The world of GLP-1 medications is evolving, and Eli Lilly’s orforglipron is leading the next wave. Unlike Rybelsus, which was the first oral GLP-1 medication but still a peptide, orforglipron is the first non-peptide oral GLP-1 receptor agonist. This key difference means it is more stable in the body, easier to absorb, and potentially offers a new level of convenience for people needing weight loss or blood sugar control.
For years, the most powerful GLP-1 medications, like Ozempic, Mounjaro, and Zepbound, have been injectables because peptides like semaglutide and tirzepatide break down quickly in the stomach. They require chemical modifications and injections to remain effective. Orforglipron, on the other hand, is a small-molecule drug, meaning it survives digestion and can be taken as a pill without the need for special coatings or absorption boosters.
If orforglipron performs as expected, it could greatly reduce the demand for injections, expand access for those hesitant about needles, and introduce more competition in the GLP-1 space, which could eventually lead to lower prices.
What We Know About Orforglipron’s Development
Orforglipron was measured in phase 2 trials at 12, 24, 36, and 45 milligram doses, showing promising results in both obesity and type 2 diabetes. Low doses of 2, 3, 6, 8 milligram doses were used in titration. The drug has since advanced into late-stage phase 3 trials, and the first key study results are expected as soon as next month.
Eli Lilly is moving fast, with a 2025 submission for obesity and an aggressive early 2026 launch timeline. The company has already stockpiled over $500 million in pre-launch inventory, signaling confidence in its success. This comes as welcome news to patients seeking to get away from the ever elusive injections that have been plagued by scarcity due to manufacturing constraints.
The phase 3 program includes studies evaluating orforglipron for type 2 diabetes, obesity, sleep apnea, adolescent obesity, and for weight maintenance post-tirzepatide . Several trials are expected to release data in 2025, with additional studies running into 2027.
Some upcoming 2025 highlights:
The ACHIEVE-1 trial, expected in April 2025, is focused on blood sugar control in type 2 diabetes.
The ATTAIN-1 trial, set for July 2025, is evaluating weight loss in people with obesity or overweight who have weight-related health conditions.
The ATTAIN-2 trial, scheduled for August 2025, is assessing weight loss in people with obesity who also have type 2 diabetes.
What We Saw in Phase 2
In earlier phase two trials, some key weight loss numbers were: Up to 10.1% weight reduction at 26 weeks in adults with type 2 diabetes, and up to 14.7% Weight Reduction at 36 Weeks in Adults with Obesity.
What Lilly Expects from Phase 3 Results
At the 45th annual Cowen Health Care Conference, Eli Lilly’s President of Oncology, Jake Van Naarden, discussed what to expect from the upcoming phase 3 readouts.
For people with type 2 diabetes, the first study to report data will have a 40-week endpoint. Prior GLP-1 studies suggest that patients with diabetes typically lose less weight than those without. Based on semaglutide trials, Eli Lilly expects a 5 to 7% body weight loss at this time point. The primary completion date for this trial is slated for April of this year.
For people without diabetes, the chronic weight management study will run for 72 weeks. Previous studies of 2.4mg of semaglutide and low-dose tirzepatide at 5 mg have shown around 15 percent weight loss at a similar time frame. Eli Lilly believes orforglipron will show a comparable effect, though the data remains blinded. The primary completion date for this trial is slated for June of this year.
Did Lilly Adjust the Dosing Strategy
What’s interesting here is that, based on the above comments from Lilly, the expected weight loss for both diabetic patients with obesity and non-diabetic individuals with obesity doesn’t seem to significantly surpass the results from phase two trials, which were conducted over shorter study periods.
Is this simply Lilly under promising to over deliver?
This begs the question of whether orforglipron’s effectiveness maxes out earlier than injectable GLP-1s. If Phase 2 already captured most of the drug’s weight loss potential, additional weeks of treatment may not add as much as expected.
Another possible explanation for the shift in phase 3 could be a slower titration process compared to phase 2. Some arms of the phase 2 trials were dosing up weekly. In these earlier trials, weight loss numbers made reaching these targets look like a slam dunk. However, along with the rapid titration schedule came gastrointestinal side effects, especially nausea and vomiting, which were the most common reason for discontinuation. Many of these issues occurred during the initial dose escalation period, suggesting that a more gradual increase in dose could improve patient retention.
Due to the risk of higher drop out numbers in the longer phase 3 trials, it’s highly likely Lilly chose to increase the dosing more slowly over time. This strategy would allow patients to adapt to the medication with fewer dropouts while still reaching the most effective doses at 36 or 45 milligrams.
Orforglipron is on track to be the first non-peptide oral GLP-1, offering a needle-free alternative for weight loss and diabetes management. While phase 2 results showed strong weight loss and blood sugar control, phase 3 will reveal how well it holds up over longer treatment periods and whether the potential changes in dosing or titration improve tolerability.
With a 2026 launch on the horizon, this medication could be a major shift in the GLP-1 landscape, giving patients another powerful tool to fight obesity and diabetes without an injection.
Peer-Reviewed Publications
Jastreboff AM, et al. Orforglipron, an Oral GLP-1 Receptor Agonist for Adults with Obesity. New England Journal of Medicine. Published June 23, 2023. https://www.nejm.org/doi/full/10.1056/NEJMoa2302392
Frias et al. Orforglipron for Adults with Type 2 Diabetes: A Phase 2 Trial. The Lancet. Published July 24, 2023. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)01302-8/abstract
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