Dementia

Observational Statin Study finds significant reductions for risk of Alzheimer Disease

Abstract
Importance  
To our knowledge, no effective treatments exist for Alzheimer disease, and new molecules are years away. However, several drugs prescribed for other conditions have been associated with reducing its risk.
Objective
To analyze the association between statin exposure and Alzheimer disease incidence among Medicare beneficiaries.
Design, Setting, and Participants  
We examined the medical and pharmacy claims of a 20% sample of Medicare beneficiaries from 2006 to 2013 and compared rates of Alzheimer disease diagnosis for 399 979 statin users 65 years of age or older with high or low exposure to statins and with drug molecules for black, Hispanic, and non-Hispanic white people, and men and women of Asian, Native American, or unkown race/ethnicity who are referred to as “other.”
Main Outcomes and Measures  
The main outcome was incident diagnosis of Alzheimer disease based on the International Classification of Diseases, Ninth Revision, Clinical Modification. We used Cox proportional hazard models to analyze the association between statin exposure and Alzheimer disease diagnosis for different sexes, races and ethnicities, and statin molecules.
Results  
The 399 979 study participants included 7794 (1.95%) black men, 24 484 (6.12%) black women, 11 200 (2.80%) Hispanic men, 21 458 (5.36%) Hispanic women, 115 059 (28.77%) white men, and 195 181 (48.80%) white women. High exposure to statins was associated with a lower risk of Alzheimer disease diagnosis for women (hazard ratio [HR], 0.85; 95% CI, 0.82-0.89; P<.001) and men (HR, 0.88; 95% CI, 0.83-0.93; P<.001). Simvastatin was associated with lower Alzheimer disease risk for white women (HR, 0.86; 95% CI, 0.81-0.92; P<.001), white men (HR, 0.90; 95% CI, 0.82-0.99; P=.02), Hispanic women (HR, 0.82; 95% CI, 0.68-0.99; P=.04), Hispanic men (HR, 0.67; 95% CI, 0.50-0.91; P=.01), and black women (HR, 0.78; 95% CI, 0.66-0.93; P=.005). Atorvastatin was associated with a reduced risk of incident Alzheimer disease diagnosis for white women (HR, 0.84, 95% CI, 0.78-0.89), black women (HR, 0.81, 95% CI, 0.67-0.98), and Hispanic men (HR, 0.61, 95% CI, 0.42-0.89) and women (HR, 0.76, 95% CI, 0.60-0.97). Pravastatin and rosuvastatin were associated with reduced Alzheimer disease risk for white women only (HR, 0.82, 95% CI, 0.70-0.95 and HR, 0.81, 95% CI, 0.67-0.98, respectively). High statin exposure was not associated with a statistically significant lower Alzheimer disease risk among black men.
Conclusions and Relevance  
The reduction in Alzheimer disease risk varied across statin molecules, sex, and race/ethnicity. Clinical trials that include racial and ethnic groups need to confirm these findings. Because statins may affect Alzheimer disease risk, physicians should consider which statin is prescribed to each patient.

Metaanalysis on inexistent cognitive impairment under statin therapy

ABSTRACT

BACKGROUND

In 2012, the United States Food and Drug Administration (FDA) issued a warning regarding potential adverse effects of HMG-CoA reductase inhibitors (statins) on cognition, based on the Adverse Events Reporting System and a review of the medical literature. We aimed to synthesize randomized clinical trial (RCTs) evidence on the association between statin therapy and cognitive outcomes.
METHODS

We searched MEDLINE, EMBASE, and Cochrane CENTRAL through December 2012, and reviewed published systematic reviews of statin treatment. We sought RCTs that compared statin treatment versus placebo or standard care, and reported at least one cognitive outcome (frequency of adverse cognitive events or measurements using standard neuropsychological cognitive test scores). Studies reporting sufficient information to calculate effect sizes were included in meta-analyses. Standardized and unstandardized mean differences were calculated for continuous outcomes for global cognition and for pre-specified cognitive domains. The main outcome was change in cognition measured by neuropsychological tests; an outcome of secondary interest was the frequency of adverse cognitive events observed during follow-up.
RESULTS

