Beyond Weight Reduction: Obesity as a Therapeutic Pivot in Cardio–Renal–Metabolic Disease and Drug Management

obesity activate the sympathetic nervous system and the renin–angiotensin–aldosterone system, leading to vasoconstriction and salt and water retention. These combined effects, obesity-related myocardial remodelling and chronic inflammation-associated myocardial fibrosis, predispose individuals to HF, particularly HF with preserved ejection fraction. 5,6 Although obesity is established as a causal risk factor for the development of HF, among patients with established HF, higher BMI appears to protect against mortality in clinical studies, a phenomenon termed the obesity survival paradox. The HF obesity survival paradox was first described >20 years ago, and this observation has been replicated across numerous studies. 7,8 Numerous mechanistic theories have been proposed to explain the paradox, assuming a causal relationship, whereas others suggest that the association is caused by index event bias, a form of collider bias that can arise when studying disease cohorts. Consequently, uncertainty persists regarding the role of weight reduction in the management of patients with HF. However, it is worth noting that paradoxical associations between risk factors and disease outcomes are common in prognostic research across clinical medicine and are often underappreciated. 9,10 Genetic studies of disease progression can provide unbiased evidence on the influence of risk factors to inform clinically important questions about disease management. In this respect, recent Mendelian randomisation studies support a positive association between a high BMI and new-onset