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Tuesday, August 30, 2011

Is Lipitor good for you?--putting statins on the hot seat

In 1971, as medical science was wrestling with the observation that elevation of cholesterol levels was associated with heart attacks, a Japanese chemist named Akira Endo discovered a substance that inhibited the enzyme HMG CoA reductase and thus lowered cholesterol levels. His original chemical was never introduced due to significant muscle toxicity and the fact that it caused tumors, but not long after, a less toxic version was introduced under the brand name Mevacor (Lovastatin.) This drug was significantly more powerful in lowering cholesterol levels than the unpleasant and relatively ineffective drugs that came before. These are still used today, but are difficult to take, including ones that taste like sand and absorb cholesterol from the gut as well as high dose niacin which causes itching, flushing, worsens diabetes and exacerbates gout.  Lovastatin could be dosed once daily, was an innocuous capsule, and lowered cholesterol strikingly.

Since that time, many more HMG CoA reductase inhibitors (statins) have been released, and they all work pretty well. That is, they all work pretty well to lower cholesterol. It is true that high cholesterol is strongly associated with vascular disease, especially heart attacks and strokes, and that use of these drugs does reduce the risk of these things. Unfortunately, it is not entirely clear that these drugs make most people healthier or make them live longer.

Many good controlled trials have shown that statins, pretty much all of the statins, and there are quite a few, reduce the risk of vascular disease AND DEATH in people who have had heart attacks or vascular procedures to prevent heart attacks. But if statins were only used in those already affected, sales would not have topped $12 billion for lipitor (atorvastatin.) A recent meta-analysis evaluating all good studies of all statins did show that normal people with elevated cholesterol who were treated with statins did not live longer than those who were not treated.

There have been many many studies that have addressed the effectiveness of statins, partly due to the fact that there is so much money going into paying for these drugs, some of which can be routed back into science. The studies address risk of all kinds of diseases, vascular and otherwise, in all kinds of people, especially sicker subpopulations. It appears, for instance, that the very old who have had heart attacks do live longer if given statins. Diabetics, at least some diabetics, have less heart attacks and strokes, and live longer when given statins regardless of their cholesterol numbers.

Statins are very powerful drugs. They work to keep the liver from making cholesterol, but they also have some pretty diverse other effects, including stabilizing blood vessels and reducing inflammation that can cause heart attacks.  They also are somewhat toxic to mitochondria, the tiny cells within cells that are responsible for   the health of a myriad of different tissues in our bodies.  Because they sometimes injure mitochondria, they can cause muscle pain, and in some cases dangerous breakdown of muscle tissue.  The muscle pain is associated with damage that can be seen on muscle biopsy, which is usually, but not always, reversible when the drug is stopped. Other tissues that can be affected include liver, kidneys, gut and brain, and a small percentage of patients who take these drugs have symptoms that arise from these effects.  Muscle pain, however, is not rare, and in my practice requires stopping the statin drug in about 1/4 of patients who would like to be able to take these medications. Symptoms associated with statins can be really subtle and many patients who experience them assume that they are just getting old. Physicians are not very sensitive to the possibility of side effects with these drugs, partly because they are such an easy way to get cholesterol down.

If an evil alien race wanted to take over the world, statin drugs might be just the ticket. They would make those who are already damaged by heart disease live longer, and cause some portion of the rest of those taking them to become weak, flatulent and stupid. A drug that was indicated for a condition such as high cholesterol, that affects nearly 1/4 of people in developed countries and offers to reduce their risk of heart attacks and strokes would be so very tempting that most of us would take it. Clever aliens.

There is near consensus among academic physicians that statins are good for us, and that complaints about side effects are overblown and irrelevant. I am having trouble trying to find support for this in the literature, and real trouble ignoring the side effects that I see in my office. It is hard to ignore the power to sway us that may be wielded by a drug company that makes 9 billion dollars in a year on one of these drugs, as Pfizer does on Lipitor.

A couple of other matters deserve note. There are quite a few statins, from the less potent pravastatin, lovastatin and fluvastatin, up through the most powerful, simvastatin, atorvastatin, rosuvastatin and pitavastatin. Several are generic, and of these, the most popular is simvastatin due to its low cost and high potency. All of the statins can cause adverse reactions, but some are worse than others. Simvastatin is probably the most likely of all of them to cause muscle pain and to interact with other drugs in ways that increase those side effects. Drugs that interact with some or all statins include various antibiotics, warfarin, antifungal and AIDS drugs and as little as a cup of grapefruit juice. Higher doses lower the cholesterol more and increase adverse effects more, and only occasionally are shown to be more effective at reducing vascular disease. The most dramatic adverse effect of statins is a severe breakdown of muscles, called rhabdomyolysis, and that is more common in the elderly, those with underlying organ dysfunction and those who take medications to lower the triglyceride levels (fibrates.)

A recent article came out in the European Heart Journal, looking at long term followup of treatment with atorvastatin in a study of various medications for high blood pressure with or without cholesterol lowering drugs. The results were nearly impossible to understand, showing that people who were initially placed on atorvastatin who had high blood pressure did live longer, but primarily due to the fact that they were less likely to get pneumonia. Huh? In addition to that, after the two or so years that the study continued ( it was stopped early because the patients on atorvastatin had so many fewer heart attacks and strokes) nearly all of the patients in either treatment or control group were put on statins, so they were pretty much identical in all ways except for the first two years. As I read this, it would suggest that taking lipitor for 2 years, 11 years ago reduces your risk for pneumonia in subsequent years, which just doesn't make a reasonable amount of sense.

Bottom line: Lipitor is probably good for you if you have had angina or a heart attack and don't want it to happen again. It can cause a myriad of side effects, some of which can be pretty subtle but can significantly impact a person's life. If your cholesterol is just high, but your heart and vessels are fine, Lipitor (or other statins) might be very good for you, and might be bad for you, and it is kind of hard to know from the studies whether to take it. It is unlikely that Lipitor was invented by evil aliens, but if it was, they are really raking in the bucks.

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