We identified 25 RCTs (all placebo-controlled) reporting cognitive outcomes in 46,836 subjects, of which 23 RCTs reported cognitive test results in 29,012 participants. Adverse cognitive outcomes attributable to statins were rarely reported in trials involving cognitively normal or impaired subjects. Furthermore, meta-analysis of cognitive test data (14 studies; 27,643 participants) failed to show significant adverse effects of statins on all tests of cognition in either cognitively normal subjects (standardized mean difference 0.01, 95 % confidence interval, CI, −0.01 to 0.03, p = 0.42) or Alzheimer’s disease subjects (standardized mean difference −0.05, 95 % CI −0.19 to 0.10, p = 0.38).
CONCLUSIONS

Statin therapy was not associated with cognitive impairment in RCTs. These results raise questions regarding the continued merit of the FDA warning about potential adverse effects of statins on cognition.

Cognitive Impairment, Alzheimer Disease and Atherosclerosis

Alzheimer disease has an increasing prevalence in Western countries and is likeli to increase costs for health care and nursing care (DemenzReportBerlin2011.pdf links to files at the end of this page). Cognitive impairment may be due to atherosclerosis or Alzheimer disease, but mixed forms are probably more common than reported (VCIStroke2011.pdf/VCICholesterol2009.pdf). A review of the literature has shown,

that there is an urgent need to increase the research between cognitive impairment and atherosclerosis
(VCIResearchNeeded2011.pdf). Based upon current knowledge, cognitive impairment is linked to the same risk factors that cause isch
emic heart disease and stroke (HeartDiseaseAndStrokeStatistcsReportAHA2011.pdf). Therefore, early detection and treatment of subjects having atherosclerosis appears mandatory in order to reduce the burden of cognitive impairment in the future. More evidence comes from an NIH study showing increased risk for cognitive impairment in subjects having stroke risk factors. In December 2013 NBCNEWS reported a link between Cholesterol  and early signs of Alzheimer Disease in the brain (Link).  More… from the NIH. A recent study from Taiwan confirmed the positive effect of Statins on Alzheimer Disease (StatinsPreventionAlzheimer112013.pdf)

New Study claims significant reduction for Dementia Incidence by the use of Statins

The studies, reported at this week’s European Society of Cardiology (ESC) 2013 Congress, both suggested that statin drugs may be linked to lower rates of dementia in older people.

Dr Tin-Tse Lin (National Taiwan University Hospital, Hsin-Chu) presented a study of 58 000 elderly patients that found a dose-related inverse relationship between statin use and new-onset nonvascular dementia [1]. Dr Min-Tsun Liao(National Taiwan University Hospital) found a lower incidence of dementia in patients taking statins compared with those not taking statins in a study of 5221 AF patients [2].

Commenting on the studies for heartwire, Prof José Gonzalez-Juanatey, (University Hospital, Santiago de Compostela, Spain) said: “These new data suggest that high-potency statins may reduce the incidence of dementia in patients with atrial fibrillation and in elderly patients. Nevertheless, before we can know for sure that statins may prevent dementia, a clinical trial confirming these findings is mandatory.”

Dr Seth S Martin (Johns Hopkins Hospital, Baltimore, MD), who is conducting a systematic review of the literature on statins and cognition/dementia, told heartwire that these current results fit in well with existing studies. “While the study of Dr Lin and colleagues could not control for all possible confounders, the dose response seen in the study is intriguing and supports a causal relationship. The work strengthens existing literature that is compatible with a protective effect of statins on dementia. Overall, statins appear to be good for the brain.”

Lin commented: “Recent reports of statin-associated cognitive impairment have led the US FDA to list statin-induced cognitive changes, especially for the older population, in its safety communications. Previous studies had considered statin therapy to exert a beneficial effect on dementia. But few large-scale studies have focused on the impact of statins on new-onset nonvascular dementia in the geriatric population. To the best of our knowledge, this is the first large-scale, nationwide study to examine the effect of different statins on new-onset nonvascular dementia in an elderly population.”

