Possible effect of Allopurinol and risk of dementia: An updated Meta-Analysis

doi:10.21203/rs.3.rs-5114989/v1

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Possible effect of Allopurinol and risk of dementia: An updated Meta-Analysis

https://doi.org/10.21203/rs.3.rs-5114989/v1

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Background: Allopurinol is frequently prescribed medication for treatment of hyperuricemia and gout, due to its uric acid lowering capacity with inhibition of xanthine oxidase in the body. However, the side effects of long term allopurinol use among gout patients, particularly related to dementia and cognitive health is not well understood.

Aims & Objectives: This meta-analysis based study aimed to provide an updated and robust assessment of relationship among the long term use of allopurinol and risk of dementia.

Methods: The “Reporting Items for Systematic Review and Meta-Analysis (PRISMA)" guidelines were followed in this study for screening and selection of research articles. Three electronic databases named PubMed, MEDLINE, and Cochrane library were used for data extraction. The primary outcomes of this study were hazard ratio or odds ratio of association of allopurinol exposure and dementia risk among gout patients. The Newcastle-Ottawa Scale (NOS) was applied for quality assessment of observational studies. The RevMan 5.3 software was used for statistical analysis of data from studies included in this study.

Results: About 650 research articles were extracted from three electronic databases after applying the above-mentioned search strategy and the final number of research articles after applying exclusion criteria was 9. Among 9 included studies, four studies were of low risks, four studies were of moderate risks and one study was high risk. Through nine prospective cohort studies, and 1462 to 1710000 patients, the findings of study reported that that exposure of allopurinol is slightly significant as it triggers the risk of dementia among cases as compared to control [RR: 2.28 (95% Cl 2.00, 2.60)] and heterogeneity reported (df =8, p=1.00, I2=0).

Conclusion: Overall, the findings of our study reported a slightly significant association between allopurinol exposure and an increased risk of dementia. This suggests that long-term use of allopurinol may be associated with a higher risk of developing dementia in patients with gout or hyperuricemia.

Health sciences/Diseases

Health sciences/Medical research

Health sciences/Molecular medicine

Health sciences/Neurology

Gout is reported as major risk factor for cardiovascular disease and other cognitive dysfunction [1]. This disease is characterized by high levels of serum uric acid which act as protector against neurodegenerative diseases due to its antioxidant capacity [2, 3]. According to certain research, a higher level of serum uric acid was associated with a lower risk of dementia or cognitive impairment. According to some, there is a correlation between an increased risk of dementia and elevated serum uric acid [3–5]. However, the association among high serum uric acid levels and risk of neurodegenerative disease is unknown.

Allopurinol is frequently prescribed medication for treatment of hyperuricemia and gout, due to its uric acid lowering capacity with inhibition of xanthine oxidase in the body [6]. Moreover, the efficacy of allopurinol in management of elevated uric acid levels and management of gout attacks is well established. However, the side effects of long term allopurinol use among gout patients, particularly related to dementia and cognitive health is not well understood.

Alzheimer’s disease and dementia have been reported as significant public health concern globally, followed by impaired physical and cognitive functions [7]. Finding factors that may affect the possibility of having dementia is becoming more and more important as the global population gets older [8]. It has been proposed that high uric acid levels could be a risk factor for dementia and cognitive impairment. The hypothesis derived from this correlation is that allopurinol may have antioxidant benefits and could alter the risk of dementia by lowering uric acid levels [9]. Allopurinol use for a longer duration of time has been linked to an increased risk of dementia, but the data is still mixed [10]. A number of studies reveal no discernible effect or potentially negative consequences, while others point to potential benefits for cognitive function or a lower risk of dementia [11, 12]. Due to these inconsistent outcomes, a thorough synthesis of the existing data is necessary to gain a deeper understanding of the connection among dementia risk and allopurinol.

Rationale

Dementia has affected approximately 55 million people that made it major public health challenge. The prevalence of dementia is predicted to increase up to double folds by 2050 due to aging population [13]. Most common subtypes of dementia are Alzheimer’s disease and vascular dementia. Due to contributions of environmental, genetic and lifestyle factors, the underlying mechanisms of dementia remain multifactorial and complex. However, the increasing burden of dementia emphasizes the identification of modifiable risk factors and sustainable management strategies [14].

