Student Forum Statin Use and Cognitive Changes in Elderly Patients with Dementia Kaitlin A. Raley, Amber M. Hutchison HMG-CoA reductase inhibitors (“statins”) are commonly prescribed for the treatment of dyslipidemia and prevention of any complications arising from this disease. The Food and Drug Administration recently published enhanced warnings for statin use, including the possible relationship between statins and cognitive impairment, especially in the elderly. Significant cognitive decline associated with statin use in elderly patients with Alzheimer’s disease has also been reported recently. However, the 2013 American College of Cardiology/American Heart Association blood cholesterol guidelines stated that no evidence is available supporting the conclusion that statins cause an adverse effect on cognition or risk of dementia. Because of the increasing number of elderly patients with dementia, this relationship needs to be examined. This article will review cognitive changes associated with statin use in elderly patients with dementia and offer clinical recommendations. Key Words: Adverse reactions, Alzheimer’s dementia,
Cognitive effects, Dementia, Dyslipidemia, Elderly, Mild cognitive impairment, Statins. abbreviations: AD = Alzheimer’s disease, CDR-SOB = Clinical Dementia Rating Sum of Boxes, CV = Cardiovascular, FDA = Food and Drug Administration, MCI = Mild cognitive impairment, MMSE = Mini-Mental State Examination. Consult Pharm 2014;29:487-9.
Background HMG CoA-reductase inhibitors, also known as statins, are commonly used in cardiovascular (CV) disease, and have become the most commonly prescribed medication for dyslipidemia.1-3 Statins can help to reduce CV events by 25% to 45%.1 Beneficial effects of statins have been proved, but now adverse cognitive effects, which are not well understood, may be associated with this class of drugs.4 It is important to evaluate a link between these cognitive changes and patients with dementia since older adults may be at an increased risk for cognitive adverse effects as a result of abnormalities in signal-transduction and cholesterol metabolism in the brain.5 In light of new warnings from the Food and Drug Administration (FDA) and the benefits associated with statins, the question becomes, what role do statins play in patients with dementia?
Discussion There have been mixed research results about whether the cognitive problems associated with statins are significant. Some studies suggest it is and can have detrimental consequences in the elderly population, while other studies show improvement in cognitive function.3 Because of the varied results of studies and public communications, more trials of statins in patients with cognitive decline or dementia need to be done.6 To be able to evaluate the literature, it is important to review the relationship between cholesterol, statins, cognition, and the central nervous system. The Hisayama Study aimed at discovering a possible link between cholesterol levels and Alzheimer’s disease (AD) and cognition problems.7 This study showed a correlation between lipid levels and neuritic plaques in the brain.7 Neuritic plaques, which are made up of amyloid β protein, are usually a pathological alteration seen in patients with AD.8 Approximately 25% of the cholesterol found in the body is contained in the brain. The majority is found in myelin, so if statins decrease the amount of cholesterol to critically low levels, then myelin production can be diminished. This can lead to demyelination, which can be related to memory loss observed in case reports.3 Many of these case reports led to FDA’s current statement on statins.4
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Student Forum In 2012, FDA issued a safety announcement regarding statins and negative cognitive effects.4 There have been infrequent reports of postmarketing cognitive effects in patients taking statins, including memory loss, confusion, memory impairment, amnesia, and other consequences.4 These adverse reactions were usually not serious and were reversible. FDA did state that symptom resolution usually occurred at a median time frame of three weeks, and cognitive changes associated with statins are not necessarily common or clinically significant.4 However, the report does state that the protective benefits outweigh the potential cognitive adverse reactions associated with statins.4 Another consideration is lipophilic versus hydrophilic statins: Is one superior?5 Theoretically, a hydrophilic statin would be a better choice in patients with neurologic dysfunction. Lipophilic statins cross the blood-brain barrier