Statins use and risk of dementia: A dose-response meta analysis.

Previous studies have indicated that statins use is associated with risk of dementia, but presented controversial results. Medline, Embase, Web of Science, and the Cochrane Database were searched update to November 2017 to identify the potential relationship between statins use and dementia. Thirty-one eligible studies involving a total of 3332,706 participants with 184,666 incident cases were included in this meta-analysis. Statins use was associated with dementia risk decrement (relevant risk [RR]: 0.85; 95% confidence interval [CI], 0.80-0.89). Subgroup analysis showed statins use was associated with Alzheimer disease (AD) (RR: 0.81; 95% CI, 0.73-0.89) and non-AD dementia (RR: 0.81; 95% CI, 0.73-0.89) risk decrement. Furthermore, statins use was associated with dementia risk decrement in female (RR: 0.89; 95% CI, 0.80-0.98) and male (RR: 0.88; 95% CI, 0.83-0.93). In addition, a dose-response showed per 1 year of duration of statins use incremental increase was associated with 20% dementia risk decrement (RR: 0.80; 95% CI, 0.73-0.87), and per 5-mg mean daily dose incremental increase in statins use was associated with 11% dementia risk decrement (RR: 0.89; 95% CI, 0.83-0.96). Statins use was associated with dementia risk decrement. The potency and the cumulative duration of statin utilized played critical roles.

Introduction

Statins is commonly known 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, and is the first-line drug therapy for the treatment of hyperlipidemia and the first choice for the prevention of coronary heart disease.[ Statins have been widely used in clinically. In addition to reducing blood lipids, it's prevention and treatment of dementia gradually drawing people's attention.[ Hypercholesterolemia may be positively correlated with dementia in middle-aged people. Statins may inhibit cholesterol metabolism by regulating cholesterol metabolism in the brain.[

According recent data, 93% of United States person use statins as the first choice to lower cholesterol levels, and statin use increased from 17.8% to 25.9% among the population 40 years of age or older, and it is still increasing.[ Although, statins use has a potential to prevent dementia, there have been safety concerns regarding their effects on statins.[ Currently, there are continued concerns, partly due to the conflicting results of the association between statins use and dementia.

Considering increasing number of patients being prescribed statins use and clinicians, pharmacists, patients, society, and governments pay more attention to the safety of these drugs; we conducted meta-analysis based on observational studies to determine whether statins use is associated with dementia risk.

Methods

Our meta-analysis was conducted according to the meta-analysis of observational studies in epidemiology checklist.[ There are no ethical issues involved in our study for our data were based on published studies.

Search strategy

“Dementia” [MeSH] OR “Amentia” [MeSH] OR “Senile Paranoid Dementia” [MeSH] OR “Alzheimer's disease” [MeSH] OR “Parkinson's disease” [MeSH] OR “Huntington's disease” [MeSH] AND “Hydroxymethylglutaryl-CoA Reductase Inhibitors” [MeSH] OR “Statins” [MeSH] OR “Atorvastatin Calcium” [MeSH] OR “Lovastatin” [MeSH] OR “Meglutol” [MeSH] OR “Pravastatin” [MeSH] OR “Rosuvastatin Calcium” [MeSH] OR “Simvastatin” [MeSH] as the retrieval words, the databases such as Medline, Embase, Web of Science, and the Cochrane Database were retrieved from the time of the database established to November 2017.

Inclusion and exclusion criteria

Literature screening, inclusion, and quality evaluation were conducted independently by 2 researchers. The contents of our data extraction include the outcome was dementia. Risk estimates on the association between statins use and dementia risk. For nonrandomized controlled trials (RCTs), quality assessment was used Newcastle–Ottawa scale to score.[

Statistical analysis

Dose–response meta analysis using the method recommended by Greenland, Longnecker, and Orsini et al[ by using STATA software 14.0 (STATA Corp, College Station, TX).

Results

Literature search results

A total of 2061 articles were screened through database retrieval and manual screening. After reading the topics and abstracts, most animal experiments and no related articles, meta-analyses, reviews, systematic reviews, randomized controls, and other forms of research were excluded and included in 51 articles. Full texts were further read and 21 articles removed. After review reference of studies, 1 article was identified. Finally, 31 studies were used for the final data synthesis.[ The flowchart of literature searching was presented in Fig. 1. The characteristics of the included studies are shown in Tables 1 and 2.

