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This paper presents a hypothesis-generating perspective piece examining the potential interaction between amylin-based therapies — including the pramlintide and cagrilintide receptor agonists, and the combination therapy CagriSema — and the renin-angiotensin system (RAS). The authors hypothesize that amylin receptor agonists may activate the RAS, which could potentially counteract the cardiorenal benefits of these obesity and type 2 diabetes treatments. However, they note the paradox that CagriSema demonstrated meaningful blood pressure reductions in phase 3 trials. The authors further hypothesize that concurrent use of RAS inhibitors (ACE inhibitors or angiotensin-receptor blockers) may redirect amylin-induced RAS activation toward the protective "alternative RAS pathway," promoting vasodilatory, anti-inflammatory, and antiproliferative effects via Mas receptors. To test these hypotheses, the authors propose a research agenda encompassing preclinical studies, post-hoc trial analyses stratified by RAS inhibitor use, biomarker studies, and prospective mechanistic human studies. No original experimental data are presented. Key limitations include the entirely speculative nature of the central claims, the absence of direct supporting evidence, and reliance on inference from existing trial-level observations.
Lancet (London, England) · Nov 2025DOI ↗ Limited · human
This study used synthetic target trial emulation and computational predictive modeling to compare amylin-pathway therapies — specifically CagriSema, cagrilintide, and amycretin formulations — for obesity and type 2 diabetes. Following PRISMA 2020 and TARGET framework guidelines, the researchers pooled data from seven randomized controlled trials (N = 5,786 participants) published through September 2025. Rather than analyzing real individual patient data, they reconstructed high-precision synthetic individual patient datasets and applied network meta-analysis, dose-response modeling, virtual head-to-head comparisons, and machine learning. The study reported that synthetic data reconstruction achieved greater than 99% fidelity to source trials, and virtual modeling suggested CagriSema outperformed subcutaneous amycretin at matched timepoints (posterior probability >0.95). Dose-response modeling identified an estimated ED80 for amycretin and benefit-risk analysis suggested a potential therapeutic window in the 10–20 mg subcutaneous range. Machine learning models predicted treatment response with 82–87% accuracy from baseline characteristics. Key limitations include reliance on reconstructed — not real — individual patient data, indirect comparisons rather than direct head-to-head trial evidence, and calibration metrics indicating moderate model uncertainty. The authors suggest these findings may inform future confirmatory trial design.
Metabolism open · Oct 2025DOI ↗ Review
This review examines the evolving pharmacological landscape for obesity management, with a focus on gut-brain axis hormones and their therapeutic potential. The authors describe how nutrient-stimulated gastroenteropancreatic hormones — including GLP-1, GIP, glucagon, and amylin — have become central targets in obesity drug development. The review covers both marketed agents and those in ongoing clinical trials. GLP-1 receptor agonists (e.g., weekly injectable or daily oral semaglutide) are reported to achieve roughly 15–17% weight loss with a favorable safety profile. The dual GLP-1/GIP agonist tirzepatide is described as achieving up to approximately 22.5% weight loss at higher doses. Combination therapies under investigation — such as cagrilintide plus semaglutide (Cagrisema), GLP-1/glucagon co-agonists, and the triple agonist retatrutide (GLP-1/GIP/glucagon) — are noted as potentially reaching weight loss comparable to bariatric surgery. The review also discusses cardiometabolic benefits and challenges around long-term treatment adherence for both patients and clinicians. As a narrative review, it synthesizes existing trial data rather than generating new primary evidence, and conclusions depend on the quality of the underlying studies cited.
