Rhabdomyolysis a result of azithromycin and statins: an unrecognized interaction

AIMS

In a systematic screening of the World Health Organization Adverse Drug Reaction database, VigiBase, in July 2008, a measure of association used to detect interactions (Omega) highlighted azithromycin with the individual statins atorvastatin, lovastatin and simvastatin and rhabdomyolysis. The aim was to examine all reports including rhabdomyolysis-azithromycin and statins in VigiBase to assess if the data were suggestive of an interaction.

METHODS

The individual case reports in VigiBase and the original files were reviewed. In order to investigate the reporting over time for rhabdomyolysis with azithromycin and statins to VigiBase, Omega values were generated retrospectively.

RESULTS

The reporting over time showed that rhabdomyolysis under concomitant use of azithromycin and statins was reported more often than expected from 2000 and onwards in Vigibase. After exclusion of possible duplicates and follow-up reports, 53 cases from five countries remained. Rhabdomyolysis occurred shortly after initiation of azithromycin in 23% of cases. In 11 patients an interaction had been suggested by the reporter. With the exception of one patient, the statin doses reported were within the recommended daily doses.

CONCLUSIONS

Case reports in VigiBase are suggestive that interactions between azithromycin and statins resulting in rhabdomyolysis may occur. This analysis showed the potential of the newly developed disproportionality measure, Omega, which can help to identify drug interactions in VigiBase in the future. The results also showed that reviewing spontaneous reports can add information to drug interactions not established previously.     

Status of documentation grading and completeness score for Indian individual case safety reports

The quality of individual case safety reports (ICSRs) generated under Pharmacovigilance Programme of India (PvPI) plays a pivotal role in detecting a signal from Indian drug safety data. Currently, more than hundred thousand ICSRs were generated under PvPI and reported to Uppsala Monitoring Centre. The documentation grading and completeness score of Indian ICSRs were rapidly increasing, and the current score was 0.94 out of 1.0. Periodical training on emphasizing the quality ICSRs is need of the hour.KEY WORDS: Completeness score, individual case safety reports, Pharmacovigilance Programme of India, Uppsala Monitoring Centre     

Statin-associated peripheral neuropathy: review of the literature

Various pharmacologic agents are available for the treatment of hypercholesterolemia, including 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly referred to as statins, which offer favorable lipid-lowering effects and reductions in morbidity and mortality. Statins are usually better tolerated than other lipid-lowering agents and therefore have become a mainstay of treatment for hypercholesterolemia. However, recent case reports of peripheral neuropathy in patients treated with statins may have gone unnoticed by health care professionals. To evaluate the possible link between statins and peripheral neuropathy, literature searches using MEDLINE (January 1993--November 2003) and International Pharmaceutical Abstracts (January 1970--June 2002) were performed. Key search terms were statin, neuropathy, and HMG-CoA reductase inhibitors. Based on epidemiologic studies as well as case reports, a risk of peripheral neuropathy associated with statin use may exist; however, the risk appears to be minimal. On the other hand, the benefits of statins are firmly established. These findings should alert prescribers to a potential risk of peripheral neuropathy in patients receiving any of the statins; that is, statins should be considered the cause of peripheral neuropathy when other etiologies have been excluded.     

Psychiatric adverse reactions with statins, fibrates and ezetimibe: implications for the use of lipid-lowering agents.

The HMG-CoA reductase inhibitors ('statins') have come into widespread use internationally. There has been a long history of their use in New Zealand and this use has increased in recent years. There has also been an increase in the number of reports to the New Zealand Centre for Adverse Reactions Monitoring (CARM) of suspected psychiatric adverse reactions associated with statins. The reactions mentioned in these reports include depression, memory loss, confusion and aggressive reactions. Convincing reports to CARM of recurrence of these reactions upon rechallenge add weight to recent studies reporting serious psychiatric disturbances in association with statin treatment. Aggressive reactions associated with statins are poorly documented in the literature. These observations emphasise the need to be vigilant in looking for these reactions as they can have a significant personal impact on a patient. The observation that other lipid-lowering agents have similar adverse effects supports the hypothesis that decreased brain cell membrane cholesterol may be important in the aetiology of these psychiatric reactions.     

