臺灣博碩士論文加值系統

研究背景
根據文獻回顧，全球糖尿病人口都在成長當中，預估在2035年全球糖尿病人口會超過5億人，這其中也包含著台灣，隨著糖尿病人口的增加，伴隨而來的問題並不僅是只有糖尿病本身的問題，還有其大小血管的併發症，醫療負擔將是更加的沉重，因此糖尿病的課題是我們當前一件重要的事情。糖尿病的治療，除了生活型態改變外，藥物的治療也是佔了相當大的一部分，目前第一線的口服降血糖藥物為metformin，二線用藥則有sulfonylurea、meglitinide、acarbose、thiazolidinedione與新型的口服降血糖藥物DPP-4 inhibitors，DPP-4 inhibitors相較於傳統的藥物副作用較少，臨床試驗也證實其降血糖的效果，但於預防大血管病變的風險，並無充足的實證比較DPP-4 inhibitors與傳統二線口服降血糖藥，且到目前為止台灣尚未有本土性實證，分析目前DPP-4 inhibitors的處方型態與臨床療效 (effectiveness)。
研究目的
1. DPP-4 inhibitors處方型態分析
2. DPP-4 inhibitors臨床療效分析 (effectiveness)
研究方法
本研究利用台灣健保資料庫中的糖尿病病人抽樣歸人檔1999-2012年承保資料，擷取第二型糖尿病病人，於處方型態分析－(1)，分析2008年至2012年口服降血糖藥的耗用量及花費；處方型態分析－(2)，擷取1999年至2010年第二型糖尿病並且接受metformin-based治療的病人，分析在2011年至2012年DPP-4 inhibitors被處方的型態；比較metformin合併二線藥物，擷取單一穩定使用metformin的第二型糖尿病病人，並且在2009年至2010年加上 (add-on) 第二線口服降血糖藥物，追蹤病人加入二線藥物後，因大血管事件 (中風、心衰竭與急性心肌梗塞) 住院的風險，利用Cox proportional hazard model作存活分析；DPP-4 inhibitors療效分析，考慮糖尿病在臨床治療上的多變性，利用time-varying Cox proportional hazard model，加入隨時間改變的變項，分析各類藥物於大血管事件的風險。
研究結果
處方型態分析－(1)的結果，DPP-4 inhibitors的耗用量比率從2009年的1.5%，至2012年成長到9.4%，花費從2009年的$126,341,610 (5.9%)，至2012年成長到$769,964,779 (33%)；處方型態分析－(2)，目前DPP-4 inhibitors在台灣的使用上，metformin單一使用組，有75%的病人會將metformin換成DPP-4 inhibitors，metformin-based組，有58.2%的病人會將DDP-4 inhibitors選擇作為第三線用藥；DPP-4 inhibitors療效分析，結果顯示DPP-4 inhibitors相較於sulfonylurea發生大血管事件的風險為1.06 (95%信賴區間，0.94-1.19)，中風風險為1.05 (95%信賴區間，0.91-1.21)；比較metformin合併二線口服降血糖藥物，合併DPP-4 inhibitors組相較於sulfonylurea組，在傾向分數 (propensity score) 1：1配對後，發生合併全部大血管事件風險為0.814 (95%信賴區間，0.668- 0.991 )，中風風險為0.755 (95%信賴區間，0.580-0.983 )，心衰竭為1.047 (95%信賴區間，0.763-1.438 )。
研究結論
研究結果顯示DPP-4 inhibitors在台灣使用趨勢顯示逐年上升，花費更是上升更為快速，但目前DPP-4 inhibitors在台灣還是被認為是二線藥物的替代選擇或三線用藥，療效分析結果顯示，DPP-4 inhibitors作為metformin的add-on用藥，降低大血管事件 (中風與急性心衰竭) 風險比sulfonylurea較為優秀，因此在臨床上，建議DPP-4 inhibitors可為二線用藥的首選。

