Understanding High Cholesterol: Statins & More

ROBERT GUTHRIE, MD

High-density lipoprotein cholesterolHeart disease has long been (and remains) the leading cause of death in the United States and in most of the industrialized world. Only during 1918, at the peak of the great influenza epidemic, did another cause of death temporarily pass heart disease as the nation’s leading cause of death.

While heart disease has many manifestations and many root causes, in general, the major cause of heart disease is hardening of the arteries of the heart (i.e., coronary arteries), leading to myocardial infarction (i.e., heart attack) that damage the heart muscle itself. The process that leads to the build-up of plaque in the arteries throughout the body is atherosclerosis, a complex process that can occur in any and all of the arteries throughout the body. When atherosclerosis occurs in the coronary arteries, it can lead to angina pectoris, or pain from lack of sufficient blood flow to the heart muscle. It can also lead to myocardial infarction, where the blood supply to the heart muscle is so severely interrupted that some of the heart muscle dies.

There are many factors that will increase an individual’s risk of coronary artery atherosclerosis. Some of these factors cannot be decreased by any treatment, including age, gender (men develop atherosclerosis at an earlier age than women), family history of early heart disease, and possibly ethnicity (South Asians may be particularly at risk). Other risk factors are treatable where lifestyle changes or medications can reduce, but not necessarily eliminate, the increased risk. Smoking cessation is the most obvious lifestyle change that will reduce one’s risk of developing heart disease. Beginning and maintaining a physical activity regimen (a walking regimen, bike riding, or use of an exercise machine) on a regular basis will decrease risk of a myocardial infarction. Clearly, dietary intake influences myocardial infarction risk, but the actual components are difficult to sort out. We can say with certainty that a diet that reduces saturated fats and emphasizes fresh fruits and vegetables appears to reduce myocardial infarction risk. Whether it is the avoidance of the saturated fats or a potential positive property to the other foods is unclear.

Whether a type A personality and chronic stress actually are causes of increased risk of myocardial infarction are not true in our current era. In the 1960s, individuals who were classified as having type A personality usually smoked two packs of cigarettes a day, which contributed to their getting heart disease. Now they eat tofu and run two miles a day, so their heart attack rates are reduced.
There are very clear medical conditions that increase an individual’s risk for developing heart disease. The most obvious of these are well known to the public, including elevated cholesterol in the blood, hypertension, and type 2 diabetes mellitus (with the elevated blood glucose that is seen in this disease), among others. For the past several decades, there has been increasing research that has documented the importance of these medical problems in contributing to our high risk for myocardial infarction. Also, following the onset of the national campaign to treat and control hypertension that started in the 1970s, we have seen a dramatic decline in the rate of death from heart disease.

In fact, the rate of death from heart disease among Americans has dropped by nearly 50% when compared with the rate in the early 1970s when efforts began to control high blood pressure. It was accelerated in the 1990s when the very potent agents to lower cholesterol, the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins), became available on the market.

For the rest of this column, I will discuss the importance of cholesterol management to prevent myocardial infarction.

Early Evidence

Early evidence for the relationship between cholesterol levels and increased risk of myocardial infarction came from studies that looked at the risk of myocardial infarction in various ethnic groups and/or nations. The rate of myocardial infarction in these different groups was seen to increase as the average cholesterol level in a population increased. These studies were followed by long-term studies, best exemplified by the Framingham Heart Study, which started in Framingham, MA, in 1948. The Framingham Study and similar studies measured and evaluated a select number of patients for various factors that might affect their myocardial infarction risk, such as smoking, cholesterol, blood pressure, weight, etc. Investigators followed these patients for many years and charted their medical history and longevity. In these studies, elevated cholesterol (along with other factors) increased the risk for early myocardial infarction.

In spite of a large number of similar studies that showed the correlation between elevated cholesterol and myocardial infarction, treatment trials that reduced cholesterol and demonstrated that this reduced cholesterol resulted in fewer myocardial infarctions were necessary to prove that treatment was beneficial.

