Obesity and Diabetes Incretin Pipeline: Next-Gen Oral GLP-1 Foundayo Outperforms Oral Semaglutide in Phase 3
At the American Diabetes Association (ADA) 86th Scientific Sessions in New Orleans (June 5–8, 2026), next-generation incretin therapies dominated the spotlight. While initial presentations focused on the unprecedented weight loss and tolerability profiles of various pipeline candidates, Eli Lilly and Company delivered a landmark update, presenting detailed Phase 3 results from three pivotal trials in its ACHIEVE program evaluating Foundayo (orforglipron).
Foundayo is a non-peptide, small-molecule, once-daily oral GLP-1 receptor agonist that can be taken without the strict food or water restrictions required by older oral peptides (such as Rybelsus). Following these trials, Lilly announced plans to submit Foundayo to the U.S. FDA for Type 2 diabetes approval by the end of the second quarter of 2026.
Head-to-Head Superiority Over Oral Semaglutide (ACHIEVE-3)
The landmark ACHIEVE-3 trial (published in The Lancet) represents the first-ever head-to-head Phase 3 trial comparing two oral GLP-1 receptor agonists in Type 2 diabetes. The 52-week study compared Foundayo (9 mg and 17.2 mg once daily) against oral semaglutide (7 mg and 14 mg once daily) in adults with Type 2 diabetes.
Foundayo demonstrated substantial statistical superiority across all primary and key secondary endpoints:
- A1C Reduction: From a baseline A1C of 8.3%, Foundayo 17.2 mg lowered A1C by 2.2% at Week 52, compared to a 1.4% reduction with oral semaglutide 14 mg. This represents a 57.1% greater relative reduction at the highest dose.
- Normal Blood Sugar Achievement: Significantly more patients on the highest dose of Foundayo achieved normal blood sugar levels (A1C < 5.7%) compared to oral semaglutide (37.1% vs. 12.5%).
- Weight Loss: From a baseline body weight of 97.0 kg (213.9 lbs), patients taking Foundayo 17.2 mg lost an average of 19.7 lbs (9.2%) compared to 11.0 lbs (5.3%) with oral semaglutide 14 mg—representing a 73.6% greater relative weight loss.
Strong Efficacy in Broad Patient Populations (ACHIEVE-2 and ACHIEVE-5)
Lilly also presented results from two other Phase 3 trials:
- ACHIEVE-2 (published in The Lancet): Foundayo was compared to the SGLT2 inhibitor dapagliflozin over 40 weeks. Foundayo 17.2 mg lowered A1C by 1.7% (vs. 0.8% for dapagliflozin) and drove weight loss of 15.0 lbs (7.3%) (vs. 6.0 lbs for dapagliflozin). Up to 68.6% of patients taking Foundayo reached the intensive A1C target of ≤6.5%.
- ACHIEVE-5 (published in JAMA): Evaluating Foundayo as an add-on to titrated insulin glargine over 40 weeks, the drug lowered A1C by up to 2.1% (vs. 0.8% for placebo) and reduced body weight by up to 11.5 lbs (6.1%) (vs. a 1.1 lb gain for placebo). Up to 69.1% of patients achieved an A1C ≤6.5%.
Safety and Tolerability
The overall safety profile of Foundayo was consistent with the GLP-1 receptor agonist class. The most common adverse events were gastrointestinal (nausea, diarrhea, vomiting, dyspepsia, and decreased appetite), occurring primarily during the dose-escalation phase. Despite these class-typical tolerability hurdles, the robust efficacy, flexible dosing, and cardiovascular risk factor improvements (including non-HDL cholesterol and systolic blood pressure) position Foundayo as a highly competitive primary-care oral option.