EAS Consensus Document Examines Safety of Statins Beyond Muscle Symptoms

LISBON, Portugal—The risk of a multitude of side effects associated with statin use is low enough that their potential benefits outweigh any downsides, according to a European Atherosclerosis Society (EAS) consensus document published last week.

The paper, which includes data from the last 17 years of literature on statins, reviews the incidence of the seven most concerning side effects with this class of drugs: statin-associated muscle symptoms (SAMS), new-onset diabetes, cognitive impairment, hemorrhagic stroke, hepatic function, renal function, and cataract. Senior author M. John Chapman, PhD (Pitie-Salpetriere University Hospital, Paris, France), told TCTMD in an email that “clinicians should be reassured by the long-term safety of statins, and the low risk of clinically relevant adverse effects. The established cardiovascular benefits of statin therapy far outweigh the risk of any adverse effect.”

Discussing the paper in a late-breaking session at the 2018 EAS meeting this week, Chapman said that while “a very significantly favorable benefit/risk ratio for statin treatment has been established,” the expert panel convened to write this statement because “there are ever wider cross-sections of the population who are actually being treated with statins, and there may in fact be a level of adverse effects which perhaps are perceived but not supported by evidence.”

Additionally, while a previous EAS consensus document addressed the issue of SAMS, the public has become more aware of some of the additional potential side effects of the commonly-used drugs. “The public perception of adverse effects associated with statin treatment may be exaggerated,” he said. “Further, as we are getting more experience with statins, it's becoming evident that there are indeed potential differences between statins, which reflect their distinct pharmacology.”

Funding for attendance of the panel members at consensus meetings was provided by unrestricted educational grants to the European Atherosclerosis Society from a range of statin and nonstatin cholesterol-lowering-drug manufacturers. Questioned about the funding, Chapman insisted to TCTMD that these companies “played no role whatsoever in any part of this exercise.”

New-Onset Diabetes Risk

Chapman cited two randomized controlled studies of people on statins that each showed the drugs to be associated with one case of new-onset diabetes per 1,000 patients per year of exposure. However, the studies also demonstrated that statins prevent five and three new cardiovascular disease events, respectively, in the same population.

It was clear to the panel though, he explained, that because many of the patients in these studies had at least one risk factor for cardiovascular disease plus another metabolic syndrome, “there was a signal in individuals with a prediabetic state.” These patients more frequently reported cases of new-onset diabetes, Chapman noted. “This risk may be higher in patients with features of the metabolic syndrome but needs to be considered in context of the background conversion rate without statin treatment.”

Also, Chapman explained that most studies have defined new-onset diabetes as an HbA1c > 6.5 without symptoms, but added it is unknown what “the relevance of this [is] to long-term morbidity and mortality.” This will be important to determine, he said, given that “there are very large numbers of individuals in the US with this profile as identified in the NHANES study.”

The mechanism for the increased risk of new-onset diabetes on statin treatment may be related to the HMGCR gene variants that are associated with low LDL cholesterol levels and that many studies have also indicated to be linked with higher blood glucose insulin levels, body mass index, waist circumference, and body weight, Chapman added.

But could the class effect somehow be mediated by LDL levels? He showed data from studies that suggest the existence of an association with the risk of increased diabetes, particularly in those with impaired glucose tolerance and individuals with the PCSK9 or NPC1L1 gene variants. Also, Chapman said, “we cannot exclude off-target effects of statins in dysglycemic effects or in switching to new-onset diabetes.”

Cognition, Renal Function, Stroke, SAMS

The addition of cognitive effects to statin labeling in 2012 as mandated by the US Food and Drug Administration was “purely observational,” he commented. “This was not based on studies which were designed to evaluate rigorously clinically or biologically the impact of statins on cognitive function. There have been variable reports in the literature and as time has evolved, particularly over the last 5 years, we're seeing a net swing to indicate no significant effect on any aspect of cognitive function associated with the use of statin therapy.”

After reviewing the literature from studies like IMPROVE-IT, FOURIER, and EBBINGHAUS, Chapman said, the consensus panel maintained that “statin treatment does not have adverse effect on cognitive function.” Specifically, he noted, statins “have no causal effect on the risk of Alzheimer's disease, vascular dementia, any form of dementia, or Parkinson's disease.”

Doctors should not give statins to all [patients], I'm against this,” he continued. “But for the good ones who are indicated, I think there is no doubt that the benefit is largely above the risk, which is small but there.” François Mach

As for renal function, he stated that “most statins are metabolized by the liver and the renal clearance is minimal.” Except for patients on dialysis or those with end-stage renal disease, clinicians should feel free to continue using statins as they have been, and dose adjustments may only be warranted based on estimated glomerular filtration rate for patients on pravastatin and rosuvastatin, Chapman said.

Examining the risk of hemorrhagic stroke associated with statins, he explained that while the SPARCL trial of high-dose atorvastatin in individuals who had undergone a previous documented ischemic stroke “showed a signal that was significant but small for an increased incidence of hemorrhagic stroke, . . . statin treatment overall clearly reduces the risk of the first or subsequent ischemic stroke by 15-30% per mmol reduction of LDL cholesterol.”

This means, Chapman continued, “the more you reduce LDL-cholesterol levels, the more we see a favorable effect on reduction of ischemic stroke events.”

The possible increased risk associated with an LDL-cholesterol reduction “has not been confirmed by analysis of a substantive evidence base of randomized controlled trials, cohort studies, and case-control studies,” he stressed. Rather, the panel’s conclusion was that there should be no alteration warranted in the statin regimens of patients with a history of cerebrovascular disease.

Lastly, Chapman stressed that the potential for SAMS to represent real or nocebo effects remains “very poorly appreciated in general.” The EAS committee defines nocebo in this context as "something caused by negative expectations about the effects of treatment, arising from information provided by clinicians and/or the media about possible side effects, which lead to higher reporting rates for adverse effects of the treatment than would otherwise be expected.”

‘Very Reassuring’ Information

François Mach, MD (Geneva University Hospital, Switzerland), who also served on the EAS consensus panel writing committee and co-chaired the session in which Chapman presented the statement, told TCTMD this information is “very reassuring for the patients.”

“Doctors should not give statins to all [patients], I'm against this,” he continued. “But for the good ones who are indicated, I think there is no doubt that the benefit is largely above the risk, which is small but there.”

Commenting on the study for TCTMD, Alexander Turchin, MD (Brigham and Women’s Hospital, Boston, MA), who was not involved in the writing of the EAS statement, said that the document is a “reasonably good assessment of the literature and I generally agree with it. I do think that the risk/benefit ratio for statin therapy [leans] toward the benefit more so than for many of the other medications that we prescribe in the cardiometabolic arena.”

There are some groups of patients for whom we need to be careful, but I think for the majority of patients who have cardiovascular risk, statin therapy will produce a benefit. Alexander Turchin

Regarding the increased risk of new-onset diabetes for patients in a prediabetic state, he said, “that is well established.” Physicians should take this into account if a patient's cardiovascular risk is not “excessively high,” but if, for example, “they already have significant prediabetes and they have family history,” Turchin suggested. “This might shift the balance of decision-making,” which should “always be at the individual patient level,” he added.

“There are some groups of patients for whom we need to be careful,” Turchin concluded, “but I think for the majority of patients who have high cardiovascular risk, statin therapy will produce a benefit.”