Despite evidence that aims to quash controversy over the safety and effectiveness of statins, uncertainty remains. Is the safety of statins as debatable as some stories suggest, or is the controversy behind this group of medicines potentially harming more people than the drug itself? We find out.

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The safety and efficacy of statins has been surrounded by controversy for decades.

Cholesterol is essential to keep the body in working order. However, having high levels of “bad cholesterol,” called low-density lipoprotein (LDL), in the blood can cause fatty deposits to build up in the arteries. Eventually, this buildup results in the arteries narrowing and hardening (a condition called atherosclerosis), which leads to a greater risk of heart attack and stroke.

Statins are a commonly prescribed medicine that helps to lower harmful levels of LDL cholesterol to mitigate the risks of cardiovascular disease.

Types of statins approved for use in the United States include atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and pitavastatin. They all work in a similar way by blocking the enzyme in the liver – HMG-CoA reductase – that produces cholesterol.

Heart disease is the leading cause of death in the U.S. In 2013, almost 801,000 people in the country died from a stroke, heart disease, or other cardiovascular diseases.

Landmark studies have investigated the use of statins in secondary prevention of cardiovascular disease.

The Scandinavian Simvastatin Survival Study (4S) studied 4,444 people who had previously had a heart attack and high cholesterol. After a follow-up period of nearly 5.5 years, simvastatin was found to lower total cholesterol by 25 percent and LDL cholesterol by 35 percent. Few adverse effects were experienced.

In the placebo group, there were 256 deaths (12 percent) compared with 182 (8 percent) in the group taking simvastatin. Essentially, simvastatin reduced the risk of death by about one third. The 4S study concluded that “long-term simvastatin treatment is safe” and improved survival in people with cardiovascular disease.

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Studies have demonstrated a correlation between reducing LDL cholesterol levels with statins and a decline in cardiovascular risk.

The Cholesterol and Recurrent Events (CARE) trial studied 4,159 people with coronary heart disease and average cholesterol levels to examine the effect of lowering LDL levels on the occurrence of coronary events.

Reducing LDL cholesterol levels from average to low with pravastatin significantly reduced the number of recurring coronary events compared to the placebo group. During the 5-year follow-up, pravastatin lowered total cholesterol by 20 percent and LDL cholesterol by 28 percent.

Individuals treated with pravastatin were 24 percent less likely to die from cardiovascular heart disease or non-fatal heart attack and had a 31 percent decrease in risk of stroke. The CARE trial concluded that treatment with pravastatin reduces the burden of cardiovascular disease in individuals with a history of heart attack.

The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study investigated 9,014 people with a history of heart attack and a broad range of cholesterol levels. Researchers aimed to evaluate the effect of pravastatin on death from cardiovascular disease.

During the first 5 years of follow-up, pravastatin decreased total cholesterol by 18 percent and LDL cholesterol by 25 percent more than the placebo group. Individuals in the pravastatin group had a 24 percent reduced risk of death from coronary heart disease or non-fatal heart disease, were 29 percent less likely to have a heart attack, and received a 19 percent reduction in risk of stroke.

The LIPID study concluded that pravastatin is associated with a reduction in mortality from coronary heart disease and overall mortality in individuals who had previously had a heart attack.

Trials have consistently demonstrated a clear correlation between reducing LDL cholesterol with statins and a decrease in cardiovascular risk. So why the controversy?

As the body of evidence evaluating statins has expanded, so too have the indications for the drug. Guidelines released in 2013 by the American College of Cardiology (ACC) and the American Heart Association (AHA) recommended that statin therapy might be beneficial for people in the following four groups:

  • people with cardiovascular disease
  • people who have high LDL cholesterol levels of 190 milligrams per deciliter or higher
  • people aged 40 to 75 years with diabetes and LDL levels of 70-189 milligrams per deciliter
  • people aged 40 to 75 years without diabetes, but with LDL cholesterol levels of 70-189 milligrams per deciliter and a predicted 10-year risk of cardiovascular disease of 7.5 percent or higher
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The 2013 guidelines on statin use may prevent between 41,000 and 63,000 cardiovascular events over a 10-year period.

Experts questioned the 2013 guidelines, arguing that a 7.5 percent threshold seemed too low. Two research teams examined this threshold in 2015 and published their findings in the Journal of the American Medical Association.

The first paper, led by Dr. Udo Hoffmann at Massachusetts General Hospital and Harvard Medical School – both in Boston – found that compared with the 2004 guidelines, the 2013 guidelines were more accurate at identifying individuals at a greater risk of cardiovascular disease. They estimated that by adopting the 2013 guidelines, between 41,000 and 63,000 cardiovascular events would be prevented over 10 years compared with previous guidelines.

The second paper, led by Drs. Ankur Pandya and Thomas A. Gaziano at the Harvard T.H. Chan School of Public Health – also in Boston – assessed the cost-effectiveness of the 10-year cardiovascular disease threshold. The researchers concluded that the risk threshold of 7.5 percent or higher had an acceptable cost-effectiveness profile.

Due to the expansion of the groups reported to benefit from statins, suspicions have been raised about the pharmaceutical industry and of the prescribing healthcare professionals. Alarm bells were starting to ring that people were being overmedicated and put at risk of adverse effects. These suspicions may be fuelled, in part, by a misunderstanding of clinical trials and how they work. Statins are one of the best-studied medications in randomized clinical trials. They have been found to reduce the number of strokes and heart attacks, even among people with normal cholesterol levels, and to extend life.

Moreover, statins have been found to improve cardiovascular health and prevent heart disease in individuals at an increased risk, even if they have already made changes to their diet and exercise levels.

