糖尿病患者使用 Metformin 與發生失智症風險之關聯性

Metformin Use and Dementia Risk Among Diabetes Mellitus Patients

吳欣珮(Sin-Pei Wu)

指導教授 ： 李建瑩

共同指導教授 ： 蔡雅芳(YA-FANG TSAI)

中山醫學大學/健康管理學院/國際健康產業經營管理碩士在職專班/碩士(2022年)

https://doi.org/10.6834/csmu202200054

摘要

研究動機與目的：台灣已邁入高齡化社會，根據研究，糖尿病(diabetes mellitus, DM)病人罹患失智症(dementia)風險會增加，metformin是第二型糖尿病治療的第一線用藥，越來越多的證據顯示metformin可延緩生物體的衰老，並減少與年齡有關的相關疾病。最近的研究顯示，接受metformin治療的糖尿病患者可以通過幾種潛在機制降低失智症的風險。然而，metformin對失智風險的證據是相互矛盾的。因此，本研究目的欲探討，糖尿病患者使用metformin治療與失智症之間的相關性。

研究方法：本研究為橫斷面研究(Cross-sectional study)，分為metformin使用者和未使用者兩組。資料來源為衛生福利部衛生福利資料科學中心之衛生福利資料，使用2001年至2018年數據作為原始分析，研究對象自2002年至2015年新生糖尿病病人，探討使用metformin 平均每日建議劑量(Defined Daily Dose, DDD)與metformin每月平均用藥強度(Intensity of metformin use, DDD/month)高低，追蹤三年及五年，觀察發生失智症風險之相關性。並以年齡、性別、收入、城市化程度、共病，做為控制變項，探討對罹患失智症風險的影響。

研究結果：三年的追蹤研究發現，接受metformin 的第二型糖尿病患者，cDDD <300 發生失智症的OR：0.92（95% CI = 0.89–0.96）。metformin使用強度（DDD/月）< 10，發生失智症的OR 0.92（95% CI = 0.87–0.97）和 10-25：OR 0.92（95% CI = 0.85–1.00）。五年的追蹤研究發現，接受metformin 的第二型糖尿病患者 cDDD <300 發生失智症的OR 0.94（95% CI = 0.91-0.97）或metformin使用強度（DDD/月）<10 : OR 0.94 (95% CI = 0.91–0.97) 和 10-25: OR 0.95 (95% CI = 0.90–1.00)。而接受metformin 的第二型糖尿病患者，cDDD 300-500、 >500 或metformin使用強度（DDD/月）>25 ，沒有神經保護作用。此外，接受metformin且DCSI評分較高的第二型糖尿病患者，發生失智症的風險較高，而接受metformin，有高血脂、腦血管疾病、焦慮、憂鬱和慢性阻塞性肺共病的患者，發生失智症的風險較高。

結論：接受metformin cDDD <300 或metformin使用強度（DDD/月）<10 和 10-25 的第二型糖尿病患者，發生失智症的風險較低，而cDDD 300-500 和 > 500 或metformin使用強度（DDD/月）>25 ，沒有神經退行性保護作用。

關鍵字

失智症 ； 糖尿病 ； metformin ； 每日平均劑量

並列摘要

Background: Taiwan has officially become an aging society, and patients with diabetes mellitus (DM) have greater risk of developing dementia. metformin is the first-line medication for treating Type 2 diabetes mellitus (T2DM), and more evidence suggest that metformin could delay the aging of organisms and reduce the incidence of age-related diseases. Recent studies have demonstrated that T2DM patients receiving metformin can lower the risk for developing dementia through several potential mechanisms. However, the evidence of metformin on dementia risk is conflicting. This study aims to investigate the association between T2DM patients receiving metformin and dementia risk.

Methods: This study was designed as cross-sectional study to investigate the risk of dementia in DM patients who are receiving metformin by using nationwide data from Taiwan’s National Health Insurance (NHI) Research Database, and designed as a retrospective cohort study to investigate the risk of dementia in new onset DM patients who were receiving metformin in three-year and five-year follow-up, respectively. We allocated subjects into metformin users and non-users. Two models were used to assess utilization of metformin, including cumulative defined daily dose (cDDD) of metformin use and intensity. We enrolled DM patients between 2001 and 2018 in the study, and analyzed 2002 to 2015 data. Additionally, age, gender, income level, the degree of urbanization, and comorbidity were used as control variables to research investigate the impact on the risk of developing dementia.

Results: After three-year follow-up period, our pooled results suggest that DM patients receiving cDDD of metformin use <300 for development dementia: 0.92 (95% CI = 0.89– 0.96) or intensity of metformin use (DDD/month) <10: OR 0.92 (95% CI = 0.87– 0.97) and 10-25: OR 0.92 (95% CI = 0.85– 1.00). After five-year follow-up period, our results also suggest that DM patients receiving cDDD of metformin use <300 for development dementia: OR 0.94 (95% CI = 0.91– 0.97) or intensity of metformin use (DDD/month) <10: OR 0.94 (95% CI = 0.91– 0.97) and 10-25: OR 0.95 (95% CI = 0.90– 1.00). While DM patients receiving cDDD of metformin use 300-500, >500 or intensity of metformin use (DDD/month) >25 had no neuroprotective effect. Our study results also showed that DM patients receiving metformin with higher scores of DCSI (The Diabetes Complications and Severity Index) had a higher risk of developing dementia, and patients receiving metformin comorbidity with hyperuricemia, cerebrovascular disease, anxiety, depression and chronic obstructive pulmonary disease had a higher risk of dementia development.

Conclusion: T2DM patients who are receiving cDDD of metformin use <300 or intensity of metformin use (DDD/month) <10 and 10-25 had a lower risk for developing dementia, while T2DM patients receiving cDDD of metformin use 300-500 and >500 or intensity of metformin use (DDD/month) >25 had no neurodegenerative protective effect.

並列關鍵字

dementia ； diabetes mellitus ； metformin ； defined daily dose

參考文獻

Ahuja, S., Uniyal, A., Akhtar, A., Sah, S. P. (2019). Alpha lipoic acid and metformin alleviates experimentally induced insulin resistance and cognitive deficit by modulation of TLR2 signalling. Pharmacol Rep, 71(4), 614-623. doi:10.1016/j.pharep.2019.02.016

Barini, E., Antico, O., Zhao, Y., Asta, F., Tucci, V., Catelani, T., . . . Gasparini, L. (2016). Metformin promotes tau aggregation and exacerbates abnormal behavior in a mouse model of tauopathy. Mol Neurodegener, 11, 16. doi:10.1186/s13024-016-0082-7

Biessels, G. J., Staekenborg, S., Brunner, E., Brayne, C., Scheltens, P. (2006). Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol, 5(1), 64-74. doi:10.1016/s1474-4422(05)70284-2

Bomfim, T. R., Forny-Germano, L., Sathler, L. B., Brito-Moreira, J., Houzel, J. C., Decker, H., . . . De Felice, F. G. (2012). An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Abeta oligomers. J Clin Invest, 122(4), 1339-1353. doi:10.1172/JCI57256

Bordier, L., Doucet, J., Boudet, J., Bauduceau, B. (2014). Update on cognitive decline and dementia in elderly patients with diabetes. Diabetes Metab, 40(5), 331-337. doi:10.1016/j.diabet.2014.02.002