This website uses cookies to store information on your computer. Some of these cookies are used for visitor analysis, others are essential to making our site function properly and improve the user experience. By using this site, you consent to the placement of these cookies. Click Accept to consent and dismiss this message or Deny to leave this website. Read our Privacy Statement for more.
Sign In   |   Register
EAS Consensus panel answers the questions on statin safety
Share |

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]

For clinicians, the key take home message is that the clinical benefits of statin treatment far outweigh the potential risk of new onset diabetes, especially in individuals with increased HbA1c.

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]

For clinicians the take home messages are:
  • Statins do not adversely affect cognitive function
  • even very low LDL-C levels attained with statin combination therapy (ezetimibe or a PCSK9 inhibitor) do not impair cognitive function.

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.

For clinicians, the take home message is that statin treatment is not associated with clinically significant deterioration of renal function. For patients with severe kidney dysfunction on intensive statin regimens dose reduction based on estimated glomerular filtration rate may be prudent.

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.

For clinicians the take home messages are:
  • Mild liver transaminase elevation in isolation in asymptomatic statin users is not clinically relevant.
  • Clinically apparent liver injury with statin therapy is very rare and likely to be a class effect of statins.
  • Routine periodic monitoring of liver enzymes is not justified. However, liver enzymes should be measured in the rare patient who develops symptoms suggestive of hepatotoxicity.

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.

For clinicians the take home messages are:
  • Statin treatment indisputably reduces the risk of first or subsequent ischaemic strokes by 15-35% per mmol/L reduction in LDL-C.
  • Despite SPARCL suggesting a small increase in haemorrhagic stroke in subjects with prior stroke, this has not been confirmed by a substantive evidence base of RCTs, cohort studies and case-control studies. Consequently, no change in the statin regimen in patients with a history of cerebrovascular disease is indicated.

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]

For clinicians, the take home message is that statin treatment is not associated with cataract development. No change in cardiovascular prevention strategies is indicated in those with cataract.

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.

