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

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

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

New trial • Diabetes • Metabolic Disorders • Type 1 Diabetes Mellitus

Endogenous Glucagon-Like Peptide 1 Enhanced by Vildagliptin Reduces Triglyceride Appearance During Intraduodenal Fat Infusion in Type 2 Diabetes. (PubMed, Diabetes) - "Fifteen participants with T2D, managed by diet and/or metformin, were studied on three occasions in a double-blind, randomized, crossover design. Vildagliptin selectively reduced TG(54:4) and TG(54:5) species, whereas exendin(9-39) increased total TGs and 10 individual TG species. The implications of our finding are that endogenous GLP-1 plays a physiological role in the regulation of postprandial lipid handling in T2D."

Journal • Cardiovascular • Diabetes • Dyslipidemia • Metabolic Disorders • Type 2 Diabetes Mellitus

A Study to Evaluate the Effect of Genetic Variation on Beta-cell Function During Fasting and Hyperglycemia in Nondiabetics (clinicaltrials.gov) - P3 | N=21 | Completed | Sponsor: Adrian Vella | Recruiting ➔ Completed | N=40 ➔ 21

Enrollment change • Trial completion

The Role of Islet GLP-1 in the Pathogenesis of Prediabetes (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Mayo Clinic | Not yet recruiting ➔ Recruiting

Enrollment open • Metabolic Disorders

The Involvement of the Peptidergic Systems in Breast Cancer Development. (PubMed, Cancers (Basel)) - "Breast cancer cells overexpress peptide receptors; at the same time they are known to interact with peptides that (a) exert an oncogenic action (adrenomedullin 2, endothelin, gastrin-releasing peptide, neurokinin A, neuromedin, neuropeptide Y, neurotensin, substance P, vasoactive intestinal peptide), (b) exert an anticancer action (angiotensin (1-7), ghrelin, peptide YY) or (c) exert dual oncogenic and anticancer effects (adrenomedullin, angiotensin II, bradykinin, corticotropin-releasing factor, β-endorphin, glucagon-like peptide 1, gonadotropin-releasing hormone, kisspeptin, methionine-enkephalin, oxytocin)...Future lines of research are suggested in breast cancer using promising anti-breast-cancer peptide receptor antagonists (HOE-140, exendin (9-39), bosentan, macitentan, PD168,368, CGP71,683A, SR48,692, aprepitant) or agonists (FR190,997, semaglutide, exendin 4, goserelin) mentioned in this review...Taken together, the available data highlight the enormous promise..."

Journal • Review • Breast Cancer • Oncology • Solid Tumor • GRP-10

Metabolic Drug, Electrophysiological Savior: Unmasking GLP-1RA's Novel Therapeutic Target in Sinoatrial Node Dysfunction (AHA 2025) - "This study identifies Supaglutide as the first GLP-1RA capable of restoring SAN electrophysiology via oxidative and calcium signaling regulation, beyond glucose control. These findings not only uncover a novel function of GLP-1RA beyond metabolic regulation but also suggest that targeting SAN-specific mechanisms may represent a broader therapeutic strategy for arrhythmogenic cardiac diseases, especially those associated with metabolic disorders."

Late-breaking abstract • Cardiovascular • Diabetes • Fibrosis • Heart Failure • Immunology • Inflammation • Metabolic Disorders • CAMK2D • CD86 • RYR2 • SIRT3 • TNFA

Developing 68Ga-Labeled Exendin(9-39) Derivatives for PET Imaging of Insulinomas. (PubMed, Bioconjug Chem) - "These findings highlight the power of combining computational screening with systematic experimental validation. In conclusion, [68Ga]Ga-E09 demonstrates superior binding affinity, cellular uptake, and imaging performance, suggesting its potential as a promising agent warranting further studies."

Journal • Hypoglycemia • Oncology • Pediatrics • Solid Tumor

Linking GLP-1 activation with steroidogenesis, redox, endoplasmic reticulum stress, mitophagy, and the apoptotic regulatory network unlocks the emerging impacts of semaglutide on 5-fluorouracil-induced testicular toxicity. (PubMed, Life Sci) - "This study highlighted the use of Sema as adjunctive therapy in the 5-FU treatment protocol to guard against the associated testicular dysfunction, via modulating oxidative stress, ERS, and mitochondrial dysfunction in the rat experimental model."

Journal • Metabolic Disorders • Oncology • ATF6 • DAZL • HSPA5

Acute effects of GIP and GLP-1 receptor antagonism in totally pancreatectomized individuals: A randomized double-blind, placebo-controlled crossover study. (PubMed, Diabetes Obes Metab) - "Endogenous GIP contributes to the regulation of postprandial bone resorption independently of pancreatic factors. In contrast, GIP receptor and/or GLP-1 receptor antagonism had no measurable effects on glucose metabolism, gastric emptying, appetite, food intake, triglycerides, or haemodynamics, supporting a pancreatic contribution to some of these effects of the endogenous hormones, although the surgical reconstruction may have influenced the sensitivity of the targets."

