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研究生:徐鳳儀
研究生(外文):Feng-Yi Hsu
論文名稱:不同血管收縮素酶轉化抑制劑和血管張力素II受體阻斷劑對於糖尿病合併蛋白尿病人之腎臟保護效果評估
論文名稱(外文):Renoprotective Effect of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Diabetic Patients with Proteinuria
指導教授:王繼娟王繼娟引用關係
指導教授(外文):Chi-Chuan Wang
口試委員:林芳如歐凰姿
口試委員(外文):Fang-Ju LinHuang-Tz Ou
口試日期:2016-06-16
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:141
中文關鍵詞:糖尿病蛋白尿糖尿病腎病變血管收縮素酶轉化抑制劑血管張力素II受體阻斷劑腎臟保護全民健康保險研究資料庫
外文關鍵詞:diabetesproteinuriadiabetic nephropathyangiotensin-converting enzyme inhibitorsangiotensin II receptor blockersrenoprotectiveNational Health Insurance Research Database (NHIRD)
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研究背景:
糖尿病是一種全球性的慢性代謝性疾病,目前血管收縮素酶轉化抑制劑(ACEIs)和血管張力素II受體阻斷劑(ARBs)為治療糖尿病腎病變的第一線藥物,然而ACEIs和ARBs這兩大分類的藥物種類繁多,但目前卻沒有任何研究指出,同一藥理分類下的藥物,對於腎臟保護的效果及安全性是否存在差異。
研究目的:
1. 比較ACEIs和ARBs兩類藥品之間的腎臟保護效果和安全性之差異
2. 比較在同藥理分類下,各個ACEI和ARB藥物的腎臟保護效果以及安全性之差異
3. 比較65歲以上老年人使用ACEIs和ARBs藥物,對於腎臟保護效果和安全性之差異
研究方法:
本研究為一回溯性世代研究,利用台灣全民健康保險研究資料庫的百萬歸人檔為資料來源,收集在2002年07月01號至2013年12月31號之中,使用單一ACEI或ARB治療的糖尿病腎病變患者,且在第一次藥物處方後的100天內,須有相同藥物之開立。
主要結果的綜合評估為末期腎臟疾病和腎臟移植的發生,死亡率為次要的結果評估,而安全性的評估則是利用高血鉀來當作分析指標;研究中使用intention-to-treat (ITT) analysis和as-treated (AT) analysis等兩種方法進行分析。
為控制干擾因子,本研究利用傾向分數(propensity score)進行加權(weighting),平衡組間的基礎變因分布。本研究利用SAS 9.4 (SAS Institute Inc., Cary, NC, USA)來進行分析。
結果與討論:
於目的1的分析中,和ACEIs類的藥物相比,使用ARBs類的藥物顯示了較差的腎臟保護效果(hazard ratio[HR], 1.44; 95% confidence intervals [CI], 1.26-1.64; P<0.01),以及較低的安全性(HR, 1.20; 95% CI, 1.05-1.36; P<0.01),為糖尿病腎病變的病人相對較差的用藥選擇。
目的2的分析結果顯示,在7個ACEI藥物中,captopril和fosinopril較無法延緩腎臟的併發症產生(captopril: HR, 1.41; 95% CI, 1.05-1.90; P=0.02 / fosinopril: HR, 1.56; 95% CI, 1.05-2.32; P=0.03),同時對死亡率的降低也較無幫助(captopril: HR, 1.35; 95% CI, 1.11-1.65; P<0.01 / fosinopril: HR, 1.37; 95% CI, 1.03-1.81; P=0.03),視為較差的用藥選擇;在4個ARB藥物中,irbesartan因為較差的腎臟保護效果(HR, 1.38; 95% CI, 1.05-1.82; P=0.02),而被認為較不適用於此類病人,相反地,losartan則因為能降低死亡率(HR, 0.28; 95% CI, 0.09-0.84; P=0.02),而被視為相對較佳的用藥選擇。
在目的3的分析中發現,和ACEIs類的藥物相比,老年人比一般的病患更不適合使用ARBs類藥物,因為對於腎臟保護較無助益(HR, 1.79; 95% CI, 1.42-2.27; P<0.01)以及安全性較低 (HR, 1.28; 95% CI, 1.07-1.54; P<0.01);另外,captopril和另外6個ACEI藥物相比之下,因為無法提升存活率(HR, 3.07; 95% CI, 1.10-8.58; P=0.03),所以較不適用於老年的糖尿病腎病變病患,相反地,相較於另外3個ARB藥物,losartan則因為對於存活率的提升有助益(HR, 0.12; 95% CI, 0.02-0.93; P=0.04),而被視為較好的用藥選擇。
結論:
在我們的研究中發現,ACEIs類藥物比ARBs藥物更適合糖尿病腎病變的病人使用,尤其在高齡的病患中更加顯著;對於一般的病人,fosinopril和irbesartan分別是7個ACEI藥物和4個ARB藥物中較不適合使用的藥物;而對於一般的病人以及老年患者這兩個族群而言,captopril相較於另外6個ACEI藥物,都是相對較差的用藥選擇,相反地,losartan相較於另外3個ARB藥物,都是相對較佳的藥物選擇。

Background:
Diabetes mellitus (DM) is a metabolic disease with high blood sugar levels over extended periods. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are the first-line medications for patients with diabetic nephropathy. While there are many ACEIs and ARBs available on the market, the differences in renoprotective effectiveness and safety among various ACEI and ARB drugs are unclear.
Objective:
1. To compare the renal effectiveness and safety of ACEIs and ARBs.
2. To individually assess the renal effectiveness and safety of different ACEI and ARB agents.
3. To analyze the effectiveness and safety of ACEIs and ARBs individually for patients aged 65 years and older.
Methods:
The present study used the Longitudinal Health Insurance Database (LHID) to conduct a retrospective cohort analyses. We selected the new users of the monotherapy of ACEI or ARB with the diagnosis of diabetic nephropathy from July 1, 2002 through December 31, 2013, and required patients to have a second prescription within 100 days following the first prescription.
The primary outcome was composited of the ESRD and renal transplant. The secondary and safety outcome were defined as the death from any cause and the hyperkalemia event respectively. The analyses were conducted on an intention-to-treat (ITT) basis and an as-treated (AT) basis.
Propensity score weighting was used to balance the numerous important baseline covariates. All analyses were conducted by using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).
Results and Discussion:
In Aim 1, ARBs seem to be a poorer treatment choice for the diabetic nephropathy patients compared with ACEIs due to the inferior renal protective effect (hazard ratio[HR], 1.44; 95% confidence intervals [CI], 1.26-1.64; P<0.01) and poorer safety outcome (HR, 1.20; 95% CI, 1.05-1.36; P<0.01).
In Aim 2, captopril and fosinopril seem to be poorer treatment choices among the 7 ACEI drugs due to the poorer renal outcome (captopril: HR, 1.41; 95% CI, 1.05-1.90; P=0.02 / fosinopril: HR, 1.56; 95% CI, 1.05-2.32; P=0.03) and the higher mortality rate (captopril: HR, 1.35; 95% CI, 1.11-1.65; P<0.01 / fosinopril: HR, 1.37; 95% CI, 1.03-1.81; P=0.03). Additionally, on account of the less renal benefit, irbesartan seems to be an inferior treatment choice among the 4 ARB drugs (HR, 1.38; 95% CI, 1.05-1.82; P=0.02). On the contrary, losartan may be the better treatment choice due to the greater reduction in the mortality (HR, 0.28; 95% CI, 0.09-0.84; P=0.02).
In Aim 3, the elderly patients seem to be even less suitable to use ARBs than ACEIs than the overall study sample owing to the higher risk of renal outcomes (HR, 1.79; 95% CI, 1.42-2.27; P<0.01) and hyperkalemia (HR, 1.28; 95% CI, 1.07-1.54; P<0.01). In addition, taking mortality into account, captopril may be inferior to other 6 ACEI drugs for the older diabetic patients with proteinuria (HR, 3.07; 95% CI, 1.10-8.58; P=0.03). On the other hand, losartan may be superior to other 3 ARB drugs for this population due to a higher decrease in mortality (HR, 0.12; 95% CI, 0.02-0.93; P=0.04).
Conclusions:
Our findings support the use of ACEIs as a relatively renoprotective and safe treatment as compare to ARBs in the diabetic nephropathy patients, especially in the elderly population. Fosinopril and irbesartan seem to poorer treatment choice for the adult population among 7 ACEI drugs and 4 ARB drugs respectively. Both in the adult population and elderly patients, captopril may be inferior to other 6 ACEI drugs, and, conversely, losartan may be superior to other 3 ARB drugs.

致謝-----I
中文摘要-----II
Abstract-----V
Contents-----VIII
List of Table-----XI
List of Figure-----XVI
Chapter 1-Introduction-----1
Chapter 2-Literature Review-----4
2-1 Introduction of Diabetes-----4
2-1-1 Classification and Diagnosis of Diabetes-----4
2-1-2 Epidemiology and Complications-----5
2-2 Treatment of Diabetes and Nephropathy-----7
2-2-1 Insulin Therapy and Other Anti-hyperglycemic Therapy Medications Classification-----7
2-2-2 Diabetic Nephropathy and Risk Management-----9
2-3 Renal Effectiveness of ACEIs and ARBs-----10
2-4 Medication Management in Elderly Adults-----12
Chapter 3-Methods-----14
3-1 Data Source-----14
3-1-1 National Health Insurance Research Database-----14
3-1-2 Longitudinal Health Insurance Database-----14
3-2 Study Design and Subjects Initiated-----15
3-3 Exposure Assessment-----17
3-4 Renal and Safety Outcomes-----18
3-5 Statistical Analysis-----19
Chapter 4-Results-----22
4-1 Sample Selection-----22
4-2 Patients Characteristics-----23
4-3 Primary Outcomes-----25
4-4 Secondary and Safety Outcome-----27
Chapter 5-Discussion-----29
5-1 Renal Effectiveness and Safety of ACEIs and ARBs-----29
5-2 Renal Effectiveness and Safety by Individual Agents-----32
5-3 Renal Effectiveness and Safety among the Elderly Population-----34
5-4 Research Limitation-----35
Chapter 6-Conclusions-----37
Tables-----38
Figures-----133
Acknowledgements-----135
Appendix-----136
References-----137

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