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Statins

We should put statins in the water supply.” I can’t count the times I have heard doctors say this, and I can hardly imagine a more wrong-headed idea. It represents a great lack of understanding of the effects of these powerful drugs and their risks versus benefits.

Here are the stories of two patients on statin therapy.

Janice is a sixty-two-year-old financial analyst with no health problems apart from a history of elevated cholesterol first noticed five years ago. She is careful about her diet—eats lots of vegetables and fruit, very little snack food, and chicken or beef only once a week. Janice exercises every other day at her health club and goes to yoga class once a week. Three years ago, her internist became concerned when her total cholesterol rose to 225 mg/dL and prescribed the cholesterol medicine simvastatin (Zocor). Follow-up labs six weeks later were normal, with a drop in total cholesterol to 165 mg/dL.

At a return visit six months later, Janice felt a bit less energetic than usual and said she had cut back on the intensity of her exercise program. One year later, at her annual checkup, she described feeling “older,” with aching legs and “arthritis pains” in her elbows and wrists. Shortly thereafter, her husband took her on a surprise anniversary trip to Italy; in the excitement of preparing for the trip, she forgot to pack her simvastatin. While in Italy, her pain disappeared, as did the achiness in her legs.

Upon her return home, Janice decided not to restart the simvastatin. She has remained pain free. Although her total cholesterol is high, so is her “good” HDL cholesterol, and her overall risk of cardiovascular disease is low.

Jim, age fifty-six, is in the emergency room because of chest pain and is informed that he is having a heart attack, his second. At the time of his first, two years ago, his cholesterol was elevated and a statin was prescribed. Although Jim was initially reluctant to take cholesterol-lowering medication, his doctor convinced him that he wouldn’t have to worry about his diet if he took a statin. Since the first heart attack, he has continued the medication but has not appreciably changed his eating habits. He wonders how he could be back in the hospital with another heart attack despite having faithfully taken a statin every day.

No class of drugs has been as venerated as the statins. Doctors have sung their praises since they first became available in the late 1980s. More recently, however, their detractors have been increasingly vocal.

In 1910, it was discovered that plaques in diseased arteries contain up to twenty times the amount of cholesterol found in normal blood vessels. These sticky lesions are also called atheromas, the Greek word for porridge. In the 1950s, a large study of the population of Framingham, Massachusetts, confirmed a link between high levels of cholesterol in the bloodstream and death from heart disease. Cholesterol circulates in blood in several forms, all bound to complexes of protein molecules, or lipoproteins. One form—high-density lipoprotein (HDL)—is known as “good” cholesterol, because it takes cholesterol from arteries and delivers it to the liver for excretion in bile. Low-density lipoprotein (LDL) is the “bad” form that deposits in arterial walls. There are also subtypes of HDL and LDL cholesterol associated with greater or lesser cardiac risk. Small, dense LDL particles, for example, are more dangerous than large, fluffy ones. A routine blood test today measures total cholesterol, LDL, HDL, and the LDL/HDL ratio (a higher number indicates higher risk of heart disease).

Nearly every cell in the human body can make cholesterol, an essential component of cell membranes and the precursor for the biosynthesis of vitamin D, steroid hormones, and bile acids. Making cholesterol involves an intricate set of chemical pathways requiring more than thirty enzymes. Work began in the 1950s to identify compounds that could interfere with these pathways. In 1978, a potent blocker of one of the key enzymes in cholesterol production, HMG-CoA reductase, was discovered in the byproducts of a fermented fungus. This was the first statin.

In 1987, the US Food and Drug Administration (FDA) approved lovastatin (Mevacor) for human use. Since then, nearly a dozen different statins have been marketed—each with a slightly different chemical twist that alters its effect. In addition to lovastatin, the list of FDA-approved statins includes simvastatin (Zocor), fluvastatin (Lescol), pravastatin (Pravachol), atorvastatin (Lipitor), rosuvastatin (Crestor), and pitavastatin (Livalo). All but rosuvastatin and pitavastatin are currently available as less-expensive generics.

Some, like simvastatin, remain in the bloodstream for only a few hours before being broken down in the liver. Others, like atorvastatin and rosuvastatin, remain in the bloodstream much longer. The body makes most of its cholesterol at night while we sleep. For that reason, the shorter-acting statins, like simvastatin, need to be taken in the evening to maximize their effect. Timing is not so important with the longer-acting drugs.

