Adverse Events Linked with Statins Get a Second Look From Cholesterol Treatment Trialists’ Collaboration

Public concern about the safety of statins has led the Cholesterol Treatment Trialists’ (CTT) Collaboration—the highly respected Oxford-based group that has been pooling randomized clinical trials of statins since 1995—to launch a new meta-analysis to assess the relative and absolute risk of adverse events associated with the lipid-lowering therapy.

The analysis, say CTT researchers, is a reaction to a wide range of reports, mostly observational studies—often picked up by the media—suggesting statins are responsible for everything from muscle pain and weakness to cognitive impairment, cataracts, and sleep disturbances.  

“This wouldn’t matter if it didn’t have any effect on people’s choices or prescription habits but there is increasing evidence these reports are influencing prescribing and influencing the public,” Colin Baigent, BMBCh (University of Oxford, England), one of the principal investigators of the CTT Collaboration, told TCTMD. “There are several studies suggesting that people are not taking statins even though they are at high risk of cardiovascular disease because of the publicity around statin safety.”

News that the CTT would be looking back at this issue comes amid mounting complaints by academics and clinicians alike that reports of statin side effects are simply not in keeping with what was seen in the early pivotal studies. The recent European Atherosclerosis Society Congress dedicated an entire session to exploring why publicly reported symptoms are so at odds with what was seen in the randomized clinical trials.

Baigent said preliminary results from their work will start to emerge in early 2017. So far, the researchers have reached agreements on data sharing with approximately half of the statin study sponsors and investigators to be included in the meta-analysis. Given the concerns about what they view as unreliable information from observational studies, the researchers want to get the information out as quickly as possible.

Seth Martin, MD (Johns Hopkins Hospital, Baltimore, MD), who is not involved in the analysis but who commented on the issue for TCTMD, said physicians often encounter a patient who is resistant to statins, even when a statin is clearly indicated to lower their risk of cardiovascular events.  

“I work in a lipid clinic and we see a lot of patients referred for statin intolerance,” said Martin. “There is a lot of reticence for statins, although we do have a biased sample, but it is an uphill climb just to get back to a point where we can consider a statin in someone’s treatment. And oftentimes the patients we’re seeing have a clear indication for a statin. I’m talking about patients with familial hypercholesterolemia or established cardiovascular disease.”

Martin agreed that the observational studies, those highlighting an association between statin therapy and adverse events, can affect the willingness of certain patients to take the lipid-lowering medication, but noted that books appearing in the popular press also have a significant impact. These books, such as The Great Cholesterol Myth and others like it, often misinterpret the evidence from statin studies and describe the side effects of statins, particularly the effects on memory, in very scary terms. In 2013, Martin, along with lead author Kristopher Swiger, MD (Johns Hopkins Hospital, Baltimore, MD), published a review in the Mayo Clinic Proceedings showing that the long-term use of statins might actually prevent dementia and memory loss and that their short-term use did not pose any cognition problems.

“We’ve looked at it, others have looked at it, the guidelines have looked at it, and really the evidence is reassuring when it comes to memory and cognitive function,” said Martin.

Deep Dive into the Statin Trials

The CTT protocol for analyzing adverse events data from the randomized trials of statin therapy is currently published in the American Heart Journal. According to the researchers, data from large randomized, controlled trials and meta-analyses suggests the risk of myopathy—defined as muscle pain, tenderness, or weakness with elevations in creatine kinase (10x upper limit of normal)—occurs in approximately 1 in 10,000 patient-years of treatment. The risk of rhabdomyolysis is even smaller.

In contrast, the European Atherosclerosis Society recently suggested, based on their review of patient registries, that anywhere from 7% to 29% of patients complain of statin-associated muscle symptoms, often with normal or only slightly elevated creatine kinase elevations. This has led to very high rates of drug discontinuation—as high as 75% at two years—with muscle-related side effects the predominant reason for stopping treatment.