Figure 1

Flow diagram of the study selection process.

Table 1

Characteristics of participants in included studies of statins use in relation to dementia.

Table 2

Outcomes and covariates of included studies of statins use in relation to dementia.

Statins use and dementia risk

Thirty-one eligible studies including 47 independent reports investigated the association between statins use and dementia risk. Compared with no statins use, statins use was associated with dementia risk decrement (relevant risk [RR]: 0.85; 95% confidence interval [CI], 0.80–0.89; P < 0.01) (Table 3). Furthermore, statins use was significantly associated with dementia risk decrement in female (RR: 0.89; 95% CI, 0.80–0.98; P < 0.01) (Table 3) and male (RR: 0.88; 95% CI, 0.83–0.93; P < 0.01) (Table 3). In addition, statins use was significantly associated with dementia risk decrement in Caucasia (RR: 0.89; 95% CI, 0.83–0.96; P < 0.01) (Table 3) and male (RR: 0.92; 95% CI, 0.84–0.97; P < 0.01) (Table 3).

Table 3

Stratified analyses of relative risk of dementia.

Twenty-one eligible studies including 23 independent reports investigated the association between statins use and Alzheimer disease (AD) risk. Compared with no statins use, statins use was associated with AD risk decrement (RR: 0.81; 95% CI, 0.73–0.89; P < 0.01) (Table 3). Furthermore, statins use was significantly associated with AD risk decrement in female (RR: 0.88; 95% CI, 0.83–0.93; P < 0.01) (Table 3) and male (RR: 0.86; 95% CI, 0.78–0.94; P < 0.01) (Table 3). In addition, statins use was significantly associated with AD risk decrement in Caucasia (RR: 0.83; 95% CI, 0.74–0.92; P < 0.01) (Table 3) and male (RR: 0.60; 95% CI, 0.36–0.97; P = 0.03) (Table 3).

Six eligible studies including 6 independent reports investigated the association between statins use and non-AD dementia risk. Compared with no statins use, statins use was associated with non-AD dementia risk decrement (RR: 0.81; 95% CI, 0.73–0.89; P < 0.01) (Table 3).

Dose–response between statins use and dementia risk

The test for a nonlinear dose–response relationship was significant (likelihood ratio test, P < 0.001), suggesting curvature in the relationship between statins use and dementia risk. Increasing per 1 year of duration of statins use incremental increase was associated with 20% dementia risk decrement (RR: 0.80; 95% CI, 0.73–87; P < 0.001) (Fig. 2), and per 5-mg mean daily dose incremental increase in statins was associated with 11% dementia risk decrement (RR: 0.89; 95% CI, 0.83–96; P < 0.001) (Fig. 3).

Figure 2

Dose–response relationship between duration of statins use in relation to risk of dementia. The solid line represents point estimates of the association of statins use and dementia risk with the use of a restricted cubic splines model, and the dashed lines indicate 95% confidence intervals.

Figure 3

Dose–response relationship between mean daily dose of statins use in relation to risk of dementia. The solid line represents point estimates of the association of statins use and dementia risk with the use of a restricted cubic splines model, and the dashed lines indicate 95% confidence intervals.

Publication bias

Results from Egger's tests indicated no evidence of publication bias among these studies (Supplementary Table 1). A funnel plot for publication bias assessment is illustrated in Supplementary Figs. 1 to 3.

