Aims/hypothesis

Several cardiovascular outcome trials on sodium–glucose cotransporter 2 inhibitors (SGLT2i) have been released recently, including trials enrolling patients with congestive heart failure (CHF) and chronic kidney disease (CKD). Comparisons of the efficacy and safety of SGLT2i, glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) thus require an update. Assessments in patient subgroups, i.e., as stratified by age or the presence of CHF, CKD or atherosclerotic cardiovascular disease (ASCVD), are also currently lacking.

Methods

We searched the PubMed, Embase and Cochrane databases for relevant studies published up until 5 December 2020. RCTs comparing SGLT2i, GLP-1RA and DPP-4i with placebo (or other controls) or with each other with cardiovascular (CV) or renal outcomes were eligible for inclusion. The primary efficacy endpoint was 3-point major adverse cardiovascular events (3P-MACE), which are defined as CV death, non-fatal myocardial infarction and non-fatal ischaemic stroke. All-cause mortality, hospitalisation for heart failure (HHF) and composite renal outcomes were also analysed. Pre-specified subgroup analyses of 3P-MACE were also performed.

Results

A total of 21 trials with 170,930 participants were included in this network meta-analysis. Both GLP-1RA and SGLT2i were associated with lower risks of 3P-MACE than placebo (RR 0.89, 95% CI 0.84, 0.94 and RR 0.88, 95% CI 0.83, 0.94, respectively). GLP-1RA and SGLT2i were also associated with lower risks of 3P-MACE than DPP-4i (RR 0.89, 95% CI 0.82, 0.98 and RR 0.89, 95% CI 0.81, 0.97, respectively). A comparison between SGLT2i and GLP-1RA demonstrated no difference in their risks of 3P-MACE (RR 0.99, 95% CI 0.91, 1.08). Only GLP-1RA was associated with a lower risk of stroke compared with placebo (RR 0.85, 95% CI 0.76, 0.94). SGLT2i is superior to GLP-1RA in reducing HHF (RR 0.76, 95% CI 0.68, 0.84) and renal outcomes (RR 0.78, 95% CI 0.65, 0.93). Subgroup analyses indicated that the benefits of SGLT2i and GLP-1RA were more pronounced in elderly patients, white and Asian patients, those with established ASCVD and those with longer durations of diabetes mellitus and worse glycaemic control.

Conclusions/interpretation

SGLT2i and GLP-1RA are superior to DPP-4i in terms of CV and renal outcomes. GLP-1RA is the only drug class that reduces the risk of stroke. SGLT2i is superior in reducing HHF and renal outcomes. Therefore, the choice between SGLT2i and GLP-1RA should be individualised according to patient profiles.

PROSPERO registration number:

CRD42020206600.

Graphical abstract

中文翻译：

---

新型降糖药物对心血管结局的疗效和安全性：随机临床试验的网络荟萃分析

目标/假设

最近发布了几项关于钠-葡萄糖协同转运蛋白 2 抑制剂 (SGLT2i) 的心血管结局试验，包括招募充血性心力衰竭 (CHF) 和慢性肾病 (CKD) 患者的试验。因此，SGLT2i、胰高血糖素样肽-1 受体激动剂 (GLP-1RA) 和二肽基肽酶-4 抑制剂 (DPP-4i) 的疗效和安全性比较需要更新。目前还缺乏对患者亚组的评估，即按年龄或存在 CHF、CKD 或动脉粥样硬化性心血管疾病 (ASCVD) 进行分层。

方法

我们在 PubMed、Embase 和 Cochrane 数据库中搜索了截至 2020 年 12 月 5 日发表的相关研究。比较 SGLT2i、GLP-1RA 和 DPP-4i 与安慰剂（或其他对照）或相互比较心血管（CV）或肾脏结果的 RCT有资格列入。主要疗效终点是 3 点主要不良心血管事件（3P-MACE），其定义为 CV 死亡、非致死性心肌梗死和非致死性缺血性卒中。还分析了全因死亡率、心力衰竭住院 (HHF) 和复合肾脏结局。还进行了预先指定的 3P-MACE 亚组分析。

结果

该网络荟萃分析共纳入 21 项试验，共有 170,930 名参与者。与安慰剂相比，GLP-1RA 和 SGLT2i 的 3P-MACE 风险较低（分别为 RR 0.89、95% CI 0.84、0.94 和 RR 0.88、95% CI 0.83、0.94）。与 DPP-4i 相比，GLP-1RA 和 SGLT2i 也与较低的 3P-MACE 风险相关（RR 0.89, 95% CI 0.82, 0.98 和 RR 0.89, 95% CI 0.81, 0.97）。SGLT2i 和 GLP-1RA 之间的比较表明它们的 3P-MACE 风险没有差异（RR 0.99, 95% CI 0.91, 1.08）。与安慰剂相比，只有 GLP-1RA 与较低的卒中风险相关（RR 0.85, 95% CI 0.76, 0.94）。SGLT2i 在降低 HHF (RR 0.76, 95% CI 0.68, 0.84) 和肾脏结局 (RR 0.78, 95% CI 0.65, 0.93) 方面优于 GLP-1RA。

结论/解释

SGLT2i 和 GLP-1RA 在心血管和肾脏结局方面优于 DPP-4i。GLP-1RA 是唯一可以降低中风风险的药物类别。SGLT2i 在降低 HHF 和肾脏结局方面具有优势。因此，SGLT2i 和 GLP-1RA 之间的选择应根据患者情况个体化。

PROSPERO 注册号：

CRD42020206600。

图形概要