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系統識別號 U0026-2308201911260500
論文名稱(中文) 比較第二型糖尿病患者使用中效人類胰島素和長效胰島素類似物之臨床效益
論文名稱(英文) Comparative effectiveness and safety of intermediate-acting human insulin versus long-acting insulin analogue in patients with type 2 diabetes: A prevalent new-user cohort study
校院名稱 成功大學
系所名稱(中) 臨床藥學與藥物科技研究所
系所名稱(英) Institute of Clinical Pharmacy and Pharmaceutical sciences
學年度 107
學期 2
出版年 108
研究生(中文) 李寬穎
研究生(英文) Kuan-Ying Li
學號 S66064018
學位類別 碩士
語文別 中文
論文頁數 116頁
口試委員 指導教授-歐凰姿
召集委員-吳宗軒
口試委員-吳晉祥
口試委員-賴嘉鎮
口試委員-郭士禎
中文關鍵字 基礎胰島素  大血管病變  小血管病變  低血糖 
英文關鍵字 basal insulin  vascular outcomes  death  hypoglycemia 
學科別分類
中文摘要 研究背景
  根據2019年美國糖尿病學會之治療指引,在第二型糖尿病患者基礎胰島素的選擇上,長效胰島素類似物有較低的低血糖風險,但如果病人有較寬鬆的糖化血色素標準、低血糖發生機率低、明顯的胰島素抗性或價錢考量,人類胰島素是合適的選擇。近年來美國胰島素價格不斷上漲且胰島素使用人口增加,基礎胰島素的選擇越來越受重視,需要更多研究去釐清基礎胰島素之間的差異。中效人類胰島素與長效胰島素類似物可能有相似的療效與安全性,但價格差異很大,目前無大型臨床試驗直接比較兩者心血管併發症的研究,而過去的觀察性研究限制,也無法完全解決這個疑問。

研究目的
  本研究將探討第二型糖尿病患者使用中效人類胰島素和長效胰島素類似物之療效(大小血管併發症)與安全性(低血糖風險),希望透過此研究提供臨床醫師更多資訊(病人的基本特徵、服藥順從性、經濟能力等)選擇適當的基礎胰島素。
研究方法
  本研究採用回溯性世代研究與prevalent new-user cohort design,研究族群為1999-2012年曾有第二型糖尿病診斷者、在2004-2012年曾於研究期間被開立基礎胰島素,且符合stable use set (有連續3筆以上相同基礎胰島素處方之開立,且連續兩筆領藥間隔不超過30天)。配對過程總共有三個步驟,依序為配對指標年份、降血糖藥物的使用型態與傾向分數,目的為校正研究族群之基本特徵差異,主要觀察結果為心血管事件總和、小血管事件總和、低血糖與死亡,設限事件為停止使用藥物、資料庫中最後一筆記錄或資料庫終止,且以Cox proportional hazard model比較兩組觀察結果之風險。為確保研究結果的穩定性,測試數種次族群分析與敏感性分析對研究結果的影響。

研究結果
  本研究發現,當中效人類胰島素比上長效胰島素類似物時,主要研究觀察結果(HR, 95% CI)如下:心血管事件總和(1.69, 1.14-2.52)、小血管事件總和(0.85, 0.82-0.89)、低血糖(1.80, 1.49-2.16)、死亡(1.60, 0.82-3.15)、重大心血管事件(1.73, 1.00-2.99)。在所有觀察結果中,除了小血管事件總和、腎病變、眼部病變與神經病變在中效人類胰島素有較低的風險之外,其餘觀察結果皆是長效胰島素類似物有較低的風險,但是統計上顯著差異之觀察結果只包含心血管事件總和、小血管事件總和、腎病變、眼部病變與低血糖。

研究結論
  本研究針對第二型糖尿病患者,探討基礎胰島素之療效與安全性,發現中效人類胰島素與長效胰島素類似物相比,有較高的低血糖之風險。此外,亦有較高的心血管事件之風險,此較高之風險很可能與中效人類胰島素有較高低血糖發生率有關;但中效人類胰島素有較低的小血管事件之風險,可能與中效人類胰島素之使用者短時間內血糖控制較好有關。
  建議未來臨床上,第二型糖尿病患者必須根據病人特質選擇適當的基礎胰島素。若要避免低血糖事件的發生,使大血管病變風險最小化,建議選用長效胰島素類似物,但需要注意預防小血管病變,例如:定期檢查腎功能、視網膜與末梢神經等;若臨床上有使用中效人類胰島素的需求,例如:長期規律使用中效人類胰島素之患者或價格因素,臨床照護者應著重於預防低血糖與心血管病變發生。
英文摘要 SUMMARY
Basal insulin is recommended for the type 2 diabetes mellitus (T2DM) patients who need initial insulin therapy. However, there is not sufficient evidence about long-term vascular effects between basal insulin in T2DM population. This study was aimed to estimate the risks of macrovascular events, microvascular events, hospitalized hypoglycemia and all-cause mortality between intermediate-acting human insulin (IAHI) and long-acting insulin analogue (LAIA) users. Selection criteria of study population included newly diagnosed T2DM during 1999-2012 and stable basal insulin use during 2004-2012. Previous studies used incident new-user cohort design who never exposed to any kinds of basal insulin. A prevalent new-user cohort design was adopted to include all possible basal insulin users and generalizability to real-world clinical practice settings. Comparability between treatment groups was achieved by matching on (1) initiation time of study drugs, (2) prior exposure to glucose-lowering agents, and (3) diabetes severity and comorbidities (propensity score). Cox proportional hazard model was employed to assess the association between treatments and study outcomes. Study primary results revealed that IAHI users were associated with higher risks of macrovascular and hospitalized hypoglycemia, and lower risks of microvascular events compared to IAHI users. The higher risks of macrovascular events in IAHI users might be partly explained by hypoglycemia, glucose variability and medication adherence. Future research is needed to explore the association between hypoglycemia event and CVD event in insulin users.
論文目次 中文摘要 I
Extended abstract IV
表目錄 X
圖目錄 XII
第一篇 比較第二型糖尿病患者使用中效人類胰島素和長效胰島素類似物之臨床效益 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簡介 2
2.1.1 糖尿病分類與定義 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症狀 3
第二節 第二型糖尿病之相關併發症 4
2.2.1 第二型糖尿病併發症之致病機轉 4
2.2.2 第二型糖尿病併發症之流行病學 4
第三節 第二型糖尿病治療 5
2.3.1 第二型糖尿病之治療指引 5
2.3.2 胰島素於第二型糖尿病之治療地位 6
2.3.3 胰島素現今於第二型糖尿病之使用型態 7
第四節 基礎胰島素 8
2.4.1 胰島素基本介紹 8
2.4.2 胰島素種類與特性 9
2.4.3 基礎胰島素之降血糖療效與低血糖風險 10
2.4.4 基礎胰島素之心血管事件風險 15
2.4.5 基礎胰島素美國市售價格與國內健保價格 16
第三章 研究目的 18
第四章 研究方法 19
第一節 研究設計 19
4.1.1 研究類型 19
4.1.2 研究材料 19
4.1.3 研究對象 20
4.1.4 藥品暴露及觀察結果之測量工具 21
4.1.5 研究變數 (variables) 21
4.1.6 設限事件 (censored points) 26
4.1.7 研究流程與觀察區間 26
4.1.8 配對(match) 27
4.1.9 人體試驗委員會核備 29
第二節 研究名詞及操作型定義 31
第三節 統計分析 40
第五章 研究結果 42
第一節 研究對象之篩選流程結果 42
第二節 研究對象之基本特徵 44
5.2.1 未經配對之基本特徵 44
5.2.2 放入propensity score model的基本特徵 44
5.2.3 配對後之基本特徵 44
第三節 研究對象之臨床療效與安全性分析 53
5.3.1 主研究分析(primary analysis) 53
5.3.2 次族群分析(subgroup analysis) 54
5.3.3 敏感性分析(sensitivity analysis) 55
第六章 研究討論 97
第一節 臨床療效之討論 97
6.1.1 主研究分析(primary analysis)結果與討論 97
6.1.2 次族群分析(subgroup analysis)結果與討論 99
6.1.3 敏感性分析(sensitivity analysis)結果與討論 101
第二節 研究方法之討論 102
第七章 研究優勢與限制 103
第一節 研究優勢 103
第二節 研究限制 104
第八章 結論及建議 106
第九章 未來研究方向 106
第二篇 臨床藥事服務 108
第一章 服務背景與目的 108
第二章 臨床藥師病房照護 108
第一節 服務內容 108
第二節 成果統計 108
第三節 討論與建議 110
第三章 生物製劑事前審查 111
第一節 服務內容 111
第二節 成果統計 111
第四章 未來建議與心得分享 111
參考資料 113
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