痛風藥物的使用和病患未來失智症或心血管疾病風險的關聯性研究

Association Between Use of Anti-gout Preparations and Dementia or Cardiovascular disease: Nested Case–Control Nationwide Population-Based Cohort Study

莊宗儒(Tsung-Ju Chuang)

指導教授 ： 葉志嶸

中山醫學大學/健康管理學院/公共衛生學系/博士(2022年)

https://doi.org/10.6834/csmu202200012

摘要

目標：痛風是最常見的炎症性關節炎，被發現與許多併發症相關，包含失智症和心血管疾病。然而，過去較少研究抗痛風藥物的使用和其他併發症風險的相關性。因此，本研究主要調查痛風病人使用降尿酸藥物是否能夠降低未來失智症和心血管疾病風險。並特別針對藥物的使用天數、依從率等來做進一步的探討。

方法: 本研究是回朔性世代研究，時間從2005年到2013年，數據來自台灣國民健康保險研究數據庫（NHIRD）。分別研究抗痛風藥物的使用跟失智症還有心血管疾病風險的相關性。痛風藥物與失智症在調整了潛在的干擾因子後，使用邏輯回歸來評估痛風病人使用不同的抗痛風藥和使用不同的天數跟未來病患得到失智症風險的相關性。在心血管疾病組別，除了使用天數之外，更進一步的探討跟藥物使用依從率(adherence rate)的相關性。

結果：在痛風藥物與失智症，經由1:1 的匹配(年齡、性別和痛風診斷)後，共3242位大於50歲的痛風患者(1621位有失智症，1621位沒有)納入最終分析。分析後發現在抗痛風製劑中，僅使用benzbromarone可降低病患發生失智症的風險（調整後的OR為 0.81；95% CI，0.68–0.97）。進一步分析發現使用benzbromarone越長時間的患者失智症的風險越低，使用benzbromarone ≥180天患者能顯著降低未來失智症的風險(調整後的OR為 0.72； 95% CI，0.58–0.89。除此之外，使用benzbromarone降低失智症的效果在男性比女性更顯著。

在心血管疾病的部分，經由1:1的propensity score match後，共 3,706名患有心血管疾病的痛風病患和3706名無心血管疾病的痛風病患被納入最終分析。結果顯示使用降尿酸藥物(allopurinol 和 benzbromarone) <180天的病人有較高的心血管疾病風險。從病人的服藥依從率來看，當 allopurinol 和 benzbromarone服藥依從率>= 0.7時，均具有較低的心血管疾病風險(allopurinol (調整後的OR為 0.66 95% CI: 0.46–0.96), benzbromarone (調整後的OR為 0.68 95% CI: 0.50–0.91))。進一步分析依照年齡(<65歲和>= 65歲)、性別、心血管疾病型態(缺血性心臟病和腦血管疾病)來分組，結果顯示降尿酸藥物的心血管保護作用(依從率≥0.7時)只有對男性和年齡<65歲的病患有統計學上顯著的效果。除此之外，這個保護關聯性在缺血性心臟病比腦血管疾病更明顯。

結論：本研究發現，使用benzbromarone藥物治療的痛風患者，未來得到失智症的風險比較低，尤其是長期的使用和男性病患。除此此外，對於心血管疾病來說，本研究發現只有當病人的服藥(allopurinol 和 benzbromarone)依從率高於0.7才可以顯著降低痛風患者的心血管風險。而且此保護作用在年齡小於65歲和男性病患特別的顯著。因此，醫療保健從業人員對於痛風患者的治療需要更加重視服藥的監測、討論、和支持，來增加病人服藥的持續性和依從性，才能夠降低之後的失智症和心血管併發症。最後，除了失智症和心血管疾病併發症之外，痛風還跟很多其他的併發症相關，包含糖尿病和癌症等，進一步研究的分析議題。

關鍵字

痛風 ； 尿酸 ； 降尿酸藥物 ； 失智症 ； 心血管疾病 ； 服藥依從率

並列摘要

Objectives: Gout is the most common form of inflammatory arthritis and was found to be independently associated with multiple comorbidities including incident dementia and future cardiovascular disease (CVD) in the elderly. However, the associations between anti-gout preparations and dementia or CVD were not well studied.

Methods: Data were collected from Taiwan’s National Health Insurance Research Database (NHIRD). A 2005-2013 retrospective cohort study was conducted, and all investigated subjects were identified by International Statistical Classification of Diseases and Related Health Problems, 9th Revision, Clinical Modification. In dementia group, patients with newly diagnosed gout from 2000 to 2008 and usage of any of urate lowering therapy (ULT) within half a year among age ≥50 years old were enrolled in the study. Conditional logistic regression was used to evaluate the odds ratio of dementia in relation to different ULT (benzbromarone, allopurinol, sulfinpyrazone, probenecid) and number of days of ULT use, after adjustment for potential confounding variables. In CVD group, patients with newly diagnosed gout from 2000 to 2012 and usage of allopurinol or benzbromarone within half a year among age ≥20 years old were enrolled in the study. The outcome of interest is CVD. New diagnosis of CVD after half a year of diagnosis of gout was included in the CVD group. Moreover, conditional logistic regression was used to evaluate the odds ratio of CVD in relation to the days of usage and to the adherence rate of ULT after the adjustment for potentially confounding variables.

Results: A total of 3242 gout patients with and without dementia were selected from the NHIRD and included in the final analysis after 1:1 matching for age, gender, and diagnosis year of gout. In the anti-gout preparations, only use of Benzbromarone decreased the risk of dementia (adjusted OR, 0.81; 95% CI, 0.68–0.97). The result of the subgroup analysis revealed a trend toward a lower risk of dementia with longer use of benzbromarone. Use of benzbromarone for ≥180 days showed a significantly lower risk of dementia (adjusted OR, 0.72; 95% CI, 0.58–0.89). Moreover, the protective effect was more pronounced in males compared with females. In CVD trial, a total of 7412 gout patients (3706 with CVD and 3706 without CVD) have been included in the final analysis after a 1:1 propensity score matched (PSM) for age, sex, comorbidities, aspirin, and statin. The days of usage of allopurinol was <180 days and benzbromarone, in its turn, presupposed a higher risk of CVD. The adherence rate of allopurinol and benzbromarone at ≥ 0.7 both have a lower CVD risk: allopurinol (adjusted OR: 0.66 95% CI: 0.46–0.96), benzbromarone (adjusted OR: 0.68 95% CI: 0.50–0.91). The subgroup analysis revealed an adherence rate of ≥0.7 of ULT with a lower CVD was only found to be present in males and at age <65. Furthermore, the correlations were more pronounced in the ischemic heart disease subgroup than in the cerebrovascular disease group.

Conclusion: This cohort study reveals that gout patients taking benzbromarone are at a decreased risk of developing incident dementia, especially with longer use and in male. The CVD trial reveals that gout patients taking ULT (allopurinol and benzbromarone) with an adherence rate of ≥0.7 are at a lower risk of developing CVD, especially with a younger age (<65) and if they are male. On top of this, the benefit is more pronounced in ischemic heart disease. Despite further prospective trials needing to be warranted to confirm our findings, health care providers may, bearing these conclusions in mind, emphasize the importance of adherence to ULT in gout patients. Further prospective trials are warranted to confirm our findings. Moreover, ULT were also correlated with other comorbidities, such as diabetes, colorectal cancer et al. Hence, the next goal of our research team is to research the associations between anti-gout preparations and these comorbidities.

並列關鍵字

gout ； uric acid ； urate lowering therapy ； dementia ； cardiovascular disease ； adherence rate

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