Re: Lipitor users experience Amnesia 38,461% more frequently than the normal population


"Sbharris[atsign]ix.netcom.com" <sbharris@xxxxxxxxxxxxx> wrote in message
news:1122399919.923742.13760@xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
>
>
> Bill wrote:
>> "Sharon Hope" <shope@xxxxxxxx> wrote in message
>> news:rsudnZbZct08m37fRVn-jg@xxxxxxxxxxxxxx
>> > http://www.medscape.com/viewarticle/458867_4
>> >
>>
>> The following is from tables in the study (which I hope transmit OK - if
>> not
>> you will need to look up the study.)
>>
>> Tables
>> Table 1. Published Prospective, Randomized, Controlled Studies of Effects
>> of
>> Statins or Diet on Cognition
>>
>>
>> Treatment No. of Patients Age Range
>> (yrs) Results
>> Simvastatin[9] 20,536 40-80 No statistically significant difference
>> in
>> cognition between statin and placebo groups.
>> Pravastatin[10] 2891 (pravastatin)
>> 2913 (placebo) 70-82 No statistically significant effects on MMSE,
>> word recall, or performance time.
>> Lovastatin[11] 98 (lovastatin)
>> 96 (placebo) 24-60 Placebo group improved from baseline on all
>> neuropsychological tests (p<0.04); lovastatin group improved from baseline
>> only on memory recall test (p=0.03).
>> Simvastatin, pravastatin[12]
>> (crossover study) 36 40-60 No statistically significant effects on
>> word recall test, profile of mood states, choice reaction time test, symbol
>> substitution, or drowsiness rating.
>> Simvastatin, pravastatin[13]
>> (crossover study) 25 20-31 No statistically significant effects on
>> EEG
>> potential, mood, sleep, or cognitive performance.
>> Simvastatin[14] 24 (simvastatin)
>> 20 (placebo) 59-77 No statistically significant effects on CSF
>> levels,
>> AB40, or AB42.
>> Low-fat diet, low-cholesterol diet[15] 52 (low-fat diet)
>> 53 (low-cholesterol diet)
>> 50 (control) 41-65 At 12 wks, results of the sustained attention
>> task
>> differed significantly (p<0.001) in groups with reduced cholesterol.
>>
>> MMSE = Mini-Mental State Examination; EEG = electroencephalogram;
>> CSF
>> = cerebrospinal fluid.
>>
>>
>>
>> Table 2. Observational Studies of Effects of Statins on Cognition
>>
>>
>> Design Statins Prescribed Treatment Group,
>> No. of Patients Age (yrs) Results
>> Epidemiologic, retrospective nested case-control study[2]
>> Atorvastatin, cerivastatin, fluvastatin, pravastatin, simvastatin Group 1:
>> Dementia, 284, Statins, 13
>>
>> Group 2: Controls, 1080, Statins, 104 >/= 50 Relative risk of
>> dementia
>> was reduced 0.29 in patients taking statins (95% CI 0.13-0.63, p=0.002).
>> Retrospective, multicenter, epidemiologic, cross-sectional
>> analysis[3]
>> Lovastatin, pravastatin, simvastatin Lovastatin, 4180
>> Pravastatin, 2326
>> Simvastatin, 3580 >/= 60 Prevalence of AD was 60-73% lower in
>> patients
>> receiving lovastatin or pravastatin than in the entire cohort (p<0.001).
>> Retrospective cohort case-control study[4] Not specified Statins,
>> 57
>> Controls, 2248 >/= 65 Statins were associated with a lower risk of
>> dementia in patients aged < 80 years (OR 0.26, 95% CI 0.08-0.88).
>> Multicenter secondary analysis[5] Simvastatin, atorvastatin,
>> pravastatin, lovastatin, fluvastatin Statins, 583
>> Controls, 454 < 80 Modified MMSE scores were higher in the statin
>> group (93.7) vs the control group (92.7) (p=0.02).
>> Retrospective study of postmenopausal women[6] Not specified
>> Statins,
>> 113
>> Controls, 542 52-98 Prevalence of dementia-AD was decreased
>> (p<0.05)
>> and MMSE scores were higher in the statin vs the control group (p=0.025).
>>
>> CI = confidence interval; AD = Alzheimer's disease; MMSE =
>> Mini-Mental
>> State Examination.
>>
>>
>>
>> Table 3. Comparison of Prescribing Information
>>
>>
>> Statin Recommended
>> Dosage
>> (mg/day) Frequency of
>> Cognitive-Related
>> Adverse Events
>> Atorvastatin[23] 10-80 < 2% (amnesia)
>> Pravastatin[21] 10-80 < 1% (memory impairment)
>> Simvastatin[22] 5-80 Not specified
>>
>>
>>
>> Table 4. Potential Mechanisms by Which Statins May Affect Brain Function
>>
>>
>> Effect Mechanism
>> Platelet activity platelet aggregation and deposition onto
>> damaged
>> vessel walls
>> Thrombin generation thrombus generation
>> generation of thrombin cleavage peptides
>> Nitric oxide formation cerebral blood flow
>> toxic production of nitric oxide
>> Antiinflammatory effects -amyloid peptides A42 and A40
>> formation of proinflammatory isoprenoids
>> expression of adhesion molecules
>> elaboration of potentially damaging cytokines from macrophages
>> during
>> cerebral ischemia
>> Antioxidant effects free radical injury and lipoprotein oxidation
>> Inhibition of cholesterol synthesis Can be good or bad. May
>> interfere
>> with neuronal function if statin is lipophilic; cholesterol essential for
>> membrane integrity.
>>
>>
>>
>> > http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=12885101&dopt=Abstract
>>
>> I think it is important to state what this says:
>>
>> "Statin-associated memory loss: analysis of 60 case reports and review of
>> the
>> literature.
>>
>> Wagstaff LR, Mitton MW, Arvik BM, Doraiswamy PM.
>>
>> Drug Information Service, Duke University Medical Center, Durham, North
>> Carolina 27710, USA.
>>
>> OBJECTIVE: To review case reports of statin-associated memory loss as well
>> as
>> the available published evidence for and against such a link. METHODS: We
>> searched the MedWatch drug surveillance system of the Food and Drug
>> Administration (FDA) from November 1997-February 2002 for reports of
>> statin-associated memory loss. We also reviewed the published literature
>> (using MEDLINE) and prescribing information for these drugs. RESULTS: Of
>> the
>> 60 patients identified who had memory loss associated with statins, 36
>> received simvastatin, 23 atorvastatin, and 1 pravastatin. About 50% of the
>> patients noted cognitive adverse effects within 2 months of therapy.
>> Fourteen
>> (56%) of 25 patients noted improvement when the statin was discontinued.
>> Memory loss recurred in four patients who were rechallenged with the drug.
>> None of the 60 reported cognitive test results. Two placebo-controlled
>> trials
>> found no benefits for statins on cognition or disability. One randomized
>> controlled trial of simvastatin found no effects on cerebrospinal amyloid
>> levels. In one small, randomized study, patients receiving statins showed a
>> trend toward lower cognitive performance than those receiving placebo. Five
>> observational studies found a lower risk of dementia among patients
>> receiving
>> statins. CONCLUSION: Current literature is conflicting with regard to the
>> effects of statins on memory loss. Experimental studies support links
>> between
>> cholesterol intake and amyloid synthesis; observational studies indicate
>> that
>> patients receiving statins have a reduced risk of dementia. However,
>> available
>> prospective studies show no cognitive or antiamyloid benefits for any
>> statin.
>> In addition, case reports raise the possibility that statins, in rare
>> cases,
>> may be associated with cognitive impairment, though causality is not
>> certain.
>>
>> Publication Types:
>> a.. Review
>> b.. Review, Multicase
>> c.. Review, Tutorial
>>
>> PMID: 12885101 [PubMed - indexed for MEDLINE] "
>>
>> Note the "rare" and "causality is not certain" in the final sentance. They
>> found 60 people after reviewing all the literature.
>>
>> Bill
>
>
>
> COMMENT:
>
> That's the best summary I've ever seen. Where's it from, again? I
> don't have the medscape account so I can't see the reference.
>
> In any case, it should spike the guns completely until Golomb comes out
> with her numbers. Current experience from other trials (summarized
> above) simply DOES NOT show that statins are big causers of mental side
> effects.
>
> SBH
>