As Xanthine oxidase inhibitor, Allopurinol is most frequently used to reduce uric acid levels among gout and hyperuricemia patients. The efficacy of allopurinol for management of gout is well established [15]. However, research evidences proved that antioxidant properties of allopurinol reduce the oxidative stress in case of neurodegenerative diseases such as dementia. On the contrary, conflicting results have been found regarding the long-term usage of allopurinol and its relationship to dementia risk [16]. It's unclear if allopurinol will be safe and effective in avoiding cognitive decline in the course of time because some research have suggested that it may lower the risk of dementia, while other studies have found neutral or even raised risks [17].

Previous research evidences have high inconsistency that reflects a significant gap, demanding for an updated and comprehensive meta-analysis to highlight association among allopurinol use and dementia risk. Research evidences have limited studies and lacked recent data on dementia risk by allopurinol use that emphasizes the need of study to explore the potential for allopurinol as a preventive agent against dementia [18–21]. Considering that allopurinol is widely used in older persons, a population already susceptible to dementia, it is essential to comprehend its long-term effects in order to optimize treatment approaches and inform clinical judgments.

Therefore, this meta-analysis based study aimed to provide an updated and robust assessment of relationship among the long term use of allopurinol and risk of dementia, addressing the conflicting results in the literature and informing future research directions. By pooled analysis of data from various studies, this study will clarify either long term use of allopurinol is associated with decreased or increased risk of dementia. The findings of this study would provide helpful insights for researchers, and physicians for decision making about therapeutic choice for gout management without any harm to cognitive health.

The “Reporting Items for Systematic Review and Meta-Analysis (PRISMA)" guidelines were followed in this study for screening and selection of research articles [22]. There is no need of additional ethical considerations due to involvement of already published cohorts.

2.1 PICO Framework

Among gout or hyperuricemia patients, what are long term effects of allopurinol medications on risk of dementia? This study used the Population Intervention Control Outcome (PICO) framework to guide the search (Table 1) [23].

Table no. 1: PICO framework for research question of this study

PICO	Description
Population	Adult gout or hyperuricemia patients
Intervention	Allopurinol medications
Control/ comparison	Control without gout and receiving other drugs
Outcome	Hazard ratio of dementia risk

2.2 Search strategy

The research papers related to the study's aims "Long term use of Allopurinol medication and risk of dementia" were extracted. Three electronic databases named PubMed, MEDLINE, and Cochrane library were used for data extraction. The MeSH keywords “(long term use OR outcomes OR side effects) AND (adverse events OR toxicity) AND (Allopurinol OR gout medication) AND (dementia risk OR probability of dementia) were used to reach authentic data. The timeline of research was set from January 2015 to August 2024, as showed in table 2.

Table no. 2: Databases and its keywords

Databases	Keywords	Timeline of search
PubMed	("allopurinol"[MeSH Terms] OR "allopurinol"[All Fields] OR "allopurinol s"[All Fields]) AND ("medic"[All Fields] OR "medical"[All Fields] OR "medicalization"[MeSH Terms] OR "medicalization"[All Fields] OR "medicalizations"[All Fields] OR "medicalize"[All Fields] OR "medicalized"[All Fields] OR "medicalizes"[All Fields] OR "medicalizing"[All Fields] OR "medically"[All Fields] OR "medicals"[All Fields] OR "medicated"[All Fields] OR "medication s"[All Fields] OR "medics"[All Fields] OR "pharmaceutical preparations"[MeSH Terms] OR ("pharmaceutical"[All Fields] AND "preparations"[All Fields]) OR "pharmaceutical preparations"[All Fields] OR "medication"[All Fields] OR "medications"[All Fields]) AND ("risk"[MeSH Terms] OR "risk"[All Fields] OR "risk of"[All Fields]) AND ("dementia"[MeSH Terms] OR "dementia"[All Fields] OR "dementias"[All Fields] OR "dementia s"[All Fields])	2015–2024
MEDLINE	Allopurinol.mp. OR Allopurinol OR Xanthine Oxidase Inhibitors OR Xanthine Oxidase Inhibitors.mp. or Xanthine Oxidase Inhibitors AND Hyperuricemia OR Gout Hyperuricemia AND Long-Term Use OR Chronic Therapy OR Drug Therapy, Chronic AND Dementia OR Alzheimer Disease.mp. OR Alzheimer Disease OR Cognitive Decline OR Neuroprotection OR Oxidative Stress AND Risk Factors OR Cohort Studies or Case-Control Studies	2015–2024
Cochrane library	Allopurinol.mp. OR Allopurinol OR Xanthine Oxidase Inhibitors OR Xanthine Oxidase Inhibitors.mp. or Xanthine Oxidase Inhibitors AND Hyperuricemia OR Gout Hyperuricemia AND Long-Term Use OR Chronic Therapy OR Drug Therapy, Chronic AND Dementia OR Alzheimer Disease.mp. OR Alzheimer Disease OR Cognitive Decline OR Neuroprotection OR Oxidative Stress AND Risk Factors OR Cohort Studies or Case-Control Studies

2.3 Eligibility Criteria

Inclusion Criteria: After searching the above-mentioned electronic databases, the predefined inclusion criteria helped in the screening of research articles [22]. We included only those articles in this study that met the following criteria: 1). Studies discussing patients with gout or hyperuricemia 2). Studies involved treatment of gout with allopurinol 3). Studies involving the outcomes related to association of drug with dementia risk 4) Studies based on longitudinal and cohort studies, 5) Studies that are published in English, and full text is available.