more easily than a hydrophilic statin and cause dangerously low levels of essential cholesterol in the brain. A review of 66 case reports related to this topic indicated that simvastatin (39) and atorvastatin (25) were the most prominently associated with cognitive adverse reactions.2,3 Most cases assessed were reported in patients taking lipophilic statins.3 There was only one case each associated with pravastatin and rosuvastatin.2,3 Based on the evidence, hydrophilic statins such as pravastatin and rosuvastatin seem to be the better choice of statins in patients at risk for cognitive complications. A longitudinal study evaluated the effect of statins on elderly patients with both normal cognition and mild cognitive impairment (MCI).6 The average follow-up was three years, and patients received repeated assessments of cognitive ability. These assessments included the Clinical Dementia Rating Sum of Boxes (CDR-SOB), Mini-Mental State Examination (MMSE), Boston Naming Test, Trials A and B, and Wechsler Adult Intelligence Scale Digit Symbol. This study found a modest benefit of statins in the group with normal cognition in regards to Trials A and B, MMSE, and CDR-SOB compared with patients not on statins. The researchers did not see this benefit in the group of patients with MCI.6 This study reiterates that patients with normal cognition show mild positive effects from statins, but this is not apparent in the patients with
488
MCI.6 Another question to consider: Do these results for patients with MCI correlate to patients with dementia or AD? One trial specifically examined statins in a patient population with AD or vascular dementia.5 The trial studied patients older than 60 years of age with AD or mixed dementia with a MMSE score of 10 or greater prior to starting the study and who were on a consistent dose of a statin. The majority of patients in the trial were either on atorvastatin or simvastatin, but some patients were on fluvastatin, pravastatin, rosuvastatin, or lovastatin.5 The study was a withdrawal and rechallenge pilot study that found both a statistically significant decrease in MMSE score with statin therapy and improvement in scores when the medication was discontinued. There was also a trend toward improvement in activities of daily living and instrumental activities of daily living scale scores (P = 0.07 and 0.06, respectively) during the statin withdrawal period; there was no trend toward change when the drug was reinitiated.5 This study suggested a more pronounced cognitive decline in elderly patients with preexisting dementia than elderly patients in general.5 Further studies need to be done to assess patients with dementia based on stage of dementia, lipophilicity of statins used, baseline characteristics, and disease markers.5
Conclusion The bottom line: Are statins safe to use in elderly patients with dementia or AD? Currently, there is no definitive evidence to recommend any changes for statin use in dyslipidemia. The 2013 American College of Cardiology/ American Heart Association blood cholesterol guidelines do not suggest any changes regarding statin use because of adverse cognitive reactions.9 It is important to take into account that these guidelines only evaluated one study assessing patients with cognitive decline as a secondary outcome.9 Based on published data, the patient population with dementia and increased CV risk because of dyslipidemia would benefit greatest from hydrophilic statins. Patients at most risk for cognitive adverse effects seem to be elderly patients diagnosed with dementia or other cognitive issues. It is important to remember these effects
The Consultant Pharmacist JULY 2014 Vol. 29, No. 7
Statin Use and Cognitive Changes in Elderly Patients with Dementia
seem to be reversible; therefore, dose reduction, changing to a more hydrophilic statin, or discontinuation of statins are possibilities for management. Based on available data, patients with dementia may benefit from the protective CV effects of statins, but this could be at the cost of worsening cognitive decline. Practitioners must always weigh risks versus benefit for their patients. Patients should be informed of the risks of untreated dyslipidemia and counseled on possible adverse reactions of statin therapy. In conclusion, patients with dementia can use statins, if indicated. They should not be used for risk-reduction of dementia in patients with MCI. If patients with cognitive problems experience worsening cognition while on statin therapy, then either reducing the dose, changing to another lipid-lowering therapy, or discontinuing the statin may be recommended.
