UK Registered DoctorsOverview of Orforglipron
Orforglipron is an oral, non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist originally discovered by the Japanese pharmaceutical company Chugai and licensed to Eli Lilly in 2018 for clinical development.1,2 Preclinical pharmacology data were published jointly by Chugai and Lilly. The small-molecule drug is being developed for the management of obesity (with at least one weight-related comorbidity) and for the treatment of adults with type 2 diabetes mellitus insufficiently controlled by diet and exercise.
Phase 3 clinical studies for both indications have been completed, with all predefined efficacy endpoints met.3 Eli Lilly has confirmed plans to submit separate regulatory filings in selected jurisdictions by the end of 2025, with market launch expected in 2026-2027, pending approval.
How does it Orforglipron work?
In a similar fashion to marketed injectable GLP-1 receptor agonists such as Novo Nordisk’s Wegovy and Eli Lilly’s Mounjaro, Orforglipron acts by activating the GLP-1 receptor, thereby stimulating insulin secretion from pancreatic β-cells. This suppresses glucagon release and helps to reduce elevated blood glucose levels in individuals with type 2 diabetes.
GLP-1 receptors are also expressed in intestinal cells, particularly in the distal ileum and colon. Their activation slows gastric emptying and digestion, reduces appetite, and consequently lowers caloric intake, leading to weight loss. Both oral and injectable GLP-1 receptor agonists share this mechanism of action.
Beyond diabetes and obesity, ongoing research is exploring the potential of Orforglipron in other medical conditions where GLP-1 receptor activation may provide therapeutic benefit. These include cardiovascular disease, chronic kidney disease and metabolic-associated steatohepatitis (MASH). The effect of GLP-1 drugs on alcohol intake, smoking and drug abuse are also under investigation.4
Eli Lilly’s marketed injectable drug, Mounjaro (tirzepatide) is a dual GLP-1 and GIP receptor agonist. GIP (glucose-dependent insulinotropic polypeptide) is another incretin hormone that, together with GLP-1, stimulates insulin secretion in response to rising blood glucose levels, providing an additional metabolic advantage. Orforglipron is selective for the GLP-1 receptor and is not an agonist for GIP.
What are the advantages of oral GLP-1 agonists and why are they being developed?
Orforglipron is the first oral, non-peptidic, small-molecule GLP-1 receptor agonist. Unlike oral Semaglutide (Rybelsus), it can be taken once daily without any specific timing, food, or water restrictions. Rybelsus, marketed by Novo Nordisk in Europe and the UK for the treatment of type 2 diabetes, is a peptidic GLP-1 analogue that is degraded in the gastrointestinal tract. To enable absorption and uptake of the peptide drug through the stomach lining it must be co-formulated with an absorption enhancer- SNAC (Sodium N-(8-[2-hydroxybenzoyl]amino) caprylate- and taken under fasting conditions with minimal amounts of water.5
Because Orforglipron is non-peptidic, it is stable in the gut and does not require absorption enhancers, allowing for a simpler and more flexible dosing regimen. A tablet format also eliminates the need for injections, helping to overcome needle aversion and improve adherence. Orforglipron tablets do not require refrigeration, making storage and travel more convenient for patients. Furthermore, as a small-molecule drug, Orforglipron is generally easier and less expensive to manufacture and formulate than peptide-based agents such as Semaglutide (Wegovy) or Tirzepatide (Mounjaro).
What do the clinical trials show?
Data from two pivotal Phase 3 clinical trials evaluating weight loss and glycaemic control have been disclosed: ATTAIN-1 and ATTAIN-2 (Orforglipron vs placebo in patients with and without type 2 diabetes) and ACHIEVE-3 (Orforglipron vs oral Semaglutide). Key results are summarised below, with detailed study design in Tables 1 and 2.6
Key Findings from Orforglipron Phase 3 Trial (ATTAIN-1 and 2):
Primary Outcome:
- Orforglipron met the primary endpoint of superior body weight reduction compared with placebo.
Weight Loss Efficacy (36 mg dose):
- Observed treatment-regimen results: Average weight loss of 11.2% vs 2.1% with placebo.
- 54.6% of participants lost >10% of body weight.
- 36% lost >15% of body weight over 72 weeks.
- Efficacy estimand (ideal adherence): Average weight loss of 12.4% vs 0.9% with placebo.
- 59.6% lost >10% of body weight.
- 39.6% lost >15% of body weight over 72 weeks.
Safety profile:
- Most common adverse events were gastrointestinal (nausea, diarrhoea, vomiting, constipation), all of which are consistent with GLP-1 class of drugs.
- No cardiovascular safety signals were observed.
- No liver enzyme elevation or indication of liver toxicity were observed.
Key Findings from Orforglipron vs oral Semaglutide Phase 3 Trial (ACHIEVE-3):
Primary outcome:
- Orforglipron showed greater weight-loss and control of blood sugar relative to oral Semaglutide.
Weight Loss Efficacy (36 mg dose):
- At the highest doses, Orforglipron (36 mg) produced 9.2% average weight loss vs 5.3% with oral semaglutide (14 mg).
