降血糖藥物之心血管結果試驗：系統回顧及統合分析

Cardiovascular Outcome Trials of Antidiabetic Agents: A Systematic Review and Meta-analysis

目的：美國食品藥物管理局建議所有2008年後新上市的降血糖藥物，需進行心血管結果試驗(CVOTs)，本研究目的為探討CVOTs，並做一系統回顧及統合分析。

方法：以EndNote X9，關鍵詞為“Cardiovascular Outcome(s) Trial(s)” OR “CVOT(s)”，AND “Diabetes”，搜尋2008/1/1至2019/11/30之PubMed medline、Cochrane及Web of Science等資料庫，再由此分別找出降血糖藥物之CVOTs。使用Comprehensive Meta-Analysis 3 軟體計算風險比(HR)、95%信賴區間(CI)及權重，並用MS-Excel 2019畫森林圖(forest plot)，若誤差線未交叉到1.0無效線，表示達統計學上顯著的差異。

結果：共收錄24個研究，其中昇糖素類似胜肽1-受體促效劑(GLP1-RA)可顯著下降12% 3項(3-point, 3-P)主要不良心血管事件(major adverse cardiovascular events, MACE) (HR 0.88, 95% CI 0.82- 0.94)，其中SUSTAIN 6 (Semaglutide) (0.61, 0.38-0.99)及REWIND (Dulaglutide) (0.76, 0.61-0.95)可顯著下降腦中風風險。鈉-葡萄糖協同轉運蛋白2抑制劑(SGLT2i)可顯著下降11% 3-P MACE(0.89, 0.83-0.96)，因心衰竭住院(HHF)顯著下降31% (0.69, 0.61-0.79)，腎臟疾病進展組合亦有極顯著下降45% (0.55, 0.48-0.64)。二肽基肽酶4抑製劑(Dipeptidyl peptidase 4 inhibitor)為中性結果(0.99, 0.94-1.05)，其中CARMELINA (Linagliptin)發現可顯著減少白蛋白尿的進展(0.86, 0.78-0.95)，但SAVOR TIMI 53(Saxagliptin)因心衰竭住院顯著上昇了27% (1.27, 1.07-1.51)。

結論：SGLT2i及GLP1-RA可下降3-P MACE，再者SGLT2i對心衰竭及腎臟亦有保護作用，部份GLP1-RA發現可下降腦中風風險，因此歐美及國內目前對第2型糖尿病治療方針有全新的改變。

 

Purpose: The US Food and Drug Administration recommends that cardiovascular outcome trials (CVOTs) should be conducted for all new antidiabetic drugs introduced into the market after 2008. The study thus initiated a systematic review and meta-analysis of the CVOTS of antidiabetic agents.

Methods: We searched PubMed, Cochrane and Web of Science in EndNote X9 for trial results published from January 1, 2008 to November 30, 2019, using the keywords: “Cardiovascular Outcome(s) Trial(s)” OR “CVOT(s)” AND “Diabetes” to identify the CVOTs of antidiabetic drugs separately. Comprehensive Meta-Analysis 3 was used to calculate the hazard ratios (HR) with 95% CI and weights, and the forest plots were drawn with MS-Excel 2019 with VBA. Significant difference was indicated if the error bars did not cross the no-effect line 1.0.

Results: A total of 24 CVOTs were cited. Overall, Glucagon-like peptide 1-receptor agonist (GLP1-RA) was able to significantly reduce 12% 3-point major adverse cardiovascular events (3-P MACE) (HR 0.88, 0.82- 0.94), while SUSTAIN 6 (0.61, 0.38-0.99) and REWIND (Dulaglutide) (0.76, 0.61-0.95) were found to significantly reduce stroke. SGLT2i was able to significantly reduce 3-P MACE by 11% (HR 0.89, 95% CI 0.83-0.96), hospitalization for heart failure (HHF) by 31% (HR 0.69, 95% CI 0.61-0.79), and renal composite by 45% (0.55, 0.48-0.64). Dipeptidyl peptidase 4 inhibitors showed neutral result (0.99, 0.94-1.05); CARMELINA (Linagliptin) could significantly reduce albuminuria progression (0.86, 0.78-0.95). SAVOR TIMI 53 (Saxagliptin), however, appeared to increase HHF by 27% (1.27, 1.07-1.51).

Conclusion: In addition to their ability to reduce 3-P MACE, SGLT2i also reports protective effects on HHF and kidneys and GLP1-RA can reduce the risk of stroke, thus facilitating recent changes in type 2 diabetes treatment in Europe, America and Taiwan.