Treatment Studies

The original studies that were designed to evaluate the treatment of cholesterol were not very successful, leading to controversy about whether lowering cholesterol with medication would be effective. The real problem with the original studies, which were completed in the 1970s and 1980s, was that the agents involved were not very potent and were often difficult for the patients to tolerate. The types of cholesterol treatment agents that were used in the original studies―resin binders such as cholestyramine, fibric acid agents such as gemfibrozil, and niacin (vitamin B3)―have now been relegated to secondary roles to be used to treat patients with a complicated disease.

The Statins

Everything in the treatment of high cholesterol changed with the arrival of the HMG-CoA reductase inhibitors (i.e., statins) in the 1990s. Lovastatin (Mevacor®; Merck & Co., Whitehouse Station, NJ) was the original agent, followed by simvastatin (Zocor®; Merck & Co., Whitehouse Station, NJ), pravastatin (Pravachol®; Bristol-Myers Squibb, Princeton NJ), fluvastatin , atorvastatin (Lipitor®; Pfizer, New York, NY),  rosuvastatin (Crestor®; AstraZeneca, Wilmington, DE), and the most recent addition, pitavastatin (Livalo®; Kowa, Montgomery Ala, and Eli Lilly, Indianapolis, IN). These agents had dramatic effects on the levels of cholesterol in the blood by increasing the clearance of the low-density lipoprotein (LDL-C) cholesterol (“bad cholesterol”) by the liver. Most of these agents also increase the high-density lipoprotein cholesterol (HDL-C) (“good cholesterol”). The reduction in the LDL-C ranges from 20% with lovastatin and pravastatin to nearly 65% with rosuvastatin.

Comparison of Normal Artery and Artery Narrowed by Plaque

Starting in 1994, a series of landmark research studies evaluating this class of agents began to be reported. These studies were extremely well done, highly scientific projects, that studied the agents in a wide variety of patients with existing heart disease (“secondary prevention”) or high-risk patients without heart disease (“primary prevention”). The studies all gave half of the patients the statin agent that was being studied and the other half were given a dummy pill (i.e., placebo). Neither the patients nor the doctors knew who was getting which (a process called “double blind”). In study after study, these statin agents were proven to reduce all forms of heart disease and its complications, including the overall death rate, the death rate from heart disease, nonfatal myocardial infarction, and even stroke. In the history of medication research, no particular class of agents has been so successful and so thoroughly studied and proven to have such positive benefits as the statins.

Safety of the Statins

As the statins began to be widely used, there was an enormous push back from certain individuals and groups, which really amounted to a scare campaign against the statins. This push back was driven more by fear than by any understanding of the science involved. This campaign especially ignored the terrific risk of not treating cholesterol in high-risk patients, as well as ignoring the early deaths and crippling heart disease that occurred as a result of untreated high cholesterol. It is unfortunate that many patients were scared away from taking these agents. It is possible, even likely, that there were many thousands of unnecessary and premature heart disease deaths caused directly by these scare tactics, aimed at persuading patients to avoid these life-saving medications.

As these agents were studied and used in everyday practice, it become clear that they were very safe, in addition to being very useful. In spite of challenges to the contrary, a careful examination of the statins shows that important side effects from them are quite rare and are usually mild and manageable.

In the studies, most of the side effects that are typically reported are seen at nearly the same rate between the patients who got placebo, or dummy pills, and the patients who received the statin drug. There were small rates of minor increases in liver enzymes in the statin-treated patients, along with some increases in muscle pains. It is not clear if the minor increases in liver enzymes really are a problem, and it is easy to check for them with a simple blood test. There has never been a clear case of liver failure, leading to death or liver transplantation, caused solely by a statin drug, in contrast to cases of liver failure every year caused by acetaminophen, the nonaspirin pain reliever in Tylenol® (McNeil, New Brunswick, NJ).The muscle ache question is somewhat more complicated. There is a tendency to see increased levels of muscle aches in individuals taking statins, but the exact rate is difficult to determine and is probably in the 2 to 3% range, slightly higher than the aches seen in the patients on the placebo. It is important for patients to remember that this is muscle pain, not joint pain, and they should not confuse it with the routine aches and pains that are part of life. Also, if a patient is having mild muscle aches from statin therapy, they shouldn’t hesitate and discuss carefully with his or her physician as to whether they should stop potentially life-saving medication because of mild muscle aches. There is a more serious muscle condition, called myopathy, where there is marked muscle pain along with a breakdown of muscle that can be detected in the blood. This happens in only about 1 per 1,000 patients on a statin (about twice the rate of the placebo-treated patients). When this occurs, the drug should be discontinued.

