ACHIEVE-3: Orforglipron Demonstrates Superiority to Semaglutide in Poorly Controlled T2D

Eli Lilly’s investigational once-daily GLP-1 receptor agonist orforglipron has outperformed oral semaglutide 7 and 14 mg in patients with type 2 diabetes inadequately controlled with metformin. Over 52 weeks, orforglipron resulted in superior improvements in weight and A1C, demonstrating superiority over the primary and all key secondary endpoints. Notably, orforglipron exhibits no food or water restrictions, setting it apart from existing oral GLP-1s.1

Diabetes Dialogue cohosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, discuss the results of ACHIEVE-3 and the promise of orforglipron as an oral GLP-1 with no dietary restrictions.

Check out the full episode on recent GLP-1 trials and results here.

In this segment, Isaacs and Bellini discuss the recently published results of the ACHIEVE-3 Trial, a phase 3 study evaluating the investigational oral GLP-1 receptor agonist Orforglipron. Unlike peptide-based GLP-1 therapies, orforglipron is a non-peptide molecule that does not require fasting administration and can be taken alongside food, beverages, and other medications, potentially improving convenience and adherence compared with Semaglutide in its oral form.

The hosts review the head-to-head trial, which enrolled 1,698 patients with type 2 diabetes already taking metformin and compared two doses of orforglipron (12 mg and 36 mg) with oral semaglutide (7 mg and 14 mg). Results showed greater glycemic reductions with orforglipron, with mean A1C decreases of approximately 1.7% and 1.9% for the two doses, compared with reductions of 1.2% and 1.5% with semaglutide. All primary noninferiority comparisons were met, and the investigational agent demonstrated statistical superiority in A1C lowering.

The conversation then turns to tolerability. Gastrointestinal adverse events were reported more frequently with orforglipron, affecting roughly 58–59% of participants compared with 37–45% among those receiving semaglutide. The hosts discuss the nuances of adverse-event reporting in clinical trials, noting that even a single episode of nausea may be recorded as an event, which can inflate incidence rates. Despite higher rates of GI symptoms, discontinuation due to these effects remained relatively low, occurring in approximately 6% of patients receiving orforglipron compared with 3% with semaglutide, suggesting that most patients were able to continue therapy.

The panel highlights the potential clinical implications of these findings. The greater glucose-lowering efficacy may reflect the drug’s potency, but clinicians will need more information on dose-titration strategies and the duration of GI side effects to determine real-world tolerability. They also note that the comparison did not include the highest available dose of semaglutide, representing a limitation when interpreting relative efficacy.

Looking ahead, the hosts discuss the regulatory outlook for orforglipron, which has reportedly been submitted to regulators in more than 40 countries, including the United States, with initial approval efforts focused on obesity. They also emphasize the importance of cardiovascular outcomes data, which are currently available for semaglutide through large trials but not yet for orforglipron, which will likely play a critical role in determining how the therapies are positioned in clinical practice.

The discussion concludes with cautious optimism about expanding oral GLP-1 options. While the convenience and potency of orforglipron are promising, the hosts stress the importance of established cardiovascular evidence when selecting therapies for patients with diabetes and obesity who are at elevated cardiovascular risk.

Editor’s Note: Isaacs reports disclosures with Dexcom, Abbott, Lilly, Novo Nordisk, Medtronic, Insulet, and others. Bellini reports disclosures with Abbott Diabetes Care, MannKind, Povention Bio, and others.

References

1. Eli Lilly. Lilly’s oral GLP-1, orforglipron, delivered superior blood sugar control and weight loss compared to oral semaglutide in head-to-head type 2 diabetes trial published in The Lancet. February 26, 2026. Accessed March 5, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-delivered-superior-blood-sugar

2. Rosenstock J, Yabe D, Cox D, et al. Efficacy and safety of once-daily oral Orforglipron compared with oral semaglutide in adults with type 2 diabetes (achieve-3): A multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial. The Lancet. Published online February 26, 2026. doi:10.1016/s0140-6736(26)00202-3