avexitide (exendin 9-39) / Amylyx - LARVOL DELTA

Semaglutide and pioglitazone restore airway mucosal homeostasis by resolving Pseudomonas aeruginosa pyocyanin-induced mucus hypersecretion, ciliostasis, and type 2 airway inflammation. (PubMed, Front Immunol) - "The protective effects of these drugs were partially abolished by respective antagonists, Exendin(9-39) and GW9662, against GLP1R and PPARγ, confirming the GLP1R signaling pathway-dependent mechanisms. Moreover, Semaglutide and Pioglitazone also attenuated type 2 immune responses and neutrophil influx, both of which are known drivers of mucus hypersecretion, and reduced the P. aeruginosa burden in a chronic bronchitis model of infection in mouse lungs. Our findings identify a promising adjunctive therapeutic avenue for COPD by repurposing FDA-approved Semaglutide and Pioglitazone, which are readily available for clinical use."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • Transplantation • MUC5AC

Efficacy and safety of avexitide for treatment of hypoglycemia following bariatric and other upper gastrointestinal surgeries: a phase 2b study. (PubMed, Metabolism) - "Avexitide significantly reduced hypoglycemia events and improved QOL in patients with hypoglycemia following bariatric and other upper GI surgeries. Avexitide may represent an effective and targeted therapeutic approach for this patient population."

Journal • P2b data • Gastrointestinal Disorder • Hypoglycemia

Islet Function in Gestational Diabetes (clinicaltrials.gov) - P1 | N=90 | Recruiting | Sponsor: Mayo Clinic

New P1 trial • Diabetes • Gestational Diabetes • Metabolic Disorders

GLP-1 reverses high glucose-induced phenotypic switching and cytoskeletal remodelling in ISMCS by modulating miR-21 and miR-143/145 axis (EASD 2026) - "Then, cells were exposed to recombinant GLP-1 (50 nM, 1h) and Exendin (9-39; 200 uM, 40 min)... In conclusion, our data suggest that GLP-1 exerts protective effects on HISMCs exposed to diabetic milieu by modulating miR-21, attenuating cytoskeletal remodeling, and preserving a contractility-associated transcriptional and protein profiles. These findings support the concept that the gastrointestinal tract may function as an active GLP-1 responsive epigenetic interface in diabetes, and highlight intestinal smooth muscle cells as a relevant target for future mechanistic studies linking myopathies to diabetic autonomic neuropathy."

Diabetes • Diabetic Neuropathy • Metabolic Disorders • ACTA2 • IL1B • IL6 • MIR143 • MIR21 • MYLK • SETD3 • TAGLN • TNFA • VIM

LUCIDITY: Avexitide for Treatment of Post-Bariatric Hypoglycemia (clinicaltrials.gov) - P3 | N=75 | Active, not recruiting | Sponsor: Amylyx Pharmaceuticals Inc. | Trial completion date: Oct 2026 ➔ Feb 2027 | Trial primary completion date: Mar 2026 ➔ Jul 2026

Trial completion date • Trial primary completion date • Hypoglycemia

Contractile effects of albiglutide in the human and mouse atrium. (PubMed, Front Endocrinol (Lausanne)) - "Conversely, the effect was not reversed by 10 µM propranolol, a β-adrenoceptor antagonist, and was less effective than the effect of 1 µM isoprenaline...Contractile force in abligutide-treated (100 nM) HAP in the presence of cilostamide was further enhanced by 100 nM GLP-1(7-36)amide or 10 nM exenatide but was not affected by 100 nM GLP-1(1-36)amide...In HAP, the positive inotropic effects of albiglutide-both alone and in the presence of 100 nM cilostamide-were attenuated by treatment with 100 nM exendin(9-39), a GLP-1R antagonist...Albiglutide acts as a partial GLP-1R agonist in HAP. This indicates that any clinical side effects of albiglutide may be less pronounced than those of full GLP-1R agonists."

Journal • Preclinical • Cardiovascular • Coronary Artery Disease • Diabetes • Heart Failure • Metabolic Disorders • Type 2 Diabetes Mellitus

Limosilactobacillus reuteri Alleviates Parkinson's Disease by Regulating CDCA Secretion. (PubMed, Probiotics Antimicrob Proteins) - "Importantly, the neuroprotective benefits of CDCA were abolished by the GLP-1 receptor (GLP-1R) antagonist Exendin (9-39), confirming the necessity of the TGR5-GLP-1-GLP-1R signaling cascade. Collectively, these findings suggest that L. reuteri may exert neuroprotective effects by modulating bile acid metabolism, particularly CDCA, and potentially involving the TGR5-GLP-1R axis. This study highlights a possible gut microbiota-bile acid-brain axis and provides a basis for microbiota-based therapeutic strategies in PD."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Contractile effects of dulaglutide in the human atrium. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "The positive inotropic effect of 100 nM dulaglutide in HAP was attenuated by 100 nM exendin (9-39). In contrast, dulaglutide alone or in the presence of phosphodiesterase inhibitor rolipram up to 100 nM failed to exert a positive inotropic effect in isolated electrically paced (1 Hz) mouse left atrial preparations and did not increase the beating rate of spontaneously beating mouse right atrial preparations. Our data suggest that dulaglutide raised force of contraction in the isolated paced human atrium via GLP-1R involving cAMP-dependent protein kinase in HAP."

