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Pleiotropic Effects of Statins

The word pleiotropic originally referred to a gene that influenced or affected more than one trait in an organism, several phenotypic expressions. The word has been borrowed to the world of pharmacology where it is used to refer to actions of drugs that are not their main or intended action. This is not the same as a side effect. Pleiotropic effects of medicines are generally beneficial. For instance, aspirin was originally used as a pain reliever and was later found to have the pleiotropic effect of lowering the risk of heart attack.

Statin drugs have pleiotropic effects, which is one reason the medical community is so enthusiastic about them. The “official” way statins benefit patients is by reducing lipid levels in the bloodstream. (Actually, by inhibiting the production of cholesterol in the liver, which ends up resulting in lower serum cholesterol numbers.) Over the past couple of decades the other beneficial cholesterol-independent effects of statin medicines have come to light.

Pleiotropic effects are the flipside of detrimental side effects. They may not be the reason to take the drug, but they may end up being a potentially significant part of the patient’s experience. Millions of people have taken various statins in many countries for years, so there is a wealth of data for epidemiological studies. We can now say that statins have pleiotropic effects in general, although they manifest more in some people than others.

Specific Effects

Statins stabilize the artery plaque that causes atherosclerosis. (The plaque is made of cholesterol, other types of fat, calcium or calcium salts, and other blood components.) While this stabilization is partly due to the reduction in LDL levels, statins also reduce markers that show inflammation of the vascular walls. They have long been known to reduce levels of C-reactive protein, the widely measured inflammation marker used for evaluating risk of cardiovascular diseases. Statins appear to interrupt the action of constituents that allow plaques to adhere to the walls. The number of inflammatory cells in the plaques appears to decline. Research shows that higher statin doses result in greater reduction in inflammation.

Statins, like many phytochemicals in the diet, have antioxidant effects. The appear to be able to scavenge superoxide (which is a chemical species that harms cell walls) and inhibit isoprenoids, which give rise to superoxide. Whether being an antioxidant means anything as far as health benefits is unclear, however. Experiments with other antioxidants show their administration did not affect the rate of adverse cardiovascular events. Lowering lipids reduces the oxidative load on the vessel wall cells, but there is evidence that statins have an additional antioxidant effect that does not depend on lipid levels. Nitric oxide appears to be a key constituent in allowing blood vessels to relax and the by reducing oxidants, statins allow more nitric oxide to remain in the bloodstream.

When a blood vessel is damaged, it can induce the proliferation of smooth muscle cells, which increase the risk for adverse cardiovascular events. Statins in the bloodstream slow this proliferation. Statins also shift the fibrinolytic balance toward fibrinolysis. This reduces the tendency of platelets to clump together and produce clots. Again, nitric oxide comes into the equation as increases in endothelial nitric oxide inhibits platelet aggregation. Also, thromobosis risk appears to be lower at least partly because the cholesterol level in the platelet membranes is lower.

The inside lining of the blood vessels is called the endothelium and injury to the endothelium starts the process of atherosclerosis. In the body statins help keep the levels of endothelial nitric oxide synthase (eNOS) high. This enzyme facilitates production of nitric oxide and it is high levels of nitric oxide that protect the endothelial cells. This could explain why long-term statin use improves the endothelium when there is atherosclerosis present. A meta-study showed statin usage cuts the risk of pancreatitis (inflammation of the pancreas).

Epidemiologists have never been able to show a relationship between ischemic stroke rates and cholesterol profiles. But studies of populations who have been on statins for years show a significant decrease in stroke incidence. The reduction in stroke risk was seen in people with different blood pressure levels and serum cholesterol levels. Again, this benefit could be due to the statins’ improvement in blood vessel wall tone and nitric oxide levels, resulting in better blood flow to the brain.

Dementia Protection

Statins might help protect the brain from dementia. High cholesterol is a risk factor for Alzheimer’s and a large British study found statins reduce dementia risk regardless of lipid levels; A Dutch study likewise found people on high doses of statins had a substantially lower risk of getting dementia.

Arthritis Risk

Statins may also forestall development of the inflammatory disease rheumatoid arthritis. The anti-inflammatory effects of statins is thought to come into play here, but the biochemistry has not been elucidated.

The Lungs, The Eyes, and More

Statins are are also suspected to protect the pulmonary system in smokers. By limiting the inflammation caused by cigarette smoke, the statins may help forestall the development of chronic obstructive pulmonary disorder. There are also suggestions statins reduce the severity of symptoms in asthma patients, which is consistent with their anti-inflammatory effects in the body.

There was hope statins would help in the battle against pneumonia, but testing found they do not.

A 2012 study found statin usage reduces the odds of developing glaucoma. Scientists looked at 300,000 people who took statins for over two years and found the drug lowered incidence of glaucoma by 8%. This was published in the journal of the American Academy of Ophthalmology. This doesn't prove that statins affect glaucoma development, but it is suggestive of a mechanism where the medicine improves blood flow to the eye tissue and reduces pressure in the eye.

There is also indication that the anti-inflammatory properties of statins may be useful in protecting against multiple sclerosis. French scientists found high doses of atorvastatin were effective in slowing the progression of MS. Patients who took the drug has significant reductions in MS Impact Score (MSIS), and minor (not statistically significant) improvements in hand dexterity and walking ability. The anti-inflammatory effects also appear to ease the symptoms of COPD.

By reducing tissue inflammation and improving blood flow, statins may actually help aid the healing or surgical wounds. They might also reduce the risk of thyroid-associated ophthalmopathy, a condition some Graves Disease patients get.

In the Elderly

An Israeli study found that statins reduced mortality in older people but that baseline cholesterol level was unrelated to cardiovascular risk for those between 70 and 90. How to explain this apparent contradiction? An explanation is that statins have benefits that are not reflected in reduction of cholesterol levels. In other words: pleiotropic effects.

Legacy Effect

The evidence on this is not strong, but the finding is exciting. A British study suggests that taking a statin drug for five years and then quitting them still yields benefits 20 years later. It takes a long time to do a study like this, and the medicine the participants took was pravastatin which was more widely used in the past. But the researchers found lower incidence of adverse events for two decades. The group of patients who took the statin had better results than the group who took a placebo. One scientists conducting the study speculated the statin altered the “natural history” of cardiovascular disease by lowering LDL levels. He also noted the "remarkable persistence" of the lower risk over the decades.

Starting a statin regimen at age 50 or so and taking the pills daily for 5 years is enough to have a lasting benefit. Even if you stop taking the medicine, your risk of CVD is lowered when you are 75 years old. That is great news, and perhaps will help alleviate the worries about side effects of long-term use. If people can take the drug for only 5 years and get a long-term benefit perhaps more patients and doctors will be willing to try statins. It should be emphasized, however, that the results here are from one study (it is not easy to replicate a long-term study like this) and even so, no formal authority recommends routine cessation of statin therapy after a few years unless there is a compelling reason.

An earlier study of people who took atorvastatin for a limited time found the patients long-term reduction in mortality years after they stopped taking the drug, mainly from a reduction in non-cardiovascular deaths.

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