| 摘要: | 研究背景及目的:
隨著人口結構的老化，近年來失智症已成為全球各國在健康照護上所面臨的重大問題。失智症是一種由多種症狀組成的疾病，會導致各種認知功能的退化，且目前尚無有效的治療方法，僅能控制症狀並減緩疾病進展。為了有效降低患上失智症的風險，需要同時針對各種前驅風險因子進行控制。近期的動物試驗和觀察性研究顯示，由於具有多重藥理作用，pioglitazone可能具有降低失智症風險的效果，因此成為一種潛在的預防性藥物。為了更準確地辨識出使用pioglitazone的潛在失智症風險族群，本研究將針對不同嚴重程度的糖尿病患者，分析其使用pioglitazone對失智症及相關特定失智症亞型的風險影響。
研究方法:
此研究資料來源取自於2000年到2019年台灣健康保險資料庫的200萬人抽樣檔，並收納其2001年到2014年間年紀大於60歲且無失智症的新發糖尿病病人，並根據aDCSI (adapted Diabetes Complication Severity Index)指標將患者分成不同嚴重程度的糖尿病研究群，並定義aDCSI 分數0-1分為低嚴重的糖尿病，aDCSI 分數在2-3分為中度嚴重的糖尿病，aDCSI分數4分以上為高嚴重度的糖尿病，在每個研究群中，將使用pioglitazone的暴露組與使用DPP-4抑制劑 (Dipeptidyl peptidase-4 inhibitors)的對照組，依照年齡、性別、干擾因子等進行1:1傾向分數配對，並統一追蹤五年，結果將以Cox比例風險模型去計算各組失智症及特定失智症亞型之風險比。此外，並進一步將暴露組累積用藥劑量及累積用藥天數利用三分位法進行失智症之風險分析。
研究結果:
在輕度糖尿病患者中，與對照組相比，使用pioglitazone的失智症風險比為0.89倍（HR = 0.892, 95% CI, 0.719-1.106）。在中度糖尿病患者中，pioglitazone的失智症風險比為0.75倍（HR = 0.751, 95% CI, 0.527-1.069）。在重度糖尿病患者中，pioglitazone的失智症風險比為2.09倍（HR = 2.09, 95% CI, 1.012-4.317）。次要結果顯示，在阿茲海默症和血管性失智症風險分析中，任一研究群的暴露組與對照組之間沒有顯著性差異。然而在累積劑量及累積使用天數的分析結果中，輕度和中度嚴重糖尿病患者，使用pioglitazone在較高累積劑量或較長累積使用天數會降低失智症風險，而在重度嚴重糖尿病患者，則會增加失智症風險。
結論:
在高嚴重程度糖尿病之病人，pioglitazone的使用可能會增加失智症之風險。而在低嚴重糖尿病及中度嚴重糖尿病之病人，使用pioglitazone在較高累積劑量或較長累積天數下，對於失智症之風險是具有保護效果的，也顯示出在pioglitazone藥物機轉多樣性下，可能成為潛在預防失智症的輔助治療。
Background and objective:
As populations age, dementia has emerged as a significant challenge in healthcare worldwide in recent years. Dementia encompasses a range of symptoms that decline irreversibly in cognitive domains. Currently, there are no medications that effectively treat dementia; treatment options are limited to managing symptoms and slowing the progression of the disease. To reduce the risk of dementia effectively, it's crucial to address various predisposing risk factors simultaneously. Pioglitazone, known for its multifaceted pharmacological mechanisms, has shown promise in reducing dementia risk, as evidenced by recent animal studies and observational research. It has become a potential candidate for dementia prevention. To better identify the use of pioglitazone in populations at risk of dementia, this study aims to evaluate its impact on dementia and its specific subtypes in patients with different degrees of diabetes severity.
Methods:
The database is based on the 2 million beneficiaries of Taiwan's National Health Insurance Research Database (NHIRD) from 2000 to 2019. It focuses on individuals aged 60 and above who were newly diagnosed with diabetes between 2001 and 2014 and did not have dementia. Patients were categorized into different severity cohorts using the adapted Diabetes Complications Severity Index (aDCSI). Within each cohort, the exposure group is pioglitazone users, and the comparison group is DPP-4 inhibitor users, with 1:1 propensity score matching based on age, sex, and confounders. Then, each patient followed up for five years. The study used Cox proportional hazards models to calculate the risk ratio for dementia and specific subtypes in each study cohort. Additionally, the pioglitazone cumulative defined daily dose and the duration of therapy were analyzed using tertiles to assess dementia risk.
Results:
In patients with mild severity of diabetes, the risk ratio for developing dementia with pioglitazone compared to the control group was 0.89 (HR, 0.892, 95% CI, 0.719-1.106). In patients with moderate severity of diabetes, the risk ratio was 0.75 (HR, 0.751, 95% CI, 0.527-1.069). However, in patients with severe diabetes severity, the risk ratio for dementia was 2.09 (HR, 2.09, 95% CI, 1.012-4.317) compared to the control group. In the secondary outcomes, including Alzheimer's disease and vascular dementia, there were no significant differences between the exposed and control groups in any study cohort. However, regarding the analysis of cumulative defined daily dose and the duration of therapy, in patients with mild and moderate severity of diabetes, the higher cumulative defined daily dose or longer duration of therapy with pioglitazone compared to the control group was associated with a reduced risk of developing dementia. Conversely, in patients with severe diabetes severity, it was associated with an increased risk of dementia.
Conclusion:
In patients with severe diabetes severity, the use of pioglitazone may increase the risk of dementia. However, for patients with mild to moderate diabetes severity, pioglitazone exhibits a protective effect against the risk of dementia with higher cumulative dosage or longer duration of use. This suggests that with its multifaceted pharmacological mechanisms, pioglitazone could serve as an adjunctive therapy for potential dementia prevention. |