References

  1. Catapano AL, Graham I, De Backer G et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis 2016;253:281-344.
  2. Piepoli MF, Hoes AW, Agewall S et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315-2381.
  3. Ference BA, Ginsberg HN, Graham I et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-2472.
  4. Collins R, Reith C, Emberson J et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532-2561.
  5. Sattar N, Preiss D, Murray HM et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735-742.
  6. Preiss D, Seshasai SR, Welsh P et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011;305:2556-2564.
  7. Mach F, Ray KK, Wiklund O, Corsini A, Catapano AL, Bruckert E, De Backer G, Hegele RA, Hovingh GK, Jacobson TA, Krauss RM, Laufs U, Leiter LA, März W, Nordestgaard BG, Raal FJ, Roden M, Santos RD, Stein EA, Stroes ES, Thompson PD, Tokgözoğlu L, Vladutiu GD, Gencer B, Stock JK, Ginsberg HN, Chapman MJ; European Atherosclerosis Society Consensus Panel. Adverse effects of statin therapy: perception versus the evidence Focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract. Eur Heart J 2018;
  8. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012;380:565-571.
  9. Waters DD, Ho JE, Boekholdt SM et al. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes. J Am Coll Cardiol 2013;61:148-152.
  10. Mora S, Glynn RJ, Hsia J et al. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation 2010;121:1069-1077.
  11. Cederberg H, Stančáková A, Yaluri N et al. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia 2015;58:1109-1117.
  12. Knowler WC, Barrett-Connor E, Fowler SE et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.
  13. Nielsen SF, Nordestgaard BG. Statin use before diabetes diagnosis and risk of microvascular disease: a nationwide nested matched study. Lancet Diabetes Endocrinol 2014;2:894-900.
  14. Ott BR, Daiello LA, Dahabreh IJ et al. Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials. J Gen Intern Med 2015;30:348-358.
  15. Joosten H, Visser ST, van Eersel ME et al. Statin use and cognitive function: population-based observational study with long-term follow-up. PLoS One 2014;9:e115755
  16. Heymann AD, Ravona-Springer R, Moshier EL et al. Statin use is associated with better cognitive function in elderly with type 2 diabetes. J Alzheimers Dis 2015;47:55-59.
  17. Song Y, Nie H, Xu Y, Zhang L, Wu Y. Association of statin use with risk of dementia: a meta-analysis of prospective cohort studies. Ger Gerontol Int 2013;13:817-824
  18. U.S. Food and Drug Administration. FDA Consumer Health Information: FDA expands advice on statin risks. 2012. www.fda.gov/consumer
  19. Giugliano RP, Wiviott SD, Blazing MA et al. Long-term safety and efficacy of achieving very low levels of low-density lipoprotein cholesterol a prespecified analysis of the IMPROVE-IT trial. JAMA Cardiol 2017;2:547-555.
  20. Giugliano RP, Pedersen TR, Park JG et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet 2017;
  21. Giugliano RP, Mach F, Zavitz K et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med 2017;377:633-643.
  22. Benn M, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Low LDL cholesterol, PCSK9 and HMGCR genetic variation, and risk of Alzheimer’s disease and Parkinson’s disease: Mendelian randomisation study. BMJ 2017;357:j1648.-
  23. Cholesterol Treatment Trialists Collaboration, Herrington WG, Emberson J et al. Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials. Lancet Diabetes Endocrinol 2016;4:829-839.
  24. Palmer SC, Navaneethan SD, Craig JC et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev 2014:CD007784.
  25. Hou W, Lv J, Perkovic V et al. Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: a systematic review and meta-analysis. Eur Heart J 2013;34:1807-1817.
  26. Dormuth CR, Hemmelgarn BR, Paterson JM et al. Use of high potency statins and rates of admission for acute kidney injury: multicenter, retrospective observational analysis of administrative databases. BMJ 2013;346:f880.
  27. Bangalore S, Fayyad R, Hovingh GK et al. Statin and the risk of renal-related serious adverse events: Analysis from the IDEAL, TNT, CARDS, ASPEN, SPARCL, and other placebo-controlled trials. Am J Cardiol 2014;113:2018-2020.
  28. Sanguankeo A, Upala S, Cheungpasitporn W et al. Effects of statins on renal outcome in chronic kidney disease patients: a systematic review and meta-analysis. PLoS One 2015;10:e0132970.
  29. Zhang Z, Wu P, Zhang J et al. The effect of statins on microalbuminuria, proteinuria, progression of kidney function, and all-cause mortality in patients with non-end stage chronic kidney disease: A meta-analysis. Pharmacol Res 2016;105:74-83.
  30. Tolman KG. The liver and lovastatin. Am J Cardiol 2002;89:1374–1380.
  31. Newman C, Tsai J, Szarek M et al. Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials in 14,236 patients. Am J Cardiol 2006;97:61–67.
  32. Björnsson E, Jacobsen EI, Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing. J Hepatol 2012;56:374-380.
  33. Food and Drug Administration. Guidance for industry. Drug-induced liver injury: Premarketing clinical evaluation. 2009. http://www.fda.gov/
  34. Russo MW, Hoofnagle JH, Gu J et al. . Spectrum of statin hepatotoxicity: experience of the drug-induced liver injury network. Hepatology 2014;60:679-686.
  35. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-1678.
  36. Vergouwen MD, de Haan RJ, Vermeulen M, Roos YB. Statin treatment and the occurrence of hemorrhagic stroke in patients with a history of cerebrovascular disease. Stroke 2008;39:497-502.
  37. Amarenco P, Bogousslavsky J, Callahan A 3rd et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006;355:549-559.
  38. Goldstein LB, Amarenco P, Szarek M et al. Hemorrhagic stroke in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study. Neurology 2008;70:2364-2370.
  39. Hackam DG, Woodward M, Newby LK et al. Statins and intracerebral hemorrhage: collaborative systematic review and meta-analysis. Circulation 2011;124:2233-2242.
  40. Boekholdt SM, Hovingh GK, Mora S et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol 2014;64:485-494.
  41. Schwartz GG, Szarek M, Bhatt DL et al. The ODYSSEY Outcomes Trial: topline results. Alirocumab in patients after acute coronary syndrome. Clinical Latebreaker, 67th Scientific Sessions of the American College of Cardiology, March 10th, 2018.
  42. Laties AM, Shear CL, Lippa EA et al. Expanded clinical evaluation of lovastatin (EXCEL) study results. II. Assessment of the human lens after 48 weeks of treatment with lovastatin. Am J Cardiol 1991;67:447-453.
  43. Harris ML, Bron AJ, Brown NA et al. Absence of effect of simvastatin on the progression of lens opacities in a randomised placebo controlled study. Oxford Cholesterol Study Group. Br J Ophthalmol 1995;79:996-1002.
  44. Yu S, Chu Y, Li G et al. Statin use and the risk of cataracts: a systematic review and meta‐Analysis. J Am Heart Assoc 2017;6:e004180.
  45. Bang CN, Greve AM, La Cour M et al. Effect of randomized lipid lLowering with simvastatin and ezetimibe on cataract development (from the Simvastatin and Ezetimibe in Aortic Stenosis Study). Am J Cardiol 2015;116:1840-1844.
Membership Software Powered by YourMembership  ::  Legal