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研究生： 陳品豪
Chen, Pin-Hao
論文名稱： 比較二線使用基礎胰島素與口服降血糖藥物於metformin治療失敗後的台灣第二型糖尿病病患之臨床效益研究
Comparative effectiveness of second-line initiation of basal insulin therapy versus oral antidiabetic drugs added to metformin therapy among Taiwanese patients with type 2 diabetes
指導教授： 歐凰姿
Ou, Huang-Tz
學位類別： 碩士
Master
系所名稱： 醫學院 - 臨床藥學與藥物科技研究所
Institute of Clinical Pharmacy and Pharmaceutical sciences
論文出版年： 2018
畢業學年度： 106
語文別： 中文
論文頁數： 185
中文關鍵詞： 基礎胰島素 、大血管病變 、小血管病變 、死亡 、低血糖
外文關鍵詞： basal insulin, vascular outcomes, death, hypoglycemia
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    • 中文摘要
    研究背景
    糖尿病全球盛行率隨著人口老化、肥胖人口增加等因素而逐年上升，因糖尿病而導致失能的人口數也逐年增加，造成全球約八千億美金的醫療負擔。第二型糖尿病有許多併發症，而糖尿病心血管併發症是造成糖尿病病人死亡的主因之一。目前已有研究證實糖尿病會增加心血管疾病的風險，目前有許多降血糖藥物可改善血糖控制，而胰島素過去在糖尿病的治療角色通常是最後一線的藥物治療，近來有研究指出早期使用基礎胰島素可以減緩身體胰島素分泌功能喪失，在後來的隨機分派研究中也發現在糖尿病前期或新發生糖尿病的病人，使用基礎胰島素與標準治療相比並不會增加心血管風險，但在觀察性研究卻發現使用胰島素可能會增加心血管風險與死亡率。基於現行臨床指引已將基礎胰島素列為第二線降血糖藥物的選擇之一，以及我們對早期使用基礎胰島素的興趣，因此我們試圖比較二線使用基礎胰島素與其他口服降血糖藥物的臨床效益與安全性。

    研究目的
    本研究對象為過去使用metformin單一治療仍無法控制糖尿病病情，在不停用metfomin的情況下，首次加上不同種類第二線降血糖藥物的台灣第二型糖尿病人。研究目的為比較第二線使用胰島素與口服降血糖藥物治療之臨床效益，包含：糖尿病相關大血管病變、糖尿病相關小血管病變、低血糖以及全因死亡。

    研究方法
    本研究為回溯性世代研究，研究材料為台灣健保資料庫糖尿病病人抽樣歸人檔1999-2013年承保資料。研究族群為2009年至2011年間首次穩定使用metfomin與研究藥物之一的雙重降血糖藥物組合，這些研究藥物包含: basal insulin, sulfonylureas (SUs), dipeptidyl peptidase-4 inhibitor (DPP4-i), acarbose,以及thiazolidinedione (TZD)。主分析中，本研究收納族群為18歲以上第二型糖尿病病人，主要觀察結果為心血管事件總和、小血管事件總和、低血糖事件、以及死亡。本研究分析方式採用意向分析(intention-to-treat analysis)，追蹤至資料終止或是病人於資料庫中最後一筆記錄，並利用傾向分數配對(propensity score matching) 校正研究族群之基本特徵差異，以Cox比例風險模式(cox proportional hazard model)比較兩組別之觀察結果之風險。為確保研究結果的穩定性，我們測試多種交互作用項(interaction term)對研究結果的影響，並調整各操作型定義以進行敏感性分析。

