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

# Amylin and the renin-angiotensin system: risk or opportunity in amylin-based therapy? *The Lancet 2025* Hypothesis Amylin and the renin-angiotensin system: risk or opportunity in amylin-based therapy? Marcel H A Muskiet, Massimo Nardone, Patrick C N Rensen, David Z I Cherney, Mark E Cooper Lancet 2025; 406: 2980–83 We hypothesise that amylin receptor agonists (eg, pramlintide) and dual amylin and calcitonin-receptor agonists Published Online (eg, cagrilintide), which are emerging treatments for obesity and type 2 diabetes, can activate the renin-angiotensin November 6, 2025 system (RAS) and potentially undermine the cardiorenal benefits of these therapies. Paradoxically, new-generation https://doi.org/10.1016/ amylin-based therapies, such as CagriSema, showed substantial blood pressure reductions in phase 3 trials. Beyond S0140-6736(25)01776-3 amylin’s weight loss-mediated effects, we hypothesise that concurrent use of RAS inhibitors (angiotensin-converting Department of Internal enzyme [ACE] inhibitors or angiotensin-receptor blockers) redirects amylin-induced RAS activation towards the Medicine, Division of Endocrinology, Leiden protective alternative RAS pathway, which is characterised by vasodilatory, anti-inflammatory, and antiproliferative University Medical Center, effects via Mas receptors, potentially explaining part of their therapeutic benefit and cardioprotective and renoprotective Leiden, Netherlands potential. To test this, we propose: (1) preclinical studies investigating amylin–RAS interactions with or without RAS (M H A Muskiet MD PhD, blockade; (2) post-hoc analyses of phase 2/3 trials stratified by RAS inhibitor use; (3) biomarker studies monitoring Prof P C N Rensen PhD); Diabetes Centre, Department renin, aldosterone, angiotensin-(1–7), and ACE2; and (4) mechanistic human studies prospectively assessing of Internal Medicine, cardiovascular–kidney metabolic effects by RAS inhibitor status. These suggestions aim to determine whether RAS Amsterdam University Medical inhibition enhances the overall efficacy of amylin-based therapies, and whether RAS blockers should be strongly Center, Amsterdam, recommended in patients receiving them. Netherlands (M H A Muskiet); Department of Medicine, Division of Nephrology, Introduction The amylin revival University Health Network, Obesity and type 2 diabetes are closely linked global Amylin receptors have recently re­emerged as a proven Toronto General Hospital health crises that contribute to increasing rates of drug target in metabolic disease management.1 Amylin is Research Institute, Toronto, ON, Canada (M H A Muskiet, morbidity, mortality, and diminished quality of life (QOL), a 37­amino acid neuropeptide and member of the M Nardone PhD, with cardiovascular and kidney complications repre­ calcitonin peptide family that is co­secreted with insulin Prof D Z I Cherney MD PhD); senting major drivers of this burden. The developm ent by pancreatic β cells in response to the intake of nutrients Einthoven Laboratory for of multihormone receptor modulators (MHRMs) such as glucose, arginine, and fatty acids. Amylin plays a Experimental Vascular Medicine, Leiden University represents a major therapeutic advance in the treatment key role in postprandial homoeostasis by indirectly Medical Center, Leiden, of these metabolic diseases, offering clinically meaning­ suppressing glucagon secretion, delaying gastric Netherlands ful weight loss and related benefits.1 These therapies emptying, and promoting satiety related to the control of (Prof P C N Rensen); typically combine central GLP­1 receptor agonism with the inter­meal interval.3–7 These effects are potentially Department of Diabetes, School of Translational agonism of other hormone receptors. MHRMs are mediated via amylin­binding sites that are broadly Medicine, Monash University, administered as coformulations (eg, CagriSema) or distributed, including at least three fully assembled Melbourne, VIC, Australia unimolecular GLP­1­based constructs that incorporate functional amylin­receptors, each consisting of a (Prof M E Cooper MD PhD) one or more additional hormone­peptide epitopes, calcitonin receptor bound to one of the receptor activity Correspondence to: enabling the simultaneous activation—or, in some cases, modifying proteins 1–3 to yield the amylin receptors 1–3 Dr Marcel H A Muskiet, Department of Internal inhibition—of hormone receptors (eg, tirzepatide, subtypes.3 Medicine, Division of maridebart cafraglutide, and retatrutide).1 Acting Although the therapeutic potential of amylin for Endocrinology, Leiden University additively or synergistically, these hormones regulate diabetes was recognised as early as the 1980s—with Medical Center, Leiden 2333 ZA, appetite, energy expenditure, and other key pathways to salmon calcitonin as a dual amylin and calcitonin Netherlands m.h.a.muskiet@lumc.nl improve metabolic control, induce and sustain weight­ receptor agonist—clinical application of native amylin loss, and potentially reduce complications, deliveri