關鍵字：糖尿病、雙基胜肽酶-4型抑制劑、大血管病變、處方型態分析

SUMMARY
We analyzed the prescription and medical expenditures of oral hypoglycemic agents in Taiwan, especially focusing on dipeptidyl peptidase-4 inhibitors (DPP4i). Then, we analyzed the effectiveness of DPP4i and comparative effectiveness of DPP4i as second-line oral hypoglycemic agents in the patient with type 2 diabetes mellitus. The trend of amount and cost of DPP4i increased rapidly from 2009 to 2012 in Taiwan. DPP4i were shown to decrease the risk of CVD by using 1 defined daily dose. And metformin plus DPP4i showed more effectiveness on CVD events as compared to metformin plus sulfonylurea.

Key words: dipeptidyl peptidase-4 inhibitors, type 2 diabetes mellitus, utilization, macrovascular diseases

INTRODUCTION
The prevalence of type 2 diabetes mellitus (T2DM) increases substantially worldwide. The burden of diabetes and associated complications will become more serious in the future. In the pharmacotherapy of T2DM, Dipeptidyl peptidase-4 inhibitors (DPP4i) are newly available antidiabetic drugs that can be used as combination therapy with other oral hypoglycemic agents (as 2nd or 3rd add-on drug). The effect of DPP4i on CVD outcomes has been investigated in clinical trials where DPP4i was not associated with an increased CVD risk or had a potential reduction of CVD events. However, comparative researches with sufficient sample and follow up are exile. Moreover, the utilization of oral hypoglycemic agents, including DPP4i, has not been analysis in Taiwan. Our study objective specified in below:
1. Prescription and medical expenditures of oral hypoglycemic agents in Taiwan, especially focusing on DPP4i.
2. Comparative effectiveness and safety of dipeptidyl peptidase-4 inhibitors in Taiwan T2DM patient.

MATERIALS AND METHODS
We utilized the Longitudinal Cohort of Diabetes Patients (LHDB), the database is sampling the diabetes patients from National Health Insurance Research database (NHIRD).

Utilization of oral hypoglycemic agents－
Study patients were derived from the LHDB if they met: aged 〉 18 years, type 2 diabetes and at least one OHAs prescribed. First, we presented the market share of each OHA per year as the percentage of amount (in terms of defined daily dose, DDD) and costs for a given OHA within total OHAs through 2009 to 2012. Second, we analyzed prescription pattern of OHAs to identify the percentage of the patients being added-on or switched to DPP4i since it was available.
Comparative effectiveness and safety of metformin plus dipeptidyl peptidase-4 inhibitors in Taiwan T2DM patient－
The 1999-2010 dataset were used to identify cases with any hospitalized event for diabetes as one of the discharge diagnoses or those with any outpatient visits for DM. The patient with stable metformin use and add-on second-line OHAs in 2009-2010 were be included in study population. The primary outcome were observation the first macro vascular disease (MCVD) related hospitalization after index date. We used Cox proportional hazards model to analysis the relative risk between each class OHAs.
Effectiveness of dipeptidyl peptidase-4 inhibitors－
We included T2DM patient with first use OHAs in 2009-2010. Because the treatment of DM may change according to patient situation. We use time-varying Cox proportional hazard to control the some variables that may change by time and analysis the relative risk between DPP4i and sulfonylurea.

RESULT
Utilization of oral hypoglycemic agents－
The average annual utilization and costs associated with DPP4i significantly increased over time. The percentage of DPP4i use in OHAs was 1.53 % in 2010 and 9.42 % in 2012 (6 fold of) which was most prescribed OHA as followed by sulfonylurea and metformin. The estimated average costs of DPP4i were $126,341,610 (NTD) and $769,964,779 (NTD) in 2012, which accounted for 33% of total healthcare spending of OHAs and was the highest spending OHA. Also, during 2010-2012, 75% of mono-therapy OHA users (n=1,647) switched to DPP4i and 13.7% of them (n=1,478) were added on DPP4i; 42.6% of dual OHA users (n=953) were switched to DPP4i and 58.2% of them (n=9,707) were added on DPP4i; 7% of triple OHA therapy users (n=2,137) switched to DPP4i.

