This review evaluates whether weight-loss interventions (lifestyle, surgical, and pharmacological — notably semaglutide and tirzepatide) can prevent or modify common obesity-related conditions across musculoskeletal, metabolic, cardiovascular, mental health, respiratory, and hepatic domains, using a triangulation framework of epidemiological, genetic (including Mendelian randomisation), and randomised trial evidence.
Robust trial evidence supports weight loss as disease-modifying in type 2 diabetes and heart failure with preserved ejection fraction; incretin-based therapies (semaglutide, tirzepatide) now achieve ~14–20% average weight loss in people without diabetes and have generated the first large-scale randomised evidence of disease modification across several conditions, though many areas (musculoskeletal, respiratory, mental health, cardiovascular) remain under-investigated.
- Many conditions lack adequate randomised trial evidence, limiting causal conclusions. - Evidence on varying magnitudes of weight loss with different agents, disease-stage effects, and long-term (legacy) outcomes is sparse. - Trials have not adequately addressed multimorbidity, mechanistic mediation, diverse global populations, or access equity.
Clinicians have strong evidence to use weight-loss therapies — especially GLP-1 receptor agonists like semaglutide and dual GLP-1/GIP agonists like tirzepatide — for disease modification in type 2 diabetes and HFpEF, but should recognise that evidence for many other obesity-related conditions is still emerging. Individualised treatment targets and long-term follow-up remain important given persistent gaps in outcome data.
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