Here is the whole thing. The tables do not transmit well. The Heart Protection
study, I think, was the most important of all the studies mentioned. It had
over 20,000 participants and lasted 5 years. No significant cognitive
difference in patients randomized to statins or placebos was found.

Bill


___________________________________________



Statin-Associated Memory Loss: Analysis of 60 Case Reports and Review of the
Literature


Leslie R. Wagstaff, Pharm.D., Melinda W. Mitton, Pharm.D., Beth McLendon
Arvik, Pharm.D., P. Murali Doraiswamy, M.D.
Pharmacotherapy 23(7):871-880, 2003. © 2003 Pharmacotherapy Publications

Posted 07/25/2003
Abstract and Introduction
Abstract
Objective: To review case reports of statin-associated memory loss as well as
the available published evidence for and against such a link.
Methods: We searched the MedWatch drug surveillance system of the Food and
Drug Administration (FDA) from November 1997-February 2002 for reports of
statin-associated memory loss. We also reviewed the published literature
(using MEDLINE) and prescribing information for these drugs.
Results: Of the 60 patients identified who had memory loss associated with
statins, 36 received simvastatin, 23 atorvastatin, and 1 pravastatin. About
50% of the patients noted cognitive adverse effects within 2 months of
therapy. Fourteen (56%) of 25 patients noted improvement when the statin was
discontinued. Memory loss recurred in four patients who were rechallenged with
the drug. None of the 60 reported cognitive test results. Two
placebo-controlled trials found no benefits for statins on cognition or
disability. One randomized controlled trial of simvastatin found no effects on
cerebrospinal amyloid levels. In one small, randomized study, patients
receiving statins showed a trend toward lower cognitive performance than those
receiving placebo. Five observational studies found a lower risk of dementia
among patients receiving statins.
Conclusion: Current literature is conflicting with regard to the effects of
statins on memory loss. Experimental studies support links between cholesterol
intake and amyloid synthesis; observational studies indicate that patients
receiving statins have a reduced risk of dementia. However, available
prospective studies show no cognitive or antiamyloid benefits for any statin.
In addition, case reports raise the possibility that statins, in rare cases,
may be associated with cognitive impairment, though causality is not certain.

Introduction
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also
known as statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and
simvastatin), are the most widely prescribed drug class for treatment of
dyslipidemias because of their convincingly proven benefits. With more
aggressive guidelines and an aging population, statins will be increasingly
prescribed, more statins will be developed, and the trend will be toward
earlier treatment and higher dosage.