Exclusion Criteria: Those studies were excluded that have: 1). Discussed other patients rather than gout or hyperuricemia 2). Involved the other drugs rather than allopurinol 3). Discussed other clinical outcomes rather than risk of dementia 4). Already published Systematic reviews, Meta-analysis, literature reviews, observational studies, scoping reviews, conferences, and letters, 5) Studies that were published in other languages (Chinese, Arabic, Spanish and German) and duplicated publications or non-full-text papers.

2.4 Data Extraction

Two researchers independently selected the research articles after screening. We extracted the information related to authors, year of study, country, study population, sample size, study follow-up, dose of allopurinol and hazard ratio of dementia risk from selected articles before pooled analysis.

2.5 Primary Outcomes

The primary outcomes of this study were hazard ratio or odds ratio of association of allopurinol exposure and dementia risk among gout patients. All these outcomes related to safety were measured among case and control groups of gout patients receiving allopurinol.

2.6 Quality Assessment

The quality of the included studies was evaluated by using proper tools on the basis of study design. The Newcastle-Ottawa Scale (NOS) was applied for quality assessment of observational studies [24]. The score of > 7 for included studies was considered low risk, scores of 5–7 for included studies indicated moderate risk and < 5 scores for included studies showed high risk. Any disagreement in risk bias assessment was resolved through consensus.

2.7 Statistical analysis

The RevMan 5.4 software was used for statistical analysis of data from studies included in this study. The p-value < 0.05 was considered significant statistically while presenting results as odds ratio (ORs) with 95% confidence interval (CI). Moreover, the heterogeneity was measured by using the Q test and I2 statistics. A random-effects model was applied in case of no significant difference detected from heterogeneity test. The odds and risk ratio were used to evaluate dichotomous data.

3.1 Search Results

The selection and screening of research articles according to research aims “Long term use of Allopurinol medication and risk of dementia” was conducted by following the PRISMA guidelines in this study [25]. About 650 research articles were extracted from three electronic databases after applying the above-mentioned search strategy. By following the PRISMA guidelines, only 162 papers were screened, and 83 articles were excluded before screening. Among those, 67 articles were assessed for eligibility criteria, and the final number of research articles after applying exclusion criteria was 9, as mentioned in Fig. 1.

Figure no. 1: Screening and selection of included studies by PRISMA Guidelines

3.2 Quality Assessment

As showed in Table 3 and Table 4, Among 9 included studies, four studies were of low risks [26–29], four studies were of moderate risks [30–33] and one study was high risk [34] as mentioned in table 1

Table 3

Quality assessment of included studies by Newcastle-Ottawa Scale
	Selection				Comparability		Outcome
Study	Representative of the exposed cohort	Selection of external control	Ascertainment of exposure	Outcome of interest not present	Main factor	Additional factor	Assessment of outcome	Sufficient follow up time	Adequacy of follow up time	Total
Engel et al., 2018 [33]	*	0	*	0	*	0	*	*	*	6/9
Min et al., 2021[32]	*	*	*	0	*	0	*	0	0	5/9
Lai et al., 2021 [29]	*	*	0	*	*	*	*	0	*	7/9
Chuang et al., 2021 [34]	0	*	*	0	*	0	*	*	0	4/9
Singh et al., 2018 [30]	*	*	0	*	*	0	*	0	0	5/9
Hong et al., 2015 [28]	*	0	*	0	*	*	*	*	*	7/9
Singh et al., 2018 [31]	*	*	*	0	*	0	*	0	0	5/9
Scheepers et al., 2019 [26]	*	*	0	*	*	*	*	0	*	8/9
Kim et al., 2023 [27]	*	*	0	*	0	*	*	*	*	8/9

