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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 2  |  Page : 78-85

Association of cognitive function, depression, and quality of sleep with statins among oldest-old individuals


1 Department of Community Medicine, Mediciti Institute of Medical Sciences, Hyderabad, Telangana, India
2 Department of Community Medicine, Mediciti Institute of Medical Sciences, Hyderabad, Telangana, India; Department of Epidemiology, University of Pittsburgh, PA, USA, and SHARE India, and Fogarty International, NIH, USA

Date of Submission26-Dec-2021
Date of Decision27-Mar-2022
Date of Acceptance10-Apr-2022
Date of Web Publication15-Jul-2022

Correspondence Address:
Enakshi Ganguly
Department of Community Medicine, Mediciti Institute of Medical Sciences, Ghanpur, Hyderabad - 501 401, Telangana

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiag.jiag_34_21

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  Abstract 


Background: Oldest-old population is rapidly increasing in all countries, with many prescribed statin therapy. Statins are associated with multiple cardiovascular benefits at various ages. The benefits of statins above the age of 75 are being questioned. The objective of this study was to measure statins use among the oldest-old population, aged 80 years and above, and to study the effect of statins on cognitive function, depression, and quality of sleep. Materials and Methods: This cross-sectional study randomly enrolled 200 community-dwelling individuals aged >80 years. Data were collected upon home visits on sociodemographic, cognitive functions, depression, sleep, chronic diseases, functional limitations, and disabilities. Cognitive function (Mini Mental State Examination), depression (Geriatric Depression Scale), and quality of sleep (Pittsburgh Sleep Quality Index) among individuals using statins versus not using statins were compared. Chi-square test and t-test were done; odds ratios (ORs) with 95% confidence interval (95% CI) were reported. Logistic regression was done to calculate adjusted OR with age, antidepressants, sedatives, antihistaminics, and sleep medicines. P < 0.05 was considered statistically significant. Results: Overall prevalence of statin use in our study population was 12%; 11.3% in women and 13.2% in men. Cognitive functions, depression, and quality of sleep improved among those using statins (P < 0.05): cognitive impairment – OR: 0.38; 95% CI: 0.16–0.91; depression – OR: 0.41; 95% CI: 0.17–1.02, and poor sleep quality – OR: 0.39; 95% CI: 0.16–0.96. On stratification by gender, men showed a significant association of improved cognitive function and quality of sleep with the use of statins, whereas women did not show any significant associations with cognitive function and quality of sleep but showed almost significant association with improvement in depression. Conclusions: The prevalence of the use of statins was low in our population. Statins had positive effects on cognitive functions, quality of sleep, and depression over 80 years of age in our population, although gender difference exists.

Keywords: Cognitive impairment, depression, oldest-old, sleep quality, statin


How to cite this article:
Regalla SS, Anaika G, Reddy BM, Sharma PK, Ganguly E. Association of cognitive function, depression, and quality of sleep with statins among oldest-old individuals. J Indian Acad Geriatr 2022;18:78-85

How to cite this URL:
Regalla SS, Anaika G, Reddy BM, Sharma PK, Ganguly E. Association of cognitive function, depression, and quality of sleep with statins among oldest-old individuals. J Indian Acad Geriatr [serial online] 2022 [cited 2022 Aug 18];18:78-85. Available from: http://www.jiag.com/text.asp?2022/18/2/78/351071




  Introduction Top


Statins that are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are considered to be the most effective medicine to lower cholesterol, especially low-density lipoprotein (LDL) and triglycerides, and elevate high-density lipoprotein. They are commonly prescribed lipid-lowering drugs used primarily to treat high cholesterol and cardiovascular disease (CVD) worldwide, to reduce atherosclerosis, coronary artery diseases, and related mortality.[1] They also have anti-inflammatory properties including reducing C-reactive protein (CRP) concentrations,[2] tumor necrosis factor (TNF) alpha, and interferon-gamma production in stimulated T-lymphocytes and inhibit the T-helper cell immune response.[3] These effects of lowering LDL cholesterol with statins may lead to anti-inflammatory actions, as evidence suggests that LDL encourages inflammation.[4] Statins act on human hepatocytes to reduce the levels of CRP induced by circulating interleukin 6 (IL-6), suggesting that the anti-inflammatory effects of statins are hepatic in nature.[5] Older individuals have a greater risk of developing atherosclerotic CVD. The incidence and prevalence of atherosclerosis increase with age and the number of cardiovascular events and lipid levels are higher in older individuals. Owing to this, the consumption of statins might be higher among older population.

