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Acknowledgements The authors would like to thank all PIONEER REAL study participants and site staff in Canada, Denmark, Italy, the Netherlands, Sweden, Switzerland, and the UK

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By examining the effects following weight loss and also effects after accounting for weight loss on the proteome throughout the trial in those with and without T2D, and by comparing proteomic profiles with those of observational cohorts, we aimed to comprehensively study the proteomic effects of semaglutide treatment and elucidate the mechanism of action driving its benefits on weight- and obesity-related complications, and to determine its potential for use in new indications