Are statins overprescribed? Why the risks and benefits are so complex

Statins, drugs typically used to lower cholesterol, are relatively safe for most people. When they are taken specifically to prevent cardiovascular disease, a new study suggests, the side effects just might outweigh the benefits, depending on your age, sex and the specific statin you're taking.

For instance, atorvastatin and rosuvastatin provided cardiovascular benefits at a lower 10-year risk than simvastatin and pravastatin, according to the study.

Overall, the benefit of statins may come with higher 10-year risks for cardiovascular disease than are reflected in most guidelines, according to the study, published Monday in the medical journal Annals of Internal Medicine.

The finding raises the question: Are statins overprescribed for the prevention of cardiovascular disease?

The study analyzed the benefits and risks only when using statins for the primary prevention of cardiovascular disease, including heart attacks and stroke, not when used after a heart attack, for example.

Many physicians recommend that patients have conversations about the risks and benefits of statins with their doctors.

"The main finding is that the risk threshold is substantially higher than what has been determined by experts before and not necessarily by research," said lead study author Dr. Milo Puhan, a professor of epidemiology and public health at the University of Zurich in Switzerland.

"It really depends on age, gender and the type of overall health status," Puhan said.

"One size doesn't fit all," he added. "So the risk threshold increases with age, which basically means that you need to have a higher cardiovascular risk in order to get the net benefit from statins."

The use of statins is increasing in the United States.

The percentage of men 60 and older who were told that their cholesterol was high and started taking statins and other lipid-lowering medications rose from 36% in 2005 and 2006 to 50% in 2015 and 2016, according to a National Health and Nutrition Examination Survey published in the US Centers for Disease Control and Prevention's Morbidity and Mortality Weekly Report in July.

The percentage of women 60 and older taking lipid-lowering medications also climbed from 33% to 38%, according to the survey.

Not all statin prescriptions are created equal

The new study involved data on the benefits and risks of four commonly used statins: atorvastatin, simvastatin, pravastatin and rosuvastatin.

The data came from 40 previously published randomized trials, several observational studies and registries, as well as a patient preference survey, Puhan said. The data were used to estimate risk-benefit across populations in the United States, the United Kingdom and Switzerland.

The researchers analyzed risks and benefits in a quantitative benefit-harm modeling study, taking a close look at nine possible outcomes or side effects of statins: myopathy or muscle weakness and muscle aches; renal or kidney dysfunction; hemorrhagic stroke; hepatic or liver dysfunction; Type 2 diabetes; any cancer; cataracts; headache or nausea; and the risk of having to stop treatment altogether because of side effects.

The researchers found that statins were likely to provide benefits at a substantially higher health risk than expected and that those risk levels were lower for atorvastatin and rosuvastatin than for simvastatin and pravastatin.

Younger men, those 40 to 44 years old, who take statins had a 10-year risk for cardiovascular disease of 14%, compared with 21% among men 70 to 75, the researchers found. Among younger women taking statins, the 10-year risk was 17%, compared with 22% among older women.

In general, taking statins is not "super risky," Puhan said.

"The most important message for individuals who consider statins is to carefully look at the cardiovascular risk of an individual -- a physician can determine that -- and then have a conversation of whether the benefits exceed the harms," he said.

The study had some limitations, including that it involved data on only the four most commonly prescribed statins and that the balance of risks and benefits was measured only for the US, the UK and Switzerland.

Puhan and his colleagues are planning to publish a followup study exploring risks and benefits within several other countries.

Another limitation of the study is that "the side effect data from randomized controlled trials are not ideal because trials are short-term and not ideal for capturing harms, so we tried to address that by including observational studies," Puhan said.

Making sense of the side effects

Weighing the risks and benefits of statins remains important because most patients are prescribed medication for the rest of their lives, said Dr. Amit Khera, a professor and director of the UT Southwestern Medical Center's Preventive Cardiology Program, who was not involved in the study.

Yet some of the statin side effects mentioned in the study have not been proved in the scientific literature or are exaggerated and could cause unnecessary worry, he said.

For instance, as a side effect, "cancer is not well-established, by any means. Despite some scares in early studies, large meta-analyses of randomized trials don't show any cancer risk," Khera said.

