EAS Consensus panel answers the questions on statin safety

Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase [HMG-CoA] inhibitors) are recommended by guidelines as first-line treatments for decreasing low-density lipoprotein cholesterol (LDL-C) to prevent atherosclerotic cardiovascular disease (ASCVD).[1,2] These recommendations are based on indisputable evidence that LDL-C is a key driver of ASCVD and thus a principal target for therapeutic intervention, as discussed in a previous European Atherosclerosis Society (EAS) Consensus Panel statement.[3] Additionally, evidence from trials shows that statins are generally safe and well tolerated.[4] However, possible unintended effects of statins may not become evident until there has been longer exposure in a more heterogeneous population than that included in clinical trials. The recognized small risk of diabetes associated with statin therapy is an example of this.[5,6]

Uncertainties also remain about a number of other possible unintended adverse effects of statins during long-term exposure. In this latest statement, therefore, the EAS Consensus Panel has turned their attention to questions about the effects of statins on glucose homeostasis, cognitive, renal and hepatic function, as well as the possible risk for haemorrhagic stroke or cataract. This was a consensus-driven statement based on comprehensive literature review and analysis covering 2000 to 2017. We summarize the key findings from this statement,[7] which is freely available on Open Access. Go to the publication.

Do statins affect glucose homeostasis?

As previously noted, statin therapy is associated with a modest risk of new-onset diabetes, equating to about one new case per 1000 patients per year of exposure.[5] This risk is higher with more intensive statin therapy,[6] and in individuals with features of the metabolic syndrome at initiation of therapy.[8-10] For example, in the Metabolic Syndrome in Men study in individuals with features of the metabolic syndrome but without a diabetes diagnosis at the time of starting statin treatment, this risk was increased 10-fold.[11] These findings, however, need to be considered in context. First, most studies have generally not included glucose tolerance testing, the gold standard for the diagnosis of diabetes, before and after statin treatment. Second, these data need to be considered against the background rate of conversion to new-onset diabetes in at-risk individuals not on a statin. For example, estimates from the Diabetes Prevention Program indicate an annual rate of conversion to diabetes of 110 per 1000 patient-years exposure in subjects with confirmed prediabetes.[12]

Outstanding questions persist regarding whether this is an on- or off-target effect of statins, and whether statins differ in their potential for effects on glucose homeostasis. In conclusion, it is important to note that while statin therapy was associated with about one new case per 1000 patients per year of exposure it also prevented five new cardiovascular events.[5] Furthermore, statin users may also have a lower risk of microvascular complications linked with diabetes.[13]

Do statins affect cognitive function?

Whether long-term statin treatment affects cognitive function is a recurring theme, fuelled by conflicting reports in the literature. Short-term data from randomized controlled trials (RCTs), together with observational studies in younger people with baseline intact cognitive function, indicated no adverse effects of statins on cognition,[14,15] and longer-term data even suggested a beneficial role for statins in delaying dementia.[16,17] Conversely, post marketing reports of statins have implicated a reversible cognitive impairing effect in some patients, prompting analysis by the Food and Drug Administration and an announcement in 2012 that statins may cause reversible cognitive impairment.[18]

A number of considerations need to be taken into account when weighing up the evidence. First, there are the limitations of trial data, in terms of short duration and lack of defined methodology for detecting adverse cognitive effects. On the other hand, post marketing data are limited by the voluntary nature of reporting and lack of placebo controls. Other factors such as race/ethnicity, gender, genotypes and physico-chemical differences between statins also need to be taken into account.

Based on extensive review and analysis, the EAS Consensus Panel concluded that there is no causal evidence for a link between statin use and impaired cognitive function. Furthermore, the suggestion that very low levels of low-density lipoprotein cholesterol (LDL-C) attained with the combination of a statin and ezetimibe or PCSK9 inhibitor are associated with increased risk for adverse cognitive effects, is also refuted by the data.[19,20] The EBBINGHAUS study, a substudy of FOURIER with the PCSK9 inhibitor evolocumab, specifically addressed this issue using the Cambridge Neuropsychological Test Automated Battery, a validated platform designed to assess cognitive function across a range of domains. This study showed no change in cognitive function compared with placebo (statin alone) over the trial duration (mean follow-up 1.8 years).[21] Finally, there is also genetic support from a Mendelian randomization study involving more than 100,000 individuals from the Danish general population, in which low LDL-C levels associated with PCSK9 and HMGCR variants had no causal effect on the risk of Alzheimer’s disease, vascular dementia, any dementia, or Parkinson’s disease.[22]

Do statins affect renal or hepatic function?

