In this mechanistic analysis of the SUMMIT trial, we found that, compared with placebo, treatment with the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist tirzepatide reduced BP and estimates of circulatory volume expansion in patients with obesity-related HFpEF. This evidence concerns the gene GIPR and obesity due to melanocortin 4 receptor deficiency.