    研究結果
    本研究結果發現，第二型糖尿病病人在接受metfomin與研究藥物 併用的雙重降血糖藥物組合之中，basal insulin和其他口服降血糖藥物相比，有較高且具顯著差異的血管病變與死亡風險。各研究組別主要觀察結果如下(HR, 95% CI): (1) basal insulin vs. SUs: 心血管事件總和(1.36, 1.08-1.71)、小血管事件總和(1.25, 1.12-1.40)、低血糖事件(1.88, 1.44-2.46)、死亡(1.50, 1.03-2.20)。(2) basal insulin vs. DPP4-i: 心血管事件總和(1.52, 1.18-1.97)、小血管事件總和(1.43, 1.27-1.61)、低血糖事件(3.28, 2.33-4.64)、死亡(2.58, 1.59-4.19)。(3) basal insulin vs. TZD: 心血管事件總和(1.20, 0.87-1.67)、小血管事件總和(1.43, 1.21-1.67)、低血糖事件(5.38, 3.03-9.57)、死亡(3.09, 1.55-6.15)。(4) basal insulin vs. acarbose: 心血管事件總和(1.25, 0.98-1.60)、小血管事件總和(1.48, 1.31-1.68)、低血糖事件(3.48, 2.39-5.07)、死亡(2.33, 1.45-3.76)。若將低血糖放入Cox比例風險模式作為校正因子時，部分觀察結果之風險比點估計值呈現下降趨勢。在敏感性分析中，研究結果的方向性，並未因操作型定義的變動而造成方向性的改變。

    研究結論
    本研究結果發現，basal insulin和其他口服降血糖藥物相比，做為第二線降血糖藥物有較高且具顯著差異的血管病變與死亡風險。本研究推估，除了藥物本身因素外，胰島素治療所帶來之低血糖風險，可能是造成第二線基礎胰島素使用者有較高血管病變與死亡風險的原因之一。未來，若病人需要使用基礎胰島素作為第二線治療用藥時，醫療人員與病人皆應嚴密注意低血糖風險，避免低血糖事件的發生。

    SUMMARY
    To investigate comparative effectiveness of basal insulin and oral anti-diabetic drugs (OADs) as 2nd line add-on treatment medication to metformin in type 2 diabetes (T2DM), this study was aimed to estimate the risks of macrovascular events, microvascular events, hypoglycemia, and all-cause mortality of 2nd basal insulin users as compared to other 2nd OADs. Selection criteria of study population included newly diagnosed T2DM during 1999-2011, and newly and stable prescribed metformin-based dual therapy with basal insulin or OADs during 2009-2011. The subjects were stratified based on their 2nd-line drug: basal insulin, sulphonylureas (SUs), dipeptidyl peptidase-4 inhibitor (DPP4-i), thiazolidinedione (TZD) or acarbose. Propensity score matching (PSM) was used to adjust for baseline imbalances in patient’s characteristics and Cox proportional hazard model was applied to evaluate the risk of study outcomes. Study primary results revealed that basal insulin users were associated with significantly higher risks of all-cause death and hypoglycemia as compared to OADs, and associated with significantly higher risk of composite cardiovascular outcome as compared to either SUs group or DPP-4i group. The higher risks of vascular outcomes and all-cause death observed in this study might be partly explained by hypoglycemia, glucose variability and medication adherence. Additionally, we found that long-acting insulin were associated with non-significantly higher risk of macrovascular events compared to SUs or DPP-4i. Future research is needed to assure the long-term effects of basal insulin agents.

