Service Hospitalo-Universitaire de Pharmacotoxicologie, Pôle Santé Publique, Hospices Civils de Lyon, Lyon, France.
Laboratoire de Biométrie et Biologie Evolutive UMR 5558, CNRS, Université Lyon 1, Université de Lyon, Villeurbanne, France.
Diabetologia. 2022 Dec;65(12):2000-2010. doi: 10.1007/s00125-022-05773-8. Epub 2022 Aug 4.
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.
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.
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.
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.
目的/假设：心血管结局试验（CVOT）已经证明了钠-葡萄糖共转运蛋白 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/获益比仍未量化。我们旨在为 2 型糖尿病患者提供对其风险/获益比的评估。
我们进行了一项系统评价（MEDLINE，截至 2021 年 9 月 14 日）和荟萃分析。我们纳入了评估 2 型糖尿病患者中 SGLT2i 的随机 CVOT，无论是否患有其他疾病。我们使用了 Cochrane“风险偏倚”评估工具。主要结局是全因死亡率、主要心血管不良事件（MACE）、心力衰竭住院（HHF）、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。对于每个结局，我们用 95%置信区间（CI）估计发生率比值（IRR）；然后计算自发发生和使用 SGLT2i 时预计发生的事件数。
来自五项双盲、安慰剂对照的国际试验（加权平均随访 3.5 年）的 46969 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”。每个结局的纳入研究数量为五项。使用 SGLT2i 降低了全因死亡的风险（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]）和 ESRD（IRR 0.67 [95%CI 0.53, 0.84]），增加了 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，但不增加截肢（IRR 1.23 [95%CI 1.00, 1.51]）的风险。对于治疗 3.5 年的 1000 名患者，预计 SGLT2i 将平均减少 70 例死亡，预防 9 例 MACE、11 例 HHF 和 2 例 ESRD，同时引起 2 例 DKA 和 36 例生殖器感染；预计 778 名患者将避免所有以下结局：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 2 型糖尿病和高 CVD 风险的人群中，尽管存在 DKA 的风险，甚至可能存在截肢的风险，SGLT2i 的心血管和肾脏获益仍然很大。
OSF 注册表：https://doi.org/10.17605/OSF.IO/J3R7Y 资金来源：这项研究没有得到任何公共、商业或非营利部门的特定资助机构的资金支持。
