Illustration by David Cutler
Illustration by David Cutler

The never-ending push-pull of statins

Statins have proven their potential to reduce end-point outcomes, such as death from cardiovascular disease. But the drug class also has some downsides, and the pros and the cons become a close call.

When U.S. Preventive Services Task Force members planted their flag amid the statin debate, they recommended a somewhat higher cutoff to start statins than their cardiology colleagues. But the guidance didn't quell the ongoing dissension over when to prescribe the drugs for primary prevention.

The Task Force determined that the strongest evidence for prescribing a low- to moderate-dose statin was in adults ages 40 to 75 with a 10-year cardiovascular risk of 10% or higher. That guidepost differed from the 7.5% threshold set by the American College of Cardiology/American Heart Association guidelines in 2014. The Task Force guidelines, published Nov. 15, 2016, in JAMA, also specified that a patient should have at least one cardiovascular risk factor, while the ACC/AHA guidelines did not.

The latest guidelines rest upon a body of randomized studies, which involve adults with at least one cardiovascular risk factor, said Kirsten Bibbins-Domingo, MD, PhD, who chairs the U.S. Preventive Services Task Force. "This is a situation where the consistency of the effects over multiple, multiple randomized controlled trials makes us have confidence that these results are robust," she said.

But she also acknowledged that the recommendations incorporate a cardiovascular risk calculator, first introduced in the ACC/AHA guidelines, that has attracted criticism for overestimating risk in some individuals. (See "Calculating risk for cholesterol drugs," ACP Internist, November/December 2015.)

"We decided in the end that because it's the calculator that is in widespread use, that we would comment on the challenges with this calculator," Dr. Bibbins-Domingo said. "But we would still issue a recommendation based on risk, and then err on the side of slightly higher [risk] thresholds than others have used."

Statins have become a mainstay in many Americans' medicine cabinets, with nearly 28% of U.S. adults ages 40 and older taking the preventive drugs by 2012-2013 compared with 17.9% a decade previously, according to an analysis published in JAMA Cardiology in January. Among physicians, though, there's been an ongoing push-pull regarding where to set the threshold to start a likely lifelong drug in individuals without heart disease, particularly given that some of the side effects are still being quantified.

As with some other Task Force guidelines, the statin recommendations have garnered some criticism. Among the concerns expressed in a January editorial in JAMA Internal Medicine were the reliability of the underlying data given that the Task Force didn't have access to the primary study findings. Plus, nearly all of the studies involved were industry-funded, the editorialists noted.

Above all, the editorialists questioned if the cardiovascular benefits were sufficiently substantial to ask individuals without known heart disease to take a drug that could cause side effects—most notably muscle aches and a possibly increased risk of diabetes. That's not an out-of-bounds argument, said Michael Hochman, MD, a general internist and an assistant professor of clinical medicine at the Keck School of Medicine at the University of Southern California in Los Angeles.

Statins have proven their potential to reduce end-point outcomes, such as death from cardiovascular disease, Dr. Hochman said. But the Task Force's own review of the existing evidence shows that more than 200 people must be treated in order to prevent one cardiovascular death within the subsequent two to six years.

"Yes, that is a modest [mortality] benefit. On the other hand, it's nothing to sneeze at entirely," Dr. Hochman said, citing a 2013 Cochrane Review analysis showing that 2,000 women have to get mammograms over 10 years in order to avert one breast cancer death.

Yet, he added, statins "also have some downsides. When you start weighing the pros and the cons against each other, it's actually a close call. That's why I think it's one of these situations where patients should be driving the decision with an understanding of these pros and cons."

Weighing risk-benefit

The Task Force guidelines were based on an analysis of 19 randomized controlled trials involving adults without heart disease but at least one risk factor. No guidance was provided for adults ages 76 and older due to a lack of evidence, said Dr. Bibbins-Domingo, a general internist and a professor of medicine and epidemiology at the University of California, San Francisco.

"This isn't to say that those people should not take statins," she said. "It is to say that we don't have enough evidence to make a recommendation for or against statins because there are no studies done in this group."

Nor does the risk for middle-aged adults begin at the 10% threshold, Dr. Bibbins-Domingo said. "We recognize that this risk is continuous."

With that in mind, the Task Force gave a C-level recommendation for adults ages 40 to 75 whose risk falls between 7.5% and 10%, saying the decision to prescribe should be based on a patient's own risk factors and concerns about potential side effects. Regardless of the precise risk calculation for the individual patient, the Task Force specified low- to moderate-dose statins for primary prevention, as some of the potential risks appear to be associated with the higher-dose statins, Dr. Bibbins-Domingo said.