Most statins are degraded in the liver, where each type is slotted to a specific elimination path. Things can get complicated when several medications are taken together, as many drugs compete for the same chemical exit. This can cause the removal process to stall, leading to excessive buildup of a statin in the bloodstream and a higher risk of adverse effects.

A recent survey shows that a whopping 26 percent of adults in the United States are now taking a statin, at an annual cost to the health care system of more than $20 billion. And that number is expected to ratchet up even more based on the latest set of cholesterol guidelines from the American College of Cardiology/American Heart Association. According to these, as many as half of all adult Americans are candidates for statin therapy.

So are many children, according to pediatric guidelines that now call for drug treatment in children as young as ten years old with risk factors and only moderately elevated cholesterol. Inherited factors can cause total cholesterol levels to rise to over 500 mg/dL in children; those relatively rare conditions certainly warrant aggressive therapy because of their poor outlook. But, for the rest, it seems absurd to try to medicate away problems rooted in poor diet and inactivity. Not only is there a lack of evidence to support the extension of statin treatment to children, it sends the wrong message. Pills are not the answer for lifestyle-related problems—a truth we must help our children understand.

The ability of statins to lower LDL cholesterol is irrefutable. Depending on the product and dose, statins can reduce the LDL level by 30 to 50 percent. Whether or not drug-induced lowering of this form of cholesterol leads to better health, however, is a subject for debate.

(Although the benefits of statins are related to their cholesterol-lowering properties, new evidence suggests that other modes of action may be at work as well. One of particular interest is their role as anti-inflammatory agents. We now understand that inflammation plays a pivotal role in the development of vascular disease. Inflammatory cells are summoned to the site of cholesterol-laden plaques, where they weaken the delicate cap that encases the plaque, increasing the risk of a heart attack. Statins reduce the inflammatory response and thus help protect the “fault lines” within plaques from catastrophic fracturing.)

WHO BENEFITS MOST?

Two groups of people can potentially benefit from statin therapy: those who are at high risk of a heart attack based on their medical history, and patients with known vascular disease—including a history of heart attack, stroke, or poor circulation in the legs.

For those who have never had heart disease, the major risk factors for a heart attack include extremely high cholesterol levels (LDL cholesterol greater than 190 mg/dL), diabetes, a strong family history of heart disease, or a combination of other medical problems including high blood pressure and smoking.

The newest cholesterol guidelines include a “risk calculator” that estimates everyone’s ten-year risk of heart disease or stroke to assess eligibility for statin treatment. Although this calculation has merit as an indicator of cardiovascular health status, an unfavorable risk assessment is better interpreted as a wake-up call to tackle lifestyle issues—in particular, diet, physical activity, and stress—than as a threshold for prescribing medication. Apart from age and family history, every one of the risk factors is exquisitely sensitive to lifestyle changes, such as adopting an anti-inflammatory diet and increasing exercise. Statins should be considered a last resort, and only for those whose risk factors can’t be lowered to an acceptable level through lifestyle modification.

Even for people who need them, relying on statins too heavily can be problematic.

Let’s put the benefits into perspective. In the best studies, statins reduce the chance of a heart attack in those at risk by no more than one-third. That’s certainly a benefit that we should take advantage of, but it leaves two-thirds of the risk still on the table. That means that, given one hundred people destined to have a heart attack, statins would be expected to protect no more than thirty-three of them, while sixty-seven others would go on to have a heart attack despite taking the drugs.

The limitation of statin use in the absence of lifestyle changes is well illustrated by the second case above. Jim took his statin every day but did not change his diet, level of physical activity, or stress and went on to suffer a second heart attack—a scenario that happens all too often.

THE PROBLEMS WITH STATINS

Although statins have a place in the treatment of high-risk patients, they can have significant, and often overlooked, consequences. The spectrum of potential adverse effects ranges from muscle aches and weakness to cognitive impairment, diabetes, and liver dysfunction. Manufacturers of these drugs and their enthusiastic proponents tend to minimize, and sometimes ignore, these problems.

Muscle Pain

Pharmaceutical companies report a very low rate of muscle-related side effects from statins, ranging from 1 to 5 percent of patients. But many patients and physicians give a very different picture. Statin-induced muscle pain is one of the most common drug side effects in all of clinical medicine. In one recent study, 25 percent of individuals on statin therapy experienced it.

