This review analyzes how obesity affects HFpEF pathophysiology and discusses novel mechanisms for the prevention of HFpEF using a glucagon-like peptide-1 receptor agonism (GLP-1 RA) in patients with obesity, with metabolic syndrome, or in obese T2D patients, specifically addressing the consequences of obesity on the heart and on HFpEF, the counter-regulatory renin angiotensin system, and prevention of cardiovascular damage in this context. This evidence concerns the gene GCG and obesity due to melanocortin 4 receptor deficiency.