While a heart-healthy diet, regular physical activity, and maintaining a healthy weight are all components that may help to reduce cholesterol and lower the risk of heart disease and stroke, certain factors are unable to be influenced – such as genetics. In some people, lifestyle changes alone are not enough to lower cholesterol.

The 2013 ACC/AHA guidelines are based on a large and consistent body of evidence that indicates the efficacy and safety of using statins to lower LDL in order to reduce the risk of cardiovascular disease.

Furthermore, subsequent independent groups that have developed guidelines – such as the 2014 Joint British Societies’ consensus recommendations for the prevention of cardiovascular disease, the 2014 Veterans’ Affairs and Department of Defense guidelines on management of dyslipidemia, and the 2016 U.S. Preventive Services Task Force recommendations for prevention of cardiovascular disease – have all used comparable rigorous approaches to reviewing evidence, which have resulted in similar treatment recommendations, thus further endorsing the ACC/AHA guidelines.

Between 2003 and 2012, statin use increased from 18 percent to 26 percent. By 2011-2012, around 93 percent of adults using a medication to lower cholesterol were using statins. Between 1999 and 2012, people with elevated blood levels of cholesterol declined from 18.3 percent to 12.9 percent. Could the decrease in blood levels of cholesterol be down to an increase in the use of statins?

According to a study published in the Journal of the American Medical Association, from 1969 to 2013, deaths from heart disease fell by 68 percent, and there were 77 percent fewer deaths from stroke.

There may be a link between the rise in statin use and the fall of deaths connected to cardiovascular disease. However, the progress made could be attributed to the “cumulative effect of better prevention, diagnosis, and treatment,” says Wayne D. Rosamond, Ph.D., professor of epidemiology at the University of North Carolina in Chapel Hill.

Efforts that may play a role in the drop of death rates include quitting smoking, improvements to heart disease emergency response, better heart treatments and procedures, advances in scientific research, legislation to build healthier environments, and an increased public awareness about having a more healthful lifestyle.

Central to the ACC/AHA approach to the 2013 guidelines was the idea of “net ASCVD risk-reduction benefit” – questioning whether the likelihood of preventing a major cardiovascular event or death is greater than the risk that the drug therapy will cause a severe adverse event.

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Some people may experience muscle pain or weakness as a side effect of taking statins.

Statins are generally considered to be safe and well tolerated. However, as with any medication, statins may have negative effects in some people.

Muscle aches and cramps are the most commonly reported symptom and may occur in 5 percent of individuals. A different statin or lower dose that is better tolerated may be prescribed in this case. Statins also increase the risk of developing type 2 diabetes in a small number of people.

The U.S. Food and Drug Administration (FDA) advise that statins are not recommended for pregnant women.

Recent research by the National Heart and Lung Institute at Imperial College London – in the United Kingdom – suggests that individuals do not report an increase in muscle problems if they are unaware they are taking statins.

The research compared adverse events reported during randomized controlled trials (where the patient is unaware whether they are taking a placebo or drug) and observational studies (where the patient is aware that they are taking the drug). Researchers found that people who knew they were taking statins were 41 percent more likely to report muscular problems – a phenomenon referred to as the nocebo effect.

“We know that statins can prevent a significant number of heart attacks and strokes. We know there is a small increase in the risk of diabetes, and at high doses there is a very small increase in myopathy, but overall the benefits greatly outweigh the harms,” says Peter Sever, professor of clinical pharmacology and therapeutics at Imperial College London. “Widespread claims of high rates of statin intolerance still prevent too many people from taking an affordable, safe, and potentially life-saving medication.”

There are people out there who are dying because they are not taking statins and the numbers are huge – the numbers are tens of thousands if not hundreds of thousands, and they are dying because of a nocebo effect, in my opinion.”

Peter Sever

This research echoes a 2014 study, published in the European Journal of Preventative Cardiology, that analyzed the results of 29 trials involving more than 80,000 people. The study concluded that statins have minimal side effects and individuals taking statins experienced fewer adverse symptoms than those taking a placebo.

A 2016 review published in The Lancet claims that the side effects of taking statins are widely exaggerated, and that the drugs are safe and effective. The review concluded that the benefits of statins outweigh the risks of an adverse reaction.

In 2015, researchers from the Centers for Disease Control and Prevention (CDC) examined data from the 2005-2012 National Health and Nutrition Examination Surveys and discovered that almost half of people eligible for cholesterol-lowering medications were not taking them.

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Statins have been shown to be safe and effective in several quality studies. The benefits outweigh the risks.

Statins have been researched for use in other conditions. Recent research shows that statins may reduce the risk of venous thromboembolism by 15 to 25 percent and Alzheimer’s disease by 12 to 15 percent.

The mounting research appears to overturn debate around statins and aims to reassure doctors and patients that the risks of not taking statins – heart attack or stroke – far outweigh concerns about side effects associated with the drug. Serious side effects are rare. Study authors agree that the substantial proven benefits of statins have been compromised by “serious misrepresentations of the evidence for its safety.”

Evidence illustrates that, at a population level, statins are safe and effective. If you have a history of heart disease or stroke, it is likely that you will be prescribed a statin without consideration for cholesterol levels. For people who do not have any known cardiovascular disease, a doctor will assess your 10-year and lifetime risk for heart attack and stroke using a validated risk model.

Lifestyle changes – including smoking cessation, following a healthful diet, and taking part in regular physical activity – can help to prevent or delay cardiovascular disease.

Before starting statin therapy, it is important to discuss the potential benefits, risks, monitoring plans, and management of other risk factors with your physician.