Glycaemic Control (HbA1c Reduction):
- Orforglipron lowered patients' HbA1c by 2.2% at the highest dose (36 mg) and by 1.9% at a 12 mg dose.
- Oral semaglutide lowered patients' HbA1c by 1.4% at the highest dose (14 mg) and by 1.1% at a 7 mg dose.
| Trial (name / NCT) | Population & design (n=patient numbers) | Dose & duration | Primary endpoint(s) |
|---|---|---|---|
| Phase 3 – Obesity (ATTAIN-1) | Adults with obesity/overweight, no diabetes; randomised, double-blind, placebo controlled. | 6/12/36 mg QD; 72 weeks | % change in body weight (treatment-regimen estimand) |
| Phase 3 – Obesity with Type-2 Diabetes (ATTAIN-2) | Adults with obesity/overweight and T2D; randomised, double-blind, placebo controlled. | 6/12/36 mg QD; 72 weeks | % weight change; HbA1c change |
| Phase 3 - Type-2 Diabetes (ACHIEVE-1) | Early T2D adults; randomised, double-blind, global | Multiple doses QD; 40 weeks | ΔHbA1c at wk 40 |
| Phase 3- Type-2 Diabetes head-to-head vs oral semaglutide (ACHIEVE-3) | Adults with T2D; randomised, double-blind, active-controlled (Semaglutide). | orforglipron 12/36 mg vs oral semaglutide 7/14 mg; 52 weeks | ΔHbA1c at wk 52 |
Table 1: Orforglipron phase 2 and 3 clinical trial design (T2D is type 2-diabetes)
| Trial (name / NCT) | Key results | What it demonstrates |
|---|---|---|
| Phase 3 – Obesity (ATTAIN-1) | Mean weight change: –7.5% (6 mg), –8.4% (12 mg), –11.2% (36 mg) vs –2.1% placebo; at a 36 mg dose, 54.6% of patients showed a ≥10% weight reduction and 36.0% of patients showed a ≥15% weight reduction | Confirms superiority to placebo over 72 wks with meaningful cardio-metabolic improvements; tolerability as expected. |
| Phase 3 – Obesity with Type-2 Diabetes (ATTAIN-2) | Highest dose: –10.5% weight (–10.4Kg) and –1.8% HbA1c; all doses met primary & key secondary endpoints; cardiometabolic markers improved | Effective for people with obesity + T2D, achieving clinically meaningful weight and HbA1c reductions. |
| Phase 3 - Type-2 Diabetes (ACHIEVE-1) | Significantly reduced HbA1c vs placebo (primary). Secondary: weight loss and metabolic improvements. | Establishes glycaemic efficacy in early T2D with added weight benefits. |
| Phase 3 -Type-2 Diabetes head-to-head vs oral semaglutide (ACHIEVE-3) | HbA1c –1.9% (12 mg) & –2.2% (36 mg) vs –1.1% & –1.4% with semaglutide; weight loss 9.2% (36 mg) vs 5.3% (14mg) with oral semaglutide | Superiority to oral semaglutide for HbA1c and greater weight loss at highest doses. |
Table 2: Orforglipron phase 2 and 3 clinical trial results and conclusions (T2D is type 2-diabetes)
In phase 3 studies, Orforglipron has been evaluated as a once-daily oral tablet (up to 36 mg). Final licensed doses, titration schedules, and tablet strengths are subject to regulatory approval.
The future of orforglipron
Orforglipron is currently an investigational medicine and has not yet received regulatory approval for use in the UK, EU, or US. As such it is not yet available for prescription or supply. Eli Lilly plans to submit data for regulatory approval in 2025 for obesity and weight management, followed by an application for type 2 diabetes in 2026. UK launch is estimated to be 2026-2027. The drug is positioned as a once-daily oral addition to Lilly’s weight-loss portfolio, offering greater convenience for patients rather than replacing its injectable therapy Mounjaro.7
To support anticipated global demand and in preparation for market launch, Lilly is constructing a dedicated manufacturing facility for large-scale production of Orforglipron.
Other small-molecule GLP-1 receptor agonists are also in development, including Pfizer’s oral candidate Danuglipron, which is currently being evaluated in Phase 2 clinical trials.
References:
- An agonist is a substance (usually a drug or natural compound) that initiates a physiological response when it binds to a receptor. For reference, an antagonist blocks the receptor and gives the opposite effect.
- Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist:
https://doi.org/10.1073/pnas.2014879117 - Eli Lilly website 17th April, 7th August, 17th September 2025
- New indications; The expanding benefits of GLP-1 medicines:
https://doi.org/10.1016/j.xcrm.2025.102214 - A new era for oral peptides: SNAC and the development of oral Semaglutide for the treatment of type 2 diabetes:
https://doi.org/10.1007/s11154-022-09735-8 - www.clinicaltrials.gov Identifiers: ATTAIN-1 trial (NCT05869903); ATTAIN-2 trial (NCT05872620) ACHIEVE-3 trial (NCT06045221)
- Lilly gets a boost from new weight-loss pill data as it weighs speedier approval in US:
Reuters September 17th, 2025
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