Oldest-old populations, >80 years of age, will increase threefold by 2050, and cognitive function is a major concern in this age group because of increasing cognitive decline, dementia, and Alzheimer's disease (AD). Cognitive impairment has proinflammatory cytokines (IL-6, TNF-alpha, IL-18, and IL-1-beta) that promote the production of circulating proteins, leading to cognitive decline. Chronic inflammation provides a basic mechanism for the pathogenesis of cognitive impairment.[6] It is believed that statins may have positive outcomes on cognitive functions. Evidence suggests that these medications, which act via a cholesterol-dependent mechanism, might reduce the production of amyloid-β peptide, the major constituent of senile plaques, and hence the risk of developing AD.[7] Numerous literature examined the relationships of these medications with odds of preventing development of AD and concluded with mixed results.[8],[9],[10],[11] Various contrasting evidences are available in the studies on associations between cognitive function and use of statins.[12],[13],[14],[15],[16] Concerns about overall benefits of statins above the age of 75 are, therefore, being raised by many researchers.

Cholesterol plays an important role in the serotonin system, so the use of statins to lower cholesterol may lead to the occurrence of depression.[17] Conversely, statins reduce inflammation and protect against oxidative damage,[18] and inflammation and oxidative stress are visible in depression; hence, statins use may reduce the risk of depression. Some reports suggest that in individuals over 40 years of age, the use of statins was associated with lower risk of depression.[19] An inflammatory model of depression has been suggested recently, emphasizing the role of inflammatory, oxidative, and nitrosamine stress pathways in the development of depression;[20],[21] furthermore, the markers of oxidative damage are shown to be increased in patients diagnosed with depression,[20] leading us to hypothesize that elements affecting inflammatory, oxidative, and nitrosamine pathways may be effective in both treating and reducing the risk of depression. Evidence suggests that statins may also have neuroprotective quality.[1]

Accumulating databases from the US Food and Drug Administration Adverse Event Reporting System suggest that statin use is associated with an increased risk of sleep disturbances, including insomnia.[22] In some studies, hallucinations and nightmares during statin therapy were also reported.[23] Few studies demonstrated a beneficial effect of statins on sleep quality,[24],[25],[26] while conversely, others presented no impact of statin treatment on sleep.[27],[28],[29]

There are wide variations in the prevalence of the use of statins among older population globally. In the United States, around 30% of the older adults use statins, and 38% of the older adults aged above 65 years in Spain use statins.[30]

Cognitive impairment, depression, and sleep disorders are key factors explaining brain functions. They are also major risk factors for chronic diseases, poor physical function, mobility disability, and independence to do daily chores among older individuals. Hence, it is imperative to explore preventive and therapeutic options for our older population to preserve their quality of life in their older ages. The objective of this study was to measure statins use among urban Indian oldest-old population, aged 80 years and above, and to study the effects of statins on cognitive function, depression, and quality of sleep.


  Materials and Methods Top


Two hundred community-dwelling individuals, 76 men and 124 women, aged 80 years and older, were included for this cross-sectional study. The individuals were randomly enrolled from Hyderabad, India, from 12 residential gated communities (population ranging from 1000 to 6000), having fair access to health-care services, located in different geographic locations of the city. A list of households was prepared with the help of societies of the gated communities having at least one age-eligible subject in the household. The list of households was randomized using random number generator software. All eligible subjects agreeing to participate from the selected households were included in the study. The enrolled participants were provided free consultation and care by Mediciti Institute of Medical Sciences Hospital, Hyderabad.