Medicina clinica · Aug 2025DOI ↗ Review
This evidence review examines the evolving landscape of incretin-based pharmacotherapy, focusing on GLP-1 receptor agonists (GLP-1RAs) and newer multi-receptor co-agonists for cardiometabolic disease management. The paper surveys established GLP-1RAs — including liraglutide, dulaglutide, albiglutide, exenatide, and semaglutide — noting their reported benefits on glycated hemoglobin, body weight, lipid profiles, liver fat, and cardiovascular outcomes (reduction in major adverse cardiovascular events, or MACE). It also covers emerging agents: dual GIP/GLP-1 agonist tirzepatide (approved for diabetes and obesity), dual GLP-1/glucagon co-agonists (notable for synergistic weight loss), and triple GLP-1/GIP/glucagon receptor agonists such as retatrutide and efocipegtrutide, described as achieving the highest pharmacotherapy-associated weight loss observed to date. Additional novel classes reviewed include GLP-1/amylin agonists (CagriSema, Amycretin), non-semaglutide oral GLP-1 agents, and peptide YY/GLP-1 dual agonists. As a narrative review, the paper does not present original trial data, and its conclusions are based on synthesized existing literature, which may introduce selection bias. The authors anticipate that metabolic benefits will translate into cardiometabolic outcomes, though direct evidence for many newer agents remains limited.
World journal of cardiology · Aug 2025DOI ↗ Animal only
This study investigated the mechanisms underlying weight loss produced by CagriSema — a combination of cagrilintide (an amylin analogue) and semaglutide (a GLP-1 analogue) — in a rat model. Researchers quantified the contributions of reduced energy intake versus preserved energy expenditure to overall weight loss. Rats treated with CagriSema achieved approximately 12% body weight loss alongside a 39% reduction in food intake. To isolate the role of energy intake, the authors used two comparison conditions: pair-feeding (matching food intake to CagriSema-treated animals) and weight matching (determining how much food restriction alone would be needed to achieve equivalent weight loss, which required a 51% reduction in intake). The gap between these conditions suggested that roughly one-third of CagriSema's weight loss effect was attributable to blunting of metabolic adaptation — the phenomenon where the body typically reduces energy expenditure in response to caloric restriction. Limitations include that findings are from an animal model and may not directly translate to humans, and the study does not address long-term outcomes. The authors conclude that CagriSema's dual action on both energy intake and expenditure may contribute to its potential effectiveness as an obesity treatment.
Nature metabolism · Jul 2025DOI ↗ Review
This review examines amylin, a neuroendocrine hormone co-secreted with insulin, exploring its physiological mechanisms and therapeutic potential in diabetes and obesity. The authors describe how amylin suppresses glucagon secretion, delays gastric emptying, increases energy expenditure, and promotes satiety — making it a candidate for addressing multi-hormonal dysregulation in both type 1 and type 2 diabetes. The paper notes that amylin is deficient in people with diabetes and that pramlintide, currently the only approved amylin analog, has shown efficacy in improving postprandial and overall glycemic control without increasing hypoglycemia risk or promoting weight gain in people with advanced β-cell dysfunction. The authors also discuss barriers to broader clinical translation, including complex receptor biology, amyloidogenic properties, and pharmacokinetic challenges. Emerging strategies covered include PEGylation, carbohydrate conjugation, oral formulations, and combination therapies — notably CagriSema, a co-formulation of a GLP-1 receptor agonist and an amylin agonist showing early promise in weight management and glucose regulation. As a narrative review, this paper synthesizes existing literature rather than generating new primary data, which limits its ability to establish causation or provide definitive efficacy conclusions.
Diabetes therapy : research, treatment and education of diabetes and related disorders · May 2025DOI ↗ Review
This review article examines the management of type 2 diabetes and obesity, with a particular focus on CagriSema, an investigational combination drug pairing cagrilintide (an amylin analog) with semaglutide (a GLP-1 receptor agonist). The authors begin by contextualizing the scale of diabetes in the United States—affecting over 37 million people—and highlight the interplay between obesity and type 2 diabetes, noting that genetic and physiological barriers often make weight loss difficult without pharmacological support. The article reviews the pathophysiology of diabetes, current clinical guidelines, and the risks associated with intensive glycemic control, particularly hypoglycemic events such as cardiac arrhythmias, confusion, coma, and death. It then surveys the existing evidence for approved weight loss and antidiabetic medications before summarizing recent clinical trial data on CagriSema, which is being investigated as a potentially superior agent for reducing both HbA1c and body weight. The authors argue that CagriSema may offer a favorable safety and efficacy profile, though they acknowledge the drug remains under investigation. Key limitations include the review format itself—primary trial data are summarized rather than independently analyzed—and the absence of long-term safety data for CagriSema in the published literature reviewed.
