- 學位論文
二肽基肽酶-4抑制劑使用對於心血管健康之影響：回溯性世代研究
Effect of Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Health: Retrospective Cohort Study
摘要
背景： DPP-4 抑制劑(二肽基肽酶-4抑制劑)可以有效的調控血糖以減緩糖尿病的病程，但其對於心血管健康的影響目前仍然沒有一致的結果。本研究利用全國性世代研究比較DPP-4 抑制劑對於心血管健康的效果。透過醫院臨床資料庫，比較DPP-4 抑制劑對於心血管相關血液生化指標的效果。 方法： 全國性世代研究以健保資料進行，使用2008到2013年間所有糖尿病病人，取追蹤期間以二甲雙胍為第一線治療且有服用至少30天第二線降血糖用藥者做為研究對象，依照使用DPP-4 抑制劑情況分組進行1比1的配對，比較兩組人重大心臟不良事件、心臟衰竭、心肌梗塞、腦血管疾病以及低血糖風險。使用台大醫院資料庫，選擇2008年到2016年40歲以上以二甲雙胍為第一線治療且至少使用半年第二線降血糖用藥之糖尿病患者做為研究對象，依照使用DPP-4 抑制劑情況分組進行1比1的配對，比較糖化血色素、空腹血糖、總膽固醇、三酸甘油脂、高/低密度脂蛋白、肌酐酸以及腎絲球過濾率的差異。 結果： 在全國性世代研究當中共有37317組配對樣本。經過平均2.1年追蹤後，DPP-4 抑制劑相對於sulfonylurea(硫醯基尿素類藥物)，有較低的重大心臟不良事件(HR, 0.79; 95% CI, 0.75 to 0.82)、心臟衰竭(HR, 0.86; 95% CI, 0.79 to 0.93)、心肌梗塞(HR, 0.76; 95% CI, 0.68 to 0.92)以及腦血管疾病(HR, 0.72; 95% CI, 0.67 to 0.77)的風險。在醫院進行的世代研究納入475組平均處方2.0年降血糖用藥之配對樣本中，DPP-4 抑制劑跟sulfonylurea都可以有效降低糖化血色素、空腹血糖、總膽固醇、三酸甘油脂以及低密度脂蛋白。DPP-4 抑制劑比起sulfonylurea更能夠有效的降低糖化血色素(effect estimate for the change of percentages = -1.96 %; 95% CI, -3.52 to -0.41%)，對於空腹血糖則有接近顯著的下降效果(effect estimate for the change of levels = -0.49 mg/dL; 95% CI, -8.54 to 0.36 mg/dL)。 結論： 本研究觀察到在以二甲雙胍做為第一線治療下，DPP-4 抑制劑比起sulfonylurea，對於重大心臟不良事件、心臟衰竭、心肌梗塞、腦血管疾病以及低血糖有較低的風險。而在血糖調控部分，亦可觀察到DPP-4 抑制劑比起sulfonylurea有較好的血糖控制。
並列摘要
Background: Dipeptidyl peptidase 4 inhibitors (DPP4i) play an important role in regulating blood glucose and delaying the progression of diabetes, but DDP4i revealed inconsistent effects on cardiovascular outcomes in patients with type 2 diabetes. The objective of this dissertation is to evaluate the effects of overall DPP4i and different types of DPP4is in primary and secondary prevention using a nationwide cohort study and hospital-based cohort study. Methods: We conducted a nationwide cohort study using claims data from the National Health Insurance in Taiwan from 2007 to 2013. We enrolled type 2 diabetes patients who received DPP4i or sulfonylureas (SU) in addition to metformin. DPP4i users were matched to SU users using propensity scores at a ratio of 1:1. The study outcomes were hospitalization for major adverse cardiac event (MACE), heart failure, acute myocardial infarction, cerebrovascular disease, coronary revascularization, and hypoglycemia. For the hospital-based cohort, we conducted a hospital-based cohort study from the Integrated Medical Database, National Taiwan University Hospital (NTUH-iMD). We included patients aged ≥ 40 years with diagnosis of type 2 diabetes during 2008 to 2016. We matched patients who received DPP4i to those who received SU in addition to metformin by propensity scores at a ratio of 1:1. The study outcomes were clinical profiles including the blood levels of hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), total cholesterol, triglyceride, low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), creatinine, and estimated glomerular filtration rate. Result: For the population-based cohort study, there were 37,317 matched pairs of DPP4i and SU users with a mean follow-up of 2.1 years. Compared with SU users, DPP4i users showed a significantly lower risk of hospitalization for MACE (hazard ratio (HR), 0.79; 95% confidence interval (CI), 0.75 to 0.82), heart failure (HR, 0.86; 95% CI, 0.79 to 0.93), acute myocardial infarction (HR, 0.76; 95% CI, 0.68 to 0.92), and cerebrovascular disease (HR, 0.72; 95% CI, 0.67 to 0.77). For the hospital-based cohort study, there were 475 matched pairs of DPP4i and SU users with a mean prescription of 2.0 years. Both DPP4i and SU significantly reduced the blood levels of HbA1c, FPG, total cholesterol, triglyceride, and LDL-C. Compared with SU, DPP4i showed a better glucose-lowering effect on HbA1c (effect estimate for the change of percentages = -1.96 %; 95% CI, -3.52 to -0.41%) and a borderline effect on FPG (effect estimate for the change of levels = -0.49 mg/dL; 95% CI, -8.54 to 0.36 mg/dL). Conclusion: In conclusion, DPP4i showed better protective effects than SU in MACE, heart failure, acute myocardial infarction, cerebrovascular disease, and hypoglycemia. In addition, DPP4i showed a better glucose-lowering effect in the improvement of HbA1c compared with SU. Compared with SU, DPP4i may be preferred as the add-on therapy to metformin in patients with type 2 diabetes.