Background

Large trials have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure or chronic kidney disease, or with type 2 diabetes and high risk of atherosclerotic cardiovascular disease. None of the trials recruiting patients with and without diabetes were designed to assess outcomes separately in patients without diabetes.

Methods

We did a systematic review and meta-analysis of SGLT2 inhibitor trials. We searched the MEDLINE and Embase databases for trials published from database inception to Sept 5, 2022. SGLT2 inhibitor trials that were double-blind, placebo-controlled, performed in adults (age ≥18 years), large (≥500 participants per group), and at least 6 months in duration were included. Summary-level data used for analysis were extracted from published reports or provided by trial investigators, and inverse-variance-weighted meta-analyses were conducted to estimate treatment effects. The main efficacy outcomes were kidney disease progression (standardised to a definition of a sustained ≥50% decrease in estimated glomerular filtration rate [eGFR] from randomisation, a sustained low eGFR, end-stage kidney disease, or death from kidney failure), acute kidney injury, and a composite of cardiovascular death or hospitalisation for heart failure. Other outcomes were death from cardiovascular and non-cardiovascular disease considered separately, and the main safety outcomes were ketoacidosis and lower limb amputation. This study is registered with PROSPERO, CRD42022351618.

Findings

We identified 13 trials involving 90 413 participants. After exclusion of four participants with uncertain diabetes status, we analysed 90 409 participants (74 804 [82·7%] participants with diabetes [>99% with type 2 diabetes] and 15 605 [17·3%] without diabetes; trial-level mean baseline eGFR range 37–85 mL/min per 1·73 m²). Compared with placebo, allocation to an SGLT2 inhibitor reduced the risk of kidney disease progression by 37% (relative risk [RR] 0·63, 95% CI 0·58–0·69) with similar RRs in patients with and without diabetes. In the four chronic kidney disease trials, RRs were similar irrespective of primary kidney diagnosis. SGLT2 inhibitors reduced the risk of acute kidney injury by 23% (0·77, 0·70–0·84) and the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77, 0·74–0·81), again with similar effects in those with and without diabetes. SGLT2 inhibitors also reduced the risk of cardiovascular death (0·86, 0·81–0·92) but did not significantly reduce the risk of non-cardiovascular death (0·94, 0·88–1·02). For these mortality outcomes, RRs were similar in patients with and without diabetes. For all outcomes, results were broadly similar irrespective of trial mean baseline eGFR. Based on estimates of absolute effects, the absolute benefits of SGLT2 inhibition outweighed any serious hazards of ketoacidosis or amputation.

Interpretation

In addition to the established cardiovascular benefits of SGLT2 inhibitors, the randomised data support their use for modifying risk of kidney disease progression and acute kidney injury, not only in patients with type 2 diabetes at high cardiovascular risk, but also in patients with chronic kidney disease or heart failure irrespective of diabetes status, primary kidney disease, or kidney function.

Funding

UK Medical Research Council and Kidney Research UK.

中文翻译：

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糖尿病对钠葡萄糖协同转运蛋白 2 抑制剂对肾脏结局的影响：大型安慰剂对照试验的协作荟萃分析

 背景

大型试验表明，钠葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂可降低心力衰竭或慢性肾脏疾病患者、或 2 型糖尿病患者和动脉粥样硬化性心血管疾病高风险患者出现不良肾脏和心血管结局的风险。招募患有和不患有糖尿病的患者的试验都没有旨在单独评估非糖尿病患者的结局。

 方法

我们对 SGLT2 抑制剂试验进行了系统回顾和荟萃分析。我们检索了 MEDLINE 和 Embase 数据库，查找从数据库建立到 2022 年 9 月 5 日发布的试验。SGLT2 抑制剂试验为双盲、安慰剂对照、在成人（年龄≥18 岁）中进行、大型（每组≥500 名受试者） ，并且持续时间至少包括 6 个月。用于分析的摘要级数据是从已发表的报告中提取的或由试验研究者提供的，并进行逆方差加权荟萃分析来估计治疗效果。主要疗效结果是肾脏疾病进展（标准化为估计肾小球滤过率[eGFR]从随机分组中持续下降≥50%的定义、持续低eGFR、终末期肾病或肾衰竭死亡）、急性肾病肾损伤，以及心血管死亡或心力衰竭住院的复合症状。其他结局是单独考虑的心血管和非心血管疾病死亡，主要安全结局是酮症酸中毒和下肢截肢。本研究已在 PROSPERO 注册，CRD42022351618。

 发现

我们确定了 13 项试验，涉及 90 413 名参与者。在排除四名糖尿病状况不确定的参与者后，我们分析了 90 409 名参与者（74 804 [82·7%] 患有糖尿病的参与者 [>99% 患有 2 型糖尿病] 和 15 605 [17·3%] 没有糖尿病的参与者；试验-水平平均基线 eGFR 范围为 37–85 mL/min 每 1·73 m ² )。与安慰剂相比，分配给 SGLT2 抑制剂可将肾脏疾病进展风险降低 37%（相对风险 [RR] 0·63，95% CI 0·58–0·69），患有和不患有糖尿病的患者的 RR 相似。在四项慢性肾脏病试验中，无论主要肾脏诊断如何，RR 均相似。 SGLT2抑制剂将急性肾损伤的风险降低了23% (0·77, 0·70–0·84)，将心血管死亡或因心力衰竭住院的风险降低了23% (0·77, 0·74–0· 81），对于糖尿病患者和非糖尿病患者也有类似的效果。 SGLT2抑制剂还降低了心血管死亡风险（0·86、0·81–0·92），但没有显着降低非心血管死亡风险（0·94、0·88–1·02）。对于这些死亡率结果，患有和不患有糖尿病的患者的 RR 相似。对于所有结果，无论试验平均基线 eGFR 为何，结果都大致相似。根据对绝对效应的估计，SGLT2 抑制的绝对益处超过了酮症酸中毒或截肢的任何严重危险。

 解释

除了已证实的 SGLT2 抑制剂对心血管的益处外，随机数据还支持其用于降低肾病进展和急性肾损伤的风险，不仅适用于心血管风险高的 2 型糖尿病患者，还适用于慢性肾病患者或心力衰竭，无论糖尿病状况、原发性肾病或肾功能如何。

 资金

英国医学研究委员会和英国肾脏研究中心。