STATINS: Are the side effects from cholesterol-lowering drugs worth the risk?

When the Food and Drug Administration (FDA) announced labeling changes to cholesterol-lowering statins in February of last year, the media were quick to sound the alarm. Headlines proclaimed that statins raise the risk of diabetes and cause memory loss. Debate arose about side effects and whether statins, taken by more than 20 million Americans, were overprescribed. Suddenly, an entire class of wonder drugs wasn’t so wonderful anymore.

But more recent evidence suggests that the there’s more to the statin story. Analyses of three major trials — including one the FDA cited in its warnings about diabetes — revealed that increased rates of diabetes in statin users depended on whether they already had risks for the disease before starting the drugs. Another study demonstrated that not only were statins well-tolerated in patients who had previously stopped taking them because of side effects, but that reports of memory problems in particular were rare. Yet this news did not garner as much attention in the mainstream consumer media.

What gives?

“A lot of media attention focuses on things that create sensation,” said Anne Carol Goldberg, MD, FACP, associate professor of medicine at the Washington University School of Medicine in St. Louis. “But what physicians have to do is educate patients on the reality, which is that these drugs save lives, particularly among people at high risk for cardiovascular disease.”

Goldberg said she encounters resistance to statins among her patients, in part because of what they hear anecdotally or in the news. “People are afraid of them and think they cause bad effects. I will show patients figures from the Cholesterol Treatment Trialists Collaboration [CTT] and explain what we actually see in terms of benefits,” she said.

The CTT is a group of physicians and researchers in the United Kingdom who conduct periodic meta-analyses large randomized trials of lipid-lowering treatments. In the November 13, 2010, issue of Th e Lancet, the CTT published a meta-analysis, of 26 randomized trials involving more than 169,000 participants wherein they found that reducing LDL cholesterol by 38 to 77 mg/dl via statins reduces the risk of vascular events such as heart attack, coronary revascularization, and stroke by 40% to 50%. More recently, in the August 11, 2012, issue of Th e Lancet, the CTT published a meta-analysis of 27 randomized trials involving more than 174,000 patients, which revealed that even low-risk patients who would not normally be considered for statin therapy derive as much risk reduction for vascular events from statins as high-risk patients do.

Diabetes Risk

The labeling for statins now includes a warning that there have been reports of increased blood glucose and A1c measurements in people who take the drugs. Among its reasons for the warning, the FDA cited findings from the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, which noted a 27% increase in investigator-reported diabetes in patients who took rosuvastatin compared to those who took placebo.

In light of the warnings, JUPITER researchers further analyzed data from the trial’s 17,603 participants to weigh the benefits of statins against the risk of diabetes. As noted in the August 11, 2012, issue of Th e Lancet, they found a 28% increase in diabetes among statin users who already had one or more major risk factor for the disease. The team also learned that 134 vascular events or deaths were avoided for every 54 new diagnoses of diabetes, leading them to conclude that the cardiovascular benefi ts of statin therapy exceed the risk of developing diabetes.

A more recent analysis of data from two other studies with a combined 15,056 participants, Treating to New Targets (TNT) and Incremental Decrease in Endpoints Through Aggressive Lipid Lowering (IDEAL), yielded similar results. In this analysis, published in the January 15, 2013, issue of the Journal of the American College of Cardiology, researchers compared 80 mg/day of atorvastatin with 10 mg/day atorvastatin or 20–40 mg/day of simvastatin to assess vascular benefits and diabetes risk. They saw a 24% increase in high-dose participants who already had two to four diabetes risk factors, and no increased diabetes in high-dose participants with no or only one risk factor for diabetes, compared to low-dose participants. Yet compared to low doses, the higher dose reduced the number of cardiovascular events in patients regardless of how many diabetes risk factors they had.

It boils down to severity, said David Waters, MD, professor emeritus at the University of California — San Francisco and lead investigator in the TNT/IDEAL analysis. “If you think about diabetes and cardiovascular disease, the two really aren’t equivalent. Developing diabetes is bad, but having a heart attack or stroke and dying is worse.”

Although diabetes itself raises the risk of cardiovascular disease, populations at risk for both tend to overlap, Waters said. “These are people with high blood pressure, higher than normal fasting glucose, high BMI, and [bad] family histories. Either way, they’re going to benefi t from statin therapy.”

