Latest Statin Risk-Benefit Analysis: More Harm Than Good?
A study sought to quantify benefits and harms but in so doing may serve only to reopen old grievances, one critic insists.
(UPDATED) A new study seeking to allay concerns about statin side effects in primary prevention may have the unintended effect of reopening a debate that many physicians have long considered as settled, a prominent cardiologist warns.
The stated aim of the meta-analysis, published in the BMJ, is to assess the benefit-to-harm ratio of the popular cholesterol-lowering drugs, given pervasive concerns about adverse events in people who haven’t already had a cardiovascular event.
“As patients get a little bit older, the potential harms of [statins and other medications] increase, and for some it may be the case that the harms of treatment might start to outweigh the potential benefits,” senior author James Sheppard, PhD (University of Oxford, England), explained to TCTMD. “And therefore, there may be some patients who are less likely to want to take these sorts of medications.
“But the problem for doctors in clinical practice is that they don't really know who these patients might be,” Sheppard continued, “and there's not great empirical evidence at the moment to the extent to which who has different outcomes. Particularly for statins, it's become quite a controversial area where you see some study saying that statins have lots of side effects and other studies saying that statins have no side effects. It becomes quite confusing quite quickly.”
However, for Steven Nissen, MD (Cleveland Clinic, OH), who commented on the analysis for TCTMD, the study “does a serious disservice to evidence-based medicine” because the researchers don’t go far enough in their wording of the title and conclusions to promote statin use.
The study by Sheppard and colleagues, with lead author Ting Cai, MPH (University of Oxford), showed 19%, 9%, and 8% absolute risk reductions in MI, stroke, and CV death, respectively, with statin use. Side effects like muscle symptoms and liver dysfunction were “really, really rare, and from what we could see, they certainly weren't on the same level as the amount of benefits that you get from taking a statin,” Sheppard said.
The authors conclude their paper saying: “Statins were associated with a small increased risk of self-reported muscle symptoms, liver dysfunction, renal insufficiency, and eye conditions in patients without a history of cardiovascular disease. These adverse effects were mild compared with the potential benefits of treatment with statins in preventing major cardiovascular events, suggesting that the benefit-to-harm balance of statins for primary prevention of cardiovascular disease is generally favorable.”
That’s too soft a stance, says Nissen.
“What I'm worried about is when you get this kind of strange study, it really has the effect of getting people who are somewhat cautious about statins to be more cautious,” he stressed. “I think we ought to be more aggressive about giving statins because we know that LDL cholesterol is in fact strongly associated with morbidity and mortality. In general, if you read the manuscript closely, they are saying that the benefits do outweigh the harms, but they are really overemphasizing the harms. These harms are not important.”
In response, Sheppard argued that the issue is not as straightforward as Nissen suggests.
“Unfortunately, many patients (rightly or wrongly) have preconceived ideas about statin treatment and the potential for harm, which stop them from accepting treatment when it is offered,” he said. “To dismiss these ideas and say that the harms are not important I think is unhelpful. In our paper, we acknowledge that these side effects are real, but also mild and very rare. I believe these data are helpful for clinicians speaking to patients who are anxious about starting statin treatment, allowing them to reassure individuals that the potential for side effects is very small, and outweighed by the potential for benefit.”
On behalf of the BMJ editors, Associate Editor Joseph Ross, MD (Yale School of Medicine, New Haven, CT), told TCTMD in an email they “made the decision to publish this study because there remains outstanding uncertainty about the risk of adverse events attributable to statins when used for the primary prevention of cardiovascular disease.
“In contrast, there have been ample studies examining the benefits,” he continued. “Our hope is that because the authors have provided the evidence for risk alongside the evidence for benefits, doing their best to meta-analyze the literature using multiple methodological approaches, patients and their primary care physicians can make more informed choices about whether to use statins for primary prevention.”
For the meta-analysis, Sheppard and colleagues included 62 statin trials comprised of more than 120,000 patients without a history of cardiovascular disease who were followed for a mean of 3.9 years.
Statins were associated with greater risks of the following side effects:
- Self-reported muscle symptoms (21 trials): OR 1.06; 95% CI 1.01-1.13
- Liver dysfunction (21 trials): OR 1.33; 95% CI 1.12-1.58
- Renal insufficiency (eight trials): OR 1.14; 95% CI 1.01-1.28
- Eye conditions (six trials): OR 1.23; 95% CI 1.04-1.47
Neither clinically confirmed muscle disorders nor diabetes were shown to be related to statin use.
On the other hand, statins significantly reduced the risks of MI (OR 0.72; 95% CI 0.66-0.78), stroke (OR 0.80; 95% CI 0.72-0.89), and CV death (OR 0.83; 95% CI 0.76-0.91) in 22, 17, and 22 trials, respectively.
“The population we looked at here were people who were at low risk of having a cardiovascular event, so the chances of benefitting from a statin were lower,” Sheppard said. “In this population, you might think actually if there were a risk you might be more cautious about starting a statin, but what we show in the results is that actually the harms associated with statins are so small that is still beneficial to take a statin even if you are at low risk of cardiovascular disease.”
What this analysis wasn’t able to show, however, is which patients are most likely to experience side effects and why, he added, saying this is where future research should focus.
Nissen also took issue with the term “liver dysfunction” used in the study, defined as a rise in serum concentration of aspartate transaminase or alanine transaminase to more than three times the upper limit of normal and other diagnosed liver disorders. “What actually happens with statins is there's a modest increase in liver enzymes that never leads to liver dysfunction,” he said. “So it's not liver dysfunction. It's isolated enzyme increases.”
Ultimately, to say statins are “generally favorable” is “an awfully weak statement of support,” Nissen said. “It's just bizarre that they would conclude that there's not clearly a benefit over a harm.”
Cai T, Abel L, Langford O, et al. Associations between statins and adverse events in primary prevention of cardiovascular disease: systematic review with pairwise, network, and dose-response meta-analyses. BMJ. 2021;374:n1537.
- This study was funded by a British Heart Foundation PhD Scholarship held by Cai.
- Sheppard is funded by a Wellcome Trust/Royal Society Sir Henry Dale Fellowship, and he also reports receiving funding from a National Institute for Health Research Oxford Biomedical Research Centre Senior Fellowship.
- Nissen reports no relevant conflicts of interest.