessary to treat 2221 individuals during five years. You could also say that to prevent one death it was necessary to treat 25 individuals for five years. Or said in another way, if you have had a heart attack the chance to avoid death from a new one during five years is 91.5%. If you eat simvastatin this chance increases to 95%.

In the CARE trial 5.7%, or 119 individuals died from a heart attack in the control group and 4.6%, or 96 individuals in the treatment group. Thus, to prevent 23 coronary deaths (1.1%) it had been necessary to treat 2081 individuals for five years, which means that 90 patients were treated for each life saved.

In the WOSCOP trial, which concerned healthy individuals with a high cholesterol, the result was even less impressive. Here, 61 died in the placebo group, 41 in the treatment group, a risk reduction of 0.6%. To save these 20 lives it had been necessary to treat 3302 healthy individuals for five years, or 165 individuals for each life.

Said in another way, the risk of dying from a heart attack during five years if you are about 55 years old and if your cholesterol is around 272 mg per dl is 1.8%. With pravastatin treatment the risk is reduced to 1.2%. You could also say that the chance to avoid death from a heart attack for five years is 98.2%; with pravastatin the chance is 98.8%.

The reason why trial results should be given in absolute figures and not in relative is because the side effects are given in absolute figures. Let us assume that a mortal side effect occurs in 0.5 percent of the patients. You may belittle that if you compare this figure for instance with a relative risk reduction of 28%. But as the absolute risk reduction was 0.6% the effect of treatment has almost disappeared.

To be fair it should be mentioned that the number of non-fatal heart attacks was reduced also. In the WOSCOP trial for instance, 248 individuals in the control group had a fatal or non-fatal coronary, in the pravastatin group the number was 174. This means that to prevent a heart attack in a healthy 55 year old man with a high cholesterol it is necessary to treat about 45 men for five years. To prevent a new heart attack it is necessary to treat 34 patients for five years according to the CARE trial and 28 patients according to the 4S trial.

It is necessary also to look at the costs, but this is not an easy task. For the drugs only the price for one extra year for one person was about $41,000 in the 4S trial, about $148,000 in the CARE trial and about $205,000 in the WOSCOP trial. To that should be added the costs for laboratory tests and doctors´ fee.

There are economical gains also, of course. The directors of the most succesful trial 4S claim that the reduced costs due to the lower number of non-fatal heart attacks outweigh the expenses. But that trial concerned patients at a very high risk of cardiovascular disease. To treat healthy individuals with a high cholesterol must be very expensive, however, because the gain was very small.

The 4S directors´ optimistic views presuppose that the effect is just as positive after ten or twenty years of treatment as it was after five. Unfortunately we cannot guarantee that. Recently, Drs. Thomas Newman and Stephen Hulley published the results from a meticulous review of what we know about cancer and lipid-lowering drugs. They found that clofibrate, gemfibrozil and all the statins stimulate cancer growth in rodents (89).

Newman and Hulley asked themselves why these drugs had been approved by the Food and Drug Administration at all. The answer was that the doses used in the animal experiments were much higher than those recommended for clinical use. But as Drs. Newman and Hulley commented, it is more relevant to compare blood levels, and the levels achieved in rodents were very close to those seen in patients.

Because the latent period between exposure to a cancersstimulating chemical and the incidence of clinical cancer in humans may be 20 years or more, the absence of any controlled trials of this duration means that we do not know whether statin treament will lead to an increased rate of cancer in coming decades. There is reason to believe that it will, because as mentioned above, treatment of old people already has resulted in an increased number of cancer. The reason is probably that many old people already have cellular changes that rapidly may develop to clinical cancer if stimulated by a cancer-provoking drug..

Other nasty effects have been reported on human beings, side effects that have been reported after the end of the trials. They include peripheral neuropathy, a painful and invalidating disease mainly located to the legs (90a), memory loss (90b), short temper (90c), aggressive behavior (90d) and muscle problem that in rare cases have led to kidney failure and death. Most scary, considering that people with very high cholesterol, so-called familial hypercholesterolemia, automatically are prescribed statin treatment already from early childhood, is the recent report in prestigious New England Journal of Medicine (90e). Here the authors reported that almost 50 % of pregnant women who took a statin drug during early pregnancy gave birth to a child with malformations, some of them more severe than those seen after thalidomide treatment.

Those who argue for statin treatment have argued that these side effects are very rare. They will most certainly become much more common considering that the new cholesterol guidelines recommend that cholesterol should be lowered as much as possible, even if it may demand an eight times higher dose than used hitherto.

Thus, millions of asymptomatic people are being treated with medications, the ultimate effects of which are not yet known. Drs. Newman and Hulley therefore recommended that the new statins should be used for patients at very high risk for coronary disease only, whereas such treatment should be avoided for individuals with life expectancies of more than 10 to 20 years. And healthy people with a high cholesterol as the only risk marker belong to that category.

The Cholesterol Myths #7

References