Comparative effectiveness and safety of metformin plus dipeptidyl peptidase-4 inhibitors in Taiwan T2DM patient－
A total of 47,346 patients who met our criteria were included in the study cohort used with SU (n=37248), DPP4i (n=3411), TZD (n=1060), Acarbose (n=2742), Meglitinde (n=2885). In adjusted analyses with metformin+SU as reference, metformin+DPP4i was associated with relative risk of 0.814 (0.668-0.991) for MCVD, 0.755 (0.580-0.983) for stroke, 0.598 (0.370-0.966) for Acute myocardial infarction, 1.047 (0.763-1.438) for heart failure.
Effectiveness of dipeptidyl peptidase-4 inhibitors－
The cohort included 123,132 new users of oral antidiabetic drugs. DPP-4 inhibitors users show similar relative risk of MCVD hospitalization to sulfonylurea users (adjusted hazard ratio 1.060, 95% confidence interval, 0.944-1.189), the adjusted hazard ratio of patients without CVD history is 0.895 (95% confidence interval, 0.745-1.074).

CONCLUSION
The use and cost of DPP-4 inhibitors have rapidly increased after DPP-4 inhibitors was approved in Taiwan. There was a reduction in MCVD relative hospitalization for patients treated with metformin combined with DPP4i versus metformin plus SU.