Alopecia associated with treatment with selective serotonin reuptake inhibitors (SSRIs)

PURPOSE: To study the association between alopecia and selective serotonin reuptake inhibitors (SSRIs) by estimating reporting rates and by making association comparisons within databases of adverse drug reactions (ADRs). METHODS: All reports of alopecia with marketed SSRIs until the end of 2004 were identified in SWEDIS, the national Swedish database for spontaneously reported ADRs, and in Vigibase, the international ADR database of the World Health Organization. Total SSRI sales volumes in Sweden until the end of 2004 were obtained from the National Corporation of Swedish Pharmacies. The Bayes' Confidence Propagation Neural Network (BCPNN) method was used to estimate associations between alopecia and each of the SSRIs within the two databases. RESULTS: A total of 27 reports of alopecia were identified in SWEDIS. As two reports concerned the use of two SSRIs, there was a total of 29 drug-ADR combinations. All except three reports concerned women (88.9%). The reporting rate of alopecia in Sweden was significantly higher with sertraline compared with citalopram; 20.1 (95%CI 10.7-34.4) reports per million patient-years versus 4.5 (95%CI 1.8-9.3) reports per million patient-years. No significant differences in reporting rates were noted for the remaining SSRIs. Sertraline also showed a statistically significant association with alopecia in both SWEDIS and Vigibase. Citalopram was significantly associated with alopecia in Vigibase, but not in SWEDIS. No statistically significant associations were found for any of the other SSRIs. CONCLUSIONS: Alopecia appears to be a rare ADR to SSRIs. The risk of alopecia seems to vary between the different SSRIs, and might be higher in women than in men.     

Statins and peripheral neuropathy

Within the past 3 years seven cases of reversible peripheral neuropathy apparently caused by statins have been reported. Here we report seven additional cases associated with long-term statin therapy, in which other causes of neuropathy were thoroughly excluded. The neuropathy was in all cases axonal and with affection of both thick and thin nerve fibers. The symptoms of neuropathy persisted during an observation period lasting from 10 weeks to 1 year in four cases after statin treatment had been withdrawn. We suggest that long-term statin treatment may be associated with chronic peripheral neuropathy. Received: 6 July 1998 / Accepted in revised form: 1 October 1998     

Statin Adverse Effects

HMG-CoA reductase inhibitors (statins) are a widely used class of drug, and like all medications, have potential for adverse effects (AEs). Here we review the statin AE literature, first focusing on muscle AEs as the most reported problem both in the literature and by patients. Evidence regarding the statin muscle AE mechanism, dose effect, drug interactions, and genetic predisposition is examined. We hypothesize, and provide evidence, that the demonstrated mitochondrial mechanisms for muscle AEs have implications to other nonmuscle AEs in patients treated with statins. In meta-analyses of randomized controlled trials (RCTs), muscle AEs are more frequent with statins than with placebo. A number of manifestations of muscle AEs have been reported, with rhabdomyolysis the most feared. AEs are dose dependent, and risk is amplified by drug interactions that functionally increase statin potency, often through inhibition of the cytochrome P450 3A4 system. An array of additional risk factors for statin AEs are those that amplify (or reflect) mitochondrial or metabolic vulnerability, such as metabolic syndrome factors, thyroid disease, and genetic mutations linked to mitochondrial dysfunction. Converging evidence supports a mitochondrial foundation for muscle AEs associated with statins, and both theoretical and empirical considerations suggest that mitochondrial dysfunction may also underlie many nonmuscle statin AEs. Evidence from RCTs and studies of other designs indicates existence of additional statin-associated AEs, such as cognitive loss, neuropathy, pancreatic and hepatic dysfunction, and sexual dysfunction. Physician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients. Awareness and vigilance for AEs should be maintained to enable informed treatment decisions, treatment modification if appropriate, improved quality of patient care, and reduced patient morbidity.     

