Far fewer people who could benefit from statins actually take the cholesterol-lowering drugs now. Many who start taking them stop. The long list of side effects, detailed in fine print on package inserts and discussed in exam rooms over the years, pose barriers to many patients, doctors say.
A new meta-analysis hopes to set the record straight on one of the most widely used, low-cost doses of cardiovascular disease prevention available.
Statins do have two well-known side effects: muscle pain in 1% of people, and a small increase in blood sugar levels, which could nudge people on the cusp into type 2 diabetes.
But among the litany of possible adverse health outcomes listed, a new analysis in The Lancet published Thursday finds that 62 of those 66 risks are unsupported by reliable evidence. The proof: People were as likely to report the same problems whether they were taking a statin or a placebo pill. In one example from a blinded study, 0.2% of people taking statins said they were experiencing brain fog, but so did 0.2% of people taking a placebo.
The Cholesterol Treatment Trialists’ Collaboration’s 10-year review of 19 large randomized clinical trials involving more than 122,000 people did find strong evidence for four possible outcomes of concern: liver test changes, minor liver abnormalities, urine changes, and tissue swelling. They characterize the related risks as very small.
“Ongoing confusion and concern, not just in patients, but also in many doctors regarding potential statin side effects, mean that many people are not willing to start statins, or have stopped them, even if they’re at high risk of having either a first or recurrent heart attack or stroke and may derive really significant benefit from them,” Christina Reith, associate professor at Oxford Population Health and lead author of the study, said in a media briefing Tuesday. “What we found is there’s no significant excess risk with statins for almost all the conditions listed in statin packaging as potential side effects.”
Statins are champions of preventive cardiology. They can cut levels of LDL, or “bad” cholesterol, in half and prevent blood vessels from being blocked, lowering the risk of heart attacks and stroke by 25%. Brand-name versions lost their patent protection decades ago, so their generic forms are inexpensive, about $40 a year in the United States. As long-term data accumulate on the power of lowering bad cholesterol, new methods to determine who might benefit point toward starting people on the medications even earlier than now recommended to avoid later risk of heart attacks and strokes.
That approach was tested by analyzing risk over 30 years, not the more typical 10 years. In a paper published last month in Circulation: Population Health and Outcomes, researchers applied 30-year estimates from relatively recent PREVENT equations to people who were 30 to 59 years old. They found that 9% had an elevated estimated 30-year risk for heart attack or stroke of 20% or greater, which could translate into 2.5 million more adults being advised to take statins. They also found that 44% had an intermediate estimated 30-year risk for heart attack or stroke, meaning 7.5% to 19.9%.
In the U.S., new guidelines from the American College of Cardiology and the American Heart Association based on the new PREVENT equations are expected by the second quarter of this year.
Primary prevention counseling to avoid cardiovascular disease typically focuses on diet and exercise first, but for people who have high blood pressure, high cholesterol, or a family history of heart disease, there has been a gap in data to guide who might benefit from starting medication earlier and who might be safe delaying that conversation for 20 years, the Circulation paper’s lead author Timothy Anderson said.
“It’s fairly clear that statins consistently reduce folks’ relative risk of a heart attack or stroke by about a quarter,” Anderson, who is a primary care physician and an assistant professor of medicine at University of Pittsburgh Medical Center, told STAT. “The question becomes, is it worth it to start it when you’re 40, or is it fine to wait 10 years until that 10-year risk has crept up?”
That conversation between doctor and patient may cover the warnings about side effects.
As effective as statins are in bringing down rates of serious cardiovascular events — progress achieved over the last 50 years in combination with falling smoking rates and improving medical treatments — the drugs have also been dogged by people’s unwillingness to take them, or any drug, long term. Similar reluctance has been voiced for blood pressure medications and the new obesity drugs, but fears about muscle soreness, including a condition called rhabdomyolysis, have taken root specifically for statins.
The four side effects are real and important for doctors and patients to consider, The Lancet authors said. Rhabdomyolysis, in which muscle tissue breaks down, is rare. Should it be confirmed, other cholesterol-lowering agents would be recommended. Less serious muscle symptoms appear in about 1% of patients, The Lancet paper concluded.
As for the increase in blood glucose, that happened most often in people already very close to the diagnostic threshold for diabetes, Reith said. Diabetes is a major cardiovascular risk factor, but the benefits of statins hugely outweigh their risks, making the presence of already diagnosed diabetes alone a trigger to prescribe statins.
And while statins caused about a 0.1% increased risk of abnormal liver blood test results, there was no increase in liver diseases such as hepatitis or liver failure. The same was true for urine test changes, the authors said.
“What we found is there’s no significant excess risk with statins for almost all the conditions listed in statin packaging as potential side effects,” Reith said. “We were able to show there’s been no increase in memory loss, depression, sleep disturbance, erectile dysfunction, weight gain, nausea, fatigue or headache, and numerous other conditions. That’s not to say that people taking statins did not experience these medical events. We now have really good evidence that although these things may well happen to people while they take statins, that statins are not the cause of these problems.”
The authors and other experts recognize the challenge to drug labeling lies in the need to point out possible harms in an appropriately conservative process that starts with early drug trials, before large amounts of data are amassed. Kausik Ray, a professor of public health at Imperial College London who was not involved in the Lancet study, pointed out the need for robust analyses free from the confounding that can plague observational data and anecdotes.
“Warning labels often come from post-marketing observations with no control arm,” he said in a statement shared by the Science Media Centre. “From a legal perspective, it makes sense but from a biological perspective it doesn’t.”
Still, those concerns may crop up in the doctor’s office after patients — or doctors — see reports that could be valid or could be overstated.
Rory Collins, emeritus professor of medicine and epidemiology at Oxford Population Health and a senior author of The Lancet paper, recalled asking his general practitioner to put him on a statin.
“The GP said to me, ‘are you sure? What about all the nasty side effects?’” he recalled at the media briefing. “So this is happening all the time. This is why doctors and their patients are not starting these treatments. And it’s why patients are at high risk of having a heart attack or stroke.”
While Pittsburgh’s Anderson didn’t find The Lancet data surprising, he suggested they might offer helpful talking points for clinicians advising patients who have concerns about uncommon side effects. Still, in his view, knocking down 62 of 66 warnings won’t be what changes the needle on wariness of statins or other long-term medications.
“I think that really is a larger trust-in-the-medical community sort of conversation,” he said, noting mistrust that has grown over the Covid-19 era and beyond. “As patients get to know their doctors, they often develop trust in that individual even if they have concerns about other aspects of society and the health care system. So the best thing we can do is get to know our patients well, and ideally, develop that trust and that bond with them.”
STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies. Our financial supporters are not involved in any decisions about our journalism.
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