ng has been limited due to its short half­life, enzymatic a level of therapeutic efficacy that increasingly instability, and tendency to form cytotoxic oligomers approaches—and could eventually rival—that of bariatric and amyloid fibrils.3 These limitations were partly surgery.1 Although the clinical development of MHRMs addressed by pramlintide, a first­in­class synthetic has primary targeted metabolic conditions and outcomes, analogue of human amylin approved by the US Food their benefits might extend beyond glycaemic control and Drug Administration in 2005 for use in type 1 and weight loss to include improvements in cardio­ diabetes and insulin­requiring type 2 diabetes.3 vascular and kidney outcomes, QOL, and potentially Pramlintide also showed weight­lowering effects in mortality. Although GLP­1 receptor agonists have already both preclinical and clinical studies, prompting interest shown these benefits,2 it remains to be seen whether in its use for obesity treatment, with observed weight these benefits can fully translate to MHRMs, since their loss of approxi mately 5–7%.3 However, the potential of additional hormone receptor modulators could pramlintide was limited by practical challenges, such as theoretically amplify or dilute the effect through receptor the requirement for thrice­daily injections and high activity in tissues such as the heart, vasculature, cost, which ultimately halted further development in and kidneys. this area.3 2980 Hypothesis Building on this foundation, a new generation of long­ Evidence that amylin influences kidney physiology acting amylin mimetics and agents derived from dates back to the 1990s.16,17 Amylin has been shown to pramlintide or salmon calcitonin scaffolds is in increase renal blood flow and vascular conductance, likely development, showing promise as effective weight loss via calcitonin receptors, and to act directly on proximal therapies. The most advanced candidate, cagrilintide, tubules to stimulate sodium and water reabsorption.16,18–20 which is a non­selective dual amylin and calcitonin Notably, studies in rats and humans showed that receptor agonist with receptor residence time similar to subcutaneous administration of amylin, at both pramlintide, has shown positive phase 3 trial results and is physiological and supraphysiological doses, rapidly expected to reach the market by 2026.8,9 Notably, increased plasma renin activity by up to 97% in humans CagriSema, a once per week co­formulation of cagrilintide and raised aldosterone concentrations by 62%, with a (2·4 mg) and semaglutide (2·4 mg), showed statistically modest vasopressor response (ie, no blood pressure drop significant greater weight loss (up to –20·4% in individuals that would trigger renin release).18,20,21 These effects were with overweight or obesity without type 2 diabetes) and blocked by amylin receptor antagonists, suggesting improved glycaemic control (HbA₁ reductions up to mediation via an amylin­like receptor,18 possibly via cyclic c –2·0% in those with type 2 diabetes) compared with either adenosine monophosphate­dependent pathways.22 The agent alone, as shown in both phase 2 and phase 3 clinical response was not inhibited by propranolol, suggesting trials, suggesting additive and potentially synergistic that the response occurs independently of sympathetic effects.8–10 In addition, amycretin, which is a dual GLP­1 nervous system activation.18 Similarly, short­term infusion and amylin receptor agonist delivered orally11 or of salmon calcitonin in humans has been shown to subcutaneously,12 has shown promising weight loss and elevate plasma renin activity, aldosterone levels, and metabolic benefits in early phase 1/2 trials,13 and other serum angiotensin­converting enzyme (ACE).17 Whether amylin­based candidates (eg, eloralintide and AZD6234) dual amylin and calcitonin receptor agonists differ from are also currently in early clinical development, amylin mono­receptor agonists in their capacity to highlighting an expanding pipeline of therapies in this activate the RAS remains unknown. re­emerging field.1,3 Amylin-based therapies and RAS blockade Amylin and the RAS Collectively, the above findings suggest that both amylin Amylin receptor agonists exhibit independent systemic receptor agonists and dual amylin and calcitonin receptor effects that extend beyond metabolic regulation and agonists can activate the RAS, potentially promoting weight loss. Amylin­binding sites have been identified sodium retention, hypertension, vascular stiffness, and across multiple organs and tissues, including the fibrosis, all of which could be detrimental to cardiovascular and renal systems, with the distribution of cardiovascular and kidney health. In this context, it is fully assembled receptors (calcitonin receptor and notable that subcutaneous amycretin,12 unlike the oral receptor activity modifying proteins heterodimers) yet to formulation,11 did not lower blood pressure despite be comprehensively mapped. This finding supports a clinically and statistically significant weight loss—an growing body of