This study was approved by the Ethics Committee of Mediciti Institute of Medical Sciences, Hyderabad, and Indian Council of Medical Research, New Delhi. The data were collected by a trained investigator upon home visits after obtaining written informed consent in the participant's comfortable language and explained by the investigator. Inclusion criteria were Indian nationality, aged ≥80 years, living in an urban area of Hyderabad city, possessing cognitive ability to understand the investigator's instructions, and consenting to participate. Those suffering from known debilitating chronic disease, mental illness, or terminal illness were excluded. Questionnaires and forms were adapted and validated from large international longitudinal studies such as the Lifestyle Interventions and Independence for Elders and Mobility and Independent Living in Elders Study study.[31],[32] It included information on sociodemographic characteristics, chronic diseases, medical history, functional disabilities, depression, cognitive function, sleep, and biomarkers. All the questionnaires and scales were interviewer rated. Investigators interviewed and recorded the response. For this research, we compared cognition, depression, and quality of sleep in individuals who were taking statin medication and individuals who were not taking statin medication.

Measurements

Cognitive functions were measured using Mini Mental State Examination (MMSE). It assesses different subset of cognitive status including attention, language, memory, orientation, and visuospatial proficiency. MMSE is scored on a scale of 0–30, with scores >24 interpreted as normal cognitive status, 0–9 as severe cognitive impairment, 10–17 as moderate cognitive impairment, 18–23 as mild cognitive impairment, and 24–30 as no cognitive impairment.[33]

Depressive symptoms were assessed using 15-point Geriatric Depression Scale (GDS).[34] GDS score ranges from 0 to 15; higher scores indicate an increase in depressive symptoms; scores ≥5 indicate the presence of depressive symptoms. Scores are classified as: 5–8 = mild depression, 9–11 = moderate depression, 12–15 = severe depression and 0–4 = no depression. The GDS is a valid tool for detecting depression among community-dwelling older individuals.

Quality of sleep was determined using Pittsburgh Sleep Quality Index,[35] a self-rated questionnaire that assessed sleep quality and disturbances using 19 individual items to generate seven “component” scores, including subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for these seven components yielded one global score. Participants having scores ≥5 were classified as having poor sleep quality.

Statistical analysis

The data were analyzed using Statistical Package for the Social Sciences (SPSS, version 25.0; SPSS Inc., Chicago, IL, USA) software. Comparison of cognitive function, depression, and quality of sleep was done among individuals taking statins and individuals not taking statins. These analyses were done using Chi-square test and t-test for categorical and continuous variables, respectively. The significance level was set at P < 0.05. The results were projected in proportions, means, odds ratio (OR), and 95% confidence interval (CI). The analysis was stratified for total population, men and women. Logistic regression was performed to calculate OR and 95% CIs of use of statins, with cognitive impairment, depression, and quality of sleep being calculated after adjusting age, antidepressants, sedatives, antihistaminics, and sleep medicines.


  Results Top


The prevalence of people taking statins was 12.0% (n = 24) (95% CI: 7.84–17.33); 11.3% of women and 13.2% of men were taking statins in our study population. There was no significant difference in statins usage by sex (P = 0.42). The sociodemographic characteristics of the study population are shown in [Table 1]. The mean ages of men and women were similar (P = 0.40). However, the proportions of women living single (P < 0.001), with no schooling (P = 0.03), having depression (P = 0.02), and having impaired cognition (P = 0.01) were significantly higher than men.
Table 1: Demographic characteristics of the study population

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[Table 2] shows the mean scores for cognitive functions, quality of sleep, and depression among those taking statins and not. Quality of sleep and depression did not differ significantly among the two groups.
Table 2: Cognitive functions, quality of sleep, and depression among individuals taking statins and not taking statins

