臺灣博碩士論文加值系統

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。

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.

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

1.International Diabetes Federation. IDF Diabetes Atlas 8th Edition 2017.
2.World Health Organization. Global report on diabetes. 2016; https://www.who.int/diabetes/en/. Accessed May 6, 2019.
3.American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(Suppl 1):S90-S102.
4.American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S13-S27.
5.Jiang YD, Chang CH, Tai TY, Chen JF, Chuang LM. Incidence and prevalence rates of diabetes mellitus in Taiwan: analysis of the 2000-2009 Nationwide Health Insurance database. J Formos Med Assoc. 2012;111(11):599-604.
6.衛生福利部. 106年死因統計結果分析. 2018; https://www.mohw.gov.tw/cp-16-41794-1.html. Accessed May 5, 2019.
7.衛生福利部統計處. 106年全民健康保險醫療統計. 2018; https://dep.mohw.gov.tw/DOS/cp-4269-45872-113.html. Accessed May 1, 2019.
8.American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37 Suppl 1(Suppl 1):S81-90.
9.Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J. 2013;34(31):2436-2443.
10.Fayfman M, Pasquel FJ, Umpierrez GE. Management of Hyperglycemic Crises: Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State. Med Clin North Am. 2017;101(3):587-606.
11.Rao Kondapally Seshasai S, Kaptoge S, Thompson A, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364(9):829-841.
12.Deshpande AD. Epidemiology of Diabetes and Diabetes-Related Complications. Physical Therapy. 2008;88(11):1254-1264.
13.Yu N-C, Chen IC. A decade of diabetes care in Taiwan. Diabetes Research and Clinical Practice. 2014;106:S305-S308.
14.Yu NC, Su HY, Tsai ST, et al. ABC control of diabetes: survey data from National Diabetes Health Promotion Centers in Taiwan. Diabetes Res Clin Pract. 2009;84(2):194-200.
15.Lin SD, Tsai ST, Tu ST, et al. Glycosylated hemoglobin level and number of oral antidiabetic drugs predict whether or not glycemic target is achieved in insulin-requiring type 2 diabetes. Prim Care Diabetes. 2015;9(2):135-141.
16.Khunti K, Damci T, Meneghini L, Pan CY, Yale JF, Group SS. Study of Once Daily Levemir (SOLVE): insights into the timing of insulin initiation in people with poorly controlled type 2 diabetes in routine clinical practice. Diabetes Obes Metab. 2012;14(7):654-661.
17.Karter AJ, Subramanian U, Saha C, et al. Barriers to insulin initiation: the translating research into action for diabetes insulin starts project. Diabetes Care. 2010;33(4):733-735.
18.Wen Chen K, Tseng H-M. The Barriers to Initiating Insulin Therapy among People with Type 2 Diabetes in Taiwan - A Qualitative Study. Journal of Diabetes ＆ Metabolism. 2012;03(05).
19.Tibaldi JM. Evolution of insulin: from human to analog. Am J Med. 2014;127(10 Suppl):S25-38.
20.Pettus J, Santos Cavaiola T, Tamborlane WV, Edelman S. The past, present, and future of basal insulins. Diabetes Metab Res Rev. 2016;32(6):478-496.
21.Lipska KJ, Hirsch IB, Riddle MC. Human Insulin for Type 2 Diabetes: An Effective, Less-Expensive Option. JAMA. 2017;318(1):23-24.
22.Horvath K, Jeitler K, Berghold A, et al. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007(2):CD005613.
23.Rys P, Wojciechowski P, Rogoz-Sitek A, et al. Systematic review and meta-analysis of randomized clinical trials comparing efficacy and safety outcomes of insulin glargine with NPH insulin, premixed insulin preparations or with insulin detemir in type 2 diabetes mellitus. Acta Diabetol. 2015;52(4):649-662.
24.Lipska KJ, Parker MM, Moffet HH, Huang ES, Karter AJ. Association of Initiation of Basal Insulin Analogs vs Neutral Protamine Hagedorn Insulin With Hypoglycemia-Related Emergency Department Visits or Hospital Admissions and With Glycemic Control in Patients With Type 2 Diabetes. JAMA. 2018;320(1):53-62.
25.Little RR, Rohlfing CL, Sacks DB, National Glycohemoglobin Standardization Program Steering C. Status of hemoglobin A1c measurement and goals for improvement: from chaos to order for improving diabetes care. Clin Chem. 2011;57(2):205-214.
26.Monami M, Adalsteinsson JE, Desideri CM, Ragghianti B, Dicembrini I, Mannucci E. Fasting and post-prandial glucose and diabetic complication. A meta-analysis. Nutr Metab Cardiovasc Dis. 2013;23(7):591-598.
27.Ra KK. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet. 2009.
28.Investigators OT, Mellbin LG, Ryden L, et al. Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. Eur Heart J. 2013;34(40):3137-3144.