The patient population receiving statins is already at risk for memory loss
because of cardiac risk factors, advancing age, and amyloidosis. However, in
contrast to the cardiovascular benefits, the effects of statins on cognition
and neuronal function are not as well studied. Since cerebrovascular disease
is known to cause memory loss, there is growing interest in examining whether
statins have cognitive benefits. Experimental studies have shown that
cholesterol-fed wild-type rabbits develop brain pathology similar to that of
Alzheimer's disease.[1] Transgenic mouse models of Alzheimer's disease
exhibited increased amyloid plaques when mice were fed a cholesterol diet.[1]
Cell culture and in vivo animal studies have shown that reducing cholesterol
can inhibit b-amyloid synthesis.[1]

Consistent with these preclinical findings, observational studies have found
that patients receiving statins have a lower risk of dementia.[2-6]
Paradoxically, published case reports[7, 8] and an increasing number of
anecdotal stories in the lay media have linked statin intake to adverse
effects of memory loss or amnesia. Because cholesterol synthesis is essential
for neurons to function normally, it is theoretically possible that excessive
inhibition of cholesterol synthetic pathways may occasionally result in
neurocognitive adverse effects. To gain further insight into links between
statins and memory loss, we systematically reviewed a sample of adverse events
reported to MedWatch, the drug surveillance system of the Food and Drug
Administration (FDA) as well as the current literature.


Methods
We searched the MedWatch data from November 1997-February 2002 for spontaneous
adverse events of cognitive impairment associated with simvastatin,
pravastatin, and atorvastatin. Simvastatin and pravastatin were selected based
on the large amount of data supporting these agents in primary and secondary
prevention of coronary events. Atorvastatin was chosen because of its large
market share and because it is being studied for its antidementia benefits.
Other statins, such as lovastatin, cerivastatin, and fluvastatin, were not
included in our MedWatch search due to research time constraints.

Our request was submitted according to the Freedom of Information Act, and we
were sent electronic files. The FDA as well as pharmaceutical companies have
dedicated proprietary software for analyzing and conducting searches of
adverse event reports. The dictionary used to code MedWatch adverse event
terms is also proprietary; neither the software nor the dictionary was
available to us.

Our initial searches were conducted on a personal computer using a word
search, and we later reviewed selected reports manually. Approximately 25,000
adverse events (~13,500 with atorvastatin, ~ 8500 with simvastatin, ~3000 with
pravastatin) were reported to MedWatch during this period. All three drug
files were searched, using the following as preferred terms: memory,
confusion, Alzheimer, think, cognition, attention, and mental. Using other
search terms (e.g., those used by the FDA) may have yielded additional cases;
however, we wished simply to identify a selection of representative cases
rather than all of them. We chose those in which the statin was considered the
primary suspect as the cause of mental status changes. About 2% of
statin-associated adverse events had a cognitive identifier (cognitive,
attentional, or amnestic disorder). The complete MedWatch reports were ordered
from the FDA and were then reviewed to eliminate duplicates as well as adverse
events that did not clearly involve memory loss or cognitive impairment. This
resulted in 60 cognitive adverse events associated with pravastatin,
simvastatin, and atorvastatin.

Documentation of statin type, reporter status, mean age, age range, sex, type
of memory loss, time to memory loss, statin dosage, and effects of drug
discontinuation and rechallenge were reviewed. Reporter status (person who
submitted the report) was classified according to the checked box on the
report form. As such, this was a descriptive study, and no statistical
analyses were performed. Because individual MedWatch reports vary in
completeness of demographics and clinical data provided, we have specified
where such data were missing. Because reporters' names are deleted from
MedWatch reports sent under the Freedom of Information Act, we could not
contact the reporters to verify or clarify any information.

Using MEDLINE, we reviewed the published literature from January
1980-September 2002. Search terms used were HMG-CoA reductase inhibitors and
statins, which were cross-referenced with each of the following terms: memory,
brain, amnesia, cognition, mental, dementia, and Alzheimer's disease. We also
used the prescribing information for atorvastatin, simvastatin, and
pravastatin (dated April, May, and October 2002, respectively) as part of our
review.


Results
Review of MedWatch Reports
Patient Data. For the 60 case reports of statin-associated memory loss
identified, the patients' mean age was 62 years (range 30-84 yrs). Age was not
documented for 14 patients. Four were in the 30-45-year age range, 22 in the
46-65-year age range, and 20 in the 66-85-year age range. Thirty-two patients
were women, 25 men; three reports did not document sex. Twenty-four (40%)
reports were submitted by health care professionals and 36 (60%) by patients
receiving statin therapy.

Nature of Memory Impairment. Seventeen patients had short-term memory loss,
six had amnesia, and 37 had unspecified memory loss. For the 30 patients with
documented time to onset of memory loss after the start of statin therapy,
median time was 60 days; approximately 50% of these patients experienced
memory impairment within the first 2 months of the start of statin therapy.
Two cases illustrate the nature of these reports.

Case No. 1. This case was reported by a 53-year-old woman who experienced
"serious brain fog and cognitive impairment" after a few days of atorvastatin
therapy. She couldn't function effectively enough to perform her daily work
tasks at her office. On her own accord, she stopped taking the drug after 5
days of therapy, and 3 days later her memory had returned to normal. She said
she had not been warned of the possibility of this adverse effect, and
apparently she had not consulted her health care provider about it. She also
reported being in "very good health except for high cholesterol and mild
osteoporosis." She took hormones and bisoprolol-hydrochlorothiazide.

Case No. 2. This report, submitted by a nurse practitioner, described a
49-year-old man who was treated with simvastatin 10 mg/day for
hypercholesterolemia; he received no concomitant drugs. About 40 days later,
he developed "memory loss, anger, aggression, and crankiness." These symptoms
lasted 3 weeks. Simvastatin was discontinued, and 2 weeks later the patient's
"personality" returned to normal. No further details were provided.

Type of Statin and Medical History. Our case reports involved simvastatin (36
patients), atorvastatin (23 patients), and pravastatin (1 patient). Mean daily
doses reported were simvastatin 18 mg and atorvastatin 25 mg; pravastatin dose
was not specified. The reports did not contain adequate information regarding
lipid levels at baseline or at the time of the memory complaint to examine as
a variable.

No specific memory test results were documented in any of the 60 reports. Four
reports documented tests such as computed tomography, magnetic resonance
imaging (MRI), intelligence quotient (IQ), and an unidentified cognitive test.
Test results were normal for three of the four patients; MRI results were
unknown for one patient.