Like Goldberg, Waters has patients who hesitate to take statins. He addresses their concerns by emphasizing risk minimization. “Say a patient has a high BMI. They’ll say they’re afraid taking a statin will give them diabetes. But if they lose weight, they can cut their risk of developing diabetes right there.” Waters has a bone to pick with what he sees as a bias against statins. “A lot of other drugs out there increase the risk of diabetes, like beta blockers, diuretics, HIV drugs, and steroids, but people rarely want to talk about that. They say they don’t want to take a statin because they’re against big bad drug companies, so they’ll take niacin instead. Well, niacin doubles your risk of getting diabetes.”

The Question of Side Effects

Statin labeling now includes a warning that cognitive effects such as memory loss and confusion have been reported in people who take the drugs. The FDA based its warning on reports received through its Adverse Event Reporting System (AERS), where clinicians and patients voluntarily report what they feel to be side effects of the drugs, and noted that the reports generally described people in their 50s or older who experienced noticeable, if poorly defined, memory loss or impairment that disappeared when they stopped taking statins.

However, a study by researchers in the April 2, 2013, Annals of Internal Medicine suggests that memory loss from statin use may actually be rather rare. In the study, which was designed to ascertain the reasons for statin discontinuation and the role of statin-related events in routine care settings over eight years, memory loss was reported in only .06% of participants, or less than 1 in 1,000.

Among the 107,835 participants in the study, 18,778 patients, or 17.4%, had documented statin-related side effects. Muscle pain was the most common side effect, experienced by 4.71% of patients in the study overall. Of those who had side effects, 11,124 stopped taking statins. Then 6,579 began taking statins again. The drugs were well-tolerated the second time around for these patients, as 92.2% of them were still taking statins a year after resuming therapy.

Alexander Turchin, MD, MS, associate physician at Brigham and Women’s Hospital, assistant professor of medicine at Harvard Medical School in Boston, and the senior author of the study, acknowledges that there is a discrepancy between clinical trials’ reported rates of adverse reactions such as muscle pain and what physicians are observing anecdotally in routine care. “If you talk to doctors on the front lines and their patients, you’re constantly hearing about these reactions,” he said. “But in the clinical trials, their incidence is similar between statin and placebo arms.”

This could be for a number of reasons, he said. “Clinical trial participants who pass eligibility criteria tend to be healthier overall. On the other hand many of the symptoms that are reported as attributable to statins are not very specific, such as muscle pain. Sometimes the symptoms are specific to an individual statin or a higher dose. Other times the symptoms might not be from statins at all, but another underlying condition. We think our data implies a range of explanations.”

Turchin added that the older age of many statin users can make it difficult to root out whether their memory loss is actually from statins. “Older patients are at higher risk for vascular dementia from multiple strokes and for the onset of Alzheimer’s disease. This can paint a mixed picture both clinically and pathologically. It’s not an easy diagnosis to make.”

William James Howard, MD, MACP, director of MedStar Washington Hospital Center’s Lipid Clinic and Lipid Consultation services in Washington, D.C., cautioned against awareness of potential side eff ects becoming a selffulfilling prophecy. “One of the problems is that we have created a monster,” he said. “Most people get some muscle or joint pain as they get older, and they tend to ignore it. But if it’s in the back of your mind because you’ve been warned about it in commercials and the news, if you have muscle pain, you’ll think, ‘Oh, it’s the statin,’ when really it might be because you’re 60 and 60-year-olds tend to have a few aches and pains.”

Howard counters the power of suggestion by having patients keep a diary for a few days before starting statin therapy. They record whether, where, and when they have pain or other symptoms so that both physician and patients know what kinds of issues already existed before starting the statin.

The sheer number of people who take statins makes compiling statistics tricky, Howard said. “If you have millions of people on any drug, you will have associations with anything imaginable, whether it’s memory loss, insomnia, peripheral neuropathy, and so on. But that doesn’t mean there’s a cause-and-effect relationship,” he said. “As we move forward with the research, we really need to separate out causation versus association.”

And so the statin story will continue to unfold.

—D’Arrigo is a health and science writer based in Holbrook, N.Y., and a regular contributor to Endocrine News

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