Pelletier Ryan, Ng Kelvin, Alkabbani Wajd, Labib Youssef, Mourad Nicolas, Gamble John-Michael
School of Pharmacy, Faculty of Science, University of Waterloo, 10A Victoria Street S., Kitchener, ON, Canada.
School of Pharmacy, University of Waterloo, 10A Victoria Street S., Kitchener, ON N2G 1C5 Canada.
Ther Adv Drug Saf. 2021 Jan 26;12:2042098621989134. doi: 10.1177/2042098621989134. eCollection 2021.
Multiple published quantitative systematic reviews have reported on adverse events associated with the use of sodium glucose co-transporter 2 (SGLT-2) inhibitors in patients with type 2 diabetes mellitus.
To summarize and appraise the quality of evidence from quantitative systematic reviews assessing adverse events of SGLT-2 inhibitors.
We searched PubMed, EMBASE and the Cochrane Library for quantitative systematic reviews assessing SGLT-2 inhibitor safety. Two reviewers extracted data and assessed methodological quality using the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2) tool. Main outcomes included pooled and single study point estimaates (in the absence of pooled estimates) with corresponding 95% confidence intervals (CIs) of SGLT-2 inhibitors s placebo or active comparators for genitourinary infections, volume depletion, acute kidney injury, bone fractures, diabetic ketoacidosis, lower limb amputations, cancers, and other notable adverse events.
Out of 1289 citations screened, 47 reviews assessed SGLT-2 inhibitor safety, of which 35 were of low quality. Canagliflozin, dapagliflozin and empagliflozin were consistently associated with an increased risk of genital tract infections s placebo (point estimates ranged from 2.5 to 9.8) and other antihyperglycemic agents (point estimates ranged from 2.7 to 12.0). Canagliflozin and dapagliflozin were associated with an increased risk of diabetic ketoacidosis. Canagliflozin was the only agent associated with an increased amputation risk; however, this was driven by results from a single trial program. Dapagliflozin was the only agent that exhibited a statistically significant increased risk of urinary tract infections. Empagliflozin was associated with a statistically significant increased risk of bladder cancer; however, this finding was susceptible to detection bias. None of the agents were associated with a statistically significant increased risk of acute kidney injury, or bone fractures compared to placebo or mixed (active or placebo) comparators. Upper 95% CI limits do not rule out clinically meaningful outcomes.
The majority of quantitative systematic reviews reporting on adverse events of SGLT-2 inhibitors were of low methodological quality. Despite almost 50 quantitative systematic reviews published on the safety of SGLT-2 inhibitors, clinicians are still left uncertain of the risks of important adverse effects.
Many published systematic reviews have reported on side effects associated with the use of sodium glucose co-transporter 2 (SGLT-2) inhibitors in patients with type 2 diabetes. We aimed to summarize and appraise the quality of evidence from quantitative systematic reviews assessing side effects of SGLT-2 inhibitors. Using the Assessment of Multiple Systematic Reviews 2 (AMSTAR 2) tool, two authors extracted data and assessed the methods of included reviews. Main outcomes included reported pooled and single study point estimates for several SGLT-2 inhibitor side effects such as genital infections, bone fractures, lower limb amputations, increased blood acidity, among others. Of the reviews included in our study, 35 of the 47 reviews assessed were of low quality. Canagliflozin and dapagliflozin were associated with an increased risk of blood acidity in a 2020 review. Canagliflozin was the only agent associated with an increased amputation risk; however, this was driven by results from a single trial program. Dapagliflozin was the only agent that exhibited a significantly increased risk of urinary tract infections. Empagliflozin was associated with an increased risk of bladder cancer; however, this finding was susceptible to bias. None of the agents were associated with an increased risk of kidney injury or bone fractures.
多项已发表的定量系统评价报告了2型糖尿病患者使用钠-葡萄糖协同转运蛋白2（SGLT-2）抑制剂相关的不良事件。
总结和评估定量系统评价中关于SGLT-2抑制剂不良事件的证据质量。
我们在PubMed、EMBASE和Cochrane图书馆中检索评估SGLT-2抑制剂安全性的定量系统评价。两名评价者提取数据，并使用多重系统评价评估工具2（AMSTAR 2）评估方法学质量。主要结局包括SGLT-2抑制剂与安慰剂或活性对照药相比，在泌尿生殖道感染、容量耗竭、急性肾损伤、骨折、糖尿病酮症酸中毒、下肢截肢、癌症及其他显著不良事件方面的合并及单研究点估计值（若无合并估计值）及相应的95%置信区间（CI）。
在筛选的1289篇文献中，47篇评价评估了SGLT-2抑制剂的安全性，其中35篇质量较低。与安慰剂（点估计值范围为2.5至9.8）及其他降糖药物（点估计值范围为2.7至12.0）相比，卡格列净、达格列净和恩格列净一直与生殖道感染风险增加相关。卡格列净和达格列净与糖尿病酮症酸中毒风险增加相关。卡格列净是唯一与截肢风险增加相关的药物；然而，这是由单个试验项目的结果驱动的。达格列净是唯一显示尿路感染风险有统计学显著增加的药物。恩格列净与膀胱癌风险有统计学显著增加相关；然而，这一发现易受检测偏倚影响。与安慰剂或混合（活性或安慰剂）对照药相比，没有一种药物与急性肾损伤或骨折风险有统计学显著增加相关。95%CI上限并未排除具有临床意义的结局。
大多数报告SGLT-2抑制剂不良事件的定量系统评价方法学质量较低。尽管已发表了近50篇关于SGLT-2抑制剂安全性的定量系统评价，但临床医生对于重要不良反应的风险仍不确定。
许多已发表的系统评价报告了2型糖尿病患者使用钠-葡萄糖协同转运蛋白2（SGLT-2）抑制剂相关的副作用。我们旨在总结和评估定量系统评价中关于SGLT-2抑制剂副作用的证据质量。使用多重系统评价评估工具2（AMSTAR 2），两名作者提取数据并评估纳入评价的方法。主要结局包括报告的几种SGLT-2抑制剂副作用的合并及单研究点估计值，如生殖器感染、骨折、下肢截肢、血液酸度增加等。在我们纳入研究的评价中，47篇评价中有35篇质量较低。在2020年的一项评价中，卡格列净和达格列净与血液酸度增加风险相关。卡格列净是唯一与截肢风险增加相关的药物；然而，这是由单个试验项目的结果驱动的。达格列净是唯一显示尿路感染风险显著增加的药物。恩格列净与膀胱癌风险增加相关；然而，这一发现易受偏倚影响。没有一种药物与肾损伤或骨折风险增加相关。
