Eli Lilly’s Orforglipron Shows Superior Efficacy Across Multiple Phase III Trials in Type 2 Diabetes

Eli Lilly has announced positive results from the Phase III ACHIEVE-2 (NCT06192108) and ACHIEVE-5 (NCT06109311) clinical trials of orforglipron, an oral GLP-1. Across two patient populations with type 2 diabetes, orforglipron met its primary and all key secondary endpoints at 40 weeks. The GLP-1 demonstrated significant A1C reduction and weight loss along with improvements in multiple cardiovascular risk factors.¹

ACHIEVE-2 assessed orforglipron versus AstraZeneca’s SGLT-2 inhibitor, dapagliflozin, in adults with type 2 diabetes inadequately controlled on metformin. The ACHIEVE-5 study evaluated orforglipron versus placebo in participants with type 2 diabetes and inadequate glycemic control with titrated insulin glargine, with or without metformin and/or SGLT-2 inhibitors.

In a press release, Jeff Emmick, MD, PhD, senior vice president of product development, Lilly Cardiometabolic Health, said: "Orforglipron has now demonstrated superiority over two active comparators in clinical trials for type 2 diabetes. In ACHIEVE-2, orforglipron outperformed dapagliflozin, a commonly used SGLT-2 therapy, and in ACHIEVE-3, showed greater efficacy than oral semaglutide. The findings from ACHIEVE-5 add to this momentum, showing significant A1C reduction and weight loss when used in combination with titrated basal insulin. Together, these results reinforce orforglipron's potential to become a new standard of care for people living with type 2 diabetes."

Study design and key endpoints

ACHIEVE-2 and ACHIEVE-5, both part of Lilly’s Phase III ACHIEVE global clinical development program for orforglipron, are 40-week, randomized trials.

• ACHIEVE-2 is an open-label study comparing orforglipron (3, 12, or 36mg) with dapagliflozin 10mg in 962 adults with type 2 diabetes inadequately controlled on metformin. The goal was to demonstrate non-inferiority in A1C reduction after 40 weeks. Participants (A1C 7.0–10.5%, BMI ≥23 kg/m²) started at 1mg orforglipron, titrated every four weeks to target dose.
• ACHIEVE-5 is a double-blind, placebo-controlled study in 546 adults with type 2 diabetes inadequately controlled on insulin glargine ± metformin/SGLT2 inhibitors. Participants were randomized to orforglipron (3, 12, or 36mg) or placebo, with dose titration every four weeks. The goal was to show superiority in A1C reduction versus placebo after 40 weeks.

Previous results strengthen orforglipron’s clinical profile

Last month, Lilly revealed trial data that showed orforglipron outperformed Novo Nordisk’s semaglutide. In the open-label, randomized Phase III ACHIEVE-3 (NCT06045221) trial, orforglipron again met all primary and key secondary endpoints, demonstrating greater improvements in A1C and weight versus oral semaglutide.2

Detailed results from the study showed:

• Orforglipron achieved greater A1C reduction than oral semaglutide at 52 weeks: –1.9% (12mg) and –2.2% (36mg) vs. –1.1% (7mg) and –1.4% (14mg), meeting the study’s primary endpoint.
• At the highest doses, 37.1% of participants on orforglipron achieved A1C < 5.7% compared with 12.5% on oral semaglutide.
• Orforglipron also produced superior weight loss: –14.6 lbs (6.7%) and –19.7 lbs (9.2%) vs. –7.9 lbs (3.7%) and –11.0 lbs (5.3%) with semaglutide.
• Clinically meaningful improvements were also observed in non-HDL cholesterol, systolic blood pressure, and triglycerides.

Global ACHIEVE program and ACHIEVE-3 design

ACHIEVE-3 is also part of Lilly’s ACHIEVE program, which has enrolled over 6,000 participants with type 2 diabetes across five global registration trials since its inception in 2023. Lilly expects to keep receiving data from the program throughout the rest of this year and into 2026.

• ACHIEVE-3 is a 52-week, open-label trial comparing orforglipron with oral semaglutide in adults with type 2 diabetes inadequately controlled on metformin.
• The study enrolled 1,698 participants across the US, Argentina, China, Japan, Mexico, and Puerto Rico, randomized 1:1:1:1 to orforglipron at four different doses.
• Participants began at low doses and escalated every four weeks to their assigned maintenance dose; one step-down for tolerability was permitted (minimum orforglipron 3mg or semaglutide 7mg).

References

1. Lilly's oral GLP-1, orforglipron, demonstrated superior glycemic control in two successful Phase 3 trials, reconfirming its potential as a foundational treatment in type 2 diabetes. News release. Eli Lilly. October 15, 2025. Accessed October 15, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-demonstrated-superior-glycemic

2. Lilly's oral GLP-1, orforglipron, superior to oral semaglutide in head-to-head trial. News release. Eli Lilly. September 17, 2025. Accessed October 15, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-superior-oral-semaglutide-head