Statins in acute coronary syndromes

The development of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) has been a very significant development in the management of coronary artery disease. Large prospective clinical trials have provided unequivocal evidence that cholesterol lowering therapy with statins reduces all-cause mortality in patients with coronary artery disease. There is now accumulating data indicating that statin treatment should be initiated early after an acute coronary syndrome. This body of evidence is based on large databases in which investigators compared outcomes among patients taking statins with those patients who were not prescribed cholesterol lowering therapy. Prospective, randomized, clinical trials also indicate that early statin therapy reduces recurrent ischemia. Finally, studies examining long-term compliance with statin therapy suggest increased adherence to therapy when statins are prescribed during the initial hospitalization for an acute coronary syndrome. In tandem with these clinical observations, there is a large body of scientific data that highlights many important cellular and molecular mechanisms through which statins may confer early benefit. These effects involve relatively rapid improvement in endothelial function, antiischemic, antithrombotic and antiinflammatory actions of statins.     

An investigation into the inter-relationships of sulphur xeno-biotransformation pathways in Parkinson's and motor neurone diseases

The role of defective 'sulphur xenobiotic' biotransformations in the aetiology of Parkinson's and motor neurone diseases has been in the literature for over a decade. Problems in the S-oxidation of aliphatic thioethers, sulphation of phenolic compounds and the S-methylation of aliphatic sulphydryl groups have all been reported. These reports have also been consistent in observing that only a 'significant minority' of patients express these problems in sulphur biotransformation pathways. However, no investigation has yet reported on the incidence of these three defective pathways in control invididuals and in patients with Parkinson's and motor neurone disease. This investigation has found that: 1. Forty percent of patients with Parkinson's and motor neurone disease have a defect in the S-oxidation of S-carboxymethyl-L-cysteine compared to 4% of controls. 2. 35-40% of patients with Parkinson's and motor neurone disease have a defect in the sulphation of paracetamol compared to 4% of controls. 3. 60% of patients with motor neurone disease have a high capacity for the S-methylation of 2-mercaptoethanol compared to 4% of controls. 4. 38% of patients with Parkinson's disease have a low capacity for the S-methylation of 2-mercaptoethanol compared to 4% of controls. 5. There is no correlation between the S-oxidation phenotype, low paracetamol sulphation phenotype and low or high S-methylation phenotype in controls or patients with Parkinson's or motor neurone disease. 6. The number of controls that expressed one of the aberrant phenotypes was 4% compared to 38% of the patients with Parkinson's disease and 47% of the patients with motor neurone disease. 7. The number of controls that expressed two of the aberrant phenotypes was 0% compared to 18% of the patients with Parkinson's disease and 19% of those with motor neurone disease. 8. No controls or patients with Parkinson's disease or motor neurone disease expressed all three of the aberrant phenotypes. The results indicate that the three xeno-biotransformation pathways are under separate genetic control in the three population groups studied and that patients with Parkinson's and motor neurone disease do not have a widespread defect in their sulphur xenobiochemistry capacity.     

Use of triage strategies in the WHO signal-detection process.

An important role for the WHO Programme for International Drug Monitoring is to identify signals of international drug safety problems as early as possible. Since 1998, Bayesian Confidence Propagation Neural Network (BCPNN) data mining has been in routine use for screening of the WHO adverse reaction database, Vigibase. The identification of drug/adverse drug reaction combinations that have disproportionately high reporting relative to the background of all reports constitutes the first, quantitative step in the Uppsala Monitoring Centre (UMC) signal-detection process. In order to improve the signal-to-noise ratio and to focus on possible signals that are less likely to be detected by individual national pharmacovigilance centres, an expert group considered a number of possible subsidiary selection algorithms to be added as a second filtering step before potential signals were sent to the UMC expert panel for clinical review. As a result of these deliberations, three selection algorithms were implemented for routine use in 2001: 'serious reaction and new drug', 'rapid reporting increase' and 'special interest terms'. The effect of applying these algorithms has been critically evaluated on the basis of the ratio of associations selected to signals found and some modifications decided. Bearing in mind that any filtering strategy is likely to exclude some potential true signals from consideration, we think that triage strategies based on a combination of pragmatic thinking and experience are effective, provided that the results are reviewed at regular intervals and the algorithms adjusted on the basis of performance.     

