Amylin receptor agonists, such as pramlintide, and dual amylin and calcitonin receptor agonists, such as cagrilintide, are new treatments for obesity and type 2 diabetes. These drugs can activate the renin-angiotensin system (RAS) and potentially compromise the cardiorenal benefits. Paradoxically, new amylin-based therapies, such as CagriSema, have shown significant reductions in blood pressure in phase 3 studies. In addition to weight loss effects, combination with RAS inhibitors, such as ACE inhibitors or angiotensin receptor blockers, is thought to redirect RAS activation to a protective pathway. This pathway acts through Mas receptors with vasodilating, anti-inflammatory and anti-proliferative effects. It has the potential to protect the heart and kidneys. The authors propose preclinical studies, clinical trial analyses, biomarker monitoring, and mechanistic studies in humans to verify these interactions.