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Cognitive impairment and poor sleep quality showed an inverse association with statins usage (P < 0.05): cognitive impairment – OR: 0.38; 95% CI: 0.16–0.91 and poor sleep quality –OR: 0.39; 95% CI: 0.16–0.96. Decreased risk of depression was nearly significant among the statins users compared with nonusers (OR: 0.41; 95% CI: 0.17–1.02) [Table 3]. Upon further stratification of statins users and nonusers by sex, it was seen that men statin users continued to show decreased risk for cognitive impairment and poor sleep quality associated with statins usage [Table 4]. These associations were nonsignificant for women [Table 5].
Table 3: Association of statins with cognitive impairment, depression, and poor quality of sleep in total population

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Table 4: Association of statins with cognitive impairment, depression, and poor quality of sleep among men

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Table 5: Association of statins with cognitive impairment, depression, and poor quality of sleep among women

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  Discussion Top


Prevalence of statins use

In our study, 12% urban community-dwelling octogenarians used statins. Our prevalence was lower than that reported by a cross-sectional survey from Vellore including 6196 participants aged 30–64 years wherein statin use was 37.7% among coronary heart disease (CHD) patients and 13.4% among diabetes mellitus (DM) patients.[36] Our prevalence of statin usage is much lower than that found by a multisite analysis of prescriptions at various clinics in eight Indian cities, showing 55% of diabetics being prescribed statins.[37]

Among studies involving the older-old persons, a cohort consisting of health plan members in the National Institutes of Health (NIH) Collaboratory Distributed Research Network aged >75 years studied between 2008 and 2018 found that 109,306 older adults out of 757,569 initiated statins, while 54,624 became long-term users. Further, it was derived that there were 143.9 initiators per 1000 member-years for CVD and DM and 114.5 initiators per 1000 member-years for CVD and no DM. It was also found that the incidence of statins was slightly higher in males than females and highest among the youngest age group (76–80 years).[38] In the Irish Longitudinal Study on Ageing, data from a nationally representative sample (n = 5618) of community-dwelling participants aged 50 years and over showed that 30.5% were taking statins.[39] Blais et al. reported that the statin prevalence increased from 2004 (1.82, 95% CI: 1.78%–1.86%) to 2015 (8.68, 95% CI: 8.60%–8.75%) in Hong Kong, which is slightly lower compared to ours.[40] Our rates match those reported by Kantor et al. from 2003 to 2004 prevalence estimate (11, 95% CI: 9.6%–12%) from the US, while slightly higher rates were reported between 2011 and 2012 (17, 95% CI: 15%–19%).[41] Few other hospital-based studies found a higher overall statins prescription rate in patients, such as 58.8% among 51,083 patients (mean [standard deviation] age, 59.78 [±13.16] years) reported from West China Hospital between 2008 and 2014.[42] O'Keeffe et al. also reported a high prescription prevalence of statins calculated as 96.53/1000 person-years in the UK in 2007.[43] Time trends for statin use showed that the prevalence of statin use for secondary prevention in the United States increased strongly from 1999 to 2013, as also the average increase in statin use was the highest in patients aged 80 and older. Patients aged 70–79 years received the most statins, and men were higher users of statins than women.[44] While most research studies proposed therapeutic or prophylactic benefits of using statins among adults and older ages with atherosclerosis, some researches argued that there was no benefit of statins above the age of 75, with statins leading to various complications such as intracerebral hemorrhage. The SPARCL study involving 4731 participants, for instance, showed that statins apparently increased the occurrence of hemorrhagic stroke among those with previous CVD. Similarly, the Heart Protection Study (HPS) also showed that statins increased the occurrence of hemorrhagic stroke without an effect on overall stroke incidence.[45] However, in a large prospective meta-analysis including more than 90,000 patients, it was found that those having no history of stroke or transient ischemic attacks showed no increase in hemorrhagic stroke occurrence, in spite of the associations shown between low serum cholesterol levels and increased incidence of hemorrhagic stroke.[46],[47],[48]

