Oral GLP-1

Extracted Attributes

• Challenges

  Scientific/logistical obstacles for oral absorption, counterfeit products, patent hacking, pricing concerns

• Drug Class

  GLP-1 receptor agonists (incretin mimetics)

• Mechanism of Action

  Activates GLP-1 receptor, mimics endogenous GLP-1, reduces blood sugar and energy intake

• Orforglipron Dosing

  Can be taken any time of day without food/water restrictions

• Expanded Indications

  Obesity, Weight Loss, Metabolic Syndrome

• Recommendation Status

  First-line therapy for Type 2 Diabetes (ADA 2022, especially with atherosclerotic cardiovascular disease or obesity)

• Nature of Orforglipron

  Once-daily, non-peptide small molecule GLP-1 receptor agonist

• Orforglipron Discovery

  Chugai Pharmaceutical Co., Ltd.

• Manufacturer of Rybelsus

  Novo Nordisk

• Approval Status of Rybelsus

  Approved for Type 2 Diabetes (not for weight loss)

• Current Oral Drug on Market

  Rybelsus (semaglutide)

• Investigational Indications

  Non-alcoholic fatty liver disease, Polycystic Ovary Syndrome, Addiction, Mental Health conditions, Brain Diseases

• Primary Indications (Initial)

  Type 2 Diabetes

• Key Oral Drug in Development (Pfizer)

  Danuglipron (development discontinued for weight loss)

• Key Oral Drug in Development (Eli Lilly)

  Orforglipron

Timeline

• Eli Lilly licensed orforglipron from Chugai Pharmaceutical Co., Ltd. (Source: web_search_results)

  2018

• The American Diabetes Association (ADA) recommends GLP-1 agonists as a first-line therapy for type 2 diabetes, especially for patients with atherosclerotic cardiovascular disease or obesity. (Source: summary, wikipedia)

  2022

• Tirzepatide (an injectable GLP-1 drug) surpassed Keytruda as the world's top-selling drug. (Source: related_documents)

  Q2 (unspecified year)

• Eli Lilly announced successful Phase 3 trial results for its oral GLP-1 drug, orforglipron, demonstrating statistically significant efficacy and a safety profile consistent with injectable GLP-1 medicines. (Source: web_search_results)

  2025-04-17

• Results from the ATTAIN-1 trial for orforglipron, led by Weill Cornell Medicine and other institutions, were published in the New England Journal of Medicine, showing significant weight loss and improved heart/metabolic risk factors in non-diabetic patients with obesity. (Source: web_search_results)

  2025-09-17

GLP-1 receptor agonist

Glucagon-like peptide-1 (GLP-1) receptor agonists, also known as GLP-1 analogs, GLP-1RAs, or incretin mimetics, are a class of anorectic drugs that reduce blood sugar and energy intake by activating the GLP-1 receptor. They mimic the actions of the endogenous incretin hormone GLP-1, which is released by the gut after eating. GLP-1 agonists were initially developed for type 2 diabetes. The 2022 American Diabetes Association standards of medical care recommend GLP-1 agonists as a first-line therapy for type 2 diabetes, specifically in patients with atherosclerotic cardiovascular disease or obesity. The drugs were also noted to reduce food intake and body weight significantly, and some have been approved to treat obesity and other components of the metabolic syndrome in the absence of diabetes. They are also in development for other indications, such as non-alcoholic fatty liver disease, polycystic ovary syndrome, and diseases of the reward system such as addictions.

Web Search Results

• Why GLP-1 Weight-Loss Drugs Are Hard to Make into Pills

  Unlike the array of new injectable GLP-1 drugs, there is only one oral GLP-1 medicine that is currently on the market: Novo Nordisk’s Rybelsus. This semaglutide pill mimics the gut hormone GLP-1 in the same way the injections do, and it must be taken daily compared with Ozempic’s once-weekly injections. Rybelsus is approved for type 2 diabetes but not for weight loss, which is likely part of the reason it has garnered less attention, says Reshmi Srinath, an endocrinologist and director of the [...] An oral version of these drugs—which are known as glucagon-like peptide 1 (GLP-1) receptor agonists—could be more accessible and would come without the inconvenience, pain or medical waste of shots. But an assortment of scientific and logistical obstacles is preventing GLP-1 pills from taking off in the same way that the injectable forms of these drugs have. Pfizer recently announced it decided to discontinue clinical trials of its oral GLP-1 medication for weight loss, called danuglipron, [...] Eli Lilly, the manufacturer of the injectable weight-loss medication Zepbound, has its own oral GLP-1 drug in the pipeline, orforglipron, which is being investigated as a treatment for both type 2 diabetes and obesity. Like Rybelsus, orforglipron would be a daily pill—but it wouldn’t have meal-timing restrictions. Early data show that people lose between 10 and 15 percent of their body weight after 36 weeks on the drug. Another recently completed phase 3 clinical trial of people with type 2

• Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity

  Semaglutide (3, 7, or 14 mg once daily) with the permeation enhancer salcaprozate sodium (SNAC)6 is the one available oral GLP-1 receptor agonist, and it has been approved for the treatment of type 2 diabetes but not for weight management. For sufficient absorption, this drug must be taken at least 30 minutes before the first intake of food, beverages, or other oral medications of the day and taken with no more than 30 ml of plain water. In the PIONEER 1 trial, the use of the highest dose of [...] restrictions and an absorption enhancer. Danuglipron, an oral small-molecule GLP-1 receptor agonist, is also under development and was associated with few adverse events in phase 1 and phase 2 trials involving patients with type 2 diabetes.10-12 [...] Orforglipron is a once-daily oral nonpeptide GLP-1 receptor agonist that is in development for weight management and the treatment of type 2 diabetes.7,8 Orforglipron is a potent partial agonist of the GLP-1 receptor that has a greater effect on cyclic AMP (cAMP) signaling than on β-arrestin recruitment — a pharmacologic profile that may offer lower receptor desensitization than full GLP-1 receptor agonists.7 The pharmacokinetic profile of orforglipron, with a half-life of 29 to 49 hours,

• Oral GLP-1 drug promotes substantial weight loss in trial

  The results from the ATTAIN-1 trial were published Sept. 17 in the New England Journal of Medicine. The trial included 3,127 non-diabetic patients with obesity or overweight with obesity-related complications such as hypertension. Each was randomized to receive a placebo or one of three daily doses (6mg, 12mg, 36mg) of orforglipron, a new oral GLP-1 drug, in addition to a healthy diet and physical activity. [...] ## By Jim Schnabel Weill Cornell Medicine Patients taking an experimental oral GLP-1 drug lost significant weight and improved heart and metabolic risk factors in a large, international phase III clinical trial led by investigators at Weill Cornell Medicine, McMaster University, York University and other institutions. [...] Injectable GLP-1 drugs are made of peptides – short proteins – that mimic the natural appetite- and digestion-regulating peptide hormone GLP-1. They cannot be taken orally unless protected because, like most peptides, they are destroyed by the enzymes and acids of the stomach. Orforglipron, by contrast, is a “small molecule” drug and is meant to be taken orally.

• Full article: Oral glucagon-like peptide-1 receptor agonists and ...

  for T2D management (2022) and chronic weight management (2023) ( [Citation21,Citation22]. In addition, a number of oral GLP-1 RAs are under development to offer an alternative option to people reluctant to injectable treatments, with early data for some of them suggesting similar efficacy in glycemia and WL to injectable GLP-1 RAs [Citation17,Citation23]. [...] A plethora of oral GLP-1 RA is under development, but not all of them will progress to approval for T2D and/or obesity. For example, the development of lotiglipron, an oral, non-peptide, GLP-1 RA for T2D and obesity has been stopped in early phase clinical trials, as its administration was associated with elevated transaminases and concerns regarding potential liver toxicity. [...] Orforglipron, an oral, non-peptide, G-protein biased GLP-1 RA (resulting in lower activation of the beta-arrestin pathway) is currently under development for the treatment of T2D and obesity [Citation29]. Orforglipron is a small molecule and may offer a less burdensome administration for individuals with T2D compared to the oral semaglutide as it has minimal dosing requirements (i.e it does not require to be taken on an empty stomach) [Citation30].

• Lilly's oral GLP-1, orforglipron, demonstrated statistically significant ...

  # News Release ## 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 April 17, 2025 Facebook LinkedIn Twitter Mail PDF Version Orforglipron is the first small molecule GLP-1 to successfully complete a Phase 3 trial, lowering A1C by an average of 1.3% to 1.6% across doses [...] About orforglipron Orforglipron (or-for-GLIP-ron) is an investigational, once-daily small molecule (non-peptide) oral glucagon-like peptide-1 receptor agonist that can be taken any time of the day without restrictions on food and water intake.5 Orforglipron was discovered by Chugai Pharmaceutical Co., Ltd. and licensed by Lilly in 2018. Chugai and Lilly published the preclinical pharmacology data of this molecule together.6 Lilly is running Phase 3 studies on orforglipron for the treatment of [...] 5. Ma X, Liu R, Pratt EJ, Benson CT, Bhattachar SN, Sloop KW. Effect of Food Consumption on the Pharmacokinetics, Safety, and Tolerability of Once-Daily Orally Administered Orforglipron (LY3502970), a Non-peptide GLP-1 Receptor Agonist. Diabetes Ther. 2024 Apr;15(4):819-832. doi: 10.1007/s13300-024-01554-1. Epub 2024 Feb 24. PMID: 38402332; PMCID: PMC10951152.