Kaitlin A. Raley is a 2014 PharmD candidate, Auburn University Harrison School of Pharmacy, Auburn University, Alabama. Amber M. Hutchison, PharmD, BCPS, is an assistant clinical professor, Auburn University Harrison School of Pharmacy, Auburn University. For correspondence: Amber M. Hutchison, PharmD, BCPS, Auburn University Harrison School of Pharmacy, 1321 Walker Building (4201F), Auburn University, AL 36849; Phone: 334-844-8401; Fax: 334-844-4410; E-mail: [email protected].
References 1. Jukema JW, Cannon C, de Craen A et al. The controversies of statin therapy. J Am Coll Cardiol 2012;60:875-81. 2. Rojas-Fernandez C, Cameron JC. Is statin-associated cognitive impairment clinically relevant? A narrative review and clinical recommendations. Ann Pharmacother 2012;46:549-57. 3. Wagstaff LR, Mitton MW, McLendon B et al. Statin-associated memory loss: analysis of 60 case reports and review of the literature. Pharmacotherapy 2003;23:871-80. 4. FDA drug safety communication: Important safety label changes to cholesterol-lowering statin drugs. U.S. Food and Drug Administration. 2012. Available at http://www.fda.gov/Drugs/DrugSafety/ucm293101. htm. Accessed July 17, 2013. 5. Padala KP, Padala PR, McNeilly DP et al. The effect of HMG-CoA reductase inhibitors on cognition in patients with Alzheimer’s dementia: a prospective withdrawal and rechallenge pilot study. Am J Geriatr Pharmacother 2012;10:296-302. 6. Steenland K, Zhao L, Goldstein FC et al. Statins and cognitive decline in older adults with normal cognition or mild cognitive impairment. J Am Geriatr Soc 2013;61:1449-55. 7. Matsuzaki T, Sasaki K, Hata J et al. Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study. Neurology 2011;77:1068-75. 8. Ly P, Cai F, Song W. Detection of neuritic plaques in Alzheimer’s disease mouse model. J Vis Exp 2011;53:e2831. 9. Stone NJ, Robinson J, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. J Am Coll Cardiol 2013;S07351097(13)06028-2 [epub ahead of print]. Available at http://content. onlinejacc.org/article.aspx?articleid=1770217. Accessed December 3, 2013.
Disclosure: No funding was received for the development of this manuscript. The authors have no potential conflicts of interest. © 2014 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2014.487.
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Cognitive effects, Dementia, Dyslipidemia, Elderly, Mild cognitive impairment, Statins. abbreviations: AD = Alzheimer’s disease, CDR-SOB = Clinical Dementia Rating Sum of Boxes, CV = Cardiovascular, FDA = Food and Drug Administration, MCI = Mild cognitive impairment, MMSE = Mini-Mental State Examination. Consult Pharm 2014;29:487-9.
Background HMG CoA-reductase inhibitors, also known as statins, are commonly used in cardiovascular (CV) disease, and have become the most commonly prescribed medication for dyslipidemia.1-3 Statins can help to reduce CV events by 25% to 45%.1 Beneficial effects of statins have been proved, but now adverse cognitive effects, which are not well understood, may be associated with this class of drugs.4 It is important to evaluate a link between these cognitive changes and patients with dementia since older adults may be at an increased risk for cognitive adverse effects as a result of abnormalities in signal-transduction and cholesterol metabolism in the brain.5 In light of new warnings from the Food and Drug Administration (FDA) and the benefits associated with statins, the question becomes, what role do statins play in patients with dementia?
