Department of Endocrinology, Institute of Post Graduate Medical Education and Research, Kolkata 700020, India.
Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
J Clin Endocrinol Metab. 2023 Jun 16;108(7):1806-1812. doi: 10.1210/clinem/dgad076.
The effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on ischemic/hemorrhagic stroke and transient ischemic attacks (TIA) in type 2 diabetes mellitus (T2DM) remains undetermined.
To pool effects of GLP-1RAs on adverse cerebrovascular outcomes and investigate impact of baseline variables on these effects.
PubMed, Embase, Web of Science, Cochrane Library, and clinical trial registry websites were searched for randomized controlled trials (RCTs) ≥24 weeks duration in adults with T2DM (PROSPERO: CRD42022331547). Adjudicated cerebrovascular events in GLP-1RA treatment vs control arms were pooled together to calculate risk ratios (RR) using fixed-effects model. Subgroup analysis was performed based on individual drugs, treatment duration, and baseline patient characteristics. Quality of evidence was assessed using GRADE framework.
We identified 28 RCTs involving 74 148 patients (57% male; median [range], age 58 [52-67] years, BMI 32 [25.4-37.2] kg/m2, T2DM duration 9 [3.5-15.4] years, treatment duration 52 [24-259] weeks). GLP-1RA use in T2DM was associated with significantly decreased risk of adverse cerebrovascular outcomes vs placebo/active comparator (RR, 0.83; 95% CI, 0.76-0.91; I2 = 0%). Pooling data from cardiovascular outcome trials (n = 8), GLP-1RA treatment vs placebo was associated with reduced risk of nonfatal stroke (RR, 0.85; 95% CI, 0.76-0.94; I2 = 0%) but not fatal stroke (RR, 0.80; 95% CI, 0.61-1.05; I2 = 0%). GLP-1RA use was associated with reduced risk of ischemic stroke (RCTs = 12; RR, 0.73; 95% CI, 0.60-0.89; I2 = 0%), composite of ischemic stroke/TIA (RCTs = 16; RR, 0.76; 95% CI, 0.65-0.90; I2 = 0%), but not hemorrhagic stroke (RCTs = 3; RR, 0.92; 95% CI, 0.51-1.64; I2 = 0%). Treatment benefits differed according to baseline eGFR and diabetes duration (P interaction < .1). Benefits were statistically significant for dulaglutide, subcutaneous/oral semaglutide (P < .05). Sensitivity analysis, excluding shorter-acting lixisenatide, eliminated the heterogeneity between individual GLP-1RA effects.
GLP-1RAs, particularly longer-acting formulations, reduced ischemic cerebrovascular events in T2DM. Observed benefits were significantly higher in patients with shorter T2DM duration and higher eGFR.
胰高血糖素样肽-1 受体激动剂（GLP-1RAs）对 2 型糖尿病（T2DM）患者的缺血性/出血性卒中和短暂性脑缺血发作（TIA）的影响仍不确定。
汇总 GLP-1RAs 对不良脑血管结局的影响，并探讨基线变量对这些影响的影响。
检索 PubMed、Embase、Web of Science、Cochrane 图书馆和临床试验注册网站，纳入了持续时间≥24 周的 T2DM 成人患者的随机对照试验（RCT）（PROSPERO：CRD42022331547）。使用固定效应模型计算 GLP-1RA 治疗与对照组之间经裁决的脑血管事件的风险比（RR）。根据个体药物、治疗持续时间和基线患者特征进行亚组分析。使用 GRADE 框架评估证据质量。
我们确定了 28 项 RCT，涉及 74148 名患者（57%为男性；中位[范围]年龄 58[52-67]岁，BMI 32[25.4-37.2]kg/m2，T2DM 病程 9[3.5-15.4]年，治疗持续时间 52[24-259]周）。与安慰剂/活性对照相比，GLP-1RA 在 T2DM 中的使用与不良脑血管结局的风险显著降低相关（RR，0.83；95%CI，0.76-0.91；I2=0%）。汇总心血管结局试验的数据（n=8），与安慰剂相比，GLP-1RA 治疗与非致死性卒中风险降低相关（RR，0.85；95%CI，0.76-0.94；I2=0%），但与致死性卒中无关（RR，0.80；95%CI，0.61-1.05；I2=0%）。GLP-1RA 治疗与缺血性卒中（RCTs=12；RR，0.73；95%CI，0.60-0.89；I2=0%）、缺血性卒中和 TIA 的复合结局（RCTs=16；RR，0.76；95%CI，0.65-0.90；I2=0%）的风险降低相关，但与出血性卒中无关（RCTs=3；RR，0.92；95%CI，0.51-1.64；I2=0%）。根据基线 eGFR 和糖尿病病程，治疗获益存在差异（P 交互<.1）。在dulaglutide 和皮下/口服 semaglutide 中观察到的获益具有统计学意义（P<.05）。敏感性分析排除了作用时间较短的 lixisenatide 后，消除了个体 GLP-1RA 作用之间的异质性。
GLP-1RAs，特别是作用时间较长的制剂，可降低 T2DM 患者的缺血性脑血管事件。在 T2DM 病程较短和 eGFR 较高的患者中观察到的获益显著更高。