The authors of the Task Force guidelines acknowledge that there are several potential side effects with statins, including self-reported muscle aches and a potential increased risk of diabetes, although they say that data were mixed. (They also describe the evidence regarding potential cognitive effects as "relatively sparse," but with no clear evidence of reduced function.)

To date, any association with diabetes appears to be linked with higher-dose statins, Dr. Bibbins-Domingo noted. It also should be kept in mind that patients taking a statin likely already have risk factors for diabetes, and there's some indication in the research that the disease develops a bit sooner in patients taking statins than it would have anyway, said Steve Kopecky, MD, a cardiologist and professor of medicine in the department of cardiovascular disease at Mayo Clinic in Rochester, Minn.

In terms of potential side effects, though, the myalgia has been difficult to quantify, Dr. Kopecky said. "Everyone gets muscle aches in life," he said, particularly later in life. Plus, a lot of the earlier statin studies were designed in such a way that muscle aches weren't identified, as they occurred before patients were randomized, he said.

So for years a lot of physicians, including Dr. Kopecky, told patients that the study data didn't show any muscle-related problems with statins. "So while we've been telling patients for decades that it's not the drug, they for some reason—and this is a shocker—they have come to distrust us," he said.

Data are still limited regarding the extent of muscle-related symptoms. But a combination of observational data as well as the findings of a randomized study—one that regularly asked about muscular aches and pains—indicates that between 5% and 10% of patients will have some symptoms, according to a viewpoint piece published in the same Nov. 15, 2016, JAMA issue as the Task Force guidelines.

Dr. Kopecky has experienced statin-related aches himself—initially he thought he might have rheumatoid arthritis—and changed his statin as a result. Still, he supports the lower ACC/AHA risk threshold for prescribing.

He cited several studies finding that fewer than half of first-time cardiovascular events occur in patients who were believed to be at high risk. So being aggressive, by using a 7.5% rather than a 10% threshold for primary prevention, makes sense, he said.

A false sense?

Unfortunately, statins also can be used as a justification for poor health habits, doctors report. "I have some patients who say, 'I want to take a statin so I can eat whatever I want,'" Dr. Kopecky recounted.

One analysis, published in 2014 in JAMA Internal Medicine and involving nearly 28,000 U.S. adults, provided some support for those anecdotes. Over the course of a decade, the calorie intake by statin users increased by 9.6% and the fat intake increased by 14.4%, while neither significantly changed among those not on the drugs during that same stretch.

To make his case to patients, Dr. Kopecky references research published in 2012 in Circulation, which shows that statins appear to be more effective in those who eat a healthier diet. Another study, published in 2013 in Lancet, found similar payoff for better fitness, he said. Among veterans who took statins, mortality risk decreased as level of physical activity increased.

Once patients are started on a statin, the Task Force doesn't provide any guidance for ongoing monitoring. "I think we are relatively new to this idea of risk-based thresholds," Dr. Bibbins-Domingo said.

"The question is how do you monitor?" she asked. "The evidence suggests that these drugs are very effective at lowering the LDL [cholesterol], but their effects on cardiovascular disease probably extend beyond the LDL."

The ACC/AHA guidelines do recommend monitoring, checking lipids within the first 12 weeks after the drug is started and then every 3 to 12 months afterward as clinically needed. One good reason to do a follow-up check is that roughly one in five patients taking a statin gets very little benefit in terms of lipid reduction but might if another statin is tried, Dr. Kopecky said. "The idea then that we check them and follow them I think is very worthwhile."

Another consideration during initial prescribing is a patient's racial or ethnic background, Dr. Kopecky said. Patients originally from China, Japan, Korea, and other parts of eastern Asia have been shown in studies to be more vulnerable to myopathy, as well as more sensitive to statin dosing, he said. Dr. Kopecky typically starts a patient with this background on roughly 25% of the dose he'd prescribe to a patient who is white or African-American.

Providing options

While researchers may debate over study underpinnings and other nuances, Dr. Hochman said that he only has time during appointments for a brief synopsis of statin pros and cons, and most of his patients readily fall into one of two camps. Either they want to take any measure to reduce their heart risk, he said, or they're resistant to pills of most any type, even if it's taking acetaminophen for a headache.

For that smaller third group of patients who are on the fence, he will provide some reading materials and suggest that they mull over their options. "This is clearly a gray area where there are pros and cons, and there is no right or wrong answer," said Dr. Hochman.

Dr. Hochman said that he would make a stronger case for starting a statin in a patient whose 10-year cardiovascular risk was approaching 15% or higher. He also talks to all his patients about nondrug strategies to improve their cardiovascular health, such as ditching the cigarettes, with some success. "That's the low-hanging fruit," he said.

Even when he does prescribe a statin, Dr. Hochman said, "One line I often tell my patients is that the medicine is the Band-Aid. The treatment is the lifestyle change."