Discussion

Dementia is a chronic acquired progressive retardation syndrome, and slow onset of intellectual decline is the main feature in clinically, accompanied by varying degrees of personality changes. It is a group of clinical syndromes, rather than an independent disease. Dementia is mainly divided into degenerative dementia and nondegenerative dementia. Degenerative dementia includes AD, fronto-temporal dementia, Louis's dementia, Parkinson's disease, and Huntington's disease, and nondegenerative dementia mainly includes vascular dementia, traumatic brain dementia, and space occupying lesions.[ There is no specific treatment for degenerative dementia, so as to improve cognitive and symptomatic treatment.[ Although some of the drugs (such as cholinesterase inhibitors) can improve the ability of patients to accept new things in short term and delay the aggravation of dementia, the long-term curative effect remains to be observed. Antipsychotic drugs can be used to combat psychotic symptoms, agitation, or aggressive behavior.[ Antidepressants can be used in patients with dementia and depression, and help to improve the dementia syndrome. But it must be noted that the anticholinergic side effects of tricyclic drugs can aggravate cognitive impairment.[ Although benzodiazepines can control the behavior problem of the dementia, it should be specially cautious because it can cause falls and drug dependence. In general, these drugs in treatment of dementia are more or less all kinds of problems, and statins have been widely used in lipid-lowering therapy, and its pleiotropic effects have expanded its clinical value and the potential therapeutic effect of statins on dementia is remarkable.

Statins is commonly known 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, including lovastatin, pravastatin, simvastatin, mevastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, and is the first-line drug therapy for the treatment of hyperlipidemia and the first choice for the prevention of coronary heart disease. Recent report presents safety problems between statins use and dementia, and statins use may contribute to the potential of dementia. Currently, there are continued concerns, partly due to the conflicting results of the association between statins use and dementia.

Previous meta-analysis has investigated the association between statins use and dementia risk but presented controversial results. Wong et al[ based on 20 observational studies found statins use was slight associated with dementia (RR: 0.82; 95% CI, 0.69–97) and AD (RR: 0.70; 95% CI, 0.60–83) risk decrement. However, Rojas-Fernandez et al[ found statins use was not associated with dementia risk.

This meta-analysis was based on 31 studies (including nine case–control studies and 22 cohort studies) update to November 2017. Our meta-analysis supported statins use was associated with dementia risk decrements, and a dose–response showed per 1 year of duration of statins use incremental increase was associated with 20% dementia risk decrement, and per 5-mg mean daily dose incremental increase in statins use was associated with 11% dementia risk decrement. This meta-analysis included enough studies; these results should be credible.

High-cholesterol diet, elevated serum cholesterol, and high blood pressure are risk factors for coronary heart disease and AD, and hypercholesterolemia in the brain can be deposited in the hippocampus, causing amyloid precursor protein to be degraded intoamyloid precursor protein, which causes degeneration of neurons, resulting in AD. Statins may reduce the formation of β-amyloid peptide by decreasing cholesterol levels. Statins have a stable effect on the homeostasis of the nervous system cholesterol, inhibit the synthesis of cholesterol, lower the cholesterol level, and thus inhibit the beta metabolism of amyloid precursor protein.[ Furthermore, the intermediate product isoprene of cholesterol biosynthesis in dementia patients is often depleted, thus affecting cell growth, mitosis, and signal transduction, while statins have a regulatory role in the above intracellular mechanisms.[ In addition, commonly known as apoE4, an important cholesterol transporter, is an important risk factor and genetic marker of sporadic and late-onset familial AD and plays an important role in Aβ deposition and the formation of senile plaques. Astrocytes and microglia are the main sources of apoE in the brain. These cells secrete apoE, which requires the isoprenylation of key proteins, while mevalproic acid is the precursor of isoprene derivatives. Statins inhibit the synthesis of mevalonate, inhibit apoE secretion, and reduce extracellular apoE levels, thereby preventing the formation of senile plaques and improving cognitive function.[

This meta-analysis also has some limitations. First, we did not included RCTs due to dementia was not a prespecified endpoint in RCTs, and RCTs should be included in the further. Second, study duration was short in these studies and person included in these studies may be different from the real life. Third, the overall sample size of the study was small, which may have a certain impact on the evaluation results.

To sum up, statins use was associated with dementia risk decrement, and it is expected to become an important auxiliary means of dementia treatment. Due to the limitation of the quality and quantity of the inclusion study, more high-quality, large sample, and multicenter RCT are needed to verify the conclusions of this study in the future.

Author contributions

Data curation: Xiaoyu Zhang, Jianzhong Wen, Zhiqiang Zhang.

Formal analysis: Xiaoyu Zhang, Jianzhong Wen, Zhiqiang Zhang.

Project administration: Zhiqiang Zhang.

Software: Xiaoyu Zhang, Jianzhong Wen, Zhiqiang Zhang.