Journal • Diabetes • Metabolic Disorders

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: Sep 2025 ➔ Dec 2025

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

Fatty acid transport protein-2 inhibition enhances glucose tolerance through α-cell-mediated GLP-1 secretion. (PubMed, J Clin Invest) - "Direct evidence of FATP2KO-induced α-cell-mediated glucagon-like peptide-1 (GLP-1) secretion included increased GLP-1-positive α-cell mass in FATP2KO db/db mice, small molecule FATP2 inhibitor enhancement of GLP-1 secretion in αTC1-6 cells and human islets, and exendin[9-39]-inhibitable insulin secretion in FATP2 inhibitor-treated human islets. FATP2-dependent enteroendocrine GLP-1 secretion was excluded by demonstration of similar glucose tolerance and plasma GLP-1 concentrations in db/db FATP2KO mice following oral versus intraperitoneal glucose loading, non-overlapping FATP2 and preproglucagon mRNA expression, and lack of FATP2/GLP-1 co-immunolocalization in intestine. We conclude that FATP2 deletion or inhibition exerts glucose-lowering effects through α-cell-mediated GLP-1 secretion and paracrine ß-cell insulin release."

Journal • Diabetes • Diabetic Nephropathy • Endocrine Disorders • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus • SLC27A2

The effect of GLP-1 receptor antagonists and agonists on islet function in non-diabetic subjects with the GLP1R polymorphism at rs3765467 (EASD 2025) - P3 | "The T allele at rs3765467 increases responsiveness of GLP1R to its endogenous ligand. These effects are relevant to the fasting state and less apparent when the islet is stimulated by hyperglycemia or liraglutide."

Clinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Glucagon-like Peptide 1, Glucose Metabolism and Gastric Bypass (clinicaltrials.gov) - P1 | N=80 | Recruiting | Sponsor: The University of Texas Health Science Center at San Antonio | Trial completion date: Aug 2026 ➔ Aug 2027 | Trial primary completion date: Aug 2025 ➔ Aug 2026

Trial completion date • Trial primary completion date

The Effects of Bariatric Surgeries on Glucose Metabolism (clinicaltrials.gov) - P1 | N=200 | Recruiting | Sponsor: The University of Texas Health Science Center at San Antonio | Trial completion date: Aug 2026 ➔ Aug 2027 | Trial primary completion date: Aug 2025 ➔ Aug 2026

Trial completion date • Trial primary completion date • Gastrointestinal Disorder • Hypoglycemia

Role of Neural and Hormonal Regulation Factors on Insulin Secretion After Gastric Bypass Surgery (clinicaltrials.gov) - P1 | N=160 | Recruiting | Sponsor: The University of Texas Health Science Center at San Antonio | Trial primary completion date: Aug 2025 ➔ Aug 2026 | Trial completion date: Aug 2026 ➔ Aug 2027

Trial completion date • Trial primary completion date • Hypoglycemia

Population PK (PopPK) and Pharmacokinetic/Pharmacodynamic (PK/PD) Analysis of Avexitide in Individuals with Post-Bariatric Hypoglycemia (ENDO 2025) - "Mechanistically, Cmin is expected to be a primary driver of avexitide efficacy. Avexitide 90 mg once daily resulted in Cmin above EC50 for 24 hours, providing evidence that this dose can have continued biological effect between daily doses and further supporting the rationale for and appropriateness of the 90 mg once daily dosing regimen in the Phase 3 LUCIDITY trial."

Clinical • PK/PD data • Hypoglycemia

Reduction in Rate of Hypoglycemic Events with Avexitide in Post-Bariatric Hypoglycemia: Results from the Phase 2 and 2b Studies (ENDO 2025) - "Avexitide 30 mg BID and 60 mg QD led to a 40% and 55% reduction in the composite rate of Level 2&3 events, respectively. The impact of avexitide on composite rates of Level 2&3 hypoglycemia in the phase 2b trial, including at the higher 90 mg QD dose being tested in LUCIDITY, will be presented. Results of the complete analysis will provide valuable context given the planned LUCIDITY trial, which has topline data anticipated in 1H 2026."