Physician response to patient reports of adverse drug effects: implications for patient-targeted adverse effect surveillance.

OBJECTIVE: Using a patient targeted survey, we sought to assess patient representations of how physicians responded when patients presented with possible adverse drug reactions (ADRs). As a demonstration case, we took one widely prescribed drug class, the HMG-CoA reductase inhibitors ('statins'). This information was used to assess whether a patient-targeted ADR surveillance approach may complement provider reporting, potentially fostering identification of additional patients with possible or probable ADRs. METHODS: A total of 650 adult patients taking statins with self-reported ADRs completed a survey. Depending on the problems reported, some patients completed additional surveys specific to the most commonly cited statin ADRs: muscle, cognitive or neuropathy related. Patients were asked to report drug, dose, ADR character, time course of onset with drug, recovery with discontinuation, recurrence with rechallenge, quality-of-life impact, and interactions with their physician in relation to the perceived ADR. This paper focuses on patients' representation of the doctor-patient interaction and physicians' attribution, when patients report perceived ADRs. RESULTS: Eighty-seven percent of patients reportedly spoke to their physician about the possible connection between statin use and their symptom. Patients reported that they and not the doctor most commonly initiated the discussion regarding the possible connection of drug to symptom (98% vs 2% cognition survey, 96% vs 4% neuropathy survey, 86% vs 14% muscle survey; p < 10(-8) for each). Physicians were reportedly more likely to deny than affirm the possibility of a connection. Rejection of a possible connection was reported to occur even for symptoms with strong literature support for a drug connection, and even in patients for whom the symptom met presumptive literature-based criteria for probable or definite drug-adverse effect causality. Assuming that physicians would not likely report ADRs in these instances, these patient-submitted ADR reports suggest that targeting patients may boost the yield of ADR reporting systems. CONCLUSIONS: Since low reporting rates are considered to contribute to delays in identification of ADRs, findings from this study suggest that additional putative cases may be identified by targeting patients as reporters, potentially speeding recognition of ADRs.     

Fluvastatin and hepatic reactions: a signal from spontaneous reporting in Italy.

BACKGROUND: Signal detection is a crucial element in recognising new adverse drug reactions (ADRs) as soon as possible. HMG-CoA reductase inhibitors ('statins'), the most potent cholesterol-lowering drugs, are generally well tolerated but can occasionally lead to liver toxicity. Pre- and postmarketing studies on statins revealed an incidence of 0.1-3% elevation in hepatic transaminase levels. However, these elevations are asymptomatic, reversible, dose related or probably due to other causes. Postmarketing studies clearly showed the lack of evidence of hepatotoxicity from statins, apart from some isolated case reports of serious hepatic damage described in the literature. It is still unclear whether serious hepatic reactions are dose related and more frequent than the expected rate in the general population. OBJECTIVE: In this study, the hypothesis that fluvastatin could cause serious liver injuries more than the other statins is investigated, in the light of a quantitative and qualitative signal analysis, drug consumption data and evidence from the literature. METHODS: The Italian Interregional Group of Pharmacovigilance (Gruppo Interregionale di Farmacovigilanza; GIF) is an example of signal detection within the Italian spontaneous ADR reporting system. The GIF database holds reports of suspected ADRs submitted by five Italian pharmacovigilance regional centres. In the GIF database, all reports of suspected ADRs are classified according to the WHO criteria for causality assessment. The reactions are coded according to the WHO Adverse Reaction Terminology and classified as serious or non-serious events on the basis of the WHO Critical Term List. Every 6 months the GIF database is analysed to extract potential signals through a qualitative case-by-case analysis and using a quantitative methodology called proportional reporting ratio (PRR). This methodology permitted us to identify the potential signal 'fluvastatin and hepatic reactions'. RESULTS: At 31 December 2004, the GIF database contained 35 757 reports with an annual reporting rate of 170 reports per million inhabitants. We found a total of 1260 reports of ADRs related to statins, including 178 of hepatic reactions. Sixty-nine reports were attributed to fluvastatin, which showed the highest PRR in comparison with the other statins. Fluvastatin was associated with 33 serious reactions, mainly hepatitis and cholestatic hepatitis. The number of reports of severe hepatotoxicity associated with fluvastatin started to increase from 2002. About half of them did not report other suspected or concomitant drugs and in one third the hepatotoxicity occurred after <1 month of therapy. Twenty-seven out of 33 patients were female, and fluvastatin was administered at 80 mg/day in 81% of cases reporting complete data on drug dosage. CONCLUSION: In the literature, serious hepatic reactions are rarely described in patients taking statins; however, data gathered by GIF suggest that cases of hepatotoxicity are reported more often than expected. In addition, GIF data seem to reveal that fluvastatin is more likely to cause hepatic reactions than the other statins. However, this is a preliminary signal and future evaluations are certainly needed to confirm it and to quantify this possible risk.     