Statins and renal function

Evidence from RCTs supports guideline recommendations for statin therapy in patients with chronic kidney disease (CKD) except those on dialysis.[1,2,23-25] While intensive statin therapy may lead to mild, usually transient, proteinuria, this is not associated with impaired renal function. Questions have been raised, however, about a possible link between high intensity statin regimens and risk for acute kidney disease, following a retrospective analysis reporting a 34% higher risk of acute renal injury within 120 days of initiation of high versus moderate intensity statin treatment.[26] Data from RCTs have not corroborated this finding; instead, there was no change in the risk of acute renal impairment, no increase in serious adverse renal events and no increase in progression of CKD on statin treatment.[27-29] Indeed, it has been suggested that statins may have potential renoprotective effects, although this warrants further study.

Statins and hepatic function

Mild elevation in liver transaminases occurs in 0.5–2.0% of patients on any statin, and in isolation, is unlikely to be clinically relevant.[30] For example, in one report based on data from 49 trials involving more than 14,000 patients, persistent elevations in hepatic transaminases (>3 x upper limit of normal) occurred in 0.1%, 0.6%, and 0.2% of patients on atorvastatin 10 mg, atorvastatin 80 mg, and placebo.[31] Additionally, statin treatment does not worsen liver disease in patients with mild liver transaminase elevation due to steatosis or non-alcoholic fatty liver disease. Justifiably, guideline groups do not recommend routine periodic monitoring of liver enzymes during statin therapy in asymptomatic patients.[1,2]

Statin-associated severe liver injury is very rare; data from European and USA adverse event reporting systems indicate ≤2 cases per one million patient-years.[32,33] Even with increasing statin prescription, there has been no increase in incidence.[33] The role of statin treatment in these cases is also difficult to discern, although it is likely to be a class effect of statins which may occur any time after initiation of statin treatment.

Does statin treatment increase the risk of haemorrhagic stroke or cataract?

Statins and risk of haemorrhagic stroke

There is indisputable evidence that statins reduce the risk of ischaemic stroke by 15-35% per mmol/L reduction in LDL-C.[35] However, there have been concerns that statin treatment may also predispose to an increased risk of haemorrhagic stroke in individuals with a history of cerebrovascular events, prompted by a recent analysis, largely driven by data from the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial.[36] In this trial, while treatment with atorvastatin 80 mg daily reduced ischaemic stroke in patients with prior stroke or transient ischaemic attack, there was also a higher number of haemorrhagic strokes, especially in older patients.[37,38] A subsequent collaborative meta-analysis of nearly 250,000 patients in RCTs, cohort studies and case control studies, however, did not corroborate this finding.[39] Moreover, there was no evidence from another meta-analysis, or the FOURIER or the ODYSSEY Outcomes studies that very low LDL-C levels increased the risk of haemorrhagic stroke.[20,40,41]

In conclusion, while the EAS Consensus Panel recognizes the possibility of an increased risk of haemorrhagic stroke in individuals with a history of cerebrovascular events as suggested by the SPARCL data, the totality of evidence does not support this, and therefore no change in the statin regimen in patients with a history of cerebrovascular disease is recommended.

Statins and cataract?

Finally, as statin treatment is given long-term, a possible risk for cataract development may be a clinical concern. The EAS Consensus Panel attempted to address this question, while also recognizing methodological issues with the available studies such as lack of definition of cataract as an outcome, and failure to take into account non-adherence with therapy.

While there are limited data (preclinical and clinical) to suggest a link between statin use and cataract, evidence from RCTs provides reassurance, with no increases in related ocular outcomes such as ocular opacities, visual outcomes, cataract development, grading or extraction.[42-44] Indeed, in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial the risk of cataract was significantly lower with the use of simvastatin and ezetimibe compared to placebo.[45]

Conclusion

This much needed Consensus statement has provided evidence-based guidance to overcome some of the exaggerated perceptions about the unintended effects of statin therapy. The overwhelming conclusion of this Consensus Panel is that the established cardiovascular benefits of statin therapy far outweigh the risk of any such adverse effects. Clinicians should be reassured about the safety of statin therapy based on this extensive evidence-based review.

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