evidence for the potential direct observation that might reflect the small sample size of involvement of amylin receptor agonists in cardiorenal the phase 1b/2a trial or the low baseline systolic pressure physiology and the pharmacological impact of their (<120 mm Hg), but which warrants further investigation, activation.3 Further research is needed to delineate which including potential RAS­activating mechanisms. of these effects are physiologically significant under Pramlintide does not appear to statistically significantly typical conditions, how they are modified in pathological affect blood pressure, although available data are sparse. states, and to what extent they reflect pharmacological However, this appears to contradict the substantial blood actions resulting from supraphysiological concentrations pressure reductions reported in clinical trials with of exogenously administered amylin. CagriSema, which have shown systolic blood pressure One particularly relevant system is the renin­ drops of up to 10·9 mm Hg in the REDEFINE­1 trial.10 angiotensin system (RAS), which is a key regulator of What might explain this paradox? In addition to the blood pressure, fluid balance, and vascular tone. There is significant weight loss reached by CagriSema, which considerable interest in the effects of nutrient­stimulated likely contributes to sustained blood pressure reduction, hormones on kidney physiology—referred to as the gut– a potential contributing factor could be a modifying kidney axis14—which could have evolved to maintain effect of concurrent RAS inhibitor use. RAS inhibitors postprandial homoeostasis and optimise the excretion of could redirect amylin­induced RAS activation towards excess solutes and metabolic waste by modulating kidney the so­called alternative RAS pathway (figure). When the haemodynamic and tubular function. Previously, we classic RAS pathway is inhibited (by ACE inhibitors or proposed that GLP­1 acts as a mediator of the gut–kidney angiotensin­receptor blockers; ARBs), angiotensin I and axis, contributing to natriuresis via putative sodium/ angiotensin II are increasingly converted by ACE2 and hydrogen exchanger 3 inhibition14 in the proximal tubule neutral endopeptidase into angiotensin­(1–7), which and modulating the RAS pathway.14,15 exerts vasodilatory, anti­inflammatory, and antifibrotic Hypothesis Classic RAS pathway Angiotensinogen Amylin-based therapy Renin Alternative RAS pathway Angiotensin I ACE2 Angiotensin (1–9) Neutral ACE inhibitor ACE endopeptidase ACE ACE inhibitor Angiotensin II ACE2 Angiotensin (1–7) ARB AT receptor AT receptor Mas receptor 1 2 Vasoconstriction Vasodilation Vasodilation Sodium retention Sodium excretion Sodium excretion Proliferation Antiproliferation Antiproliferation Inflammation Antihypertrophy Antiarrhythmic Oxidative stress Anti-inflammation Cardiac remodelling Aldosterone secretion Positive inotropic Renin inhibition Potential cardio–kidney protection Figure: Rationale for the potential benefit of combining amylin-based therapies with RAS inhibitors Combining amylin receptor agonists with ACE inhibitors or ARBs could improve cardiovascular and kidney outcomes by shifting RAS activity towards the increased stimulation of protective pathways such as the alternative RAS pathway involving AT and Mas-receptors. ACE=angiotensin-converting enzyme. ARB=angiotensin receptor blocker. AT1=type 1 angiotensin II receptor. AT2=type 2 angiotensin II receptor. RAS=renin-angiotensin system. effects via the Mas receptor.23,24 In this context, amylin­ that RAS inhibitor use was not reported in the current induced RAS activation could be repurposed into a REDEFINE publications.10,8 In REDEFINE­1, only protective mechanism under RAS blockade. If this 36·3% of participants had hypertension,10 and neither hypothesis is confirmed, the potential cardiorenal phase 3 trial of CagriSema10,8 provided details on benefits of amylin­based therapies could be influenced antihypertensive therapy or other common indications by patients’ concurrent use of RAS inhibitors. This for RAS inhibitors (eg, chronic kidney disease or heart hypothesis raises an important translational question: failure), limiting the feasibility and relevance of evaluating are these therapies effects reliant on or enhanced by this interaction. Biomarker studies tracking plasma renin ongoing RAS blockade? activity, aldosterone, angiotensin­(1–7), and ACE2 over To investigate this, we propose several approaches. time could offer further insight. Mechanistic trials could Where possible, these experimental approaches should prosp ectively randomly assign patients based on RAS include appropriate controls for changes in bodyweight inhibitor use to assess whether RAS blockade modifies or and glycaemia (eg, metabolic surgery) to distinguish mediates therapeutic effects—including systemic and primary from secondary effects of amylin receptor potentially complex kidney haemodynamic responses— agonists on the RAS. Preclinical studies should examine which is key for high­risk populations where RAS how amylin signalling