Statins for Management of High Cholesterol

Despite promising evidence from observational studies, existing clinical trials suggest that statins are not useful for preventing or treating dementia. However, statins continue to be a relatively safe and effective method to maintain healthy cholesterol levels for many people. Statins carry some risks and the choice to take statins or not should be done in consultation with your doctor.

with   Moderate  evidence
Some risks
with   Strong  evidence

Statins comprise a group of 7 cholesterol-lowering drugs: atorvastatin (Lipitor™), fluvastatin (Lescol™), lovastatin (Mevacor™, Altocor™), pitavastatin (Livalo™), pravastatin (Pravachol™), rosuvastatin (Crestor™) and simvastatin (Zocor™). Of these drugs, simvastatin, lovastatin and atorvastatin have a chemical structure that makes them most likely to get into the brain. They work by inhibiting an enzyme called HMG CoA reductase, a key enzyme in the cholesterol synthesis pathway.

Did You Know? The first statin was isolated in Japan in 1971 from the fungus Penicillium citrinum.

Unlikely, based on moderate evidence.

Despite initial promising results from observational studies, subsequent meta-analyses and clinical trials suggest that statins do not prevent dementia.

The first clues that statins may reduce the risk of dementia came from two independent observational studies published in 2000 [1,2], which both suggested that lovastatin and pravastatin could reduce dementia risk by approximately 70% in older adults. However, the designs of these studies have since been criticized for their tendency to over-estimate potential protective results [3]. Since the initial observations in 2000, nearly 30 published observational studies of different designs and in different groups of people have reported degrees of protective or null associations with statin use [4-6]. The scientists behind, with funding from the Alzheimer’s Drug Discovery Foundation, worked to combine all these studies into one analysis. The evidence did not convince them that statins protect from dementia. They observed no association between long-term statin use and dementia. People diagnosed with dementia were less likely to have been using statins recently but that association may have less to do with a protective effect of statins and more to do with a tendency of doctors to stop prescribing statins for patients with deteriorating cognitive abilities [7]. To read more about this analysis visit the AlzRisk website.

Indeed, randomized clinical trials suggest that statins do not protect against dementia. When analyzed collectively in 2009 [3], results from two large trials comprising over 26,000 patients [8,9] suggested no reduction of dementia risk among older adults using statins (simvastatin or pravastatin), although both studies found statin use lowered levels of LDL (the “bad” cholesterol) and lowered the risk of total heart-related death and non-fatal heart attack and stroke. However, these trials only tested the use of statin for 5 years or less.

Even if statin use does protect against dementia, the effect probably is due to lowered cholesterol rather than to other effects of a specific type of statin on the brain. For example, the meta-analysis of 24 observational studies described above found no differences in risk reduction among different types of statins, regardless of whether the statins can penetrate into the brain. They also found no differences between the dementia risks with statins versus other LDL-lowering agents like fibrates that act by different mechanisms than statins. Taken together, these findings strongly suggest that, if statins do protect against dementia, they do so by lowering cholesterol rather than by another mechanism such as an effect on beta-amyloid.

There have been rare reports of statins causing cognitive impairment. For more information see the Safety section below.

Statin use and APOE4 genotype:  Evidence is mixed for whether statins will have different effects on brain health in people who carry at least one APOE4 allele. At least three observational studies on the relationship of statin use with dementia risk found no effect of an APOE4 allele [10-12] while one study suggested that statin use might have a slightly stronger protective association in people who carry at least one APOE4 allele [13]. One trial in Alzheimer’s patients also suggested that atorvastatin might contribute to the preservation of cognitive function specifically in patients with at least one APOE4 allele [14].  To learn more about what the APOE genotype means for your health, visit our APOE4 information page.

Unlikely, based on moderate evidence.

Evidence that statins may be useful in treating Alzheimer’s is conflicting between observational and clinical trial studies. A 35-month observational study in patients with Alzheimer’s disease concluded that LDL-lowering agents (both fibrates and statins) did slow cognitive decline compared to patients with untreated high cholesterol [15]. However, Alzheimer’s patients who took statins did not have slower cognitive decline when studied in several shorter (5 to 6 month) clinical trials for a type of Alzheimer’s drug [16] and randomized clinical trials have generally not observed cognitive benefits of statins in Alzheimer’s patients.

In 2010, three well-controlled clinical trials were collectively analyzed, representing nearly 750 patients taking either 80 mg per day atorvastatin or simvastatin [17]. Statins did not improve cognition in patients, although one of the trials suggested possible improvements in patients with higher starting cholesterol, patients with higher starting cognition, and patients that carried at least one APOE4 allele [14]. In a more recent clinical trial, simvastatin failed to improve cognition in patients with Alzheimer’s disease [18].