    目錄 中文摘要 II Extended abstract VI 表目錄 IV 圖目錄 VII 第一篇 比較二線使用基礎胰島素與口服降血糖藥物於metformin治療失敗後的台灣第二型糖尿病病患之臨床效益研究 1 第一章 研究背景 1 第二章 文獻回顧 2 第一節 第二型糖尿病之疾病概述 2 2.1.1糖尿病定義與分類 2 2.1.2 糖尿病盛行率與醫療負擔 2 2.1.3第二型糖尿病之致病機轉與臨床表徵 3 2.1.4 第二型糖尿病之相關併發症 3 2.1.5 第二型糖尿病之藥物治療 4 第二節 糖尿病與心血管疾病之關聯性 5 2.2.1糖尿病導致心血管疾病之病理機轉 5 2.2.2糖尿病與心血管疾病之相關研究 6 2.2.3 降血糖藥物與心血管疾病之關聯性 7 第三節 第二型糖尿病病人使用胰島素與心血管疾病之關聯性 7 2.3.1 胰島素於第二型糖尿病病人之治療定位 7 2.3.2 胰島素於心血管系統之作用機轉 8 2.3.3 第二型糖尿病病人使用胰島素之臨床效益相關研究 8 第四節 第二型糖尿病病人於第二線使用胰島素之臨床效益相關研究 10 2.4.1 第二線使用胰島素的效益與安全性 10 2.4.2 第二線使用胰島素與Sulfonylureas之效益與安全性比較 11 2.4.3 第二線使用胰島素與DPP4 inhibitors之效益與安全性比較 12 第三章 研究目的 13 第四章 研究方法 14 第一節 研究設計 14 4.1.1 研究類型 14 4.1.2 研究材料 14 4.1.3 研究對象 14 4.1.4 研究族群收錄區間 16 4.1.5 藥品暴露及觀察結果之測量工具 16 4.1.6 研究變數 (variables) 20 4.1.7 設限事件 (censored points) 20 4.1.8 研究流程與觀察區間 21 4.1.9 人體試驗委員會核備 22 第二節 研究名詞及操作型定義 23 第三節 統計分析 35 第五章 研究結果 37 第一節 研究結果圖表目錄 37 第二節 研究對象之篩選流程結果 38 第三節 研究對象之基本特徵 40 5.3.1 未經 Propensity score matching (PSM) 之基本特徵 40 5.3.2 放入Propensity score matching的基本特徵 40 5.3.3 經 Propensity score matching (PSM) 後之基本特徵 40 第四節 研究對象之臨床療效與安全性分析 63 5.4.1 主分析研究結果 (primary analysis) 63 5.4.2 次族群分析 (subgroup analysis) 67 5.4.3 敏感性分析 (sensitivity analysis) 70 第六章 研究討論 124 第一節 研究對象之臨床療效: 主分析(primary analysis)結果與討論 124 6.1.1 主分析結果與過去研究結果之比較 124 6.2.2 主分析結果之探討 133 6.2.3 次族群分析 (sensitivity analysis) 138 6.2.3 敏感性分析 (sensitivity analysis) 140 第七章 研究優勢與限制 142 第一節 研究優勢 142 第二節 研究限制 142 第八章 結論及建議 144 第九章 未來研究方向 144 第二篇 臨床藥事服務：孕婦用藥警訊系統之精進與推動計畫 145 第一章 服務背景 145 第一節 孕婦用藥安全與懷孕分級 145 第二節 美國懷孕分級變革 146 第三節 美國懷孕分級變革對台灣造成的影響 147 第三章、服務目的 147 第四章、執行方式 148 第五章、執行成果 149 第六章、討論與未來展望 161 參考資料 162 表目錄 表 1、健保收載清單中，中長效胰島素製劑與其對應之藥品許可證號 16 表 2、口服降血糖藥品之ATC 代碼 17 表 3、研究族群觀察結果之疾病診斷與處置代碼 18 表 4、研究族群之共病症疾病診斷與處置代碼 28 表 5、慢性疾病複雜度指標及其對應之ICD-9-CM 診斷碼 30 表 6、修正版糖尿病併發症嚴重度指標 (adapted Diabetes Complications Severity Index, aDCSI)及其對應之ICD-9-CM 診斷碼與權重 32 表 7、主分析研究族群於PSM 前之基本特徵 41 表 8、主分析研究族群於PSM 前後之基本特徵: SUs vs Basal insulin 47 表 9、主分析研究族群於PSM 前後之基本特徵: DPP4-i vs Basal insulin 51 表 10、主分析研究族群於PSM 前後之基本特徵: TZD vs Basal insulin 55 表 11、主分析研究族群於PSM 前後之基本特徵: Acarbose vs Basal insulin 59 表 12、主分析族群 (primary analysis) 之臨床療效與安全性分析: Basal insulin vs. SUs 72 表 13、主分析族群 (primary analysis) 之臨床療效與安全性分析: Basal insulin vs. DPP4-i 74 表 14、主分析族群 (primary analysis) 之臨床療效與安全性分析: Basal insulin vs. TZD 76 表 15、主分析族群 (primary analysis) 之臨床療效與安全性分析: Basal insulin vs. Acarbose 78 表 16、主分析族群 (primary analysis) 各觀察結果之追蹤時間長度 80 表 17、主分析族群 (primary analysis) 各觀察結果之發生事件時間長度 82 表 18、次分析族群之臨床療效與安全性分析: Long-acting(LA) insulin vs. SUs 90 表 19、次分析族群之臨床療效與安全性分析: Long-acting(LA) insulin vs. DPP4-i 92 表 20、次分析族群 - 各觀察結果之追蹤時間長度 94 表 21、次分析族群 - 各觀察結果之發生事件時間長度 96 表 22、主分析研究族群因用藥型態改變而被終止觀察之比例 98 表 23、敏感性分析：on treatment analysis (領藥間隔定義為30天) - Basal insulin vs. SUs 100 表 24、敏感性分析：on treatment analysis (領藥間隔定義為30天) - Basal insulin vs. DPP4-i 102 表 25、敏感性分析(領藥間隔定義為30天) - 各觀察結果之發生事件時間長度 104 表 26、敏感性分析(領藥間隔定義為30天) - 各觀察結果之追蹤時間長度 106 表 27、敏感性分析：on treatment analysis (領藥間隔定義為90天) - Basal insulin vs. SUs 108 表 28、敏感性分析：on treatment analysis (領藥間隔定義為90天) - Basal insulin vs. DPP4-i 110 表 29、敏感性分析(領藥間隔定義為90天) - 各觀察結果之追蹤時間長度 112 表 30、敏感性分析(領藥間隔定義為90天) - 各觀察結果之發生事件時間長度 114 表 31、敏感性分析: window period analysis (觀察結果自指標日期30天後開始計算) - Basal insulin vs. SUs 116 表 32、敏感性分析: window period analysis (觀察結果自指標日期30天後開始計算) - Basal insulin vs. DPP4-i 118 表 33、敏感性分析: window period analysis (觀察結果自指標日期90天後開始計算) - Basal insulin vs. SUs 120 表 34、敏感性分析: window period analysis (觀察結果自指標日期90天後開始計算) - Basal insulin vs. DPP4-i 122 表 35、主分析族群臨床療效與安全性風險比較 127 表 36、本研究與過去二線使用 insulin vs. SUs於第二型糖尿病之心血管相關性研究比較 129 表 37、本研究與過去使用 insulin vs. DPP4-i於第二型糖尿病之心血管相關性研究比較 131 表 38、主分析族群 (primary analysis) 之高血糖與相關併發症分析 136 表 39、具危害程度編碼警語與編碼: 第一版 150 表 40、具危害程度編碼警語與編碼: 第二版 159   圖目錄 圖 1、納入條件步驟與示意圖 15 圖 2、研究族群篩選流程 21 圖 3、研究結果圖表目錄 37 圖 4、研究對象之篩選流程結果 39 圖 5、PSM 前研究族群之propensity score分佈: SUs vs. Basal insulin (左：PSM前，右：PSM後) 45 圖 6、PSM 前研究族群之propensity score分佈: DPP4-i vs. Basal insulin (左：PSM前，右：PSM後) 45 圖 7、PSM 前研究族群之propensity score分佈: TZD vs. Basal insulin (左：PSM前，右：PSM後) 46 圖 8、PSM 前研究族群之propensity score分佈: Acarbose vs. Basal insulin (左：PSM前，右：PSM後) 46 圖 9、主分析族群之交互作用項分析: Basal insulin vs. SUs 84 圖 10、主分析族群之交互作用項分析: Basal insulin vs. DPP4-i 87 圖 11、制定具危害程度編碼警語: 文獻判定流程 152 圖 12、經專家會議修訂後問卷版本 155 圖 13、問卷調查統計資料 158

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