He added that in 2012, the FDA concluded that serious liver injury with statins is rare, and safety labels were revised to remove mentions of needing routine liver monitoring in patients taking statins.

Evidence also appears to be lacking on the side effect of cataracts, he said.

Additionally, whether a side effect outweighs the benefit of a statin depends on an individual patient's needs and preferences.

When it comes to headache or nausea, for instance, "if I told you hypothetically that statins can prevent five heart attacks but cause five people to get mild headaches, are those equal?" Khera asked.

"I feel like this is sensationalism, and it's unfortunate, because it takes away from a balanced and important discussion on risks and side effects," he said of the study.

Khera often counsels his own patients about their statin prescriptions. The three side effects they most commonly ask about are muscle aches, changes in cognitive function and liver function.

"Statins can cause muscle aches, but even if it's as high as one in 10 who get muscle aches, that means 9 in 10 will not. For the vast majority, that won't happen, and it generally goes away when we stop the statin," Khera said.

As for concerns about cognitive decline, "it is not something seen in large studies, so if it does occur, it is infrequent and hard to separate from the usual cognitive decline of aging," he said.

For concerns about liver injury, "we realized over time that minor increases in liver function tests are not clinically significant, as statins very rarely cause serious liver damage for patients," he said.

The new guidelines on cholesterol and statins

All in all, Khera praised the new study for raising the importance of having conversations about statin side effects.

He said the study seems to align with new cholesterol guidelines announced during the American Heart Association's annual scientific conference in November.

The new guidelines encourage collaboration and "shared decision-making" between doctors and their patients, Khera said.

The recommendations also address many of the concerns raised when the guidelines were last updated five years ago.

Those 2013 cholesterol guidelines were troublesome for a number of reasons, explained Dr. Steven Nissen, chairman of cardiovascular medicine at the Cleveland Clinic: The previous guidelines used a risk calculator that left out crucial components such as family history; they didn't address the issue of people older than 75 or younger than 40; they overhyped the risks many patients faced while lowering the threshold needed to warrant statin drug therapy; and they did away with the use of LDL (bad) cholesterol target levels, which helped patients set meaningful goals.

People with LDL levels of 100 or lower "tend to have lower rates of heart disease and stroke, supporting a 'lower is better' philosophy," according to a statement from the American Heart Association and American College of Cardiology about the new guidelines.

A level of above 160 is considered "very high," according to a release from Johns Hopkins Medicine, which also outlined the new guidelines. For high-risk patients, the recommendation is to lower "bad" cholesterol to levels below 70.

The main takeaway from the new study and the new cholesterol guidelines is that "the threshold for starting statins in primary prevention is a complex one and must be individualized to the patient," said Dr. Michael Blaha, an associate professor and director of clinical research at the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, who was not involved in the study.

"Those guidelines feature a detailed discussion between clinician and patient before ever prescribing a statin. The guidelines recommend a thorough assessment of risk and a careful assessment of patient preferences before initiating what could be lifelong therapy," Blaha said.

"Statins are very safe. For patients with prior heart attacks or strokes, statins lead to overwhelming cardiovascular benefit. However, in primary prevention, the margin of benefit of these drugs can be small. In lower risk primary prevention patients, statins may not lead to a net benefit," he said. "That is why it is critical to conduct careful risk assessment and consider patient preferences before initiating statin therapy."

Give weight to harms or benefits? You decide

Drs. Ilana Richman and Joseph Ross, physicians and faculty members at Yale School of Medicine, co-authored an editorial that accompanied the new study in the Annals of Internal Medicine.

"Some patients may favor a risk-averse approach in which harms associated with therapy are given greater weight than potential benefits, but others may prefer to give greater weight to potential benefits," they wrote.

"The onus is on physicians to fairly summarize the evidence and guide patients through the decision-making process," they wrote, adding that perhaps the new study can support that decision-making.

"Indeed, primary prevention of [cardiovascular disease] must be patient-centered, because healthy patients are asked to assume risk, benefits are experienced only as the absence of disease, and uncertainty lurks beneath every choice."