From adiposity to multisystem morbidity: the case for weight loss as disease modification

Obesity (ie, excess adiposity) is a major driver of multisystem morbidity, spanning musculoskeletal (eg, osteoarthritis), metabolic (eg, type 2 diabetes), cardiovascular (eg, heart failure), mental health (eg, depression), respiratory (eg, obstructive sleep apnoea), and gastrointestinal and hepatic (eg, metabolic dysfunction-associated steatotic liver disease) disorders. However, the extent to which weight-loss interventions can prevent or modify these conditions varies considerably. In this Review, we synthesise evidence from epidemiological studies, genetic analyses (including Mendelian randomisation), observational weight-change studies, and randomised trials, using a triangulation framework to assess causal links between adiposity and common diseases. Although robust trial evidence supports weight loss as a disease-modifying strategy in some conditions, including but not limited to type 2 diabetes and heart failure with preserved ejection fraction, many other conditions, including musculoskeletal, respiratory, cardiovascular, and mental health disorders, remain under-investigated. Incretin-based therapies, in particular the glucagon-like peptide 1 receptor agonist semaglutide and the dual glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptor agonist tirzepatide, now achieve average weight losses of approximately 14-20% in people without diabetes and have generated the first large-scale randomised evidence of disease modification across several of these conditions. We highlight key gaps and propose priorities for future trials, including the need for studies across different disease stages, incorporation of mechanistic and mediation analyses, and evaluation of the impact on disease outcomes of varying magnitudes of weight loss with differing agents. Future research should also consider multimorbidity, individualised treatment targets, and long-term outcomes-including potential legacy effects. Addressing global access gaps and conducting trials in diverse populations will be essential to inform scalable and equitable obesity care.