Journal • Cardiovascular • Coronary Artery Disease • Diabetes • Genetic Disorders • Heart Failure • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Semaglutide alleviates osteoarthritis independent of weight loss via GLP-1R-mediated activation of autophagy through AKT/mTOR inhibition. (PubMed, J Orthop Translat) - "To verify the functional loss, the GLP-1R antagonist Exendin (9-39) and the autophagy inhibitor Bafilomycin A1 were employed...These findings provide robust preclinical evidence supporting the repositioning of semaglutide as a disease-modifying therapy, particularly for patients with OA and comorbid metabolic disorders such as diabetes. Furthermore, they indicate that GLP-1R and its downstream signaling pathways may represent potential therapeutic targets for OA, thereby opening new avenues for drug repurposing and precision interventions in metabolic OA."

Journal • Diabetes • Immunology • Inflammation • Metabolic Disorders • Osteoarthritis • Pain • Rheumatology • IL1B

Inhibitory Effects of Oxytocin on Jejunal Migrating Myoelectric Complex Activity in Fasted Rats: Role of Oxytocin and GLP-1 Receptors. (PubMed, Life (Basel)) - "To assess mechanisms, rats were pretreated with the OTR antagonist atosiban (2 mg/kg), the GLP-1R antagonist exendin (9-39) (200 µg/kg), or the nitric oxide synthase inhibitor NG-nitro-L-arginine (L-NNA; 5 mg/kg) before OT (16 µg/kg). L-NNA showed no significant effect. These findings indicate that OT inhibits jejunal MMC activity via OTR-dependent mechanisms with partial involvement of GLP-1R signaling but not NO pathways."

Journal • Preclinical • CNS Disorders

Participant-Informed Design Considerations in Phase 3 LUCIDITY Trial of Avexitide for Post-Bariatric Hypoglycemia (ENDO 2026) - P3 | "The detailed study design will be presented at the meeting, focusing on participant-informed considerations and the endpoint strategy developed to capture PBH disease burden. This trial aims to address a critical unmet need among individuals living with post-bariatric hypoglycemia. Topline clinical trial data are expected in Q3 2026."

P3 data • Hypoglycemia

A Novel SSTR2a, ZT-01, Enhances First-Phase Insulin Secretion from Pancreatic Islets Isolated from Healthy Male Mice (ADA 2026) - "Introduction and Objective: Pharmacological blockade of somatostatin receptor 2 (SSTR2a) enhances glucagon secretion during hypoglycemia in diabetic rats. Removing the inhibitory effect of somatostatin from pancreatic α-cells enhances glucagon secretion, which in turn amplifies FPIR via the GLP1Rs signaling pathway in β-cells. This work suggests that SST modulates the temporal dynamics of insulin secretion via a glucagon-dependent GLP-1R mechanism."

Late-breaking abstract • Preclinical • Hypoglycemia • Metabolic Disorders • SSTR • SSTR2

Understanding the Implications of Constitutive Activity of Proglucagon Peptide Receptors (ADA 2026) - "The GLP-1R has been reported to have constitutive activity in immortalized β-cells based on reduced basal cAMP levels and insulin secretion upon GLP-1R antagonist exendin[9-39] (Ex9) treatment... Constitutive activity of the GLP-1R or the GCGR is insufficient to influence β-cell function in mice. Rather, Ex9 reduces insulin secretion as a competitive antagonist by interrupting α- to β-cell communication. There is sufficient constitutive activity of the GCGR in mouse hepatocytes to regulate amino acid levels."

Metabolic Disorders • GCG

Understanding the Implications of Constitutive Activity of Proglucagon Peptide Receptors (ADA 2026) - "The GLP-1R has been reported to have constitutive activity in immortalized β-cells based on reduced basal cAMP levels and insulin secretion upon GLP-1R antagonist exendin[9-39] (Ex9) treatment... Constitutive activity of the GLP-1R or the GCGR is insufficient to influence β-cell function in mice. Rather, Ex9 reduces insulin secretion as a competitive antagonist by interrupting α- to β-cell communication. There is sufficient constitutive activity of the GCGR in mouse hepatocytes to regulate amino acid levels."

Metabolic Disorders • GCG

An Expanded Access Protocol to Provide Avexitide in Patients With Post-Bariatric Hypoglycemia (clinicaltrials.gov) - P=N/A | N=0 | Available | Sponsor: Amylyx Pharmaceuticals Inc.

