Caruso Irene, Di Gioia Ludovico, Di Molfetta Sergio, Cignarelli Angelo, Palmer Suetonia Cressida, Natale Patrizia, Strippoli Giovanni F M, Perrini Sebastio, Natalicchio Annalisa, Laviola Luigi, Giorgino Francesco
Department of Precision and Regenerative Medicine and Ionian Area, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.
EClinicalMedicine. 2023 Sep 12;64:102181. doi: 10.1016/j.eclinm.2023.102181. eCollection 2023 Oct.
Innovative GLP-1 receptor agonist (GLP-1RA)-based treatment strategies-such as tirzepatide, GLP-1RA plus basal insulin fixed-ratio combinations [FRC], GLP-1RA plus sodium glucose cotransporter-2 inhibitors [SGLT-2i] combinations, and high-dose GLP-1RA-have been listed among the most efficacious options for type 2 diabetes management. However, differences in their glucometabolic effects have not been assessed in dedicated head-to-head trials. In the absence of such trials, we aimed to provide a useful comparison among these treatment strategies to guide clinical practice.
In this network meta-analysis, we searched PubMed, MEDLINE, and Web of Science (from database inception to June 24, 2023) for randomised controlled studies, published in English, that enrolled individuals with type 2 diabetes treated with tirzepatide, iGlarLixi, iDegLira, GLP-1RA plus SGLT-2i combination, or high-dose GLP-1RA (dulaglutide 3 mg and 4.5 mg, semaglutide 2 mg) compared with placebo or active comparators. Eligible studies reported change from baseline in HbA1c as an outcome, which was the primary outcome of this analysis. Secondary outcomes were changes in fasting and post-prandial glucose, bodyweight, LDL-cholesterol, blood pressure and risk of hypoglycaemia. We assessed risk of bias through the Cochrane Collaboration's tool (RoB2 tool), publication bias through visual inspection of funnel plots and Egger's test, and heterogeneity by comparing the magnitude of the common between-study variance (τ) for each outcome with empirical distributions of heterogeneity variances. This network meta-analysis was registered in PROSPERO (CRD42022329878).
40 trials were included. Tirzepatide 15 mg ranked first in terms of HbA1c reduction compared to other GLP-1RA-based strategies, even those including insulin (vs. iDegLira MD -0.40%, 95% CI [-0.66; -0.14], low certainty; vs. iGlarLixi MD -0.48%, 95% CI [-0.75; -0.21], low certainty), without increasing the risk of hypoglycaemia (vs. iDegLira OR 0.35, 95% CI [0.16; 0.79], high certainty; vs. iGlarLixi OR 0.31, 95% CI [0.20; 0.48], high certainty). Tirzepatide 15 mg was also the most efficacious on weight lowering, even compared to high-dose GLP-1RA (eg, semaglutide 2 mg MD -6.56 kg, 95% CI [-7.38; -5.73], low certainty) and GLP-1RA plus SGLT-2i combination (MD -4.61 kg, 95% CI [-5.29; -3.93], low certainty). Risk of bias and publication bias were generally low throughout studies, while high levels of heterogeneity were detected for most outcomes.
Aiming to support clinicians in tailoring treatment to patients' needs, we suggest that a hierarchy among treatment strategies be devised considering the best options for type 2 diabetes. Tirzepatide, followed by GLP-1RA plus basal insulin FRC and GLP-1RA plus SGLT-2i combination, was associated with greater benefit on HbA1c than high-dose GLP-1RA.
Fondazione per la Ricerca Biomedica "Saverio e Isabella Cianciola" and Next Generation EU, in the context of the National Recovery and Resilience Plan, Investment PE8-Project Age-It: Ageing Well in an Ageing Society.
基于创新型胰高血糖素样肽-1受体激动剂（GLP-1RA）的治疗策略，如替尔泊肽、GLP-1RA加基础胰岛素固定比例组合（FRC）、GLP-1RA加钠-葡萄糖协同转运蛋白2抑制剂（SGLT-2i）组合以及高剂量GLP-1RA，已被列为2型糖尿病管理最有效的选择之一。然而，尚未在专门的头对头试验中评估它们在糖代谢效应方面的差异。在缺乏此类试验的情况下，我们旨在对这些治疗策略进行有益的比较，以指导临床实践。
在这项网状Meta分析中，我们检索了PubMed、MEDLINE和Web of Science（从数据库创建至2023年6月24日），以查找发表于英文的随机对照研究，这些研究纳入了接受替尔泊肽、甘精胰岛素利司那肽、德谷胰岛素利拉鲁肽、GLP-1RA加SGLT-2i组合或高剂量GLP-1RA（度拉糖肽3mg和4.5mg、司美格鲁肽2mg）治疗的2型糖尿病患者，并与安慰剂或活性对照进行比较。符合条件的研究报告了糖化血红蛋白（HbA1c）相对于基线的变化作为结果，这是本分析的主要结果。次要结果包括空腹和餐后血糖、体重、低密度脂蛋白胆固醇、血压和低血糖风险的变化。我们通过Cochrane协作工具（RoB2工具）评估偏倚风险，通过漏斗图的视觉检查和Egger检验评估发表偏倚，并通过将每个结果的研究间共同方差（τ）的大小与异质性方差的经验分布进行比较来评估异质性。这项网状Meta分析已在PROSPERO（CRD42022329878）注册。
纳入40项试验。与其他基于GLP-1RA的策略相比，15mg替尔泊肽在降低HbA1c方面排名第一，即使是那些包含胰岛素的策略（与德谷胰岛素利拉鲁肽相比，平均差[MD]为-0.40%，95%置信区间[-0.66；-0.14]，低确定性；与甘精胰岛素利司那肽相比，MD为-0.48%，95%置信区间[-0.75；-0.21]，低确定性），且不增加低血糖风险（与德谷胰岛素利拉鲁肽相比，比值比[OR]为0.35，95%置信区间[0.16；0.79]，高确定性；与甘精胰岛素利司那肽相比，OR为0.31，95%置信区间[0.20；0.48]，高确定性）。15mg替尔泊肽在降低体重方面也是最有效的，甚至与高剂量GLP-1RA（如2mg司美格鲁肽，MD为-6.56kg，95%置信区间[-7.38；-5.73]，低确定性）和GLP-1RA加SGLT-2i组合（MD为-4.61kg，95%置信区间[-5.29；-3.93]，低确定性）相比也是如此。在整个研究中，偏倚风险和发表偏倚总体较低，而大多数结果检测到高度异质性。
为了支持临床医生根据患者需求定制治疗方案，我们建议制定治疗策略的层级，考虑2型糖尿病的最佳选择。替尔泊肽，其次是GLP-1RA加基础胰岛素FRC和GLP-1RA加SGLT-2i组合，与高剂量GLP-1RA相比，在HbA1c方面具有更大的益处。
“萨维里奥和伊莎贝拉·钱乔拉”生物医学研究基金会以及下一代欧盟，在国家复苏与韧性计划的背景下，投资PE8 - 项目Age - It：老龄化社会中的健康老龄化。
