Eli Lilly’s Orforglipron Outperforms Oral Semaglutide in ACHIEVE‑3 Trial

Eli Lilly and Company has announced detailed Phase 3 results from the ACHIEVE‑3 trial evaluating its investigational oral GLP‑1 receptor agonist, orforglipron, versus oral semaglutide in adults with type 2 diabetes inadequately controlled on metformin monotherapy. The data, published in The Lancet, show that orforglipron produced statistically and clinically superior reductions in HbA1c and body weight compared with both diabetes‑approved doses of oral semaglutide, establishing the first head‑to‑head comparison of two oral GLP‑1 agents in this population.

Eli Lilly states that orforglipron 12 mg and 36 mg outperform oral semaglutide 7 mg and 14 mg on the primary endpoint (HbA1c reduction at 52 weeks) and all key secondary endpoints, including weight loss and achievement of lower glycemic targets, and emphasizes that orforglipron can be taken without food or water‑timing restrictions, positioning it as a convenient, high‑efficacy oral GLP‑1 option for patients and clinicians.

Dr. Kenneth Custer, executive vice president and president of Lilly Cardiometabolic Health, emphasized that orforglipron offers greater glycemic control, more weight loss, and the practical advantage of being taken without food or water‑timing restrictions—attributes that may significantly improve adherence and daily disease management for people with type 2 diabetes.

ACHIEVE‑3 Trial

ACHIEVE‑3 (NCT06045221) is a 52‑week, randomized, open‑label Phase 3 trial that enrolled 1,698 adults with type 2 diabetes inadequately controlled on metformin across the U.S., Argentina, China, Japan, Mexico, and Puerto Rico. Participants were randomized 1:1:1:1 to receive oral semaglutide 7 mg, oral semaglutide 14 mg, orforglipron 12 mg, or orforglipron 36 mg, with both agents titrated in a step‑wise fashion and efficacy data summarized under both efficacy and treatment‑regimen estimand.

Results

Using the efficacy estimand at week 52, ACHIEVE‑3 showed that orforglipron produced significantly greater HbA1c reductions than oral semaglutide. In the semaglutide arms, mean HbA1c declines were −1.1% with 7 mg and −1.4% with 14 mg, whereas orforglipron 12 mg lowered HbA1c by −1.9% and orforglipron 36 mg by −2.2%; all differences were p<0.001 versus semaglutide 7 mg, with orforglipron 36 mg also p<0.001 versus semaglutide 14 mg.

In terms of weight change, baseline body weight averaged 97.0 kg (213.9 lb). Oral semaglutide reduced weight by −3.7% (−3.6 kg; −7.9 lb) with 7 mg and −5.3% (−5.0 kg; −11.0 lb) with 14 mg, while orforglipron 12 mg reduced weight by −6.7% (−6.6 kg; −14.6 lb) and orforglipron 36 mg by −9.2% (−8.9 kg; −19.7 lb), again with multiple statistically significant differences versus both semaglutide doses.

Improvements in HbA1c and weight with orforglipron were evident as early as four weeks and were sustained through week 52, and orforglipron also achieved higher proportions of participants reaching stringent glycemic targets, including HbA1c <7% and HbA1c ≤6.5%, compared with both oral semaglutide doses.

Safety Profile

Orforglipron’s safety and tolerability profile in ACHIEVE‑3 was consistent with prior GLP‑1 trials and with the class‑typical gastrointestinal adverse events seen with oral semaglutide. The most commonly reported adverse events across all arms orforglipron 12 mg, orforglipron 36 mg, oral semaglutide 7 mg, and oral semaglutide 14 mg were nausea, diarrhea, vomiting, dyspepsia, and decreased appetite, which were generally mild to moderate in severity. Treatment‑emergent discontinuation rates due to adverse events were 8.7% with orforglipron 12 mg and 9.7% with orforglipron 36 mg, compared with 4.5% with oral semaglutide 7 mg and 4.9% with oral semaglutide 14 mg.

These findings indicate that orforglipron delivers greater efficacy than oral semaglutide but is associated with a modestly higher rate of discontinuation, largely driven by gastrointestinal‑related tolerability issues.

Dr. Julio Rosenstock, lead investigator and clinical professor of medicine at the University of Texas Southwestern Medical Center, noted that ACHIEVE‑3 provides the first head‑to‑head comparison of two oral GLP‑1 agents and that the differences in HbA1c and weight loss were clinically meaningful, with improvements apparent as early as four weeks.

About Orforglipron

Orforglipron is an investigational, once‑daily, small‑molecule (non‑peptide) oral GLP‑1 receptor agonist discovered by Chugai Pharmaceutical and licensed by Lilly in 2018. It binds to the GLP‑1 receptor and activates downstream signaling pathways that enhance glucose‑dependent insulin secretion, suppress glucagon release, slow gastric emptying, and reduce appetite effects that collectively lower blood glucose and body weight. As a small‑molecule agent, orforglipron does not require reconstitution or parenteral administration and is formulated for oral ingestion without the strict fasting or water‑timing restrictions required for oral semaglutide, potentially improving real‑world dosing convenience and adherence.

In addition to its benefits in type 2 diabetes, orforglipron has demonstrated that it can help adults with obesity or overweight maintain clinically meaningful weight loss after switching from injectable incretin therapies in the Phase 3 ATTAIN‑MAINTAIN trial.

Eli Lilly has submitted orforglipron to regulatory authorities in more than 40 countries and indicates that a U.S. application for use in type 2 diabetes is planned later this year, while regulatory action for obesity indications is anticipated in the second quarter of 2026.

References

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, 26 February 2026, 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 | Eli Lilly and Company

Rosenstock, JulioManghi, Federico Perez 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, Volume 0, Issue 0, https://doi.org/10.1016/S0140-6736(26)00202-3

A Study of Orforglipron (LY3502970) Compared with Semaglutide in Participants with Type 2 Diabetes Inadequately Controlled with Metformin (ACHIEVE-3), ClinicalTrials.gov ID NCT06045221, https://clinicaltrials.gov/study/NCT06045221