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By exploring human studies and mechanistic insights, this review underscores irisins potential to address global health challenges, such as obesity and type 2 diabetes, while advancing strategies for personalized exercise interventions.

Method We systematically searched PubMed and Embase from inception to 1 May 2025 for cohort studies comparing the effect of combination therapy with SGLT2 inhibitor or GLP-1 RA monotherapy on (cardiovascular) mortality and cardiovascular or kidney endpoints in individuals with type 2 diabetes