Clinical trials have also identified an increased risk of diabetes. In JUPITER, for example, treatment with rosuvastatin increased the risk of new-onset diabetes by 27% compared with placebo. However, a meta-analysis of 13 major cardiovascular trials published in 2010 by Naveed Sattar, MD (University of Glasgow, UK) suggested the risk of new-onset diabetes was actually closer to 9%. In the observational studies, the risk of diabetes can be as much as 50% higher with statin therapy.

As such, the new meta-analysis will focus on the risk of myopathy, diabetes, and hemorrhagic stroke in order to assess the “magnitude, timing, and duration of the excess risks” in the overall population and in various subgroups. Regarding these previously identified risks of statin therapy, Baigent said the magnitude of benefit, in all except the very low-risk primary-prevention population, exceeds the hazards.

“However, it will be useful to know how these known hazards vary by different baseline characteristics,” he said.

In addition, the group plans to extensively study muscle-related symptoms separate from myopathy, such as muscle pain and weakness without elevations in creatine kinase, to determine if statins increase the risk of these adverse events. Finally, the CTT collaboration will assess the risk of other possible effects of statin therapy, including cognitive impairment, depression, sleep disturbances, sexual dysfunction, and interstitial lung disease, among others.

Regulatory authorities, including the FDA, already require information about some of these adverse events in the drug label, with a 2012 update warning of the potential for “generally nonserious and reversible cognitive side effects.” The label also warns of the potential for increased blood sugar and glycosylated hemoglobin levels.

The latest CTT collaborative meta-analysis will include 28 published trials and more than 178,000 patients. The trials include numerous studies of statin therapy versus placebo, such as the lipid-lowering arm of ASCOT, 4D, SPARCL, AFCAPS/TexCAPS, WOSCOPS, PROSPER, JUPITER, and the Heart Protection Study, among others. The meta-analysis also includes studies comparing more versus less intensive statin therapy, such as PROVE-IT, TNT, and SEARCH, as well as trials comparing statins versus an open-control arm or usual care. The statins studied include atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin.

Previous analyses from the CTT Collaboration have shown there is an approximate 20% reduction in the risk of major vascular events and vascular mortality with each 1-mmol/L (39 mg/dL) reduction in LDL cholesterol levels. In 2010, the group showed that more intensive statin therapy led to even larger reductions in the risk of major cardiovascular events than regular statin doses, with the benefit achieved directly proportional to the reduction in LDL cholesterol.   

“Potentially Misleading”

To TCTMD, Baigent said the CTT collaboration emerged in the 1990s when the large-scale statin trials were being conducted. Initially, there was a fear that treatment with statins would increase the risk of nonvascular mortality, including the risk of cancer. Although the risk of cancer has since been debunked, reports from observational studies have raised the specter of an even larger range of adverse events, such as but not limited to liver dysfunction, acute kidney injury, fractures, and Parkinson’s disease.

These observational analyses have been “potentially misleading” given the lack of evidence from randomized trials, according to Baigent. Their previous meta-analyses never specifically focused on these adverse events, outside of the known events linked with statin therapy, since none of these issues had turned up in the randomized trials.

“There’s an idea out there that there’s been some conspiracy, that the companies are concealing hazards, but any trial that is going to contribute to getting a label is going to be seen by the FDA and other drug regulators,” said Baigent. “There is typically a great deal of attention paid to adverse events. Given the magnitude of these studies, they would have detected even quite modest elevations in the risk of common outcomes. It is unlikely that we’re going to find big increases in risk of outcomes as they would have likely been discovered by individual trials. However, we might find signals that haven’t been apparent when the individual trials have been examined and we’re not prejudging the issue.”

For Martin, he said he is pleased the CTT collaboration is tackling the issue head-on to clarify any potential adverse events associated with statin therapy. When treating patients who are wary of statins, he said his first task is to present the evidence so the patient can make a decision based on the data rather than opinion.

“I have to say, though, when you sit down with people and give them reliable sources of information, they actually do come around and want to try a statin again,” he said. “It’s just they come in very misled ahead of time. It takes a lot of time to talk through these issues with patients. Luckily I have a little extra time in a specialized lipid clinic but it’s going to be even more difficult where most of this happens, which is primary care practices.”

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