Although loop diuretics have been the de facto the first-line decongestive treatment for HF across the LVEF spectrum for over 60 years, they can cause electrolyte abnormalities, worsening kidney function, and hypotension.1 In obesity-related HFpEF, with the availability of SGLT2 inhibitors, MRAs, and now semaglutide, the need for loop diuretics, particularly at higher doses, may need to be reconsidered and substituted for these agents as first-line therapies. The gene discussed is SLC5A2; the disease is obesity disorder.