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Aims: This systematic review was aimed to assess the association between magnitude of body weight loss (BWL) in type 2 diabetes (T2D) patients and cardiovascular (CV) risk in CV outcome trials (CVOTs)., Methods: We searched electronic databases (PubMed, Cochrane and Scopus) for available CVOTs, observational cohort studies or post hoc analyses of clinical trials of adult T2D patients investigated the association of BWL with CV outcomes and/or all-cause mortality., Results: 19 RCTs of novel glucose-lowering drugs (GLP-1RA, DPP-4i and SGLT2i) and 6 RCT or observational trial of different strategies (intensive treatment or standard care) were included (379.904 T2D patients). Higher BWL during GLP-1RA treatment, in comaprison to lower BWL, was associated with higher decrease in risk of MACE, while DPP-4i had not that effect. With SGLT2i the higher decrease in risk of MACE was associated with lower BWL. In contrast, in other different strategies, higher BWL lead to increase in risk for MACE and all-cause mortality., Conclusions: In CVOTs, treatment of T2D patients resulted in BWL, which correlated with reduction in risk for CV outcomes, particularly with GLP-1 RAs. However, interventional non-CVOTs are warning that in the absence of structured behavioral intervention and relevant medication, the large BWL might be harmful for CV outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)