Concomitant disorders commonly documented in MedWatch reports were
hypercholesterolemia (32 patients), hypertension (6), other cognitive
disorders (4), history of stroke (3), history of myocardial infarction or
other heart problems (3), osteoporosis (3), and head trauma (1). Concomitant
drugs commonly documented were over-the-counter (10 patients), thyroid
replacement (8), hormone replacement (7), -blockers (7),
angiotensin-converting enzyme inhibitors (4), calcium channel blockers (4),
anticoagulants (4), and steroids (4).

Statin Withdrawal and Rechallenge. Thirty-three reports documented withdrawal
of statin therapy after the appearance of memory loss (17 patients were taking
simvastatin, 16 atorvastatin). Statin therapy was continued in 11 patients;
statin withdrawal was not documented for 16. Of the 33 patients, memory loss
resolved or improved in 14 when the statin was withdrawn. Eleven reports
indicated no improvement in memory loss, and eight indicated unknown cognitive
function after statin withdrawal. Of the four reports (three patients taking
atorvastatin, one simvastatin) documenting the effects of rechallenge with the
statin, all four reported reappearance of memory loss symptoms.

Overall details were sparse in these reports. Memory loss resolved within 1
week of statin withdrawal for one of the three patients receiving
atorvastatin; memory loss occurred after 2 weeks of the start of statin
therapy in another. In the third patient, memory loss occurred 6 weeks after
the start of therapy and 6 weeks after rechallenge, with amnesia lasting 6-12
hours each time. For the patient receiving simvastatin, memory loss resolved
within 1 month after drug discontinuation. No other details were available.

Published Reports of Statin-Associated Memory Loss
We identified two published case reports of statin-associated memory loss by
searching MEDLINE. One report described a 51-year-old man who experienced
delayed-onset, progressive memory loss after approximately 12 months of
receiving simvastatin 40 mg at bedtime for hypercholesterolemia. His memory
continued to worsen over the next 3 months. The memory loss was attributed to
simvastatin, which was discontinued, and pravastatin 40 mg at bedtime was
initiated. The patient's short-term memory loss resolved after 1 month.[7]

The second report described a 67-year-old woman who had been treated with
atorvastatin 10 mg/day for hypercholesterolemia for the past year with no
reported adverse effects. Two months after the patient's atorvastatin dosage
was increased to 20 mg/day, she experienced short-term memory loss, mood
alterations, and social impairment. After discontinuation of atorvastatin, she
experienced a marked improvement in short-term memory.[8]

Neither patient in these two case reports was rechallenged with the suspected
drug. No cognitive tests were noted for the patient receiving simvastatin; the
report of the patient receiving atorvastatin described repeated tests of
mental status but provided no specific details.

Cognitive Outcomes in Randomized Trials of Statins
We identified several randomized studies of statins in which objective
neuropsychological testing or brain amyloid levels were examined as a primary
or secondary outcome.[9-14] One study also examined cognitive function and
cholesterol reduction by means of low-fat diets.[15] These trials are
described in Table 1.

The Heart Protection Study[9] involved 20,536 patients who were randomized to
simvastatin 40 mg/day or placebo and were followed for 5 years. Patients in
the study met the following criteria: aged 40-80 years, nonfasting serum total
cholesterol level of 135 mg/dl, and at a considerable risk of death in 5 years
from coronary heart disease based on medical history. Primary outcomes
measured were mortality and fatal or nonfatal vascular events. In addition,
the investigators used the validated modified Telephone Interview for
Cognitive Status questionnaire[16] during the final phase of the trial to
monitor cognitive decline. No significant differences were noted in cognition
between patients who received statin therapy and those who received placebo,
either overall or in subgroups defined with respect to age at study entry or
to previous stroke history.[9]

In the Prospective Study of Pravastatin in the Elderly at Risk of Vascular
Disease (PROSPER),[10] 5804 patients aged 70-82 years, with a history of or
risk factors for vascular disease, randomized to either pravastatin 40 mg/day
or placebo, were followed for an average of 3.2 years. Pravastatin lowered
low-density lipoprotein cholesterol (LDL) by 34% (hazard ratio [HR] 0.85, 95%
CI 0.74-0.97, p=0.014) and reduced coronary mortality by about 24% (HR 0.76,
95% CI 0.58-0.99, p=0.043). Stroke risk was unaffected although the hazard
ratio for transient ischemic attack was lower. Pravastatin had no significant
effects on disability or on cognition (measured by the Mini-Mental State
Examination [MMSE], word recall tests, or performance time).[10]

A double-blind, placebo-controlled trial[11] assessed cognitive function and
psychological well-being in 194 healthy adults. Subjects were aged 24-60 years
and had an LDL level of 160 mg/dl or higher. Each was randomly assigned to
receive lovastatin 20 mg/day or placebo for 6 months. Serum lipid levels were
measured throughout the study. At baseline and at completion of treatment,
comprehensive neuropsychological tests were conducted for attention (digit
vigilance, letter rotation, digit span, recurring words), psychomotor speed
(grooved pegboard, maze, digit symbol), mental flexibility (Stroop
interference, trail making, digit vigilance, letter rotation), working memory
(associative learning, digit span), and memory retrieval (controlled oral word
association, digit symbol recall, verbal recall, complex figure).