New trial • Hypoglycemia

EX-HYPO: The Effect of Endogenous GLP-1 on Glucagon Secretion in Type 1 Diabetes (clinicaltrials.gov) - P=N/A | N=12 | Completed | Sponsor: Asger Lund, MD | Recruiting ➔ Completed

Trial completion • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus

Yueju pill exerts rapid antidepressant effects via sequential activation of hippocampal GLP-1 receptor and PACAP signaling in mice. (PubMed, J Ethnopharmacol) - "These findings demonstrate that YJ produces rapid antidepressant effects through activation of hippocampal GLP-1r-dependent PACAP signaling, providing scientific evidence for the traditional "resolving depression" (Jieyu) function of this classical formula and identifying a novel polyherbal strategy for rapid-acting antidepressant therapy."

Journal • Preclinical • CNS Disorders • Depression • Mood Disorders • Psychiatry • ADCYAP1 • DLG4 • Napsin A

Dendrobium huoshanense polysaccharides alleviate DSS-induced ulcerative colitis in mice: comparison between different parts of plant and role of GLP-1/GLP-1R axis. (PubMed, J Ethnopharmacol) - "DHPS is the most effective polysaccharide for alleviating DSS-induced UC through GLP-1/GLP-1R axis, proposing DHPS is a valid candidate for UC treatment using D. huoshanense."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Ulcerative Colitis

ORAL ADMINISTRATION OF ALLULOSE ATTENUATES CISPLATIN-INDUCED AKI VIA GLP-1 RELEASE (ISN-WCN 2026) - "Moreover, the renoprotection was partially canceled by exendin (9-39) administration and completely canceled in Glp1r global knock out mice.Conclusion Oral administration of allulose has renoprotective effect for cisplatin-induced AKI probably through the release of GLP-1. Further studies including vagal afferent ablation will be needed to elucidate the precise mechanism."

Acute Kidney Injury • Cardiovascular • Nephrology • Renal Disease • Reperfusion Injury

Dendrobium huoshanense stem polysaccharide protects against Alzheimer's disease by modulating SCFAs/GLP-1 axis-mediated neuroinflammation suppression. (PubMed, Int J Biol Macromol) - "However, the treatment of exendin 9-39, a GLP-1 receptor antagonist, weakened the protective effect of cDHPS against AD, and the depletion of SCFAs reversed the beneficial effects of cDHPS on cognitive dysfunction, hippocampal neuronal injury, neuroinflammation, and GLP-1 secretion in AD mice. These results suggest that cDHPS could protect against AD by modulating the SCFAs/GLP-1 axis-mediated neuroinflammation suppression."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • CASP1 • NLRP3

LUCIDITY: Avexitide for Treatment of Post-Bariatric Hypoglycemia (clinicaltrials.gov) - P3 | N=75 | Active, not recruiting | Sponsor: Amylyx Pharmaceuticals Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Hypoglycemia

Potential treatment benefits of a GLP-1R antagonist in combination with immune checkpoint inhibitors in colorectal cancer. (PubMed, Oncol Lett) - "The present study aimed to evaluate the antitumor effects of the GLP-1R antagonist Exendin 9-39 (Exe-9) combined with anti-programmed cell death protein-1 (PD-1) treatment in preclinical CRC models...Furthermore, combination therapy with the GLP-1R antagonist and anti-PD-1 yielded an improved antitumor effect compared with either treatment alone, and high GLP-1R ex2pression in clinical samples correlated with poor ICI response. These findings suggest that GLP-1R antagonism potentiates T-cell-mediated antitumor immunity and may provide a promising adjunctive therapeutic strategy for patients with CRC when combined with ICIs in the future."

Checkpoint inhibition • IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor

Intestinal interleukin-22 enhances GLP-1 production via the STAT3 pathway to improve glucose homeostasis during high-fat diet induced obesity in a study with male mice. (PubMed, Nat Commun) - "Conversely, the GLP-1 receptor antagonist exendin-9-39 abolished the glucose-lowering effects of IL-22, demonstrating that IL-22 acts primarily through GLP-1-dependent pathways. These findings identify IL-22 as an important regulator of intestinal GLP-1 production and glucose homeostasis during diet-induced obesity and highlight IL-22-GLP-1 signaling as a potential therapeutic axis for metabolic disorders."

Journal • Preclinical • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • GCG • IL22 • STAT3

O-Acetyl-Serine Supplementation Enhances Insulin Secretion and Improves Postprandial Glycaemia in Lean and Prediabetic Mice. (PubMed, FASEB J) - "However, in vivo treatment with the GLP-1 receptor antagonist exendin (9-39) revealed that GLP-1 signaling only partially mediates OAS's effects, consistent with OAS direct action on insulin secretion...This improvement was associated with increased postprandial insulin and GLP-1 levels. Together, these findings identify OAS as a glucose-dependent insulin secretagogue with therapeutic potential to enhance insulin secretion and prevent progression from prediabetes to T2D."

Journal • Preclinical • Metabolic Disorders • Type 2 Diabetes Mellitus

The Effect of rs7903146 Genotype on Islet GLP-1 Production in Humans (clinicaltrials.gov) - P2 | N=80 | Not yet recruiting | Sponsor: Mayo Clinic | Initiation date: Dec 2025 ➔ Oct 2026

Trial initiation date • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus