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研究生： 邵時傑
Shao, Shih-Chieh
論文名稱： 利用長庚醫學研究資料庫進行藥物效果比較研究: 以第二型糖尿病人接受Empagliflozin和Dapagliflozin 治療後的心血管事件為例
Comparative Drug Effectiveness Studies Using the Chang Gung Research Database: Comparison of Cardiovascular Events between Empagliflozin and Dapagliflozin in Patients with Type 2 Diabetes as an Example
指導教授： 賴嘉鎮
Lai, Chia-Cheng
學位類別： 博士
Doctor
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： 2023
畢業學年度： 111
語文別： 英文
論文頁數： 101
中文關鍵詞： 長庚醫學研究資料庫 、研究效度 、藥物比較研究 、第二型鈉-葡萄糖共同轉運蛋白抑制劑 、重大不良心血管事件 、心衰竭住院
外文關鍵詞： Chang Gung Research Database, study validity, comparative drug effectiveness research, sodium glucose co-transporter 2 inhibitors, major adverse cardiovascular events, hospitalization due to heart failure
相關次數： 點閱：65  下載：6 
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    • 背景：真實世界證據可做為臨床決策參考，而我國常用的數據資料庫包含保險申報數據及醫院電子病歷資料。長庚醫學研究資料庫為台灣藥物比較研究的重要醫院電子病歷資料來源，但運用於藥物流行病學的研究實例有限。第二型鈉-葡萄糖共同轉運蛋白抑制劑為近年糖尿病治療之突破性新藥，臨床試驗證實可降低重大心血管不良事件及心衰竭發生風險，但不同藥物間的效果可能存有差異。
    目的：以比較不同第二型鈉-葡萄糖共同轉運蛋白抑制劑(empagliflozin和dapagliflozin) 的心血管事件效果為例，善用長庚醫學研究資料庫之電子病歷資料優點來增加藥物比較研究的效度。
    方法：本研究使用長庚醫學研究資料庫進行回溯性世代研究。首先利用2016-2017年間的資料，納入首次接受empagliflozin或dapagliflozin 的第二型糖尿病且過去未有動脈粥樣硬化心血管疾病史 (包含冠心病、缺血性中風和周邊動脈疾病) 及心衰竭病人，利用多變項COX迴歸分析比較用藥後首次發生重大不良心血管事件 (包含心因性死亡、心肌梗塞、缺血性中風) 和心衰竭的風險。為了驗證研究效度，我們透過電子病歷回顧方式評估研究結果診斷碼的正確性。接續利用2016-2019年間的資料，納入首次接受empagliflozin或dapagliflozin的第二型糖尿病人，利用傾向分數配對分析動脈粥樣硬化心血管疾病史是否會影響用藥後心衰竭住院的發生風險。為了驗證結果穩健度，我們利用心房利鈉肽數值重新定義心衰竭住院結果，進行敏感度分析。
    結果：第二型糖尿病且過去未有動脈粥樣硬化心血管疾病史的病人接受empagliflozin (n=6,869) 和dapagliflozin (n=5,812) 治療後，病人有相似的重大不良心血管事件發生風險 (hazard ratio, HR: 0.91; 95% CI: 0.73, 1.14)，但dapagliflozin會顯著地減少心衰竭發生風險 (HR: 0.68; 95% CI: 0.49, 0.95)。整體而言，重大不良心血管事件和心衰竭的診斷碼正確率為75.0-95.8%，研究結果定義適當。利用傾向分數配對分析9,586組接受empagliflozin和dapagliflozin治療的第二型糖尿病病人後，發現動脈粥樣硬化心血管疾病史會造成empagliflozin和dapagliflozin治療後有不同的心衰竭住院風險 (p-value: 0.0097)。病人過去沒有動脈粥樣硬化心血管疾病史時，dapagliflozin會有顯著較低的心衰竭住院發生風險 (HR: 0.67; 95% CI: 0.49, 0.90)；過去有動脈硬化心血管疾病史時，empagliflozin和dapagliflozin治療後有相似的心衰竭住院發生風險 (HR: 1.12; 95% CI: 0.87, 1.45)。利用心房利鈉肽數值進行心衰竭住院的重新定義後，分析結果與主分析相似。
    結論：本研究以empagliflozin和dapagliflozin的藥物比較研究為例，利用長庚醫學研究資料庫電子病歷資料特性，驗證重大不良心血管事件的診斷碼定義有足夠正確性，並發現dapagliflozin可能會有較低的心衰竭發生風險。此外。動脈粥樣硬化心血管疾病史可能會影響SGLT2抑制劑改善心衰竭住院風險的比較效果，應用生化檢驗數據的敏感度分析亦驗證結果的穩健度。

    Background: Real-world evidence can serve as an important reference for clinical decisions, with common data sources including claims data and electronic medical records (EMR) in Taiwan. The Chang Gung Research Database (CGRD) is an important source of EMR data for comparative drug effectiveness research in Taiwan, but related examples are limited. Sodium glucose co-transporter 2 (SGLT2) inhibitors, which are breakthrough novel drugs for type 2 diabetes (T2D), have been proven to have beneficial effects on major adverse cardiovascular events (MACE) and heart failure outcomes in patients with T2D, but the treatment effects of individual SGLT2 inhibitors may differ.
    Purpose: To take advantage of CGRD to increase study validity, by comparing cardiovascular disease event effects in T2D patients who are newly initiating different SGLT2 inhibitors (i.e., empagliflozin and dapagliflozin) as an example.
    Methods: This retrospective cohort study analyzed Taiwan’s CGRD. First, we included T2D patients who were newly receiving empagliflozin and dapagliflozin from 2016 to 2017, but had no baseline history of heart failure or atherosclerotic cardiovascular diseases (ASCVD) such as coronary heart disease, ischemic stroke and peripheral artery diseases. We applied multivariable Cox proportional hazards models to calculate the effects on MACE and heart failure. To confirm the study validity, we reviewed the original EMRs from the CGRD to assess the accuracy of outcome coding. Second, we included all T2D patients who were newly receiving empagliflozin or dapagliflozin from 2016 to 2019. We performed propensity-score matching methods to evaluate if a baseline history of ASCVD modified the effects with regard to hospitalization due to heart failure (hHF), comparing between empagliflozin and dapagliflozin. To confirm the result robustness, we re-defined the hHF outcomes by incorporating levels of B-type Natriuretic Peptide (BNP) in the sensitivity analysis.
    Results: We found similar MACE effects (hazard ratio, HR: 0.91; 95% CI: 0.73, 1.14) for empagliflozin (n=6,869) and dapagliflozin (n=5,812), but observed a lower incidence of heart failure with dapagliflozin (HR: 0.68; 95% CI: 0.49, 0.95) in patients with no ASCVD history at baseline. In our cohort of 9,586 propensity-score matched pairs of empagliflozin and dapagliflozin new users, we found that a baseline history of ASCVD modified the hHF effects differently for the two SGLT2 inhibitors (p-value for interaction: 0.0097). In patients without baseline history of ASCVD, there was a lower incidence of hHF in those receiving dapagliflozin (HR: 0.67; 95% CI: 0.49, 0.90), while similar incidence was found in patients with a baseline history of ASCVD (HR: 1.12; 95% CI: 0.87, 1.45). Results from the sensitivity analysis were consistent with the main analysis.
    Conclusion: Based on the example of a comparison between empagliflozin and dapagliflozin, this study found that the coding validity of MACE outcomes could be optimized by reviewing the original EMR from the CGRD. It also found a lower incidence of heart failure with dapagliflozin use, and that a baseline ASCVD history may modify the hHF effects of the two studied SGLT2 inhibitors. The sensitivity analysis incorporating BNP levels confirmed the result robustness.

    Chinese Abstract i English Abstract iii Acknowledgements v Contents vi Table Index ix Figure Index x Appendix Table Index xi Appendix Figure Index xii Chapter 1. Introduction 1.1 Introduction to the Chang Gung Research Database 1 1.2 Comparisons between Chang Gung Research Database and Taiwan’s National Health Insurance Research Database 1 1.3 Data representativeness of Chang Gung Research Database 3 1.4 Validation of diagnosis codes in the Chang Gung Research Database 3 1.5 Benefit of using Chang Gung Research Database for real-world studies 4 1.6 Comparative drug effectiveness research using Chang Gung Research Database 5 1.7 Research questions 7 1.8 Specific aims 8 Chapter 2. Literature Review 2.1 Background 10 2.1.1 Pharmacological actions of SGLT2 inhibitors 10 2.1.2 Pharmacokinetics of SGLT2 inhibitors 11 2.2 SGLT2 inhibitors and cardiovascular outcomes 13 2.2.1 Clinical trials 13 2.2.2 Real-world studies 16 2.2.3 Therapeutic roles in practice guidelines 18 2.3 Real-world prescribing patterns of SGLT2 inhibitors 19 2.4. Possible different magnitudes of treatment effects for cardiovascular events among SGLT2 inhibitors 19 2.4.1 Pharmacokinetic differences 19 2.4.2 Atherosclerotic cardiovascular disease history 20 Chapter 3. Methods 3.1 Comparison of cardiovascular event effects associated with dapagliflozin and empagliflozin in patients with type 2 diabetes 22 3.1.1 Study design 22 3.1.2 Outcome definition and follow-up 23 3.1.3 Validation of outcome definitions 23 3.1.4 Covariates 23 3.1.5 Unmeasured confounders 24 3.1.6 Statistical analysis 24 3.1.7 Sensitivity and subgroup analyses 25 3.2 Differences in outcome of hospitalization for heart failure after SGLT2 inhibitor treatment: effect modification by atherosclerotic cardiovascular disease 26 3.2.1 Study design 26 3.2.2 Outcome definition and follow-up 27 3.2.3 Covariates 27 3.2.4 Unmeasured confounders 28 3.2.5 Statistical analysis 28 3.2.6 Sensitivity analyses 29 Chapter 4. Results 30 4.1 Comparison of cardiovascular event effects associated with dapagliflozin and empagliflozin in patients with type 2 diabetes 30 4.1.1 Baseline characteristics 30 4.1.2 Main outcomes 30 4.1.3 Sensitivity and subgroup analyses 31 4.2 Differences in outcome of hospitalization for heart failure after SGLT2 inhibitor treatment: effect modification by atherosclerotic cardiovascular disease 32 4.2.1 Baseline characteristics 32 4.2.2 Main outcomes 32 4.2.3 Sensitivity analysis 33 Chapter 5. Discussion 5.1 Comparison of cardiovascular event effects associated with dapagliflozin and empagliflozin in patients with type 2 diabetes 34 5.1.1 General findings 34 5.1.2 Strengths and limitations 37 5.2 Differences in outcome of hospitalization for heart failure after SGLT2 inhibitor treatment: effect modification by atherosclerotic cardiovascular disease 39 5.2.1 General findings 39 5.2.2 Strengths and limitations 42 Chapter 6. Summary of findings and implications for future studies 44 Chapter 7. References 46

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