Because muscle pain is so common, it can be difficult to sort out whether a new ache is caused by a statin or by something else. But all too often, patients who suspect a statin-related problem don’t even get the benefit of the doubt. A study of how physicians react to these complaints was revealing: among patients who reported muscle symptoms, 47 percent of the time physicians immediately dismissed the possibility that the drug was to blame.

These symptoms typically develop within the first month of use. However, their onset can range from a few days to several months, a time lag that can obscure the connection between symptoms and statin use. For some, the muscle problem develops quickly and with a vengeance, leaving little room for doubt that the medication is to blame. For others, like Janice described at the beginning of the chapter, the symptoms are insidious, slow to develop, and frequently mistaken for age-related changes.

In rare cases, statins can cause life-threatening muscle damage—rhabdomyolysis—leading to liver and kidney failure. This is more likely to happen with very high doses and interactions with other drugs.

Cognitive Impairment

Statins can also affect brain function. The list of cognitive problems linked to their use includes cloudy thinking, memory deficits, and depression. Of course, these symptoms are common in an aging population, and older people are more likely to be on statin therapy. The association of cognitive problems with statin use may be coincidental. Regardless, in many patients the problems resolve quickly once the drug is discontinued.

Unfortunately, there is no specific test to identify statins as the cause of cognitive decline. The only way to sort it out is to stop the drug for a few weeks and check for improvement. If cloudy thinking or memory impairment dissipates substantially, the statin is likely to blame. No major improvement suggests another cause.

Increased Risk of Diabetes

We already face a public health crisis: 50 percent of Americans are now either diabetic or pre-diabetic. It is especially concerning that statins could be contributing to this epidemic.

To keep this in perspective, know that only one new case of statin-induced diabetes will occur among 250 patients after four years of treatment. But given the magnitude of current statin use—in more than 40 million Americans—even a small increase in risk is significant.

For people at high risk of a heart attack, especially those who already have vascular disease, the benefit of taking a statin outweighs the risk of diabetes. A bigger problem arises, however, when statins are prescribed to those at low risk, in whom the potential for benefit is exceedingly small and the chance of inducing diabetes is not trivial. For people at low risk of heart disease, the overzealous use of statins may cause more illness than it prevents.

Liver Irritation

The liver is responsible for the breakdown and elimination of statins. This process occasionally overworks the organ, causing irritation indicated by elevation of liver enzymes in the blood. Typically, this side effect is inconsequential, but serious liver problems from statins have been reported. Before they are prescribed, blood tests are run to make sure the liver is healthy, and these may be repeated at intervals once the drug is started. If liver function tests suggest a problem, the dose may be lowered or even discontinued. If you are on a statin, you can reduce the risk of liver dysfunction by limiting your intake of alcohol and working with your health provider to trim your use of other medications that tax the liver.

TIPS TO HELP DEAL WITH STATIN SIDE EFFECTS

The development of a suspected statin side effect is a good opportunity to revisit the need for a statin in the first place. Those at lower risk might look to their health providers for alternative prevention options, including intensification of lifestyle efforts.

If a statin needs to be continued, a number of strategies can be useful to minimize side effects. It’s important to know that different statins behave differently in the body, and each individual responds differently. Sometimes, switching to another statin or to a lower dose is all that’s needed. (Some statins can be taken every other day or even twice a week to reduce side effects.)

It turns out that grapefruit contains a chemical that blocks a key pathway used by the liver to rid itself of certain statins, especially lovastatin, atorvastatin, and simvastatin. People on these medications should limit their intake of grapefruit and grapefruit juice to avoid high drug levels and associated side effects.

Milk thistle (Silybum marianum) is a safe botanical remedy that protects the liver from toxic injury. It can be taken along with a statin by those who experience liver irritation or have a history of liver disease.

A supplement that might help manage statin side effects is coenzyme Q10, abbreviated CoQ10. The body makes this compound and uses it to produce ATP, the most important source of energy for cells, including muscle cells. Statins lower the level of CoQ10 in the blood, which may explain the muscle pain and other side effects of these drugs.

Several small studies have examined the use of CoQ10 supplements in statin-treated patients. Although some CoQ10 studies have shown an improvement in statin side effects, most have not. Nevertheless, many anecdotal reports describe benefit. Since the safety profile of CoQ10 is excellent, I believe that supplementation may well be worth a try when statin side effects are suspected. The usual dose is 60 to 100 milligrams twice a day of a softgel form taken with a fat-containing meal to ensure absorption.

