Amylin and the renin-angiotensin system: risk or opportunity in amylin-based therapy?
The paper suggests that amylin-based therapies may interact with the renin-angiotensin system, potentially impacting their effectiveness, but specific data is lacking.
Where it sits
this study against the rest of the pramlintide corpusSummary and findings
This paper hypothesizes that amylin receptor agonists, such as pramlintide, may activate the renin-angiotensin system (RAS) and affect the benefits of these therapies. It also discusses the potential for concurrent use of RAS inhibitors to redirect this activation towards protective pathways. The study proposes various research approaches to investigate these interactions.
Abstract
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.
Background
The paper addresses the interaction between amylin receptor agonists and the renin-angiotensin system (RAS), which is relevant given the emerging use of these therapies in obesity and type 2 diabetes. Previous studies have indicated potential cardiovascular benefits associated with amylin-based therapies, but the implications of RAS activation remain unclear. Understanding these interactions could inform clinical practice and enhance therapeutic strategies.
Methods
The authors propose a series of studies including preclinical investigations of amylin-RAS interactions, post-hoc analyses of existing phase 2/3 trial data stratified by RAS inhibitor use, and biomarker studies to monitor relevant cardiovascular and metabolic markers. Specifics regarding sample sizes, doses, and durations are not provided in the abstract.
Results
Not reported in abstract.
Interpretation
The hypotheses presented suggest a complex relationship between amylin therapies and RAS, which may influence their clinical efficacy. However, without specific data or results, it is difficult to determine the clinical significance of these findings or their implications for practice. The proposed studies may help clarify these relationships, but potential confounds such as reliance on post-hoc analyses and the lack of direct evidence from human trials limit the conclusions that can be drawn at this stage.
Key findings
- CagriSema showed substantial blood pressure reductions in phase 3 trials.
- Proposed studies include preclinical investigations and post-hoc analyses of phase 2/3 trials.
- Monitoring of biomarkers such as renin, aldosterone, angiotensin-(1-7), and ACE2 is suggested.
Limitations
- Not reported in abstract.
- No specific numeric findings or results provided.
- Proposed studies are hypothetical and not yet conducted.
- Potential reliance on post-hoc analyses.
- No human data presented in the abstract.