Statins and cognitive functions

Our data showed an association between statins use and better cognitive functions among the oldest-old users versus nonusers of statins. Many others have similarly shown that an association exists between dose and duration of statins usage and cognitive functions. Alsehli et al., for instance, showed that statins improved reaction time in older persons and fluid intelligence in both middle and older age groups. They however observed an influential effect of age to suggest that statin cognitive effects varied with the specific cognitive function tested.[49] Our study findings are concordant with most longitudinal studies that found no adverse association between statins and cognition, in the cognitively intact,[15] in impaired cognition,[50],[51] or for memory change[52] in all ages. A recent systematic review, in contrast, reported neither beneficial nor detrimental associations between statins and cognition in the elderly cohort with normal baseline cognition, impaired cognition, or incident dementia.[53]

A prospective observational study of community-dwelling elderly Australians aged 70–90 years found that there was no difference in the rate of decline in memory or global cognition between statin users and never users, over 6 years of observation, but statin initiation during the observation period was associated with blunting the rate of memory decline.[53]

Few randomized controlled trials (RCTs) including the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, HPS, and Pravastatin in Elderly Individuals at Risk of Vascular Disease similarly did not find an increased cognitive impairment with statin use.[54]

Age related changes in brain are highly linked to cognitive decline and increased risk of dementias.[55] Increased vulnerability and susceptibility to metabolic disorders due to advancing age[56] lead to impaired brain energy metabolism,[57] accumulation of cholesterol, and vascular damage.[58] It is thought that statins ameliorate these age- related brain-deteriorating changes. Statins have been found to improve metabolic function, reduce cholesterol levels, and improve vascular health,[59] thereby explaining possible mechanisms for beneficial effects on cognitive function during aging. Few researchers have also argued that improved cognition might result from the beneficial effects of statins on the prevention of ischemic stroke, by decreasing severity of cerebrovascular disease.[60] The differences detected in cognitive impairment by gender in our study may be interpreted with caution since few researchers suggest that MMSE score for educated and uneducated patients has different cutoffs, and hence, the variation in results as per gender may be ascribed to variation in the literacy rate between genders.

Statins and sleep quality

While most studies on statins and sleep quality have shown a detrimental impact of statins on various stages of sleep, our findings were contrary, showing positive association with sleep quality. Our findings are supported by the only meta-analysis on impact of statin therapy on polysomnography (PSG) indices of sleep including nine treatment arms, which showed that while statins had no significant adverse effect on sleep duration and efficiency, entry to stage I, or latency to stage I sleep, they were found to significantly reduce wake time and number of awakenings. The authors also suggested that lipophilic statins, such as lovastatin and simvastatin, might be associated with a higher rate of central nervous system disturbances in comparison with hydrophilic statins.[29] Although we did not describe types of statins used by our population, predominantly, our study population used lipophilic statins.

The JUPITER trial also reported no differences in rates of adverse sleep events in the rosuvastatin and placebo groups.[61]

A possible reason for our discordance may be that most studies were conducted on younger populations where other side effects of statins are also frequently reported. At a deeper level, PSG studies are available that reported the impact of statins on phases of sleep cycle; they too, however, have been mostly done among younger subjects and neglected the elderly. Our positive association may have resulted from the reporting biases that accompany self-reported sleep quality by the elderly, who already suffer from poor sleep due to multiple comorbidities and conditions, whereby statins usage confounds resultant improvements in other neuropsychological parameters. There also may be a bleak possibility of some statins acting synergistically to improve melatonin function,[62] primarily responsible for sleep quality. Cholesterol-independent mechanism of action of statins such as atorvastatin to enhance Endothelial Nitric Oxide Synthase (eNOS) expression causing vasodilation, thereby reducing depression through an indirect pathway, may also be implicated to improve sleep in older adults who frequently report depression.

