orforglipron (OWL833) / Roche, Eli Lilly - LARVOL DELTA

Development and Characterization of a Humanized GLP-1 Receptor Mouse Model for the Evaluation of Small-Molecule GLP1R Agonists (ADA 2025) - "These findings validate the Gubra hGLP1R mouse as a relevant preclinical model to advance preclinical development of small-molecule GLP1RAs for the treatment of obesity and related metabolic disorders."

Late-breaking abstract • Preclinical • Diabetes • Metabolic Disorders • Obesity

Cellular Characterisation of Signalling and Receptor Trafficking Induced by MET-097, a G Protein-Biased GLP-1R Agonist (ADA 2025) - "We aimed to further elucidate the signalling and trafficking profile of MET-097. In vitro BRET-based biosensors were used to compare clinically relevant GLP-1R agonists. Compared to reference agonists (GLP-1/exendin-4/semaglutide), MET-097 acted as a partial agonist for Gαs and Gαq recruitment at both the plasma membrane (36% and 22% of exendin-4) and endosomal compartments (34% and 37% of exendin-4), yet still showed full cAMP response (115% of exendin-4). We speculate the pharmacological attributes of MET-097 may contribute to a unique pharmacodynamic profile. Of particular interest will be to align these attributes with the efficacy and tolerability observed in clinical trials."

Metabolic Disorders • Obesity • ARRB1

First Report of a Phase 3 RCT of Orforglipron, a Small Nonpeptide GLP-1RA, as Monotherapy in Drug-Naïve Type 2 Diabetes with Inadequate Glycemic Control—The ACHIEVE-1 Trial (ADA 2025) - No abstract available

Monotherapy • P3 data • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Treatment with orforglipron, an oral glucagon like peptide-1 receptor agonist, is associated with improvements of CV risk biomarkers in participants with type 2 diabetes or obesity without diabetes. (PubMed, Cardiovasc Diabetol) - P2 | "Orforglipron treatment was associated with beneficial changes in CV risk markers in participants with T2D and in participants with overweight/obesity without T2D. (Clinicaltrials.gov: NCT05048719, NCT05051579)."

Biomarker • Clinical • Journal • Cardiovascular • Diabetes • Dyslipidemia • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • APOB • CRP • IL6

Treatment with orforglipron, an oral glucagon like peptide-1 receptor agonist, is associated with improvements of CV risk biomarkers in participants with type 2 diabetes or obesity without diabetes (Biomed Central) - P=NA | N=NA | "Significant placebo-adjusted decreases from baseline in blood pressure, low-density lipoprotein (LDL) cholesterol, triglycerides, ApoB, ApoC3, and hsCRP were observed following orforglipron treatment in participants with T2D and/or overweight or obesity. In both studies, improvements in blood pressure, lipid parameters, and most of the evaluated biomarkers were of similar magnitude after treatment with 12 mg orforglipron as with 24, 36, and 45 mg."

Clinical data • Obesity • Type 2 Diabetes Mellitus

A Study of Orforglipron (LY3502970) in Participants With Obesity or Overweight and at Least One Weight-Related Comorbidity (clinicaltrials.gov) - P3 | N=600 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

A Master Protocol for Orforglipron (LY3502970) in Participants With Obesity or Overweight With and Without Type 2 Diabetes (clinicaltrials.gov) - P3 | N=1200 | Recruiting | Sponsor: Eli Lilly and Company

New P3 trial • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Orforglipron Impovered Markers of Beta-Cell Function and Insulin Sensitivity in Type 2 Diabetes (DDG 2025) - "How does Orforlipron (OFG) IMPRONE Markers of Beta-Cell Function and Insulin Sensitivity in Comparison to Dulaglutide (Dula) in Patients With Type 2 Diabetes (T2D)?...Participants with T2D (Mean Age, 58.9 Years; Baseline HBA1C, 8.1%; Weight, 100.3 kg) Treated with Diet and Exercise, With/Without Metformin, Were Randomized to PBO, du 1.5 mg, or once-daily Ofg 3, 12, 36, or 45 mg... Thesis Analyses Suggest Improved Glycemic Control with VS Du May Be Partly Explained by Improved β-Cell Function and Insulin Sensitivity. Additional studies are ongoing to understand thesis Mechanisms."

Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

A Master Protocol for Orforglipron (LY3502970) in Participants With Hypertension and Obesity or Overweight: (ATTAIN-Hypertension Screening) (clinicaltrials.gov) - P3 | N=974 | Recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Genetic Disorders • Hypertension • Obesity

A Study of Orforglipron (LY3502970) in Participants With Obesity or Overweight and at Least One Weight-Related Comorbidity (clinicaltrials.gov) - P3 | N=600 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P3 trial • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

A Study of Orforglipron (LY3502970) in Participants With Obesity or Overweight and Type 2 Diabetes (clinicaltrials.gov) - P3 | N=600 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P3 trial • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

A Master Protocol Study of Orforglipron (LY3502970) in Participants With Hypertension and Obesity or Overweight (ATTAIN-Hypertension) GZL2 (clinicaltrials.gov) - P3 | N=487 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P3 trial • Cardiovascular • Genetic Disorders • Hypertension • Obesity

Orforglipron: Primary completion and completion of P1 trial (NCT06824051) for obesity in Dec 2025 (Eli Lilly) - Q1 2025 Results

Trial completion date • Trial primary completion date • Obesity

A Master Protocol Study of Orforglipron (LY3502970) in Participants With Hypertension and Obesity or Overweight (ATTAIN-Hypertension) GZL1 (clinicaltrials.gov) - P3 | N=487 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P3 trial • Cardiovascular • Genetic Disorders • Hypertension • Obesity

A Master Protocol for Orforglipron (LY3502970) in Participants With Hypertension and Obesity or Overweight: (ATTAIN-Hypertension Screening) (clinicaltrials.gov) - P3 | N=974 | Not yet recruiting | Sponsor: Eli Lilly and Company

New P3 trial • Cardiovascular • Genetic Disorders • Hypertension • Obesity

A Study of Orforglipron (LY3502970) in Adult Participants With Obesity or Overweight (clinicaltrials.gov) - P1 | N=120 | Active, not recruiting | Sponsor: Eli Lilly and Company | Not yet recruiting ➔ Active, not recruiting

Enrollment closed • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity

NVO Stock Dips as Eli Lilly's Oral Weight Loss Drug Shows Promising Results (Gurufocus) - "Novo Nordisk...saw its stock take a significant hit, plunging nearly 8%. This decline followed the announcement from competitor Eli Lilly about its promising Phase 3 trials for a new oral weight loss medication, orforglipron."

Commercial • Obesity

A Study of Orforglipron for the Maintenance of Body Weight Reduction in Participants Who Have Obesity or Overweight With Weight-Related Comorbidities (ATTAIN-MAINTAIN) (clinicaltrials.gov) - P3 | N=300 | Active, not recruiting | Sponsor: Eli Lilly and Company | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Obesity

ACHIEVE-1: A Study of Orforglipron (LY3502970) in Adult Participants With Type 2 Diabetes and Inadequate Glycemic Control With Diet and Exercise Alone (clinicaltrials.gov) - P3 | N=520 | Completed | Sponsor: Eli Lilly and Company | Active, not recruiting ➔ Completed

Trial completion • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Lilly's oral GLP-1, orforglipron, demonstrated statistically significant efficacy results and a safety profile consistent with injectable GLP-1 medicines in successful Phase 3 trial (PRNewswire) - P3 | N=520 | ACHIEVE-1 (NCT05971940) | Sponsor: Eli Lilly and Company | "Eli Lilly and Company...announced positive topline Phase 3 results from ACHIEVE-1...orforglipron met the primary endpoint of superior A1C reduction compared to placebo at 40 weeks, lowering A1C by an average of 1.3% to 1.6% from a baseline of 8.0%, using the efficacy estimand. In a key secondary endpoint, more than 65% of participants taking the highest dose of orforglipron achieved an A1C less than or equal to 6.5%...The overall safety profile of orforglipron in ACHIEVE-1 was consistent with the established GLP-1 class...The ACHIEVE-1 results will be presented at ADA's 85th...More results from the ACHIEVE Phase 3 clinical trial program will be shared later this year....Lilly expects to submit orforglipron for weight management to global regulatory agencies by the end of this year, with the submission for the treatment of type 2 diabetes anticipated in 2026."

