Objective To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults with type 2 diabetes. Design Systematic review and network meta-analysis. Data sources PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase from database inception to 19 August 2023. Eligibility criteria for selecting studies Eligible randomised controlled trials enrolled adults with type 2 diabetes who received GLP-1RA treatments and compared effects with placebo or any GLP-1RA drug, with a follow-up duration of at least 12 weeks. Trials with a crossover design, non-inferiority studies comparing GLP-1RA and other drug classes without a placebo group, using withdrawn drugs, and non-English studies were deemed ineligible. Results 76 eligible trials involving 15 GLP-1RA drugs and 39 246 participants were included in this network meta-analysis; all subsequent estimates refer to the comparison with placebo. All 15 GLP-1RAs effectively lowered haemoglobin A1c and fasting plasma glucose concentrations. Tirzepatide induced the largest reduction of haemoglobin A1c concentrations (mean difference −2.10% (95% confidence interval −2.47% to −1.74%), surface under the cumulative ranking curve 94.2%; high confidence of evidence), and fasting plasma glucose concentrations (−3.12 mmol/L (−3.59 to −2.66), 97.2%; high confidence), and proved the most effective GLP-1RA drug for glycaemic control. Furthermore, GLP-1RAs were shown to have strong benefits to weight management for patients with type 2 diabetes. CagriSema (semaglutide with cagrilintide) resulted in the highest weight loss (mean difference −14.03 kg (95% confidence interval −17.05 to −11.00); high confidence of evidence), followed by tirzepatide (−8.47 kg (−9.68 to −7.26); high confidence). Semaglutide was effective in lowering the concentration of low density lipoprotein (−0.16 mmol/L (−0.30 to −0.02)) and total cholesterol (−0.48 mmol/L (−0.84 to −0.11)). Moreover, this study also raises awareness of gastrointestinal adverse events induced by GLP-1RAs, and concerns about safety are especially warranted for high dose administration. Conclusions GLP-1RAs are efficacious in treating adults with type 2 diabetes. Compared with the placebo, tirzepatide was the most effective GLP-1RA drug for glycaemic control by reducing haemoglobin A1c and fasting plasma glucose concentrations. GLP-1RAs also significantly improved weight management for type 2 diabetes, with CagriSema performing the best for weight loss. The results prompt safety concerns for GLP-1RAs, especially with high dose administration, regarding gastrointestinal adverse events. Systematic review registration PROSPERO CRD42022342845. All data are publicly available.

中文翻译：

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GLP-1 受体激动剂对 2 型糖尿病的血糖控制、体重和血脂的有效性比较：系统评价和网络荟萃分析

目的 评估胰高血糖素样肽 1 受体激动剂 (GLP-1RA) 对成人 2 型糖尿病患者的血糖控制、体重和血脂的比较疗效和安全性。设计系统回顾和网络荟萃分析。数据来源 PubMed、Web of Science、Cochrane 对照试验中央注册库 (CENTRAL) 和 Embase，从数据库建立到 2023 年 8 月 19 日。 选择研究的资格标准 合格的随机对照试验纳入了接受 GLP-1RA 治疗和治疗的 2 型糖尿病成人患者与安慰剂或任何 GLP-1RA 药物的效果进行比较，随访时间至少为 12 周。交叉设计试验、在没有安慰剂组的情况下比较 GLP-1RA 和其他药物类别的非劣效性研究、使用撤回药物的试验以及非英国研究均被视为不合格。结果 本次网络荟萃分析纳入了 76 项符合条件的试验，涉及 15 种 GLP-1RA 药物和 39 246 名受试者；所有后续估计均指与安慰剂的比较。所有 15 种 GLP-1RA 均可有效降低血红蛋白 A1c 和空腹血糖浓度。替泽帕肽诱导血红蛋白 A1c 浓度最大程度降低（平均差 -2.10%（95% 置信区间 -2.47% 至 -1.74%），累积排序曲线下表面 94.2%；证据可信度高）和空腹血糖浓度（ −3.12 mmol/L（-3.59至-2.66），97.2%；高置信度），并被证明是控制血糖最有效的GLP-1RA药物。此外，GLP-1RA 对 2 型糖尿病患者的体重管理具有显着益处。CagriSema（索马鲁肽加卡格里林肽）导致体重减轻最高（平均差−14.03 kg（95%置信区间−17.05至−11.00）；证据置信度高），其次是替泽帕肽（−8.47 kg（−9.68至−7.26） ；高置信度）。索马鲁肽可有效降低低密度脂蛋白（-0.16 mmol/L（-0.30至-0.02））和总胆固醇（-0.48 mmol/L（-0.84至-0.11））的浓度。此外，这项研究还提高了人们对 GLP-1RA 引起的胃肠道不良事件的认识，尤其是高剂量给药时对安全性的担忧。结论 GLP-1RA 可有效治疗成人 2 型糖尿病。与安慰剂相比，替泽帕肽是通过降低血红蛋白 A1c 和空腹血糖浓度来控制血糖最有效的 GLP-1RA 药物。GLP-1RA 还显着改善了 2 型糖尿病的体重管理，其中 CagriSema 的减肥效果最佳。结果引发了 GLP-1RA 的安全性担忧，特别是高剂量给药时，与胃肠道不良事件有关。系统审评注册PROSPERO CRD42022342845。所有数据都是公开的。