There is a much more serious, but fortunately very rare, muscle condition called rhabdomyolysis. The causes of this very rare condition are not completely clear. It involves severe muscle breakdown, with so much muscle protein in the blood stream that it can lead to kidney failure. This can be fatal and requires prompt hospitalization. Information from the Food and Drug Administration (FDA) shows that the fatal form of this condition occurs only once in 7 million statin prescriptions in one year in the United States, about the risk of being killed in a commercial jet airplane accident in the United States. Remember that if we had 7 million people who needed statin therapy and we did not treat them with a statin, many thousands of them would die from myocardial infarction during that year. Therefore, we need to be much more afraid of the risks of not taking a statin than of the limited risk of a statin side effect.

Other Cholesterol-Lowering Treatments

Dietary therapy actually has a very modest effect on the overall cholesterol level, and also a very modest benefit on the LDL-C. In spite of the popular misconception about dietary effects on cholesterol, most diets lower the bad cholesterol by about 7%, much less than the lowering achieved with statin medication. While it is true that the very severe diets, like a vegan diet or the Pritikin diet, can achieve a better lowering of the LDL-C, these diets are so severe that very few Americans can tolerate and maintain them. A low-fat, low-carbohydrate diet can lower the triglyceride level, but there is no evidence that lowering triglycerides might reduce myocardial infarction risk.

Niacin

Niacin is one of the B vitamins that also affects cholesterol. At lower doses (usually 1,500 mg daily or less), niacin elevates the HDL-C, which is often too low in individuals with cholesterol problems. At higher doses, of about 2,000 to 3,500 mg, niacin will also lower the LDL-C. However, those doses are very difficult for most patients to tolerate, and thus are rarely used today.

Recently, niacin has become popular as a single drug treatment for cholesterol problems, but it’s mainly used as a second drug, usually in combination with a statin drug, to raise the HDL in patients who have the combination of elevated LDL and reduced HDL. This use of a combination of two different cholesterol agents is driven by the logical assumption that more treatment of cholesterol abnormalities is better than treatment with just a statin agent alone. However, medicine is not a logical exercise but rather a scientific one, and the recent scientific research into the use of this combination did not show any benefit. The study was run by the National Institutes of Health, and it compared treatment with both a statin (simvastatin in this case) and niacin added in versus simvastatin with only a placebo (dummy pill) added in. This study, called Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH), was stopped early in May of 2011 because there was no benefit to adding the niacin to the simvastatin. In fact, there was a small and unclear increase in stroke in patients receiving the combination of niacin and simvastatin. Therefore, I will not institute niacin/ statin combination in any patients and will look at whether I should stop it in the few patients that I have on the combination.

Ezetimibe

Ezetimibe (Zetia®; Merck, Whitehouse Station, NJ) is a relatively new agent that blocks cholesterol absorption in the intestine, and it thus lowers the bad cholesterol (i.e, LDL-C) by about 18%. It has been used as a secondary treatment on top of statin therapy, either as a Zetia® dose along with the statin, or as Vytorin® (Merck, Whitehouse Station, NJ and Schering-Plough, Kenilworth, NJ), a single pill that combines ezetimibe with simvastatin. With a major marketing effort for Vytorin®, this combination pill was quite popular for several years. However, several preliminary studies have raised questions as to whether Zetia® offers any benefit in preventing the process of hardening of the arteries. Whether the addition of Zetia® to a statin will mean additional protection against myocardial infarction is being studied now and will be answered in a few years. Until that study is reported, I think that Zetia® should be reserved for use only as a secondary agent in addition to maximal statin therapy, such as Crestor® 40 mg, recognizing that it may not further reduce the risk of myocardial infarction beyond the protection of the statin.