Psychological well-being was assessed by daily diaries and subject interviews.
At 6-month follow-up, the placebo group had improved significantly in all five
domains of cognitive function (p<0.04). The lovastatin group improved only on
memory recall tests (p=0.03). Improvement in the placebo group was significant
compared with the lovastatin group in tests of attention (p=0.03) and
psychomotor speed (p=0.004). Cognitive function decreased in subjects whose
mean LDL level was 109 ± 11 mg/dl (p=0.007).[11]

A crossover study[12] investigated the effects of simvastatin and pravastatin
on cognitive function in 36 patients (aged 40-60 years) who had
hypercholesterolemia. Patients were randomized to receive simvastatin 20
mg/day or pravastatin 40 mg/day in a double-blind, placebo-controlled fashion
for two 4-week periods separated by a 1-week washout period. Both simvastatin
and pravastatin produced a statistically significant reduction in total
cholesterol and LDL levels compared with placebo. Neither drug produced any
significant differences compared with placebo in central nervous function.

A randomized, double-blind, placebo-controlled crossover trial[13] measured
the effects of simvastatin and pravastatin on central nervous system activity
in 25 healthy subjects. Two 4-week periods were separated by a washout period
of 4-6 weeks. No significant differences in electroencephalographic evoked
potentials, mood, sleep, or cognitive performance (assessed by the digit
symbol substitution test) were observed with either drug compared with
placebo.[13]

A randomized, double-blind study[14] investigated whether statins would alter
cholesterol metabolites and reduce amyloid- levels in the cerebrospinal (CSF)
fluid of 44 patients with Alzheimer's disease. Overall, simvastatin did not
significantly alter CSF levels of either A40 or A42.

A randomized study of 155 healthy adults[15] examined low-fat diets as a way
to lower cholesterol and assess whether a low-cholesterol diet would adversely
affect mood and/or cognitive function. After 12 weeks, subjects consuming a
low-cholesterol diet had significantly lower total serum cholesterol levels
(p<0.001); all three groups (low-fat diet, low-cholesterol diet, and control)
showed some improvement on three of four psychological tests. Subjects
consuming a low-cholesterol diet had significantly worse (p<0.001) results
than the control group on a fourth psychological measure, which required the
greatest amount of processing. The change in performance on the
sustained-attention cognitive test was correlated with the change in total
serum cholesterol level (r=0.21, p=0.01).

Observational Studies of Statin Therapy and Risk of Dementia
We identified five published observational studies[2-6] (Table 2) examining
the effects of statin use on cognitive function or risk of dementia.

In a retrospective analysis of a research database from 368 general
practitioners in the United Kingdom, 284 patients with dementia were each
matched with up to four controls (1080 controls).[2] Patients who started
receiving lipid-lowering or statin therapy 180 days before the index date were
considered users. The risk of dementia for patients aged 50 years or older who
received statins (adjusted relative risk 0.29, 95% CI 0.13-0.63, p=0.002) was
significantly lower than for those with untreated hyperlipidemia or those
prescribed nonstatin lipid-lowering agents. This study did not distinguish
between the risk of Alzheimer's disease and the risk of other forms of
dementia. Also, it did not examine whether the effects were related to lipid
levels or verify the charts to confirm the accuracy of dementia diagnoses.

A retrospective, cross-sectional analysis of rates of diagnosis of probable
Alzheimer's disease, reviewed all medical records over a 2-year period from
three different hospitals.[3] Patients receiving statins were compared with
those receiving drugs to treat hypertension or cardiovascular disease. The
overall frequency of dementia diagnosis was 1.28%. The frequency of diagnosed
Alzheimer's disease in patients taking lovastatin or pravastatin was 60-73%
lower than in the total population or those taking other drugs (p<0.001).
Simvastatin was not associated with this effect. Two of the study authors have
submitted a patent application for administration of statins in treating
Alzheimer's disease.

A retrospective case-control study analyzed data from a subset of 2305
patients, aged 65 years or older, for whom health information, drug use, and
cognitive status were known.[4] Use of lipid-lowering agents was significantly
more common in younger (65-79 yrs) than older (>/= 80 yrs) patients (p<0.001).
Statins as well as other lipid-lowering agents reduced the risk of Alzheimer's
disease in patients younger than 80 years (odds ratio [OR] 0.26, 95% CI
0.08-0.88), but not in those aged 80 years or older.[4]

A multicenter observational study examined the cognitive correlates of use of
statins and changes in serum lipoprotein levels.[5] This was a secondary
analysis of data from 1037 post-menopausal women with coronary disease who
were enrolled in an estrogen-progestin replace-ment research study; 583 (56%)
were taking statins. Patients receiving statins had a minimally higher mean
modified MMSE score than those not receiving statins, (93.7 vs 92.7,
respectively, p=0.02). This translated into a 1% difference on this test.
Women in the highest quartile for LDL levels had lower mean MMSE scores by
about 2% (93.7 vs 91.9) and an increased likelihood of cognitive impairment
(OR 1.76, 95% CI 1.04-2.97).

A retrospective, case-control cohort study investigated the association
between statin use and prevalence of dementia.[6] The study involved a
convenience sample (655 patients, mean age 78.7 yrs) derived from the
population, based on easy availability and/or accessibility, in a general
practice. Cognitive tests such as the MMSE, clock-drawing test, and geriatric
depression scale were performed at baseline and follow-up. Among the patients
selected, 233 (36%) were positive for dementia. At the initial visit, 113
(17%) patients were receiving statin therapy; the other 542 patients served as
controls. At baseline, the mean MMSE score for the statin group was 26.5 vs
21.4 for the control group (p<0.0001). The number of dementia diagnoses at
baseline was also higher in the control group. Compared with baseline
cognitive test results, at follow-up the statin group showed improvement in
MMSE scores by 0.7 versus a 0.5-point decline in the control group
(p=0.025).[6]


Discussion
The cardiovascular benefits of statins are well established, and they reduce
the risk of death by 14-28% in specific populations.[17] However, the effects
of these agents on the human brain are not as well established. The more
lipid-soluble the statin, the greater propensity it has to cross the
blood-brain barrier and affect the central nervous system.[18] According to
some reports,[1, 8] simvastatin is the most lipophilic drug in its class;
pravastatin is the least lipophilic. Some reports state that atorvastatin does
not cross the blood-brain barrier, whereas others state that the drug has
intermediate lipophilicity.[1, 8] If the effects of statins on memory and
dementia are mediated directly at the neural level, then one would predict
that lipophilicity would be correlated with both the protective and the
adverse neural effects associated with statins.

As reported above, there is great interest in developing statins as a
treatment for dementia and as an agent for prevention of dementia in healthy
elderly individuals. Our study was initiated because of this interest, along
with reports in the lay press and consumer forums regarding statin-associated
memory loss. Because an initial literature search yielded few such published
cases, we searched MedWatch to study the clinical characteristics of reported
statin-associated memory loss. As such, this is the first scientific endeavor
to systematically analyze a relatively large series of cases (60) of
documented memory loss associated with statins. In our series, more than half
the reports were from consumers. The main symptom appeared to be short-term
memory loss that occurred a few months after the start of statin therapy or
after a dosage increase.

Global or partial amnesia was also reported. All but one of the reports
identified using our search criteria involved atorvastatin or simvastatin. In
some cases, memory loss resolved completely after discontinuation of the
statin; in others it did not. In four cases, rechallenge appeared to reproduce
memory loss. Most reports contained only subjective information. No
dose-effect relationship could be demonstrated because of insufficient data.
Similarly, no relationship between any laboratory parameters (e.g., lipid
levels) and memory could be demonstrated because of the lack of such data in
the reports. Confounding concomitant variables (e.g., transient ischemic
attacks or other drugs that may cause memory loss) were present in some but
not all reports. Information on medical history, or concomitant diseases or
drugs, was absent or incomplete in most reports. Because many of the reports
were from consumers, there is some reason to be cautious about the accuracy of
reported medical information. However, lay persons can accurately notice
short-term cognitive impairments caused by drugs such as alcohol or
benzodiazepines.

The information in the 60 reports of spontaneous adverse events we analyzed do
not permit conclusive judgments about causality. The high background rate of
memory loss in this population due to aging and vascular risk factors could
lead to detection bias. Likewise, the absence of objective memory tests or
lipid data made it difficult to confirm the memory change and establish a
dose-severity relationship or links with cholesterol levels. Cognitively
high-functioning individuals may often experience subtle memory loss that they
can accurately report but is often not detectable even with neuropsychological
testing.

A review of the randomized clinical trial data does not shed additional light
on this issue. Many large published cardiovascular trials of statins did not
use a formal neuropsychological test battery to assess for memory outcomes,
but used quality-of-life measures, which are not as sensitive or specific for
memory. There may be a number of other statin studies that collected such
memory data but are not published.

In one published placebo-controlled trial of lovastatin, the placebo appeared
to have greater consistent cognitive benefits than lovastatin on some measures
over a 6-month period.[11] It has been suggested that a very low cholesterol
level in neuronal membranes may decrease cognitive function, whereas others
have disagreed with this hypothesis.[19] More important, one large prospective
study (PROSPER) found no significant benefit for pravastatin regarding stroke
risk, cognition, or disability.[10] As cognitive measures, this study used a
global measure of cognition as well as measures of memory and speed of
per-formance. Although cognition was a secondary outcome, it can be reasonably
concluded from this study that pravastatin over a 3-year period does not
provide any cognitive benefits.[10]

A review of observational studies in the literature[2-6] yielded several large
case-control studies that suggest a substantial protective effect of statins
on lowering the risk of dementia. These studies used statistical adjustments
or case-control matching to account for potential biases (e.g., concomitant
illnesses or other baseline differences). The fact that these findings were
present in diverse population samples across five studies in the United States
and the United Kingdom is a strength. Because any protective effect against
dementia must be associated with a slower rate of memory loss, these data
argue against an adverse effect of statins on memory.

The observational studies[2-6] may have been limited by their retrospective
design, inaccurate diagnoses of dementia, and indication biases. These studies
did not distinguish type of statin, dosage, or duration of therapy. In the
absence of dosage or duration effects and retrospective data analyses, their
findings are at best preliminary. Patients with dementia, lower economic
status, or less education may be less likely to be prescribed statins than
those without dementia; hence, there could be a cohort bias as well.[20]

Our report does not estimate frequency or prevalence of statin-associated
memory loss since MedWatch case reports are likely to underestimate the true
rates of adverse events. Approximately 2% of all reports or statin-associated
adverse events in MedWatch appear to have a cognitive or amnestic identifier.
Likewise, the prescribing information for pravastatin lists memory loss as an
adverse event in less than 1% of patients,[21] whereas that for simvastatin
reports memory loss as a class effect.[22] The prescribing information for
atorvastatin lists amnesia as an adverse event in less than 2% of patients[23]
(Table 3). Hence, these are likely to be rare.

According to a written communication from the manufacturer of atorvastatin (O.
J. Lopena, Pharm.D., Pfizer Inc., written communication, 2002), amnesia during
clinical trials occurred in 7 (0.3%) of 2502 patients receiving atorvastatin
and in 2 (0.3%) of 742 subjects during comparative trials with other statins
(lovastatin, pravastatin, simvastatin). Abnormal thinking was reported in 4
(0.2%) of 2502 patients receiving atorvastatin therapy and in none of 742
patients receiving other statins (lovastatin, pravastatin, simvastatin).[24]
None of these data may provide a true estimate of the frequency or prevalence
since memory loss was not specifically studied in many of these trials.
Incidence studies of other adverse events (e.g., sexual dysfunction with
antidepressants) have shown that spontaneous reporting may underestimate
prevalence, in some cases by 5-20-fold.