Cardiology in review · May 2025DOI ↗ In vitroPreprint
This preprint describes a computational study aimed at designing improved semaglutide analogues — variants of the GLP-1 receptor agonist used in weight-loss and diabetes treatment — in the context of the underperforming CagriSema Phase III trial. The researchers used an automated "natural amino acid scanning" approach, systematically introducing single amino acid mutations across the semaglutide peptide backbone. Using the crystal structure of the GLP-1–GLP-1R complex (PDB: 4ZGM) as a structural template, they performed high-throughput computational modeling with Modeller and estimated binding affinities (Kd) using the Prodigy tool. From this pipeline, the study identified 564 computationally designed semaglutide analogues predicted to show improved binding affinity to the extracellular domain (ECD) of GLP-1R. The authors propose a conceptual "interfacial electrostatic scaffold" consisting of four salt bridges at the peptide–receptor interface as a framework for next-generation GLP-1R agonist development, drawing an analogy to the century-long iterative optimization of insulin. Key limitations include the fully computational nature of the study — no experimental validation (biochemical, cellular, or in vivo) is presented — and reliance on a single structural template and computational binding affinity estimators, which may not fully capture dynamic receptor behavior.
Unknown journal · Apr 2025DOI ↗ Review
This review article provides a comprehensive overview of approved and emerging hormone-based anti-obesity medications (AOMs), situating them within the broader context of obesity as a complex, chronic, global disease. The authors summarize the current regulatory landscape, noting that the GLP-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide have received FDA and EMA approval for weight management. The review also covers pipeline agents, including oral GLP-1RAs (semaglutide, danuglipron, orforglipron), the amylin receptor agonist cagrilintide (alone and in combination with semaglutide), and dual agonists such as tirzepatide (GIP/GLP-1), survodutide, mazdutide, and pemvidutide (GLP-1R/GCGR). The authors highlight tirzepatide's placebo-subtracted weight reduction of 17.8% in a 72-week RCT and retatrutide's (a GLP-1R/GCGR/GIPR tri-agonist) placebo-subtracted reduction of 22.1% in a 48-week phase-II trial. The review cautions that long-term safety and cardiovascular outcome data for many of these agents remain incomplete. As a narrative review, it does not conduct original research or meta-analysis, and conclusions are limited by the quality and heterogeneity of the underlying primary studies it synthesizes.
Indian journal of endocrinology and metabolism · Sep 2024DOI ↗ Moderate · human
This systematic review and meta-analysis examined the weight-loss efficacy and safety of cagrilintide (an amylin analogue) alone and in combination with semaglutide 2.4 mg (referred to as "Cagrisema") compared to placebo or active comparators (semaglutide or liraglutide) in adults with obesity. Researchers searched electronic databases and identified 3 eligible randomized controlled trials encompassing 430 participants. The pooled analysis found that Cagrisema was associated with significantly greater percentage and absolute body weight reduction compared to semaglutide 2.4 mg alone over 20–32 weeks, though with notably high statistical heterogeneity (I² up to 98%). Cagrilintide monotherapy showed statistically similar weight loss to semaglutide or liraglutide over 26–32 weeks. Regarding safety, treatment-emergent and serious adverse events were broadly comparable across groups; however, gastrointestinal adverse events and vomiting were significantly more frequent with Cagrisema versus semaglutide, while vomiting was significantly lower with cagrilintide monotherapy versus semaglutide or liraglutide. Key limitations include the very small number of included trials (n=3), limited total sample size, short-to-medium follow-up durations, and very high heterogeneity, which tempers confidence in the pooled estimates.
Indian journal of endocrinology and metabolism · Sep 2024DOI ↗