Dose-dependent inverse relationship

Dr Tin-Tse Lin
Dr Tin-Tse Lin

For the study, Lin and colleagues examined whether statin use was associated with new diagnoses of dementia in a random sample of one million people covered by Taiwan’s national health insurance. From this they identified 57 669 individuals aged over 65 years who had no history of dementia in 1997 and 1998. Of these, 15 200 were taking statins. Propensity scoring was used to match these patients with controls not taking statins. Patients on statins were divided into tertiles according to dose.

The researchers identified 5516 new diagnoses of dementia (excluding vascular dementia) during the 4.5 years of follow-up. Results showed an inverse relationship between statin use and dementia, with the risk of dementia reducing with increasing statin dose. This trend remained in different age, gender, and cardiovascular risk subgroups.

Hazard ratio (vs control) of developing dementia with statins at different dosage tertiles 

Statin Lowest-dose tertile  Mid-dose tertile  Highest-dose tertile  p for trend 
Atorvastatin  0.680 0.543 0.305 <0.001
Rosuvastatin  0.365 0.134 0.129 0.011
Fluvastatin  0.971 0.578 0.255 0.058
Simvastatin  0.747 0.664 0.510 0.064
Pravastatin  0.662 0.933 0.491 0.422
Lovastatin  1.382 0.930 1.626 0.116
All statins  0.923 0.806 0.311 <0.001

Lin said: “The adjusted risks for dementia were significantly inversely associated with increased total or daily equivalent statin dosage. Patients who received the highest doses of statins had a threefold decrease in the risk of developing dementia. High-potency statins such as atorvastatin and rosuvastatin [Crestor, AstraZeneca] showed a significant inverse association with developing dementia in a dose-response manner. Higher doses of high-potency statins gave the strongest protective effects against dementia.”

All the statins except lovastatin were associated with a decreased risk for new-onset dementia when taken at higher daily doses. Lin suggested lovastatin may have shown different results as it has less cholesterol-lowering effect than other statins.

Statins halved dementia risk in AF patients

The second study included 5221 patients with atrial fibrillation, which is known to be a predisposing factor for dementia. Of these, 1652 were taking statins.

During a six-year follow-up, 2.1% of the patients taking statins developed dementia compared with 3.5% of the nonstatin group, a statistically significant difference (p=0.002).

Cox-regression analysis showed an odds ratio of 0.565 for statin use and the risk of new-onset dementia. Other factors that were associated with a reduced risk of dementia included male sex and lower CHADS2 score. History of MI, peripheral artery disease, coronary artery disease, chronic kidney disease, and valvular heart disease were not associated with new-onset dementia.

Sources

  1. Wu C, Lin T. Statin use and the incidence of dementia in the elderly: A nationwide data survey. European Society of Cardiology 2013 Congress; August 31, 2013; Amsterdam, the Netherlands. Abstract 1609.
  2. Liao MT, Tsai CT, Lin JL. Statins reduce the incidence of dementia in patients with atrial fibrillation: A nationwide cohort study. European Society of Cardiology 2013 Congress; August 31, 2013; Amsterdam, the Netherlands. Abstract P4077.

Midlife Hypertension and Dementia

Another hint to the high importance of controlling risk factors early in midlife comes from a long-term observational study, where poorly controlled midlife hypertension was associated with increases risk for cognitive impairment at the older age (link)

Need for action

There is a need to perform cohort studies linking expression of atherosclerosis with the incidence of cognitive impairment in Switzerland. The Vascular Risk Foundation is increasing the database on cardiovascular risk factors, carotid plaque burden and offers a unique opportunity to study near 2000 subjects for outcome. It has been recognised for Switzerland, that the burden of Dementia will increase (DemenzObsan052011.pdf). Therefore it appears mandatory to increase research on prevention of cognitive impairment for the future.