Lilly's Oral GLP-1 Foundayo Outperforms Oral Semaglutide in Phase 3 Type 2 Diabetes Trial

Eli Lilly and Company announced detailed results from three pivotal Phase 3 studies demonstrating that its oral glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron (brand name Foundayo) significantly improved glycemic control and weight loss in adults with type 2 diabetes. The findings included results from the ACHIEVE-3 trial, the first phase 3 head-to-head comparison of two oral GLP-1 therapies, in which Foundayo outperformed oral semaglutide across primary and key secondary endpoints, according to a company announcement.¹

Results from ACHIEVE-2, ACHIEVE-3, and ACHIEVE-5 were presented at the American Diabetes Association 86th Scientific Sessions. The ACHIEVE-3 findings were simultaneously published in The Lancet, while ACHIEVE-2 and ACHIEVE-5 appeared in The Lancet and JAMA, respectively.¹

How did Foundayo perform against oral semaglutide?

The ACHIEVE-3 study enrolled 1,698 adults with type 2 diabetes inadequately controlled on metformin and compared two doses of Foundayo with approved doses of oral semaglutide over 52 weeks.¹

At the highest dose comparison, Foundayo 17.2 mg reduced A1C by an average of 2.2% from a baseline of 8.3%, compared with a 1.4% reduction for oral semaglutide 14 mg.¹ The difference represented a 57.1% greater relative reduction in A1C.¹

The treatment also produced greater weight loss. Patients receiving Foundayo 17.2 mg lost an average of 19.7 pounds, compared with 11.0 pounds among those receiving oral semaglutide 14 mg, corresponding to a 73.6% greater relative weight reduction.¹

Notably, 37.1% of patients receiving the higher dose of Foundayo achieved an A1C below 5.7%, a threshold generally considered within the normal glycemic range, compared with 12.5% of patients receiving oral semaglutide.¹

"ACHIEVE-3 provides the first head-to-head data on oral GLP-1s in type 2 diabetes, with orforglipron showing greater A1C and weight reductions than oral semaglutide," said Julio Rosenstock, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center and lead investigator for ACHIEVE-3.¹

What did the additional ACHIEVE studies show?

The ACHIEVE-2 trial compared Foundayo with the sodium-glucose cotransporter-2 (SGLT-2) inhibitor dapagliflozin in 962 adults with inadequate glycemic control on metformin.¹

Participants receiving the highest dose of Foundayo achieved average A1C reductions of up to 1.7%, compared with 0.8% for dapagliflozin after 40 weeks.¹ Additionally, 68.6% of participants receiving the highest dose of Foundayo achieved an A1C goal of 6.5% or lower, compared with 21.6% of those receiving dapagliflozin.¹

In ACHIEVE-5, which evaluated Foundayo in combination with insulin glargine, the oral therapy reduced A1C by up to 2.1% compared with 0.8% for placebo at 40 weeks.¹ Up to 69.1% of participants receiving Foundayo achieved an A1C of 6.5% or lower, compared with 11.1% of participants receiving placebo.¹

Across all three studies, Foundayo also produced clinically meaningful improvements in multiple cardiometabolic risk factors, including cholesterol measures, triglycerides, and systolic blood pressure.¹

Why could oral GLP-1 therapies change diabetes treatment?

GLP-1 receptor agonists have become a cornerstone of type 2 diabetes management because of their ability to improve glycemic control while promoting weight loss and reducing cardiovascular risk in appropriate patient populations.²˒³

Foundayo is a once-daily, non-peptide oral GLP-1 receptor agonist that can be taken without food or water restrictions.¹ The convenience of oral administration could expand access to GLP-1 therapy and potentially encourage earlier use in primary care settings.¹˒²

The ACHIEVE-3 findings are particularly notable because they provide the first direct phase 3 comparison between two oral GLP-1 therapies. According to Lilly, the results suggest that oral GLP-1 agents may increasingly compete not only with injectable therapies but also with established oral diabetes medications.¹

What safety findings were observed?

The safety profile observed across the ACHIEVE studies was consistent with previous investigations of GLP-1 receptor agonists.¹ Gastrointestinal adverse events, including nausea, diarrhea, vomiting, dyspepsia, and decreased appetite, were the most commonly reported side effects.¹

Treatment discontinuations due to adverse events increased with higher doses of Foundayo but remained generally consistent with expectations for the GLP-1 class.¹ No new safety signals were reported.¹

Based on findings from ACHIEVE-1 through ACHIEVE-5, Lilly announced plans to submit Foundayo to the US Food and Drug Administration for the treatment of type 2 diabetes by the end of the second quarter.¹

References

1. Lilly's oral GLP-1 Foundayo (orforglipron) delivered superior A1C control and weight loss in three pivotal type 2 diabetes trials. (2026 Jun 8). PR Newswire. https://prnmedia.prnewswire.com/news-releases/lillys-oral-glp-1-foundayo-orforglipron-delivered-superior-a1c-control-and-weight-loss-in-three-pivotal-type-2-diabetes-trials-302793407.html
2. Diabetes Management. American Diabetes Association. Standards of Care in Diabetes—2026. Diabetes Care. https://professional.diabetes.org/standards-of-care
3. Salvador, R., Moutinho, C. G., Sousa, C., Vinha, A. F., Carvalho, M., & Matos, C. (2025 Mar 12). Semaglutide as a GLP-1 Agonist: A Breakthrough in Obesity Treatment. Pharmaceuticals (Basel, Switzerland). https://doi.org/10.3390/ph18030399