P2 data • CNS Disorders • Epilepsy • Gastrointestinal Disorder • Hypoglycemia

Reduction in Rate of Hypoglycemic Events with Avexitide in Post-Bariatric Hypoglycemia: Results from the Phase 2 and 2b Studies (ENDO 2025) - "Avexitide 30 mg BID and 60 mg QD led to a 40% and 55% reduction in the composite rate of Level 2&3 events, respectively. The impact of avexitide on composite rates of Level 2&3 hypoglycemia in the phase 2b trial, including at the higher 90 mg QD dose being tested in LUCIDITY, will be presented. Results of the complete analysis will provide valuable context given the planned LUCIDITY trial, which has topline data anticipated in 1H 2026."

P2 data • CNS Disorders • Epilepsy • Gastrointestinal Disorder • Hypoglycemia

HIF-2a signaling in L-cells is crucial for GLP-1 secretion in response to luminal lipids (ENDO 2025) - "This improvement in glucose tolerance is reversed when the GLP-1 receptor antagonist Exendin 9-39 is administered, confirming that L-cell HIF-2α enhances glucose homeostasis through GLP-1...We also investigated whether pharmacological activation of HIF-2α with FG-4592 affects intestinal lipid sensing and GLP-1 secretion...Mechanistically, we found that HIF-2α enhances lipid sensing in L-cells through the GPR40 receptor, leading to increased GLP-1 secretion. Thus, our study identifies a target to improve the endogenous production of GLP-1 in response to luminal nutrients, specifically lipids."

Genetic Disorders • Obesity • EPAS1 • GCG

Glucagon-like peptide-1 is involved in fasting and postprandial blood flow regulation of subcutaneous adipose tissue. (PubMed, Diabetes Obes Metab) - "GLP-1 seems to be involved in ATBF regulation, which is reduced when GLP-1 action is blocked in situ, but has no role in the blunting of ATBF response in non-responders. Blunted postprandial ATBF may be implicated in higher postprandial circulating TAG levels."

Journal

Effect of Central UAG on Metabolic Associated Fatty Liver Disease: a Possible Mechanism involving in GLP-1 Neural Pathway. (PubMed, Peptides) - "These findings suggest that central UAG might alleviate MAFLD by modulating GLP-1 neuronal pathway from NTS to PVN and VTA. Further studies are needed to identify the specific receptor for UAG and its potential interaction with GLP-1 or GLP-1R, which could provide direct evidence for the role of central UAG in regulating food intake and lipid metabolism in MAFLD."

Journal • Hepatology • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • FASN • SCD

A Study to Evaluate the Effect of Genetic Variation on Beta-cell Function During Fasting and Hyperglycemia in Nondiabetics (clinicaltrials.gov) - P3 | N=40 | Recruiting | Sponsor: Adrian Vella | Trial primary completion date: Jun 2025 ➔ Sep 2025

Trial primary completion date

Effect of GLP-1 Receptor Antagonism or Incretin Enhancer on Ad-Libitum Energy Intake in Subjects with and without Bariatric Surgery (ADA 2025) - "We compared the acute effects of increased incretin concentrations or GLP-1R blockade on ad-libitum energy intake (AdLibEI) among 3 BMI- and age-matched non-diabetic obese cohorts of GB (n=7), SG (n=9), and non-operated controls (CN, n=7). Participants were studied with 3-h meal test on 4 separate days: (A) 50-gram glucose ingestion with (OGT+S) and without (OGT) 200 mg sitagliptin (S) taken orally 2-h prior to OGT; (B) 50-gram whey protein ingestion with (OPT+Ex9) and without intravenous infusion of GLP-1R antagonist (exendin-(9-39) [Ex9], 750 pm/kg/min). These data indicate that, in the current model, enhancing or blocking endogenous GLP-1R signal has an acute affect on food intake in humans with intact gastrointestinal system. Unaffected energy intake by GLP-1R manipulation in GB and SG subjects, however, undermines a significant role for GLP-1 in mediating surgical-induced weight loss."

Bariatric surgery • Clinical • Surgery • Metabolic Disorders • Obesity

GLP-1 Receptor Agonists Induce Lasting Cyclic-AMP Generation and Insulin Secretion in Beta Cells (ADA 2025) - "This study investigated the mechanisms underlying these differences, with a focus on cAMP, the crucial second messenger involved in incretin-induced potentiation of insulin secretion. Islets from mice expressing a genetically encoded cAMP sensor in beta cells were perfused with GIP and GLP-1 receptor (GLP-1R) agonists (GLP-1, exendin-4, and semaglutide), and kinetics of cAMP levels and glucose-stimulated insulin secretion were assessed. Acute GIP treatment induced a transient cAMP response that dissipated with peptide washout. These data show that beta cells respond with distinct kinetics of cAMP generation in response to different incretins, with GLP-1R agonists capable of triggering lasting cAMP generation and insulin secretion. These findings reveal the mechanism(s) that underlie the effectiveness of incretin-based drugs."

Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus