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.

Disclosures

Pharmacotherapy. 2003;23(7) 

In This Article

Results

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.

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.

We identified several randomized studies of statins in which objective neuropsychological testing or brain amyloid levels were examined as a primary or secondary outcome.[9,10,11,12,13,14] 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 A 40 or A 42.

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).

We identified five published observational studies[2,3,4,5,6] ( 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]

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