SGLT2抑制劑之心血管和腎臟結果試驗及嚴重副作用：統合分析
 
蔡崇煌^1,2　張加憲¹　王俊堯¹　曾立年³

 
背景：國內使用的3種口服降血糖藥之鈉-葡萄糖協同轉運蛋白2抑制劑(SGLT2i)的大型心血管結果試驗(CVOTs)皆已發表，但尚缺乏其分析比較，本研究目的為探討SGLT2i的CVOTs和腎臟結果試驗及較嚴重副作用，並做一統合分析。
方法：以關鍵字“SGLT2 inhibitor”OR “SGLT2 inhibitors”，AND “metaanalysis”OR “systematic review”，搜尋2018年11月24日前之PubMed medline、Cochrane、Web of Science及CEPS中文思博網等資料庫。使用Review Manager 5.3軟體計算風險比(HRs)、95%信賴區間(CIs)及權重，並用MS-Excel及其VBA (Visual Basic for Applications)做森林圖(forest plot)，若誤差線(error bar)未交叉到1.0無效線，表示達統計學上顯著的差異。
結果：共找到3篇相關文獻做引用，整體而言，SGLT2i可顯著地降低因心衰竭住院(HHF) 31% (HR 0.69, 0.61-0.79)和腎臟疾病進展組合(renal composite) 45% (0.55, 0.48-0.64)，且在3個研究中有相當一致的結果，其HRs皆相差不多。其餘除了心血管死亡(CVM)、非死亡腦中風及全因死亡率(ACM)外之變項亦皆有相當一致的結果。在主要不良心血管事件(MACE)雖只降低11% (0.89, 0.83-0.96)，但有統計學上顯著差異。Canagliflozin在截肢(1.97, 1.41-2.75)、骨折(1.55, 1.21-1.97)及糖尿病酮酸中毒(DKA) (2.33, 0.76-7.17)皆有較高風險，且其前2項皆達統計學上顯著的差異，三種藥物之三者副作用之統合分析依序上昇26% (1.26, 1.06-1.51)、11% (1.11, 1.00-1.23)及120% (2.20, 1.25-3.87)，且皆達統計學上顯著的差異。
結論：SGLT2i可降低MACE、HHF和renal composite，除了CVM、非死亡腦中風及ACM外之變項皆有相當一致的結果。截肢、骨折及DKA皆以canagliflozin有較高風險。
（台灣家醫誌2019; 29: 57-67）DOI: 10.3966/168232812019062902001
 
關鍵詞：心血管結果試驗、因心衰竭住院、主要不良心血管事件、腎臟疾病進展組合
 

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¹澄清綜合醫院中港分院家庭醫學科、³內分泌暨新陳代謝科；²東海大學運動休閒與健康管理進修學士班學位學程
受理日期：107年12月10日　　修改日期：108年1月14日　　接受刊登：108年1月19日
通訊作者：曾立年　　通訊地址：407台中市西屯區台灣大道四段966號　澄清醫院中港分院內分泌暨新陳代謝科

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Cardiovascular and Renal Outcomes and Serious Side Effects of SGLT2 Inhibitors: A Meta-analysis
 
Chung-Huang Tsai^1,2, Chia-Hsien Chang¹, Jiun-Yao Wang¹and Li-Nien Tseng³
 

 
Purpose:In spite of the publication of three large-scale cardiovascular outcome trials (CVOTs) of sodium-glucose cotransporters 2 inhibitors (SGLT2i), comparative analysis remains rare. The study accordingly aimed to compare the cardiovascular and renal outcomes and serious side effects of SGLT2i and to conduct a meta-analysis (M-A).
Methods: We searched PubMed, Cochrane and Web of Science in EndNote X9 for trials published up to November 24, 2018, using the following keywords: “SGLT2 inhibitor” OR “SGLT2 inhibitors” AND “meta-analysis” OR “systematic review.” The study also searched CEPS with the same keywords in Chinese. Review Manager was used to calculate the hazard ratios (HRs) with 95% CI and weights, and forest plots drawn with MS-Excel with VBA. Significant difference was indicated if the error bars did not cross the no-effect line 1.0.
Results: A total of three references were cited. Overall, SGLT2i was able to robustly reduce 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), and the results appeared to be fairly consistent in three of the four references. Except cardiovascular mortality (CVM), non-fatal stroke, and all-cause mortality (ACM), the results concerning other variables stayed consistent. SGLT2i moderately reduce major adverse cardiovascular events (MACE) by 11.0% with significant difference (0.89, 0.83-0.96) noted. Compared to the other two agents, Canagliflozin incurred a higher risk in amputation (1.97, 1.41-2.75), fracture (1.55, 1.21-1.97) and diabetic ketoacidosis (DKA) (2.33, 0.76-7.17), while the M-A found all the three side effects reaching significant differences with 26% (1.26, 1.06-1.51), 11% (1.11, 1.00-1.23), and 120% (2.20, 1.25-3.87) respectively.
Conclusion: SGLT2i helps reduce MACE, HHF and the progression of renal disease. Except CVM, non-fatal stroke, and ACM, variables are marked with fairly consistent results. Canagliflozin poses greater risks on amputation, fracture and DKA than the other two agents.
(Taiwan J Fam Med 2019; 29: 57-67) DOI: 10.3966/168232812019062902001
 
Key words: CVOTs, EndNote, HHF, MACE, renal composite

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¹Departments of Family Medicine, ³Endocrinology and Metabolism, Chung-Kang Branch, Cheng Ching Hospital, Taichung, Taiwan; ²Tunghai University Sports Recreation and Health Management Continuing Studies - Bachelor's Degree Completion Program, Taichung, Taiwan.
Received: December 10, 2018; Revised: January 14, 2019; Accepted: January 19, 2019.