Our review of MedWatch reports and the literature provided no definite
evidence that a particular statin is more likely than others to be associated
with cognitive adverse effects or benefits. Because of limited resources, we
examined only three statins. There appear to be fewer cases of memory loss
associated with pravastatin in the 60 case reports we selected, although this
may simply reflect our selection criteria or less frequent use of the drug.

There are many possible mechanisms by which statins may benefit or impair
cognition. Statins may increase endothelial nitric oxide synthase and reduce
endothelin-1, thereby increasing cerebral blood flow.[25] The antioxidant,
antiinflammatory, and platelet effects of statins may also play a role in
neuroprotection (Table 4).[25-27]

In vitro and in vivo experimental animal studies indicate that statins reduce
amyloidogenesis,[1, 26] although a human study found no effects of simvastatin
on amyloid.[14] Cholesterol is critically involved in cell membrane integrity
and function; thus, one could speculate that cognitive function may worsen if
excess inhibition of cholesterol synthesis reduces neuronal membrane levels.
Optimal harnessing of the cardiac and neural benefits of statins remains a
desirable goal.


Conclusion
The cardiovascular benefits of statins are established; we reviewed the
emerging links between statins and human memory. Research using MedWatch data
has many limitations, such as incomplete data, lack of controls, and various
biases, such as detection or attribution bias. Nevertheless, MedWatch reports
can provide a signal for infrequent adverse events. In particular, the reports
of statin-associated memory loss suggest that some patients may experience
subjective memory loss after statin therapy is begun. In some patients the
memory loss appeared to resolve after discontinuation of the statin. The
relationship between statin dosage, lipid levels, and memory loss could not be
determined in our series because of lack of information. More reports of
memory loss were associated with lipophilic statins (e.g., atorvastatin and
simvastatin), although it is not clear whether atorvastatin actually crosses
the blood-brain barrier. Until causality is assessed in more rigorous studies,
awareness of this issue may help clinicians better counsel patients and
improve monitoring of adverse events.

Neither observational studies nor case reports can prove causality. There is
no prospective evidence of any neurocognitive benefits or risks associated
with statins. Overall, statins clearly offer substantial cardiovascular
benefits, and a small number of case reports of memory loss should not
discourage appropriate statin administration. Because cholesterol synthesis is
essential for neuronal function, greater attention to cognitive outcomes in
patients receiving statins is warranted, especially in populations already at
risk for memory loss. Although the evidence does not yet support routine
administration of serial bedside memory tests in otherwise healthy patients
receiving statins, clinicians must be able to detect memory changes among
their patients and routinely inquire about mental status. Given the high
background rate of memory loss in the population receiving statins,
prospective controlled studies comparing the short- and long-term effects of
various statins on cognitive function are warranted.


Tables
Table 1. Published Prospective, Randomized, Controlled Studies of Effects of
Statins or Diet on Cognition


Treatment No. of Patients Age Range
(yrs) Results
Simvastatin[9] 20,536 40-80 No statistically significant difference in
cognition between statin and placebo groups.
Pravastatin[10] 2891 (pravastatin)
2913 (placebo) 70-82 No statistically significant effects on MMSE,
word recall, or performance time.
Lovastatin[11] 98 (lovastatin)
96 (placebo) 24-60 Placebo group improved from baseline on all
neuropsychological tests (p<0.04); lovastatin group improved from baseline
only on memory recall test (p=0.03).
Simvastatin, pravastatin[12]
(crossover study) 36 40-60 No statistically significant effects on
word recall test, profile of mood states, choice reaction time test, symbol
substitution, or drowsiness rating.
Simvastatin, pravastatin[13]
(crossover study) 25 20-31 No statistically significant effects on EEG
potential, mood, sleep, or cognitive performance.
Simvastatin[14] 24 (simvastatin)
20 (placebo) 59-77 No statistically significant effects on CSF levels,
AB40, or AB42.
Low-fat diet, low-cholesterol diet[15] 52 (low-fat diet)
53 (low-cholesterol diet)
50 (control) 41-65 At 12 wks, results of the sustained attention task
differed significantly (p<0.001) in groups with reduced cholesterol.

MMSE = Mini-Mental State Examination; EEG = electroencephalogram; CSF
= cerebrospinal fluid.



Table 2. Observational Studies of Effects of Statins on Cognition


Design Statins Prescribed Treatment Group,
No. of Patients Age (yrs) Results
Epidemiologic, retrospective nested case-control study[2]
Atorvastatin, cerivastatin, fluvastatin, pravastatin, simvastatin Group 1:
Dementia, 284, Statins, 13

Group 2: Controls, 1080, Statins, 104 >/= 50 Relative risk of dementia
was reduced 0.29 in patients taking statins (95% CI 0.13-0.63, p=0.002).
Retrospective, multicenter, epidemiologic, cross-sectional analysis[3]
Lovastatin, pravastatin, simvastatin Lovastatin, 4180
Pravastatin, 2326
Simvastatin, 3580 >/= 60 Prevalence of AD was 60-73% lower in patients
receiving lovastatin or pravastatin than in the entire cohort (p<0.001).
Retrospective cohort case-control study[4] Not specified Statins, 57
Controls, 2248 >/= 65 Statins were associated with a lower risk of
dementia in patients aged < 80 years (OR 0.26, 95% CI 0.08-0.88).
Multicenter secondary analysis[5] Simvastatin, atorvastatin,
pravastatin, lovastatin, fluvastatin Statins, 583
Controls, 454 < 80 Modified MMSE scores were higher in the statin
group (93.7) vs the control group (92.7) (p=0.02).
Retrospective study of postmenopausal women[6] Not specified Statins,
113
Controls, 542 52-98 Prevalence of dementia-AD was decreased (p<0.05)
and MMSE scores were higher in the statin vs the control group (p=0.025).

CI = confidence interval; AD = Alzheimer's disease; MMSE = Mini-Mental
State Examination.