Certain metabolic issues can also trigger statin-related problems. Vitamin D deficiency impacts cellular function on multiple levels and can thus lower the threshold for statin side effects. Replenishment of low vitamin D levels through supplementation can completely eliminate adverse reactions for some. I recommend 2000 IU a day for most people. If you have not had your blood level of vitamin D measured, do so: you may need to take higher doses initially if it is very low.

An underactive thyroid also increases the likelihood of statin-related problems. Diagnosis of this is easy to miss, however, because symptoms are vague and common with age: fatigue, intolerance to cold, and dry skin, for example. Blood tests for thyroid function should be checked when statin side effects are suspected.

INTEGRATIVE MEDICINE APPROACHES TO MANAGING HIGH CHOLESTEROL

An integrative approach to heart health goes beyond medication alone to take a wide-angle view of prevention. It begins with an anti-inflammatory diet, with abundant servings of vegetables, fruit, legumes, nuts, whole grains, less red meat and more fish, and high-quality extra-virgin olive oil.

Regular physical activity is essential for maintaining heart health. Even modest activity helps—as little as thirty minutes of walking every day has a sizeable impact. For those who are overweight, it’s comforting to know that even when an exercise program does not lead to weight loss, it still appreciably lowers the odds of a heart attack.

Optimal heart health depends upon balance of the mind-body connection. Stress, anger, anxiety, and depression accelerate coronary disease, while optimism and gratitude are balms for the heart. Fortunately, positive moods and emotions can be cultivated.

Breath work offers a unique access to the involuntary nervous system and is a powerful method of relaxation. One very effective technique is the 4-7-8 breathing exercise: inhale for 4 counts, hold for 7 counts, then exhale for 8 counts. Repeat this sequence several times throughout the day. (A video showing the practice can be found at DrWeil.com.) Meditation is also remarkably beneficial, as documented in a study showing that regular practice reduces the likelihood of a cardiac emergency by 48 percent.

For those who cannot get their cholesterol level down enough through lifestyle change and also cannot tolerate prescription statins, a supplement called red yeast rice can be effective. Red yeast rice is a fermentation product of the yeast Monascus purpureus that has been used for centuries in China as an ingredient in food, mainly to add red color but also for its perceived health benefits. It contains several cholesterol-lowering compounds, all of which share the chemical structure of statins. (Interestingly, one of them, monacolin K, is the same compound as the first FDA-approved prescription statin, lovastatin.)

Although red yeast rice can cause the same side effects as prescription statins, it is much less likely to do so, probably because the body tolerates the natural mixture of similar molecules better than a single one. (The reason for this is not clear, but it is a pattern I observe with other complex natural products compared to purified pharmaceuticals.) In a randomized trial, 85 percent of patients who could not tolerate prescription statins were able to take red yeast rice without side effects. The trade-off with red yeast rice, however, is lower potency. The usual doses (1200 to 2400 mg/day) reduce LDL cholesterol by 20 to 25 percent, compared to 30 to 55 percent for prescription statins. It is available over the counter, and the recommended starting dose is 600 milligrams twice a day with food.

Other products that can help lower cholesterol include fiber, especially psyllium husk, as well as plant stanols and sterols that slightly reduce the amount of cholesterol absorbed from food. These are found in fruits, vegetables, legumes, nuts, and seeds, as well as fortified foods (some brands of orange juice, cereal, and granola bars). They are also available as dietary supplements.

BOTTOM LINE

Medication alone affords only limited protection against heart disease. Statins are very effective at decreasing LDL cholesterol, but that is only one of many risk factors. We would also like to able to raise HDL cholesterol and change the size of LDL particles, but we have no drugs to do that. Furthermore, half of those who have a first heart attack have normal blood cholesterol levels. Stress, anger, a sedentary lifestyle, and a diet that favors inflammation also predispose to blockages of coronary arteries. Too many doctors think they can deal with patients at risk for heart disease simply by prescribing a statin, ignoring its complex causes.

Based on the foundation of nutrition and lifestyle, an integrative approach to heart health recognizes the value of statins. But because these drugs have the limited effect of lowering LDL cholesterol and are not risk-free, judicious use is warranted. Current emphasis on statin therapy should be balanced by equal emphasis on lifestyle changes.

To put it bluntly: statins are no panacea and they do not belong in our drinking water.