Amylin and the renin-angiotensin system: risk or opportunity in amylin-based therapy?

We hypothesise that amylin receptor agonists (eg, pramlintide) and dual amylin and calcitonin-receptor agonists (eg, cagrilintide), which are emerging treatments for obesity and type 2 diabetes, can activate the renin-angiotensin system (RAS) and potentially undermine the cardiorenal benefits of these therapies. Paradoxically, new-generation amylin-based therapies, such as CagriSema, showed substantial blood pressure reductions in phase 3 trials. Beyond amylin's weight loss-mediated effects, we hypothesise that concurrent use of RAS inhibitors (angiotensin-converting enzyme [ACE] inhibitors or angiotensin-receptor blockers) redirects amylin-induced RAS activation towards the protective alternative RAS pathway, which is characterised by vasodilatory, anti-inflammatory, and antiproliferative effects via Mas receptors, potentially explaining part of their therapeutic benefit and cardioprotective and renoprotective potential. To test this, we propose: (1) preclinical studies investigating amylin-RAS interactions with or without RAS blockade; (2) post-hoc analyses of phase 2/3 trials stratified by RAS inhibitor use; (3) biomarker studies monitoring renin, aldosterone, angiotensin-(1-7), and ACE2; and (4) mechanistic human studies prospectively assessing cardiovascular-kidney metabolic effects by RAS inhibitor status. These suggestions aim to determine whether RAS inhibition enhances the overall efficacy of amylin-based therapies, and whether RAS blockers should be strongly recommended in patients receiving them.