Statins and depression

We found a positive association between statins use and lower depression in our population, although not significant. Another study with concurrent findings found that use of any statin reduced the odds of depression by 8%, They also reported stepwise decrease in OR of depression with increasing age; the highest adjusted decrease in risk (approximately 20%) was witnessed among those aged 70+ years.[19] These findings were hypothesized to have occurred due to the anti-inflammatory and antioxidative properties of statins, due to which they exert a protective effect on the development of depression. Other authors include Feng et al.,[63] who examined the relationship between statin use and depressive symptoms measured using a depression rating scale designed specifically for older people in a population-based sample of 2804 community-dwelling adults aged 55 years and over, to report a significant negative association between statin use and depressive symptoms. Otte et al.,[64] in a prospective cohort study involving 965 outpatients with CHD, found a 34% decrease in risk of depressive symptoms among statin users compared to nonstatin use at baseline and also after 6 years of follow-up.

In contrast, the Singapore Longitudinal Ageing Study did not find any associations between statin use and depressive symptom scores among 55 years and older subjects. The authors, however, went on to suggest that statin use may be associated with fewer depressive symptoms in women in the cohort, and more depressive symptoms in men having medical comorbidities and multiple drug use in a post hoc analysis, but inferred that these associations might be spurious.[65]

Others have attempted to describe the positive association of statin usage with low depression levels using several explanations, of which interference with the inflammatory pathways seems the most plausible.

A possible explanation for the lack of protective effect of statins against depression in our study is the factual associations of late-life depression with irreversible vascular damage and morphologic alterations of brain structures in the oldest-old population,[66] which is unlikely to benefit from anti-inflammatory drugs.

Strengths and limitations

Ours is a pioneer study from the Indian population to report associations of statins usage with neuropsychological parameters, including cognition, depression, and sleep quality, among the oldest-old population aged 80 years and older, on a sufficiently large representative urban sample. We performed a comprehensive assessment of individuals using validated instruments for measurement of cognition, sleep quality, and depression and other measurements. The questionnaire yielded robust data on mental and physical conditions. Our data were helpful to explore relationships of objectively measured parameters with statins usage, while adjusting for a variety of confounders including medicines and physical conditions, in oldest-old population. The prevalence of the use of statins in our population was low; therefore, the authors avoided overadjustment using selected covariates in logistic regression. In this study, we tested the hypothesis that there is a significant association of statins usage with cognitive function, depression, and quality of sleep. This study is a cross-sectional study and does not comment on the dose of statins. Hence, it may be important to explore these associations in further research (longitudinal or RCTs) with large samples to establish conclusive evidence of effect of statins.

However, the cross-sectional study design brings some limitations, especially with respect to biases associated with questionnaires and recall, and finding associations only. Potential undermining of internal validity due to unknown and unequally distributed confounding factors across the groups being compared may also have been a methodological limitation. We adjusted for the known potential confounders; nevertheless, the possibility of other unidentified confounders (such as other medications, physical comorbidities, or lifestyle factors) having an impact on the results cannot be ruled out. We did not have data related to initiation, duration, and dose of statins usage, which have been frequently shown to be influencing the sleep quality and neuropsychological parameters under study. Further, we excluded subjects with severe diseases and dementia, where statins may have more psychological benefits as inferred by various researchers. Finally, our choice of measurement tools, although highly sensitive, present with limitations for diagnostic capabilities owing to suboptimal specificity. Extrapolation of our results to the general population therefore warrants caution.


  Conclusions Top


Statins have positive effects on cognitive functions, quality of sleep, and depression over 80 years of age in our population, although differences in both genders exist. The prevalence of use of statins was found to be low in our population of over 80 years of age. Clearly, there is a need for further longitudinal exploration in oldest-old population to measure the noncardiovascular benefits of statins.

Acknowledgments

Research reported in this publication was conducted by scholars, PKS and EG, in the Fogarty International Center of the NIH training program under Award no. D43 TW 009078. The authors sincerely thank the Indian Council of Medical Research for approval to conduct the study under the STS grant, 2017, and SHARE INDIA for providing logistical support.

Financial support and sponsorship

The authors sincerely thank the Indian Council of Medical Research for approval to conduct the study under the STS grant, 2017, and SHARE INDIA for providing logistical support.

Conflicts of interest

There are no conflicts of interest.



 
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