目錄
中文摘要 i
Extended abstract iii
表目錄… xii
圖目錄… xiv
第一篇 利用台灣健保資料庫比較Dipeptidyl Peptidase-4抑制劑於 第二型糖尿病病患之大血管病變療效分析 1
第一章 研究背景 1
第二章 文獻回顧 2
第二章 第一節 糖尿病介紹 2
2.1.1 糖尿病定義與臨床症狀 2
2.1.2 糖尿病流行病學 4
2.1.3 糖尿病相關併發症 6
2.1.4 糖尿病併發症流行病學 8
2.1.5 糖尿病的治療 10
第二章 第二節 DPP-4 inhibitors (DPP4i) efficacy 11
2.2.1 簡介口服降血糖藥 ─ DPP-4 inhibitors 11
2.2.2 DPP-4 inhibitors (DPP4i) 臨床療效 14
第二章 第三節 DPP-4 inhibitors effectiveness 16
第二章 第四節 DPP-4 inhibitors safety 21
第三章 研究目的 22
3.1.1 文獻回顧總結 22
3.1.2 論文研究目的 23
3.1.3 論文研究假設 23
第四章 研究方法 24
第四章 第一節 研究架構 24
4.1.1 研究類型 24
4.1.2 研究材料 24
4.1.3 研究架構 24
第四章 第二節 DPP-4 inhibitors 處方型態研究 – (1) 25
4.2.1 研究背景及研究設計 25
4.2.2 納入條件 25
第四章 第二節 DPP-4 inhibitors 處方型態研究 – (2) 26
4.2.1 研究設計 26
4.2.2 納入條件 27
4.2.3 排除條件 27
4.2.4 各研究組別分析結果圖示 27
第四章 第三節 DPP-4 inhibitors 於大血管病變療效分析 28
4.3.1 研究背景及研究設計 28
4.3.2 納入條件 29
4.3.3 排除條件 29
4.3.4 研究流程 30
第四章 第四節 於糖尿病二線藥物中比較Metformin合併DPP-4 inhibitors與傳統Metformin合併sulfonylurea於大血管病變療效分析 31
4.4.1 研究背景及研究設計 31
4.4.2 納入條件 32
4.4.3 排除條件 33
4.4.4 研究流程 33
第四章 第五節 研究名詞及操作型定義 34
4.5.1 研究名詞及操作型定義 34
第四章 第六節 統計分析 48
4.6.1 統計工具 48
4.6.2 統計模式設定 48
4.6.3 資料分析方法 48
第五章 研究結果 49
第五章 第一節 DPP-4 inhibitors 處方型態分析－(1) 研究結果 49
5.1.1 處方型態分析研究流程 49
5.1.2 各類口服降血糖藥物使用量分析結果 50
5.1.3 各類口服降血糖藥物花費 54
第五章 第二節 DPP-4 inhibitors 處方型態分析－(2) 研究結果 58
5.2.1 研究流程及病人摘選 58
5.2.2 糖尿病病人換藥或加藥的選擇 59
第五章 第三節 DPP-4 inhibitors 於大血管事件療效分析結果 62
5.3.1 研究流程 62
5.3.2 世代研究病人臨床特質 62
5.3.3 各組預防大血管事件的風險 65
5.3.4 DPP-4 inhibitors於大血管事件療效分析總結 68
第五章 第四節 於糖尿病二線藥物中比較Metformin合併DPP-4 inhibitors與傳統Metformin合併sulfonylurea於大血管病變療效分析 69
5.4.1 世代研究病人篩選 69
5.4.2 各研究組病人臨床特質 71
5.4.3 以所有變項計算出各組的傾向分數 (propensity score) 74
5.4.4 各組利用傾向分數配對後的病人特質 74
5.4.5 各組尚未配對前大血管事件及死亡的發生百分比 85
5.4.6 各組配對後發生大血管事件的比率與相對風險 87
5.4.7 次分析 ─ 各組發生死亡的風險 89
5.4.8次分析 ─ 增加觀察終點 (censor point) 後各組大血管事件的風險 95
5.4.9 次分析 ─ 加入隨時間改變的變項後大血管事件的風險 98
5.4.10 次分析－加入指標日期後病人metformin藥品持有率的排除條件 101
5.4.11次分析 ─ DPP-4 inhibitors 做為第三線口服降血糖藥物的療效 103
5.4.12 安全性分析 ─ DPP-4 inhibitors發生低血糖及胰臟炎之風險 108
5.4.13比較Metformin合併DPP-4 inhibitors或其他二線藥物與傳統Metformin合併sulfonylurea於大血管病變療效分析研究結果總結 109
第六章 研究結果討論 110
第六章 第一節 處方型態分析 ─ (1) 結果討論 110
6.1.1 口服降血糖藥耗用量結果討論 110
6.1.2 口服降血糖藥物花費結果討論 112
第六章 第二節 處方型態分析 ─ (2) 結果討論 113
第六章 第三節 DPP-4 inhibitors療效分析結果討論 114
6.3.1 病人臨床特質分布 114
6.3.2 研究方法與研究結果討論 115
第六章 第四節 於糖尿病二線藥物中Metformin合併DPP-4 inhibitors與傳統Metformin合併sulfonylurea於大血管病變療效分析結果討論 117
6.4.1 世代研究病人臨床特質討論 117
6.4.2 大血管事件風險結果討論 119
6.4.3 DPP-4 inhibitors心衰竭風險討論 123
6.3.4 安全性討論 128
第六章 第四節 研究優勢 131
第六章 第五節 研究限制 132
第六章 第六節 研究結果總論與臨床建議 133
第六章 第七節 未來研究方向 134
第二篇 臨床藥事服務 ─ 評估糖尿病病人生活品質 135
第一章 服務背景 135
第二章 服務目標 136
第三章 服務方法及服務材料 136
第三章 第一節 服務方法 136
3.1.1 服務對象 136
3.1.2 服務地點 137
第三章 第二節 服務材料 137
第四章 服務結果 138
第五章 服務討論與未來方向 138
參考文獻 139
附錄…… 147

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