FDA filing • P3 data: top line • Type 2 Diabetes Mellitus

Current Insights, Advantages and Challenges of Small Molecule Glucagon-like Peptide 1 Receptor Agonists: A Scoping Review. (PubMed, J Brown Hosp Med) - "These small molecules offer enhanced tissue permeability, extended half-lives, and the potential for fixed-dose combinations, addressing limitations of injectable formulations. This review explores the preclinical and clinical progress of small-molecule GLP-1RAs, highlighting their potential to redefine diabetes care by improving convenience, adherence, and accessibility for patients."

Journal • Review • Cardiovascular • Diabetes • Genetic Disorders • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Incretin-based therapies for the treatment of obesity-related diseases (ATTD 2025) - "Liraglutide, semaglutide and tirzepatide are incretin-based therapies currently approved by FDA for the management of obesity, while triple GIPR/GCGR/GLP-1R agonist retatrutide (LY3437943), the cagrilintide/semaglutide (CagriSema) 2.4 mg combination, high-dose oral semaglutide, and oral orforglipron are in advanced stages of development...Liraglutide, semaglutide and tirzepatide are incretin-based therapies currently approved by FDA for the management of obesity, while triple GIPR/GCGR/GLP-1R agonist retatrutide (LY3437943), the cagrilintide/semaglutide (CagriSema) 2.4 mg combination, high-dose oral semaglutide, and oral orforglipron are in advanced stages of development...Moreover, incretin-based therapies have also been proven beneficial on obesity-related comorbidities, such as knee osteoarthritis (KOA), obstructive sleep apnea (OSA) syndrome, and MASLD. Further research is needed to improve our understanding of their effects on obesity-related comorbidities and the..."

Cardiovascular • Congestive Heart Failure • Diabetes • Genetic Disorders • Heart Failure • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Obstructive Sleep Apnea • Osteoarthritis • Pain • Respiratory Diseases • Rheumatology • Sleep Disorder • Type 2 Diabetes Mellitus

Eli Lilly's first weight loss pill could expand access to GLP-1s around the globe, executive says (Yahoo Finance) - "Orforglipron is currently in a phase 3 trial....Eli Lilly CEO Dave Ricks told Bloomberg News in January that phase 3 trial results are expected before the middle of 2025. That could lead to regulatory approval for the drug in 2026."

Approval • P3 data • Obesity • Type 2 Diabetes Mellitus

Glucagon-like peptide-1 receptor agonists: a new pharmacological treatment option for psychiatric illnesses? (PubMed, Nervenarzt) - "Albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, orforglipron and semaglutide are glucagon-like peptide‑1 (GLP-1) receptor agonists. Tirzepatide targets not only GLP‑1 but also glucose-dependent insulinotropic peptide (GIP) receptors and retatrutide is a triple GLP‑1, GIP and glucagon receptor agonist...Typical accompanying adverse reactions are gastrointestinal side effects, such as nausea, vomiting, diarrhea, eructation and gastroesophageal reflux. More severe side effects include pancreatitis, allergic reactions, renal function disorders and possibly an increased risk of thyroid cancer."

Journal • Review • Addiction (Opioid and Alcohol) • Allergy • Alzheimer's Disease • Binge Eating Disorder • Cardiovascular • CNS Disorders • Cognitive Disorders • Dementia • Depression • Diabetes • Endocrine Cancer • Gastroenterology • Gastroesophageal Reflux Disease • Gastrointestinal Disorder • Mental Retardation • Metabolic Disorders • Mood Disorders • Oncology • Pancreatitis • Psychiatry • Solid Tumor • Thyroid Gland Carcinoma

A Study to Compare Tablets and Capsules of Orforglipron (LY3502970) in Healthy Participants Who Are Obese or Overweight (clinicaltrials.gov) - P1 | N=508 | Active, not recruiting | Sponsor: Eli Lilly and Company | Recruiting ➔ Active, not recruiting

Enrollment closed • Genetic Disorders • Obesity