Aims/hypothesis

Cardiovascular outcome trials (CVOTs) have demonstrated the benefits of sodium–glucose cotransporter 2 inhibitors (SGLT2i). However, serious adverse drug reactions have been reported. The risk/benefit ratio of SGLT2i remains unquantified. We aimed to provide an estimation of their risk/benefit ratio in individuals with type 2 diabetes.

Methods

We conducted a systematic review (MEDLINE, up to 14 September 2021) and meta-analysis. We included randomised CVOTs assessing SGLT2i in individuals with type 2 diabetes with or without other diseases. We used the Cochrane ‘Risk of bias’ assessment tool. The primary outcomes were overall mortality, major adverse cardiovascular events (MACE), hospitalisation for heart failure (HHF), end-stage renal disease (ESRD), amputation, diabetic ketoacidosis (DKA) and reported genital infections. For each outcome, we estimated the incidence rate ratio (IRR) with a 95% CI; we then computed the number of events expected spontaneously and with SGLT2i.

Results

A total of 46,969 participants from five double-blind, placebo-controlled international trials (weighted mean follow-up 3.5 years) were included. The prevalence of previous CVD ranged from 40.6% to 99.2%. The definition of reported genital infections ranged from ‘genital mycotic infection’ to ‘genital infections that led to discontinuation of the trial regimen or were considered to be serious adverse events’. The number of included studies for each outcomes was five. The use of SGLT2i decreased the risk of all-cause death (IRR 0.86 [95% CI 0.78, 0.95]), MACE (IRR 0.91 [95% CI 0.86, 0.96]), HHF (IRR 0.69 [95% CI 0.62, 0.76]) and ESRD (IRR 0.67 [95% CI 0.53, 0.84]), and increased the risk of DKA (IRR 2.59 [95% CI 1.57, 4.27]) and genital infection (IRR 3.50 [95% CI 3.09, 3.95]) but not of amputation (IRR 1.23 [95% CI 1.00, 1.51]). For 1000 individuals treated over 3.5 years, SGLT2i are expected, on average, to decrease the number of deaths from 70 to 61, to prevent nine MACE, 11 HHF and two cases of ESRD, while inducing two DKA occurrences and 36 genital infections; 778 individuals are expected to avoid all the following outcomes: MACE, HHF, ESRD, amputation, DKA and genital infection.

Conclusions/interpretation

Our study is limited to aggregate data. In a population of individuals with type 2 diabetes and a high CVD risk, the cardiovascular and renal benefits of SGLT2i remain substantial despite the risk of DKA and even the hypothetical risk of amputation.

Trial registration

OSF Registries: https://doi.org/10.17605/OSF.IO/J3R7Y

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Graphical abstract

中文翻译：

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SGLT2 抑制剂治疗 2 型糖尿病：心血管结局试验的系统评价和荟萃分析，平衡了风险和获益

目标/假设

心血管结局试验 (CVOT) 已经证明了钠-葡萄糖协同转运蛋白 2 抑制剂 (SGLT2i) 的益处。然而，已经报道了严重的药物不良反应。SGLT2i 的风险/收益比仍未量化。我们的目的是估计 2 型糖尿病患者的风险/收益比。

方法

我们进行了系统回顾（MEDLINE，截至 2021 年 9 月 14 日）和荟萃分析。我们纳入了评估伴有或不伴有其他疾病的 2 型糖尿病患者 SGLT2i 的随机 CVOT。我们使用了 Cochrane 的“偏倚风险”评估工具。主要结局是总体死亡率、主要不良心血管事件 (MACE)、因心力衰竭 (HHF) 住院、终末期肾病 (ESRD)、截肢、糖尿病酮症酸中毒 (DKA) 和报告的生殖器感染。对于每个结果，我们用 95% CI 估计了发生率比 (IRR)；然后我们计算了自发和使用 SGLT2i 预期的事件数量。

结果

共有来自五项双盲、安慰剂对照国际试验（加权平均随访 3.5 年）的 46,969 名参与者被纳入。既往 CVD 的患病率从 40.6% 到 99.2% 不等。报告的生殖器感染的定义范围从“生殖器真菌感染”到“导致试验方案中断或被认为是严重不良事件的生殖器感染”。每个结果的纳入研究数量为 5。使用 SGLT2i 可降低全因死亡 (IRR 0.86 [95% CI 0.78, 0.95])、MACE (IRR 0.91 [95% CI 0.86, 0.96])、HHF (IRR 0.69 [95% CI 0.62, 0.76]) 的风险]) 和 ESRD (IRR 0.67 [95% CI 0.53, 0.84])，并增加 DKA (IRR 2.59 [95% CI 1.57, 4.27]) 和生殖器感染 (IRR 3.50 [95% CI 3.09, 3.95]) 的风险但不是截肢（IRR 1.23 [95% CI 1.00, 1.51]）。对于接受治疗超过 3.5 年的 1000 名患者，SGLT2i 预计平均可将死亡人数从 70 人减少到 61 人，预防 9 例 MACE、11 例 HHF 和 2 例 ESRD，同时诱发 2 例 DKA 和 36 例生殖器感染；预计 778 人将避免以下所有结果：MACE、HHF、ESRD、截肢、DKA 和生殖器感染。

结论/解释

我们的研究仅限于汇总数据。在患有 2 型糖尿病和高 CVD 风险的人群中，尽管存在 DKA 风险甚至截肢的假设风险，但 SGLT2i 的心血管和肾脏益处仍然很大。

试用注册

OSF 注册中心：https://doi.org/10.17605/OSF.IO/J3R7Y

资金

这项研究没有从公共、商业或非营利部门的任何资助机构获得具体资助。

图形概要