Discussion There have been mixed research results about whether the cognitive problems associated with statins are significant. Some studies suggest it is and can have detrimental consequences in the elderly population, while other studies show improvement in cognitive function.3 Because of the varied results of studies and public communications, more trials of statins in patients with cognitive decline or dementia need to be done.6 To be able to evaluate the literature, it is important to review the relationship between cholesterol, statins, cognition, and the central nervous system. The Hisayama Study aimed at discovering a possible link between cholesterol levels and Alzheimer’s disease (AD) and cognition problems.7 This study showed a correlation between lipid levels and neuritic plaques in the brain.7 Neuritic plaques, which are made up of amyloid β protein, are usually a pathological alteration seen in patients with AD.8 Approximately 25% of the cholesterol found in the body is contained in the brain. The majority is found in myelin, so if statins decrease the amount of cholesterol to critically low levels, then myelin production can be diminished. This can lead to demyelination, which can be related to memory loss observed in case reports.3 Many of these case reports led to FDA’s current statement on statins.4
The Consultant Pharmacist JULY 2014 Vol. 29, No. 7
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Student Forum In 2012, FDA issued a safety announcement regarding statins and negative cognitive effects.4 There have been infrequent reports of postmarketing cognitive effects in patients taking statins, including memory loss, confusion, memory impairment, amnesia, and other consequences.4 These adverse reactions were usually not serious and were reversible. FDA did state that symptom resolution usually occurred at a median time frame of three weeks, and cognitive changes associated with statins are not necessarily common or clinically significant.4 However, the report does state that the protective benefits outweigh the potential cognitive adverse reactions associated with statins.4 Another consideration is lipophilic versus hydrophilic statins: Is one superior?5 Theoretically, a hydrophilic statin would be a better choice in patients with neurologic dysfunction. Lipophilic statins cross the blood-brain barrier more easily than a hydrophilic statin and cause dangerously low levels of essential cholesterol in the brain. A review of 66 case reports related to this topic indicated that simvastatin (39) and atorvastatin (25) were the most prominently associated with cognitive adverse reactions.2,3 Most cases assessed were reported in patients taking lipophilic statins.3 There was only one case each associated with pravastatin and rosuvastatin.2,3 Based on the evidence, hydrophilic statins such as pravastatin and rosuvastatin seem to be the better choice of statins in patients at risk for cognitive complications. A longitudinal study evaluated the effect of statins on elderly patients with both normal cognition and mild cognitive impairment (MCI).6 The average follow-up was three years, and patients received repeated assessments of cognitive ability. These assessments included the Clinical Dementia Rating Sum of Boxes (CDR-SOB), Mini-Mental State Examination (MMSE), Boston Naming Test, Trials A and B, and Wechsler Adult Intelligence Scale Digit Symbol. This study found a modest benefit of statins in the group with normal cognition in regards to Trials A and B, MMSE, and CDR-SOB compared with patients not on statins. The researchers did not see this benefit in the group of patients with MCI.6 This study reiterates that patients with normal cognition show mild positive effects from statins, but this is not apparent in the patients with
488
MCI.6 Another question to consider: Do these results for patients with MCI correlate to patients with dementia or AD? One trial specifically examined statins in a patient population with AD or vascular dementia.5 The trial studied patients older than 60 years of age with AD or mixed dementia with a MMSE score of 10 or greater prior to starting the study and who were on a consistent dose of a statin. The majority of patients in the trial were either on atorvastatin or simvastatin, but some patients were on fluvastatin, pravastatin, rosuvastatin, or lovastatin.5 The study was a withdrawal and rechallenge pilot study that found both a statistically significant decrease in MMSE score with statin therapy and improvement in scores when the medication was discontinued. There was also a trend toward improvement in activities of daily living and instrumental activities of daily living scale scores (P = 0.07 and 0.06, respectively) during the statin withdrawal period; there was no trend toward change when the drug was reinitiated.5 This study suggested a more pronounced cognitive decline in elderly patients with preexisting dementia than elderly patients in general.5 Further studies need to be done to assess patients with dementia based on stage of dementia, lipophilicity of statins used, baseline characteristics, and disease markers.5