Fibric Acid Agents

Several fibric acid agents are currently available on the U.S. market. They include an older agent, gemfibrozil (Lopid®), and a newer agent, fenofibric acid (Trilipix®; Abbott, Chicago, IL). These agents cause a modest, if any, lowering of LDL-C, but they do lower triglycerides and raise HDL-C. When these agents are used as the sole therapy of elevated cholesterol, they have had limited and inconsistent success in reducing myocardial infarction and other events like fatal myocardial infarction or the overall death rate. They have enjoyed some popularity as a second agent added on to statin therapy, with the aim of lowering triglycerides and raising HDL-C. However, this type of combination therapy is fraught with problems. First, gemfibrozil should never be taken with a statin drug, since gemfibrozil can interfere with the breakdown of the statin and lead to very serious, even fatal, side effects. Secondly, there is no evidence that lowering elevated triglycerides can actually reduce myocardial infarction, so the idea behind combination therapy may be completely in error. Indeed, a number of the statin studies show that elevated triglycerides do not lead to an increase myocardial infarction risk if the patient is already taking a statin, so the whole theory behind combining additional agents with a statin is probably wrong. Finally, there has been a recent study that looked at diabetic patients with elevated triglycerides and reduced HDL. One group was given simvastatin and a placebo, and the other group was given the combination of simvastatin and fenofibric acid. There was no benefit seen in the combination group, showing that adding the fenofibric acid to simvastatin did not reduce myocardial infarction or other heart problems. Therefore, at this point, there is no clear evidence that using a second cholesterol agent along with a statin offers any benefit above that offered by the statin agent alone.

Recent Developments

The more intriguing questions focus on two issues: What dose of statin agent is safe and appropriate, and what should be the target value to which we want to lower the LDL-C (i.e., the bad cholesterol)? There has been a recent recommendation from the FDA warning that the 80 mg dose of simvastatin (Zocor®) is dangerous, leading to a dangerous risk of muscle problems at a much higher rate than the 40 mg or lower doses. I have always believed that the 80 mg dose of any of the statins was too high a dose, with an increased risk of muscle problems, and this recommendation only confirms my caution.

The second issue comes from the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study. In this study, patients with modestly elevated LDL-C cholesterol had the LDL lowered into the range of 50 mg, down to where it was when they were children or teenagers. This study showed a dramatic reduction in all of the myocardial infarction, stroke, and death rates studied. The JUPITER study raises the question as to whether the treatment targets for cholesterol should be lower than we have them now, in the < 100 mg range. This is an intriguing question that will be debated for some time.

Summary

Elevated cholesterol is one of the leading factors for the development of heart disease and death from heart disease. Fortunately, we can clearly reduce cholesterol, and with it the increased risk of myocardial infarction, by use of the statin agents, as the HMG-CoA reductase inhibitors, are known. These agents are extremely safe and generally have very low levels of side effects. There is no evidence that adding a second agent to a statin further lowers myocardial infarction risk better than just taking the statin alone. With such powerful evidence that we now have about the benefits of lowering cholesterol with the statin agents, I urge all of our readers to check with their physicians about having their cholesterol measured and possibly treated.

ABOUT THE AUTHOR

Robert Guthrie M.D., will be the author of a regular column in Colliers. Dr Guthrie is both a family physician and a general internist, and he currently is a professor at The Ohio State University in Columbus, OH. At Ohio State, he conducts research projects to develop new medications for the treatment of common disorders like high blood pressure and diabetes. He has published one book, numerous medical articles, has lectured extensively nationally and internationally, and been a long-term participant on local and national radio broadcasts. This column will discuss a wide variety of health topics of interest to the general public.