As this review highlights the central role of SGLT-2 inhibitors in HFpEF and the promising potential of GLP-1 receptor agonists, particularly for obesity or diabetes-related HFpEF, the disparity in evidence between these drug classes underscores the urgent need for large-scale, multicenter RCTs with long-term follow-ups to evaluate GLP-1 receptor agonists and their combination with SGLT-2 inhibitors. This evidence concerns the gene GLP1R and obesity due to melanocortin 4 receptor deficiency.