GLP-1s may be the hottest drug class to emerge in recent memory, but their popularity is limited, in part, by cost, lack of payer coverage and the fact that they are generally injectable. For many patients, the prospect of self-injection presents a significant psychological barrier. Studies show that needle aversion affects a substantial portion of diabetes patients, with many delaying or avoiding treatment altogether resulting from injection anxiety. Now, Lilly has announced that its novel oral small molecule glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron was effective at reducing blood sugar and has a safety profile consistent with injectable GLP-1s in a Phase 3 study. In the ACHIEVE-1 study involving people with type 2 diabetes, once-daily oral orforglipron reduced A1C by 1.3% to 1.6% across doses on average. Investigators saw improvements as early as four weeks in adults with type 2 diabetes.
The complete trial results, published today in The New England Journal of Medicine, demonstrated that orforglipron met all primary and key secondary endpoints. In the 40-week study of 559 participants, up to 76% achieved the ADA target A1C of less than 7%, with 26% reaching normal A1C values below 5.7%. As with traditional GLP-1s, The most common side effects were gastrointestinal-related and generally mild to moderate. Discontinuation rates were 4–8% compared to 1% for placebo.
Promising efficacy
The study authors noted the drug’s strong glycemic efficacy: “A glycated hemoglobin level of less than 5.7% (near normoglycemia) was reached in up to 24% of participants with orforglipron.”
The trial’s dose-escalation strategy proved effective, with investigators reporting that gastrointestinal side effects “occurred primarily during the dose-escalation period; the prevalence of gastrointestinal side effects generally decreased over time.”
Orforglipron thus promises to address a core unmet need in the GLP-1 market. Unlike the only currently available oral GLP-1, Novo Nordisk’s Rybelsus, which must be taken 30 minutes before eating with strict water restrictions, orforglipron can be taken at any time without regard to food or water intake. This convenience factor, combined with efficacy data showing weight loss of up to 16 pounds at the highest dose, positions orforglipron to potentially expand the GLP-1 market to millions of patients who have been reluctant to begin injectable therapy.
The researchers observed that “changes in body weight appear not to have reached a plateau at 40 weeks.” Thus, even greater weight loss could be possible with longer treatment duration.
An evolving oral GLP-1 landscape
The landscape is evolving, but the playing field narrower than it once was. Novo Nordisk is working on a “long-acting, once-daily oral semaglutide” which is in Phase 3 development. Pfizer, however, announced in April 2025 the discontinuation of its oral GLP-1 drug danuglipron development citing a case of “potential drug-induced liver injury” in one participant. That drug had shown high discontinuation rates (22-34% at higher doses) due to adverse events in Phase 2 trials. The competitive landscape has been further winnowed by the withdrawal of lotiglipron, another oral GLP-1 candidate, also owing to liver toxicity concerns.
The narrowing of the oral GLP-1 pipeline leaves Lilly’s orforglipron as one of the few oral GLP-1s left standing at the late-stage trial stage without major safety red flags. If approved, the drug could provide Lilly with a significant first-mover advantage in what analysts predict could become a $105 billion market by 2030, according to Morgan Stanley projections.
Filed Under: Metabolic disease/endicrinology