Table 4

Characteristics of included studies
Author, Year	Country	Study population	Cases of Alzheimer’s disease or dementia (receiving allopurinol)	Control	Mean age	Study design	Study period	Dose of intervention	Adjusted HR (%95 Cl)
Engel et al., 2018 [33]	Germany	137,640 patients	27,528	110,112	73.9 ± 6.5 years	Case control design	9 years	200–300 mg/d	0.89 (0.83,0.95)
Min et al., 2021[32]	Korea	22,178 gout patients	2,557	19621	< 60 years	retrospective cohort study	11 years	200 mg/d	0.63 (0.60–0.66)
Lai et al., 2021 [29]	Taiwan	1574 patients	680	691	< 65 years	case–control study	13 years	200–300 mg/d	0.97 ( 0.79–1.20)
Chuang et al., 2021 [34]	Taiwan	3,242 gout patients	1621	1621	50–64 years	retrospective cohort study	8 years	200 mg/d	0.81 (0.68–0.97
Singh et al., 2018 [30]	USA	42,704 gout patients	36,760	5944	< 60 years	Cohort study	6 years	300 mg/day	0.80 (95% CI 0.64, 0.98)
Hong et al., 2015 [28]	Taiwan	28,769 gout patients	1,214	5,905	< 50 years	Cohort study	6 years	300 mg/day	0.77 (0.72–0.83)
Singh et al., 2018 [31]	USA	1.71 million patients	111,656	1598344	65 to < 75 years	cohort study	8 years	200 mg/d	1.15 (95% CI, 1.12, 1.18)
Scheepers et al., 2019 [26]	Sweden	1462 hyperuricemia patients	1447		38 to 60 years	cohort study	44 years	200 mg/d	0.81 (0.72–0.91
Kim et al., 2023 [27]	Korea	30,312 patients	5,052	25,260	65 years	Cohort study	7 years	200 mg/d	0.79 (0.62–1.00)

3.4 Pooled Analysis of OR

Among nine included studies, all reported the Odds ratio or hazard ratio of association among allopurinol use and risk of dementia in gout or hyperuricemia patients. The pooled analysis showed that exposure of allopurinol is slightly significant as it triggers the risk of dementia among cases as compared to control [RR: 2.28 (95% Cl 2.00, 2.60)] and heterogeneity reported (df = 8, p = 1.00, I2 = 0) as showed in Fig. 2.

The symmetrical arrangement of studies were observed in the funnel plot (Fig. 3), where studies with larger sample sizes and large effect sizes are presented, may indicate publication bias. However, our included studies have smaller effect size that disturb the publication of bias.

Our meta-analysis aimed to evaluate the association among long term use of Allopurinol medication and risk of dementia among gout or hyperuricemia patients through pooled analysis. Through nine prospective cohort studies, and 1462 to 1710000 patients, this study conducted pooled analysis of association among long term use of allopurinol medications and dementia risk among gout or hyperuricemia patients. The follow up of included studies ranged from 6 to 44 years which assisted in evaluation of long term effects of allopurinol medications. The average dose of allopurinol was among 200-300mg/d, given to gout or hyperuricemia patients to reduce serum uric acid levels. As this drug has antioxidant effects for control of serum uric acid so, it alternatively acts as protection against neurodegenerative diseases. The outcomes of study were odd ratio or hazard ratio of association among allopurinol exposure and dementia risk among gout patients. The findings of study reported that that exposure of allopurinol is slightly significant as it triggers the risk of dementia among cases as compared to control [RR: 2.28 (95% Cl 2.00, 2.60)] and heterogeneity reported (df = 8, p = 1.00, I2 = 0). The quality assessment of included cohort studies was evaluated by Newcastle scale (NOS). Among 9 included studies, four studies were of low risks [26–29], four studies were of moderate risks [30–33] and one study was high risk [34]. However, the publication bias was zero due to involvement of studies with large effect sizes. The reason behind zero heterogeneity is inclusion of studies with large study population and long term follow ups. The existence of high-risk trials raises the likelihood of hidden biases that may not be readily apparent in heterogeneity statistics, even though our analysis revealed low heterogeneity (I2 = 0%).

The findings of this study somehow establish the evidence related to long term allopurinol exposure and its association with dementia risk. Although, our evidence redirects towards the more future investigations to evaluate both negative and positive effects [35, 36], but it is not enough strong to effect the clinical implications of allopurinol medications for gout patients [37, 38]. When administering allopurinol, medical professionals need to take the needs of the patient into account. The choice to use allopurinol for patients with gout or hyperuricemia who are susceptible to cognitive loss should balance the medication's known advantages against its unclear effects on cognitive function.