There have been rare reports of statins causing cognitive impairment. For more information see the Safety section below.

Possibly, based on very limited evidence.

One study in animals suggests that statin treatment might extend healthy lifespan. A recent study in fruit flies demonstrated that simvastatin increased average lifespan by ~30% and improved heart function [25]. However, these results have not yet been validated in mammals. Statins also appear to decrease all-cause mortality in humans. A 2013 review of 19 clinical trials that included more than 50,000 patients with no heart disease found a 14% reduction in mortality in statin users without an excess of adverse side effects [26].

Experimental results from both animal disease models and in human patients with Alzheimer’s disease suggest that statins may protect brain cells by reducing the number of beta-amyloid plaques [19,20] and slowing the production of beta-amyloid [21]. Additionally, atorvastatin appears to decrease brain inflammation in genetically-engineered rats [22] while simvastatin may protect the connections between neurons (synapses) in mouse models of Alzheimer’s [23].

Statins, particularly simvastatin, might protect the brain independently of their effect on cholesterol production. A recent study in mice suggests simvastatin, which is more likely to enter the brain than some other statins, may increase production of chemicals called “neurotrophins” which are thought to promote brain cell growth and may protect them from damage [24]. It remains unclear if the same is happening in humans.

Some risks, based on strong evidence.

NOTE: This is not a comprehensive safety evaluation or complete list of potentially harmful drug interactions. It is important to discuss safety issues with your physician before taking any new supplement or medication.

Multiple clinical trials and nearly 20 years of patient use have proven statins to be generally safe, with some important caveats. Statin treatment carries the risk of both muscle damage and diabetes and even in rare occasions, cognitive impairment. Analyses by the physicians group behind the (Numbers Needed to Treat) website concludes that current data suggests as many as 2% of statin users with no history of heart disease have developed diabetes and as many as 10% have incurred muscle damage. The choice for healthy individuals to take statins to prevent heart disease must be based on population-based studies that may not accurately reflect their personal risk/benefit situation.

Statins carry additional risks if taken by someone with certain types of acute liver disease. Also, excessive amounts of grapefruit juice should be avoided if taking statins, as it can increase blood levels of the statin and affect its activity. Similar effects have been reported by people taking statins and the acid reflux medicine esomeprazole (Nexium™), so consult with your physician if any of these apply to you. This is not a complete list of drug interactions; visit the drug interaction checker and consult with a pharmacist or health care provider for more information on potential interactions between statins and other medications.

Doses: Statin dosing in clinical trials for cholesterol-lowering indications have ranged from, ~20 to 80 mg per day orally, but the appropriate dose for you must be determined by your health care provider.

Cognitive impairment: Rare reports of statins causing impaired cognition have appeared in the literature over the years. In a 2014 review, the Statin Cognitive Safety Taskforce (a working group of the American Lipid Association) acknowledged the possibility that statins may impair cognitive function in some people  but concluded the evidence was of insufficient quality to warrant changing physician guidelines [27]. If you or a loved one is taking a statin and experience cognitive problems it is important to discuss this with your physician.

Statins are prescribed to help maintain healthy cholesterol levels in some people with high cholesterol. Despite initial promising studies, the strongest available evidence does not support the idea that statin use will protect against dementia or cognitive decline

Statins can vary in cost, from $50 per month to $600 per month and are usually taken for an extended period of time, often many years or decades. However, some generic statins can cost as little as $4.00 per month through some discount chain stores. There are many different choices of statins that are available, but which one, if any, are right for you should be a decision made by you and your physician.

Statins are not for everyone and should only be taken as directed by your health care provider.

Rare reports of statins negatively impacting cognition have appeared in the literature over the years. See the Safety section above for more information.

Despite disappointing results from randomized clinical trials so far, statins, especially simvastatin, continue to be explored for prevention and treatment of both mild cognitive impairment (MCI) and Alzheimer’s disease. The Trial of Simvastatin in Amnestic Mild Cognitive Impairment Patients (SIMaMCI) (NCT00842920) should be reporting results in 2019. Also, two trials should be reporting results soon: the Evaluating Simvastatin’s Potential Role in Therapy trial (ESPRIT) (NCT00486044) and the Do HMG CoA Reductase Inhibitors Affect Abeta Levels trial (NCT00303277).

Large, randomized, well-controlled clinical trials of this nature are required to resolve the discrepancies between observational data (which largely suggest statins may be useful at preventing and treating dementia) and past clinical trials (which largely suggest they are not useful for dementia prevention or treatment). Sources of potential confounding are so great that observational studies alone may not be able to provide clear answers on whether statins can slow cognitive decline.