29.Bedenis R, Price AH, Robertson CM, et al. Association between severe hypoglycemia, adverse macrovascular events, and inflammation in the Edinburgh Type 2 Diabetes Study. Diabetes Care. 2014;37(12):3301-3308.
30.Lee AK, Warren B, Lee CJ, et al. The Association of Severe Hypoglycemia With Incident Cardiovascular Events and Mortality in Adults With Type 2 Diabetes. Diabetes Care. 2018;41(1):104-111.
31.Ou HT, Lee TY, Du YF, Li CY. Comparative risks of diabetes-related complications of basal insulins: a longitudinal population-based cohort of type 1 diabetes 1999-2013 in Taiwan. Br J Clin Pharmacol. 2018;84(2):379-391.
32.Juhaeri J, Gao S, Dai WS. Incidence rates of heart failure, stroke, and acute myocardial infarction among Type 2 diabetic patients using insulin glargine and other insulin. Pharmacoepidemiol Drug Saf. 2009;18(6):497-503.
33.Cammarota S, Bruzzese D, Catapano AL, et al. Lower incidence of macrovascular complications in patients on insulin glargine versus those on basal human insulins: a population-based cohort study in Italy. Nutr Metab Cardiovasc Dis. 2014;24(1):10-17.
34.Cefalu WT, Dawes DE, Gavlak G, et al. Insulin Access and Affordability Working Group: Conclusions and Recommendations. Diabetes Care. 2018;41(6):1299-1311.
35.衛生福利部中央健康保險署. 健保用藥品項查詢. 2019; https://www1.nhi.gov.tw/QueryN/Query1.aspx. Accessed May 31, 2019.
36.Suissa S, Moodie EE, Dell'Aniello S. Prevalent new-user cohort designs for comparative drug effect studies by time-conditional propensity scores. Pharmacoepidemiol Drug Saf. 2017;26(4):459-468.
37.1992年ICD-9-CM疾病碼一覽表. https://www.nhi.gov.tw/Content_List.aspx?n=B2F4F9610CEB71C0＆topn=D39E2B72B0BDFA15. Accessed July 11, 2019.
38.李宗穎. 利用台灣健保資料庫比較第一型糖尿病病患使用長效胰島素和中效胰島素在糖尿病急、慢性併發症和死亡的風險. 成功大學臨床藥學與藥物科技研究所學位論文. 2016:1-128.
39.Chang HY, Weiner JP, Richards TM, Bleich SN, Segal JB. Validating the adapted Diabetes Complications Severity Index in claims data. The American journal of managed care. 2012;18(11):721-726.
40.Lopez-de-Andres A, Jimenez-Garcia R, Hernandez-Barrera V, et al. National trends in utilization and outcomes of coronary revascularization procedures among people with and without type 2 diabetes in Spain (2001-2011). Cardiovascular diabetology. 2014;13:3.
41.ADA. Economic costs of diabetes in the U.S. In 2007. Diabetes Care. 2008;31(3):596-615.
42.Ginde AA, Blanc PG, Lieberman RM, Camargo CA, Jr. Validation of ICD-9-CM coding algorithm for improved identification of hypoglycemia visits. BMC endocrine disorders. 2008;8:4.
43.Chang GM, Tung YC. Factors Associated with Pneumonia Outcomes: A Nationwide Population-Based Study over the 1997–2008 Period. Journal of General Internal Medicine. 2012;27(5):527-533.
44.Lien HM, Chou SY, Liu JT. Hospital ownership and performance: evidence from stroke and cardiac treatment in Taiwan. Journal of health economics. 2008;27(5):1208-1223.
45.Anyanwagu U, Mamza J, Mehta R, Donnelly R, Idris I. Cardiovascular events and all-cause mortality with insulin versus glucagon-like peptide-1 analogue in type 2 diabetes. Heart (British Cardiac Society). 2016;102(19):1581-1587.
46.Morgan CL, Mukherjee J, Jenkins-Jones S, Holden SE, Currie CJ. Combination therapy with metformin plus sulphonylureas versus metformin plus DPP-4 inhibitors: association with major adverse cardiovascular events and all-cause mortality. Diabetes, obesity ＆ metabolism. 2014;16(10):977-983.
47.Meduru P, Helmer D, Rajan M, Tseng CL, Pogach L, Sambamoorthi U. Chronic illness with complexity: implications for performance measurement of optimal glycemic control. Journal of General Internal Medicine. 2007;22 Suppl 3:408-418.
48.Hsieh HM, Tsai SL, Shin SJ, Mau LW, Chiu HC. Cost-effectiveness of diabetes pay-for-performance incentive designs. Medical care. 2015;53(2):106-115.
49.楊珺婷. 台灣第二型糖尿病病人於胰島素介入治療後之長期糖尿病併發症與安全性之分析. 成功大學臨床藥學與藥物科技研究所學位論文. 2017:1-160.
50.Davis IC, Ahmadizadeh I, Randell J, Younk L, Davis SN. Understanding the impact of hypoglycemia on the cardiovascular system. Expert review of endocrinology ＆ metabolism. 2017;12(1):21-33.
51.Stratton IM, Adler AI, Neil HAW, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. 2000;321(7258):405-412.
52.Bash LD, Selvin E, Steffes M, Coresh J, Astor BC. Poor glycemic control in diabetes and the risk of incident chronic kidney disease even in the absence of albuminuria and retinopathy: Atherosclerosis Risk in Communities (ARIC) Study. Archives of internal medicine. 2008;168(22):2440-2447.
53.Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-853.