Previous research evidences reported that allopurinol use among patients of dementia have positive effects in improving the symptoms of aggressive behavior. Lara et al., [39] conducted case control study to evaluate the efficacy and tolerability of pharmacological treatments such allopurinol among dementia patients with aggressive behavior. As mentioned, allopurinol is an inhibitor of the enzyme xanthine oxidase and anti-aggressive agent. In this study, six patients of dementia were treated with allopurinol 300 mg a day orally for 6 weeks to reduce aggressiveness symptoms. The findings reported that allopurinol was helpful in management of mild to moderate symptoms of aggressive behavior, but failed in case of severe symptoms among dementia patients. Allopurinol may have a therapeutic effect because it inhibits the enzyme xanthine oxidase, which may reduce the generation of oxygen-free radicals or encourage the buildup of purines. Further research is necessary to validate these first findings. Another study, Lai et al., [40] reported the association among risk of dementia and exposure of allopurinol for case and control groups with gout or hyperuricemia. Through 4 case-control studies discussing the exposure of allopurinol and possible risk of dementia among gout patients during follow up 9–14 years. The pooled analysis of allopurinol exposure and risk of dementia were higher among cases as compared to controls. Overall, the findings of this study reported the association among exposure of allopurinol and risk of dementia. However, this study was not enough strong to support the association among allopurinol exposure and risk of dementia or other cognitive dysfunctions. Additionally, drugs used to treat gout and hyperuricemia have neuroprotective benefits against neurodegenerative disorders; allopurinol, for example, reduces the risk of Alzhiemer's disease by 24% [41]. Research has demonstrated that allopurinol reduces AD mitochondrial dysfunction by blocking the enzyme alcohol dehydrogenase that binds to amyloid [42]. In conclusion, there is inconsistent evidence about the association among uric acid and the risk of neurodegenerative disorders, and further research into the potential side effects of antihyperuricemia drugs is justified.

The strengths of our study include the evaluation of association among allopurinol use and dementia risk which assessed by nine included cohort studies, as compared to previous research in this domain [40]. The study provided the pooled analysis of hazard ratio of association among allopurinol exposure and dementia risk among gout patients. This study will provide the evidence for clinical implications and decision making related to the allopurinol medications for management of gout patients with dementia.

However, there are few limitations in this study with enormous advantages. Firstly, the number of included studies was small to fulfill research aims. Larger number of studies is required to evaluate long term allopurinol exposure and risk of dementia. Secondly, the publication bias was high due to small effect size in this study. Due to long term follow ups of included studies, the authenticity of result might disturb as patient may face other medical conditions. Thirdly, the outcomes of our study were limited. Broad range of outcomes should be studied for evaluation of association among allopurinol exposure and dementia risk among gout patients. Though by methodological aspect, our study lacked sensitivity analysis and subgroup analysis that weaken study’s authenticity. The variability in outcome measures and these long term follow ups also affects study’s results.

Although this meta-analysis offers insightful information about the possible relationship between long-term allopurinol use and dementia risk, additional research is necessary in a few important areas to fill in existing gaps in the evidence and improve the body of knowledge. Future research should look into the underlying molecular mechanisms that could account for allopurinol's either neuroprotective or neurotoxic effects in addition of explaining the connection.

Overall, the findings of our study reported a slightly significant association between allopurinol exposure and an increased risk of dementia. This suggests that long-term use of allopurinol may be associated with a higher risk of developing dementia in patients with gout or hyperuricemia. However, the presence of publication bias, likely due to the inclusion of studies with small effect sizes, influenced the overall results and interpretation of the findings. Further investigations are required for evaluation of long term use of Allopurinol medication and risk of dementia among gout patients.

Author Contribution

A.A. (Ahmed Alenezi) conceptualized the study, performed the meta-analysis, and wrote the main manuscript text. M.A. (Mai Ahmad) contributed to the literature search, data extraction, and quality assessment of included studies. I.A. (Ibrahim Ayyoub) assisted with the statistical analysis and interpretation of results. All authors contributed to the study design, reviewed and edited the manuscript, and approved the final version for submission.

Data Availability

• The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

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No competing interests reported.

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Possible effect of Allopurinol and risk of dementia: An updated Meta-Analysis

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Abstract

Figures

1. Background

2. Methods

2.1 PICO Framework

2.2 Search strategy

2.3 Eligibility Criteria

2.4 Data Extraction

2.5 Primary Outcomes

2.6 Quality Assessment

2.7 Statistical analysis

3. Results

3.1 Search Results

3.2 Quality Assessment

3.4 Pooled Analysis of OR

Discussion

Conclusion

Declarations

Author Contribution

Data Availability

References

Additional Declarations

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