Effects of statins on cognitive function in patients with Alzheimer's disease in galantamine clinical trials

BACKGROUND AND OBJECTIVE: A number of reports have been published on the possible involvement of changes in brain cholesterol metabolism in the origin of Alzheimer's disease (AD) and the potential for influencing these changes by administration of HMG-CoA reductase inhibitors ('statins'). The aim of this study was to evaluate a potential association between use of statins and maintenance of cognitive function in patients with AD in galantamine clinical trials. METHOD: A post hoc analysis was conducted on data pooled from three double-blind, placebo-controlled, clinical trials of galantamine in patients with AD. Patients were divided into four treatment groups: statin plus galantamine (n = 42), statin alone (n = 50), galantamine alone (n = 614) or neither galantamine nor statin (n = 619). RESULTS: Galantamine was associated with a significant beneficial effect on cognitive status (p < 0.001). The association of use of statins with changes in cognitive status was not significant (p = 0.083). There was no significant interaction between the effects on cognition of statins and galantamine (p = 0.183) and no statistically significant changes in adverse effect rates were observed. CONCLUSION: These findings suggest the need for larger long-term trials to confirm or refute possible effects of statins on cognitive function and the potential interaction of statins with acetylcholinesterase inhibitors in the treatment of AD.     

Statins and the risk of Parkinson disease: an update on the controversy

Background: Parkinson disease (PD) is the second most common neuro- degenerative disease and the number of affected patients is growing. Until now, information on either risk factors (genetic or environmental) or neuro- protective agents is still scarce. Recently, hydroxymethylglutary-coenzyme A reductase inhibitors have been related to protective as well as to potential harmful effects with regard to the development of a PD diagnosis. Objective: To give an overview and comment on the data available so far on this topic. Methods: Relevant literature was identified using a PubMed search of articles published up to October 2008. Search terms included: ‘Parkinson disease’, ‘statins’, and ‘epidemiology’. Original articles were reviewed and relevant citations from these articles were also considered. Results/conclusion: Results of the available observational studies were inconsistent with most studies reporting a protective effect of statins on the risk of PD. Others found no altered risk of PD in statin users compared to non-users or even an increased risk. Studies largely varied in size and analysis methods. Thus, comparison of the results is difficult. Until now, no definite conclusion on this topic can be made.     

Drug costs associated with non-adherence to cholesterol management guidelines for primary prevention of cardiovascular disease in an elderly population: the Rotterdam study

BACKGROUND: In The Netherlands, costs of HMG-CoA reductase inhibitor (statin) use have recently increased sharply compared with costs of other drugs. However, several studies have established both undertreatment and non-guidelines-indicated treatment with statins, suggesting a suboptimal use of resources. OBJECTIVE: To estimate the drug costs associated with non-guidelines-indicated treatment and undertreatment with statins in an elderly population. PATIENTS AND SETTING: Data were obtained from the Rotterdam Study, a population-based prospective cohort study which began in 1990 with 7983 participants aged > or =55 years. Subjects with a history of cardiovascular disease (CVD) were excluded. Pharmacy records were used to assess patterns of medication use in daily medical practice. MAIN OUTCOME MEASURE: Non-guidelines-indicated treatment and undertreatment with statins were established in relation to Dutch cholesterol management guidelines for all participants. We calculated the costs of statin therapy associated with non-guidelines-indicated treatment, and the costs of statins if all those undertreated were to receive statins. The results were projected on to the Dutch population to determine the economic implications of non-adherence to cholesterol management guidelines in the elderly. RESULTS: Of the participants who started treatment with statins for the primary prevention of CVD during follow-up, 69% received non-guidelines-indicated treatment. More men (7.5%) were undertreated than women (1.6%) and more women (6.2%) received non-guidelines-indicated treatment than men (1.5%). Among the participants without CVD who were still alive at 1 January 2002, 14% were eligible for statin therapy but were untreated. After projection of the prevalence of non-guidelines-indicated treatment and undertreatment to the Dutch population, the absolute costs for non-guidelines-indicated treatment with statins in 2005 were estimated to be approximately 23 million euro(uncertainty limits [UL]: 19-28 million euro), while the cost to eliminate undertreatment was also 23 million euro (UL: 19-28 million euro). CONCLUSION: Reallocation of resources used for statin therapy from those receiving non-guidelines-indicated treatment to those being undertreated could lead to a more efficient use of resources.     

老年慢性冠脉综合征患者入院前他汀类药物使用及LDL-C控制情况分析

目的：了解老年慢性冠脉综合征（chronic coronary syndrome，CCS）患者入院前他汀类药物使用及低密度脂蛋白胆固醇（low-density lipoprotein cholesterol，LDL-C）达标情况，分析影响达标的相关因素，为CCS血脂管理提供一定的参考。方法：选取2019年10月1日至2020年9月30日心血管内科收治的老年CCS患者345例，进行横断面、非干预性调查。结果：老年CCS患者入院前他汀类药物使用率66.4%（单用他汀94.8%，联合治疗5.2%），以中等强度他汀为主。LDL-C达标率39.1%，其中74.1%的患者入院前应用他汀类药物。多因素回归分析证实入院前应用他汀类药物促进LDL-C达标，整体及用药组均提示女性及病史5年以上降低LDL-C达标率。出院时他汀类药物处方上升至94.5%，联合治疗占10.7%。结论：老年CCS患者LDL-C达标率低，他汀类药物使用与指南推荐仍有差距；建议临床药师参与或加强对老年CCS患者血脂的综合规范化管理。     

Statin-associated gynecomastia: evidence coming from the Italian spontaneous ADR reporting database and literature

Purpose

The aim of this study was to add to the body of evidence on statin-induced gynecomastia based on data retrieved from the Italian spontaneous adverse drug reaction (ADR) reporting database.

Methods

Spontaneous ADR reports collected in the Italian database up to 31 December 2010 were assessed on a case-by-case basis in a search for evidence of a possible causal association between statins and gynecomastia. Cases of gynecomastia or possible gynecomastia, according to the Medical Dictionary of Regulatory Activities (MedDRA) classification, associated with statin use were retrieved from the database. The findings were compared with the available literature in PubMed.

Results

The database contained 90,448 ADR reports on 21 December 2010. At least one statin was listed as the suspected drug in 2,862 reports, of which 1,334 concerned a male patient. Among these reports, we identified eight cases with the preferred term “gynecomastia” with a statin as suspected drug: four reports of rosuvastatin and four of atorvastatin. One additional report of an unspecified “breast disorder” in a male patient attributed to fluvastatin was identified and included as a possible case. Four case-reports of statin-induced gynecomastia published between 2006 and 2010 were retrieved from PubMed.

Conclusions

Our findings suggest an association between gynecomastia and statins as a drug class, and the occurrence of this ADR would appear to be more likely with active substances that show an higher potency in inhibiting HMG-CoA reductase enzyme. To date, the safety information provided on the labels of different statin-containing medicines is not standardized. Harmonization of this information would be helpful for both healthcare practitioners and patients.     

Statin-associated memory loss: analysis of 60 case reports and review of the literature

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.