Table 3. Comparison of Prescribing Information


Statin Recommended
Dosage
(mg/day) Frequency of
Cognitive-Related
Adverse Events
Atorvastatin[23] 10-80 < 2% (amnesia)
Pravastatin[21] 10-80 < 1% (memory impairment)
Simvastatin[22] 5-80 Not specified



Table 4. Potential Mechanisms by Which Statins May Affect Brain Function


Effect Mechanism
Platelet activity platelet aggregation and deposition onto damaged
vessel walls
Thrombin generation thrombus generation
generation of thrombin cleavage peptides
Nitric oxide formation cerebral blood flow
toxic production of nitric oxide
Antiinflammatory effects -amyloid peptides A42 and A40
formation of proinflammatory isoprenoids
expression of adhesion molecules
elaboration of potentially damaging cytokines from macrophages during
cerebral ischemia
Antioxidant effects free radical injury and lipoprotein oxidation
Inhibition of cholesterol synthesis Can be good or bad. May interfere
with neuronal function if statin is lipophilic; cholesterol essential for
membrane integrity.

Data from references 1, 25-27.



References
1.. Sparks DL, Connor DJ, Browne PJ, et al. HMG-CoA reductase inhibitors
(statins) in the treatment of Alzheimer's disease and why it would be
ill-advised to use one that crosses the blood-brain barrier. J Nutr Health
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risk of dementia. Lancet 2000;356:1627-31.
3.. Wolozin B, Kellman W, Rousseau P, Celesia GG, Siegel G. Decrease
prevalence of Alzheimer's disease associated with 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitors. Arch Neurol 2000;57:1439-43.
4.. Rockwood K, Kirkland S, Hogan D, at al. Use of lipid-lowering agents,
indication bias, and the risk of dementia in community-dwelling elderly
people. Arch Neurol 2002;59:223-7.
5.. Yaffe K, Barrett-Connor E, Lin F, Grady D. Serum lipoprotein levels,
statin use, and cognitive function in older women. Arch Neurol 2002;59:378-84.
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use of statins on the prevalence of dementia and the progression of cognitive
impairment. J Gerontol 2002;57:M414-18.
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Cognitive impairment associated with atorvastatin [abstr]. Pharmacotherapy
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9.. Heart Protection Study Collaborative Group. MRC/BHF heart protection
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10.. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly
individuals at risk of vascular disease (PROSPER): a randomised controlled
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11.. Muldoon MF, Barger SD, Ryan CM, et al. Effects of lovastatin on
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12.. Cutler N, Sramek J, Veroff A, Block G, Stauffer L, Lines C. Effects of
treatment with simvastatin and pravastatin on cognitive function in patients
with hypercholesterolemia. Br J Clin Pharmacol 1995;39:333-6.
13.. Harrison RWS, Ashton CH. Do cholesterol-lowering agents affect brain
activity? A comparison of simvastatin, pravastatin, and placebo in healthy
volunteers. Br J Clin Pharmacol 1994;37:231-6.
14.. Simons M, Schwärzler F, Lutjohann D, et al. Treatment with simvastatin
in normocholesterolemic patients with Alzheimer's disease: a 26-week
randomized, placebo-controlled, double-blind trial. Ann Neurol 2002;52:346-50.
15.. Wardle J, Rogers P, Judd P, et al. Randomized trial of the effects of
cholesterol-lowering dietary treatment on psychological function. Am J Med
2000;108:547-53.
16.. Prince MJ, Macdonald AM, Sham PC, et al. The development and initial
validation of a telephone-administered cognitive test battery (TACT). Int J
Methods Psych Res 1999;8:49-57.
17.. Larosa JC, He J, Vupputuri S. Effect of statins on risk of coronary
disease. JAMA 1999;282(24):2340-6.
18.. Serajuddin AT, Ranadive SA, Mahoney EM. Relative lipophilicities,
solubilities, and structure-pharmacological considerations of HMG-Co A
reductase inhibitors pravastatin, lovastatin, mevastatin, and simvastatin. J
Pharm Sci 1991;80:830-4.
19.. Wolozin B, Siegal G. Report on statins and dementia disputed [reply].
Arch Neurol 2001;58:1167.
20.. Birkenhäger WH, Wang JG, Staessen JA. Dementia and statins [letter].
Lancet 2001;357:880.
21.. Bristol-Myers Squibb Pharmaceutical. Pravachol (pravastatin) package
insert, Princeton, NJ; 2002.
22.. Merck & Co., Inc. Zocor (simvastatin) package insert, Whitehouse
Station, NJ; 2002.
23.. Pfizer, Inc. Lipitor (atorvastatin) package insert, New York, NY; 2002.
24.. Pfizer, Inc. Data on file. New York, NY; 2002.
25.. Cucchiara B, Kasner SE. Use of statins in CNS disorders. J Neurol Sci
2001;187:81-9.
26.. Fassbender K, Simons M, Bergmann C, et al. Simvastatin strongly reduces
levels of Alzheimer's disease b-amyloid peptides Ab42 and Ab40 in vitro and in
vivo. Proc Natl Acad Sci U S A 2001;98:5856-61.
27.. Crisby M, Carlson LA, Winblad B. Statins in the prevention and
treatment of Alzheimer's disease. Alzheimer Dis Assoc Disord 2002;16:131-6.
Reprint Address

Address reprint requests to P. Murali Doraiswamy, M.D., Duke University
Medical Center, Box 3018, Durham, NC 27710; e-mail: dorai001@xxxxxxxxxxxx




>From the Drug Information Service (Drs. Wagstaff, Mitton, and Arvik) and the
Departments of Psychiatry and Medicine (Dr. Doraiswamy), Duke University
Medical Center, Durham, North Carolina.


--------------------------------------------------------------------------------


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