It was a slow week in new GLP-1 / incretin trials being reported, likely in part due to the U.S. government shutdown. There was important press, though, regarding Lilly’s orforglipron trials. I’ve therefore also chosen oral GLP-1s for the Mechanism Explained section. Another newsletter, GLP-1 Digest (no affiliation), wrote about oral GLP-1s for obesity recently in an analysis piece worth checking out. For the new trials section below and for the Trial Spotlight, I dipped into the non-incretin mechanism bucket with an interesting one, also coincidentally from Eli Lilly.
🔥 THIS WEEK’S KEY DEVELOPMENTS
Lilly’s orforglipron meets endpoints in Phase 3 diabetes trials.
Eli Lilly announced positive topline results from the Phase 3 ACHIEVE-2 and ACHIEVE-5 trials for its oral GLP-1, orforglipron, in adults with type 2 diabetes. In the ACHIEVE-2 trial, orforglipron lowered A1C by up to 1.7% at 40 weeks compared to 0.8% for dapagliflozin, while in ACHIEVE-5, it lowered A1C by up to 2.1% versus 0.8% for placebo when added to insulin glargine. Lilly plans to submit orforglipron for the treatment of type 2 diabetes to global regulatory agencies in 2026.
Press | Mechanism: oral GLP-1
🆕 NEWLY REGISTERED TRIALS
LY3938577 Phase 2 trial evaluating the drug in participants with Type 2 Diabetes who were previously treated with basal insulin (Eli Lilly, n=100) [Novel mechanism]
NCT07215312 | Mechanism: Not an incretin but an experimental, “glucose-sensing” insulin
💡 TRIAL SPOTLIGHT
Educational spotlight selected by editors
A Study of LY3938577 in Participants With Type 2 Diabetes Previously Treated With Basal Insulin
Eli Lilly is advancing its next-generation diabetes portfolio with a Phase 2 trial for LY3938577, an investigational glucose-sensing insulin. This randomized, open-label study will enroll 100 adults with type 2 diabetes who are already being treated with basal insulin and compare LY3938577 against insulin degludec. The trial’s primary endpoint will evaluate the change in time participants’ blood glucose levels stay within the target range of 70-180 mg/dL over approximately 20 weeks. With recruitment expected to begin around November 2025, this study is strategically significant as it tests a “smart insulin” designed to activate in response to high glucose levels, potentially offering better glycemic control with a reduced risk of hypoglycemia. This approach could represent a major improvement in insulin therapy for patients requiring more advanced treatment.
🔬 MECHANISM EXPLAINED
Understanding the science behind the therapeutics
Oral GLP-1s (Example drug: orforglipron)
Oral glucagon-like peptide-1 (GLP-1) receptor agonists represent an important evolution in metabolic disease treatment, translating the power of injectable therapies into a convenient pill (although with somewhat less weight loss). These drugs work by mimicking the native GLP-1 hormone, which stimulates glucose-dependent insulin secretion, suppresses appetite, and slows gastric emptying to improve glycemic control and induce weight loss. The primary challenge, and key innovation, lies in designing these peptide or small-molecule drugs to survive the harsh environment of the digestive system and be absorbed into the bloodstream. This oral route of administration is a significant differentiator in a market dominated by injectables like Ozempic, offering a less invasive option that can dramatically improve patient adherence and quality of life. As companies like Eli Lilly advance their next-generation oral candidates like orforglipron, they aim to compete directly with established oral options such as Novo Nordisk’s Rybelsus (oral semaglutide) by potentially offering more flexible dosing without strict food and water requirements.
This newsletter compiles publicly available information from company press releases and ClinicalTrials.gov. Not investment advice.