Observational Statin Study finds significant reductions for risk of Alzheimer Disease
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.
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.
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).
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.
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 . 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 .
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.”
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|
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.
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.
- 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.
- 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.