Conclusion The bottom line: Are statins safe to use in elderly patients with dementia or AD? Currently, there is no definitive evidence to recommend any changes for statin use in dyslipidemia. The 2013 American College of Cardiology/ American Heart Association blood cholesterol guidelines do not suggest any changes regarding statin use because of adverse cognitive reactions.9 It is important to take into account that these guidelines only evaluated one study assessing patients with cognitive decline as a secondary outcome.9 Based on published data, the patient population with dementia and increased CV risk because of dyslipidemia would benefit greatest from hydrophilic statins. Patients at most risk for cognitive adverse effects seem to be elderly patients diagnosed with dementia or other cognitive issues. It is important to remember these effects
The Consultant Pharmacist JULY 2014 Vol. 29, No. 7
Statin Use and Cognitive Changes in Elderly Patients with Dementia
seem to be reversible; therefore, dose reduction, changing to a more hydrophilic statin, or discontinuation of statins are possibilities for management. Based on available data, patients with dementia may benefit from the protective CV effects of statins, but this could be at the cost of worsening cognitive decline. Practitioners must always weigh risks versus benefit for their patients. Patients should be informed of the risks of untreated dyslipidemia and counseled on possible adverse reactions of statin therapy. In conclusion, patients with dementia can use statins, if indicated. They should not be used for risk-reduction of dementia in patients with MCI. If patients with cognitive problems experience worsening cognition while on statin therapy, then either reducing the dose, changing to another lipid-lowering therapy, or discontinuing the statin may be recommended.
Kaitlin A. Raley is a 2014 PharmD candidate, Auburn University Harrison School of Pharmacy, Auburn University, Alabama. Amber M. Hutchison, PharmD, BCPS, is an assistant clinical professor, Auburn University Harrison School of Pharmacy, Auburn University. For correspondence: Amber M. Hutchison, PharmD, BCPS, Auburn University Harrison School of Pharmacy, 1321 Walker Building (4201F), Auburn University, AL 36849; Phone: 334-844-8401; Fax: 334-844-4410; E-mail: [email protected].
References 1. Jukema JW, Cannon C, de Craen A et al. The controversies of statin therapy. J Am Coll Cardiol 2012;60:875-81. 2. Rojas-Fernandez C, Cameron JC. Is statin-associated cognitive impairment clinically relevant? A narrative review and clinical recommendations. Ann Pharmacother 2012;46:549-57. 3. Wagstaff LR, Mitton MW, McLendon B et al. Statin-associated memory loss: analysis of 60 case reports and review of the literature. Pharmacotherapy 2003;23:871-80. 4. FDA drug safety communication: Important safety label changes to cholesterol-lowering statin drugs. U.S. Food and Drug Administration. 2012. Available at http://www.fda.gov/Drugs/DrugSafety/ucm293101. htm. Accessed July 17, 2013. 5. Padala KP, Padala PR, McNeilly DP et al. The effect of HMG-CoA reductase inhibitors on cognition in patients with Alzheimer’s dementia: a prospective withdrawal and rechallenge pilot study. Am J Geriatr Pharmacother 2012;10:296-302. 6. Steenland K, Zhao L, Goldstein FC et al. Statins and cognitive decline in older adults with normal cognition or mild cognitive impairment. J Am Geriatr Soc 2013;61:1449-55. 7. Matsuzaki T, Sasaki K, Hata J et al. Association of Alzheimer disease pathology with abnormal lipid metabolism: the Hisayama Study. Neurology 2011;77:1068-75. 8. Ly P, Cai F, Song W. Detection of neuritic plaques in Alzheimer’s disease mouse model. J Vis Exp 2011;53:e2831. 9. Stone NJ, Robinson J, Lichtenstein AH et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. J Am Coll Cardiol 2013;S07351097(13)06028-2 [epub ahead of print]. Available at http://content. onlinejacc.org/article.aspx?articleid=1770217. Accessed December 3, 2013.
Disclosure: No funding was received for the development of this manuscript. The authors have no potential conflicts of interest. © 2014 American Society of Consultant Pharmacists, Inc. All rights reserved. Doi:10.4140/TCP.n.2014.487.
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