Background

GLP-1 receptor agonists reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes. However, uncertainty regarding kidney outcomes persists and whether benefits extend to exendin-4-based GLP-1 receptor remains uncertain. We aimed to meta-analyse the most up-to-date evidence on the cardiovascular benefits and risks of GLP-1 receptor agonists from outcome trials in patients with type 2 diabetes.

Methods

We did a meta-analysis, including new data from AMPLITUDE-O, using a random effects model to estimate overall hazard ratio (HR) for MACE; its components; all-cause mortality; hospital admission for heart failure; a composite kidney outcome consisting of development of macroalbuminuria, doubling of serum creatinine, or at least 40% decline in estimated glomerular filtration rate (eGFR), kidney replacement therapy, or death due to kidney disease; worsening of kidney function, based on eGFR change; and odds ratios for key safety outcomes (severe hypoglycaemia, retinopathy, pancreatitis, and pancreatic cancer). We also examined MACE outcome in patient subgroups on the basis of MACE incidence rates in the placebo group, presence or absence of cardiovascular disease, HbA_1c level, trial duration, treatment dosing interval, structural homology to human GLP-1 or exendin-4, BMI, age, and eGFR. We searched PubMed for eligible trials reporting MACE (ie, cardiovascular death, myocardial infarction, or stroke), up to June 9, 2021. We meta-analysed data from published randomised placebo-controlled trials testing either injectable or oral GLP-1 receptor agonists in patients with type 2 diabetes. We restricted the search to trials of more than 500 patients with a primary outcome that included cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. This meta-analysis was registered on PROSPERO, CRD42021259711.

Findings

Of 98 articles screened, eight trials comprising 60 080 patients fulfilled the prespecified criteria and were included. Overall, GLP-1 receptor agonists reduced MACE by 14% (HR 0·86 [95% CI 0·80–0·93]; p<0·0001), with no significant heterogeneity across GLP-1 receptor agonist structural homology or eight other examined subgroups (all p_interaction≥0·14). GLP-1 receptor agonists reduced all-cause mortality by 12% (HR 0·88 [95% CI 0·82–0·94]; p=0·0001), hospital admission for heart failure by 11% (HR 0·89 [95% CI 0·82–0·98]; p=0·013), and the composite kidney outcome by 21% (HR 0·79 [95% CI 0·73–0·87]; p<0·0001), with no increase in risk of severe hypoglycaemia, retinopathy, or pancreatic adverse effects. In sensitivity analyses removing the only trial restricted to patients with an acute coronary syndrome (ELIXA), all benefits marginally increased, including the outcome of worsening of kidney function, based on eGFR change (HR 0·82 [95% CI 0·69–0·98]; p=0·030).

Interpretation

GLP-1 receptor agonists, regardless of structural homology, reduced the risk of individual MACE components, all-cause mortality, hospital admission for heart failure, and worsening kidney function in patients with type 2 diabetes.

Funding

None.

中文翻译：

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GLP-1 受体激动剂治疗 2 型糖尿病患者的心血管、死亡率和肾脏结局：随机试验的系统评价和荟萃分析

背景

GLP-1 受体激动剂可减少 2 型糖尿病患者的主要不良心血管事件 (MACE)。然而，关于肾脏结果的不确定性仍然存在，并且益处是否扩展到基于 exendin-4 的 GLP-1 受体仍然不确定。我们旨在对来自 2 型糖尿病患者的结果试验中 GLP-1 受体激动剂的心血管益处和风险的最新证据进行荟萃分析。

方法

我们进行了荟萃分析，包括来自 AMPLITUDE-O 的新数据，使用随机效应模型来估计 MACE 的总体风险比 (HR)；其组成部分；全因死亡率；因心力衰竭住院；复合肾脏结局包括大量白蛋白尿、血清肌酐加倍或估计肾小球滤过率 (eGFR) 下降至少 40%、肾脏替代疗法或因肾脏疾病而死亡；基于 eGFR 变化的肾功能恶化；和关键安全性结果（严重低血糖、视网膜病变、胰腺炎和胰腺癌）的优势比。我们还根据安慰剂组的 MACE 发生率、是否存在心血管疾病、HbA _1c检测了患者亚组的 MACE 结果水平、试验持续时间、治疗给药间隔、与人 GLP-1 或 exendin-4 的结构同源性、BMI、年龄和 eGFR。我们在 PubMed 中搜索了截至 2021 年 6 月 9 日报告 MACE（即心血管死亡、心肌梗塞或中风）的合格试验。我们对已发表的随机安慰剂对照试验的数据进行了荟萃分析，这些试验测试了注射剂或口服 GLP-1 受体激动剂在 2 型糖尿病患者中。我们将搜索限制在 500 多名患者的试验中，这些患者的主要结局包括心血管死亡、非致命性心肌梗死和非致命性中风。该荟萃分析注册于 PROSPERO，CRD42021259711。

发现

在筛选的 98 篇文章中，包含 60 080 名患者的 8 项试验符合预先指定的标准并被纳入。总体而言，GLP-1 受体激动剂将 MACE 降低了 14%（HR 0·86 [95% CI 0·80–0·93]；p<0·0001），在 GLP-1 受体激动剂结构同源性或八个其他检查的亚组（所有 p_相互作用≥0·14)。GLP-1 受体激动剂将全因死亡率降低 12%（HR 0·88 [95% CI 0·82–0·94]；p=0·0001），因心力衰竭住院减少 11%（HR 0· 89 [95% CI 0·82–0·98]；p=0·013），复合肾脏结果降低 21%（HR 0·79 [95% CI 0·73-0·87]；p<0 ·0001)，不会增加严重低血糖、视网膜病变或胰腺不良反应的风险。在敏感性分析中，排除了仅限于急性冠脉综合征 (ELIXA) 患者的唯一试验，所有获益均略有增加，包括肾功能恶化的结果，基于 eGFR 变化（HR 0·82 [95% CI 0·69– 0·98]；p=0·030)。

解释

GLP-1 受体激动剂，无论结构同源性如何，都能降低 2 型糖尿病患者出现个别 MACE 成分、全因死亡率、心力衰竭住院和肾功能恶化的风险。

资金

没有任何。