interacts with classic and blockade is recommended but not always implemented alternative RAS pathways in the heart and kidneys, in clinical practice. measuring outcomes such as fibrosis, hypertrophy, proteinuria, and glomerular injury in amylin­treated Conclusion models with and without RAS inhibition. Clinically, Amylin­based therapies represent a promising new drug post­hoc analyses of clinical trials involving CagriSema class for obesity and type 2 diabetes care. Understanding and other amylin­based therapies—many of which are the interaction of amylin­based therapies with the RAS still in early­phase clinical development25 and will likely and how this might be modulated by existing RAS be tested across diverse patient cohorts—should stratify inhibitor therapy could be pivotal in optimising the safety participants by RAS inhibitor use to assess whether and efficacy of amylin­based treatments. We believe that patients who are receiving ACE inhibitors or ARBs this is a crucial and timely hypothesis that is deserving of experience greater improvements in blood pressure, targeted exploration in both preclinical and clinical albuminuria, estimated glomerular filtration rate domains, with the potential to refine treatment guidelines trajectories, and cardiovascular–kidney events. We note by labelling RAS inhibitor and amylin­based therapies as 2982 Hypothesis exploratory combination therapy needing further study, 11 Gasiorek A, Heydorn A, Gabery S, et al. Safety, tolerability, which prioritises precision­based combination therapy pharmacokinetics, and pharmacodynamics of the first­in­class GLP­1 and amylin receptor agonist, amycretin: a first­in­human, approaches and minimises polypharmacy to reduce phase 1, double­blind, randomised, placebo­controlled trial. Lancet complexity, cost, and adverse effects. 2025; 406: 135–48. 12 Dahl K, Toubro S, Dey S, et al. Amycretin, a novel, unimolecular Contributors GLP­1 and amylin receptor agonist administered subcutaneously: MHAM and MEC conceived and developed the central hypothesis and results from a phase 1b/2a randomised controlled study. Lancet overall direction of the manuscript. MHAM drafted the initial version 2025; 406: 149–62. and created the figure. MN, PCNR, DZIC, and MEC contributed to the 13 Khoo B, Tan TM. GLP­1 and amylin receptor multiagonism with critical discussion, refinement of the hypothesis, and manuscript amycretin for obesity management. Lancet 2025; 406: 104–06. revisions. All authors reviewed and approved the final manuscript. 14 Muskiet MHA, Tonneijck L, Smits MM, et al. GLP­1 and the kidney: Declaration of interests from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol 2017; 13: 605–28. MHAM has received consulting fees to their institution from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. 15 Tonneijck L, Muskiet MH, Smits MM, van Raalte DH, Diamant M. Combining incretin­based drugs and RAAS inhibitors: more cons PCNR has received consulting fees from Novo Nordisk and MSD; and has than pros? Lancet Diabetes Endocrinol 2014; 2: 684–85. received research grants from Eli Lilly (payments to their institution). 16 Wookey PJ, Xuereb L, Tikellis C, Cooper ME. Amylin in the DZIC has received consulting fees, speaking honoraria, or both from periphery. ScientificWorldJournal 2003; 3: 163–75. Janssen, Bayer, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Merck, 17 Malatino LS, Fiore CE, Foti R, Guzzardi F, Tamburino G. Acute Prometic, and Sanofi; and has received operating funds from Janssen, effects of salmon calcitonin in man include stimulation of the Boehringer Ingelheim, Eli Lilly, Sanofi, AstraZeneca, and Merck. renin­angiotensin­aldosterone system. Miner Electrolyte Metab 1987; MEC has received consulting fees and speaking honorarium from Novo 13: 316–22. Nordisk. MN declares no competing interests. 18 Young A. Renal effects. Adv Pharmacol 2005; 52: 251–68. References 19 Harris PJ, Cooper ME, Hiranyachattada S, et al. Amylin stimulates 1 Drucker DJ. GLP­1­based therapies for diabetes, obesity and proximal tubular sodium transport and cell proliferation in the rat beyond. Nat Rev Drug Discov 2025; 24: 631–50. kidney. 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N Engl J Med Nat Rev Drug Discov 2025; 24: 403–06. 2025; 393: 648–59. 9 Frias JP, Deenadayalan S, Erichsen L, et al. Efficacy and safety of Copyright © 2025 Elsevier Ltd. All rights reserved, including those for co­administered once­weekly cagrilintide 2·4 mg with once­weekly text and data mining, AI training, and similar technologies. semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double­blind, active­controlled, phase 2 trial. Lancet 2023; 402: 720–30. 10 Garvey WT, Blüher M, Osorto Contreras CK, et al. Coadministered cagrilintide and semaglutide in adults with overweight or obesity. N Engl J Med 2025; 393: 635–47. --- [PDF原文](https://sci-net.xyz/storage/8010893/0c8098aa1c721af3980611bc725de5a0e0c0fddead69f455927186913e628bc0/Amylin-and-the-renin-angiotensin-system-risk-or-opportunity-in-amylin-based-therapy.pdf) DOI: 10.1016/S0140-6736(25)01776-3