  • More information about statins and whether or not they are right for you can be found by reading this Mayo Clinic article.
  • For more information about the potential side effects of taking statins, read this WebMD article.

1. Jick, H., et al., Statins and the risk of dementia. Lancet, 2000. 356(9242): p. 1627-31.

2. Wolozin, B., et al., Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors. Arch Neurol, 2000. 57(10): p. 1439-43.

3. McGuinness, B., et al., Statins for the prevention of dementia. Cochrane Database Syst Rev, 2009(2): p. CD003160.

4. Swiger, K.J., et al., Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc, 2013. 88(11): p. 1213-21.

5. Wong, W.B., et al., Statins in the prevention of dementia and Alzheimer's disease: a meta-analysis of observational studies and an assessment of confounding. Pharmacoepidemiol Drug Saf, 2013. 22(4): p. 345-58.

6. Signorello, L.B., et al., Confounding by indication in epidemiologic studies of commonly used analgesics. Am J Ther, 2002. 9(3): p. 199-205.

7. Power, M.C., et al., Statins, cognition, and dementia-systematic review and methodological commentary. Nat Rev Neurol, 2015. 11(4): p. 220-9.

8. Heart Protection Study Collaborative, G., MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet, 2002. 360(9326): p. 7-22.

9. Shepherd, J., et al., Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet, 2002. 360(9346): p. 1623-30.

10. Dufouil, C., et al., APOE genotype, cholesterol level, lipid-lowering treatment, and dementia: the Three-City Study. Neurology, 2005. 64(9): p. 1531-8.

11. Li, G., et al., Age-varying association between statin use and incident Alzheimer's disease. J Am Geriatr Soc, 2010. 58(7): p. 1311-7.

12. Sparks, D.L., et al., Reduced risk of incident AD with elective statin use in a clinical trial cohort. Curr Alzheimer Res, 2008. 5(4): p. 416-21.

13. Li, G., et al., Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study. Neurology, 2004. 63(9): p. 1624-8.

14. Sparks, D.L., et al., Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch Neurol, 2005. 62(5): p. 753-7.

15. Masse, I., et al., Lipid lowering agents are associated with a slower cognitive decline in Alzheimer's disease. J Neurol Neurosurg Psychiatry, 2005. 76(12): p. 1624-9.

16. Winblad, B., et al., Effects of statins on cognitive function in patients with Alzheimer's disease in galantamine clinical trials. Drugs Aging, 2007. 24(1): p. 57-61.

17. McGuinness, B., et al., Statins for the treatment of dementia. Cochrane Database Syst Rev, 2010(8): p. CD007514.

18. Sano, M., et al., A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology, 2011. 77(6): p. 556-63.

19. Papadopoulos, P., X.K. Tong, and E. Hamel, Selective benefits of simvastatin in bitransgenic APPSwe,Ind/TGF-beta1 mice. Neurobiol Aging, 2014. 35(1): p. 203-12.

20. Petanceska, S.S., et al., Statin therapy for Alzheimer's disease: will it work? J Mol Neurosci, 2002. 19(1-2): p. 155-61.

21. Hoglund, K., et al., The effect of simvastatin treatment on the amyloid precursor protein and brain cholesterol metabolism in patients with Alzheimer's disease. Dement Geriatr Cogn Disord, 2005. 19(5-6): p. 256-65.

22. Zhang, Y.Y., et al., Atorvastatin attenuates the production of IL-1beta, IL-6, and TNF-alpha in the hippocampus of an amyloid beta1-42-induced rat model of Alzheimer's disease. Clin Interv Aging, 2013. 8: p. 103-10.

23. Metais, C., et al., Simvastatin treatment preserves synaptic plasticity in AbetaPPswe/PS1dE9 mice. J Alzheimers Dis, 2014. 39(2): p. 315-29.

24. Roy, A., et al., HMG-CoA Reductase Inhibitors Bind to PPARalpha to Upregulate Neurotrophin Expression in the Brain and Improve Memory in Mice. Cell Metab, 2015.

25. Spindler, S.R., et al., Statin treatment increases lifespan and improves cardiac health in Drosophila by decreasing specific protein prenylation. PLoS One, 2012. 7(6): p. e39581.

26. Taylor, F., et al., Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev, 2013. 1: p. CD004816.

27. Rojas-Fernandez, C.H., et al., An assessment by the Statin Cognitive Safety Task Force: 2014 update. J Clin Lipidol, 2014. 8(3 Suppl): p. S5-16.


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