Eli Lilly’s Oral Small Molecule Orforglipron Shows Superior Glycemic Control and Weight Loss in Three Phase 3 Studies

In the ACHIEVE-3 study, the orforglipron 17.2 mg group achieved superior reductions in glycated hemoglobin (A1C) and body weight compared to the oral semaglutide 14 mg group, with a 57.1% greater relative reduction in A1C and a 73.6% greater relative reduction in body weight.

In the ACHIEVE-2 and ACHIEVE-5 studies, orforglipron significantly improved glycemic control and reduced body weight, with up to 68.6% and 69.1% of participants, respectively, achieving the treatment target of A1C ≤ 6.5%.

Eli Lilly plans to submit a marketing application for orforglipron for the treatment of type 2 diabetes to the U.S. Food and Drug Administration (FDA) by the end of the second quarter.

ShanghaiJune 9, 2026 /PRNewswire/ — On June 8, 2026, Eli Lilly and Company (whose tirzepatide has been approved for marketing in the U.S.) announced detailed results from three Phase 3 clinical trials in the ACHIEVE series. This series of studies evaluated the efficacy and safety of orforglipron in adult patients with type 2 diabetes. Orforglipron is an oral small molecule (non-peptide) glucagon-like peptide-1 receptor agonist (GLP-1 RA) that can be taken at any time of day without restrictions on food or drink. In the landmark head-to-head study ACHIEVE-3, orforglipron demonstrated superiority over oral semaglutide on the primary endpoint and all key secondary endpoints. In the ACHIEVE-2 and ACHIEVE-5 studies, orforglipron also met its primary and key secondary endpoints, showing superior A1C reduction and weight loss compared to dapagliflozin and placebo added to titrated insulin glargine, respectively^[1],[2]. These study results were presented at the 86th Scientific Sessions of the American Diabetes Association (ADA). Results from the ACHIEVE-3 study were previously published in The Lancet, and results from ACHIEVE-2 and ACHIEVE-5 were published in The Lancet and the Journal of the American Medical Association, respectively.

“ACHIEVE-3 provides the first head-to-head data comparing two oral GLP-1 receptor agonists in adults with type 2 diabetes. The study results showed that orforglipron demonstrated superior reductions in glycated hemoglobin (A1C) and body weight compared to oral semaglutide,” said Dr. Julio Rosenstock, Principal Investigator for ACHIEVE-3 and Clinical Professor of Medicine at the University of Texas Southwestern Medical Center. “These efficacy results were further validated in the ACHIEVE-2 and ACHIEVE-5 studies, where consistent and robust treatment effects were observed across different patient populations. These findings support the potential for earlier use of oral GLP-1 receptor agonists like orforglipron in the treatment of type 2 diabetes and suggest they could become an important foundational therapy in disease management.”

Professor Jia Weiping from Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine stated: “At this ADA conference, the oral small molecule GLP-1 RA orforglipron announced multiple positive results. Its head-to-head study demonstrated orforglipron’s superior competitiveness in glucose lowering and weight reduction compared to existing treatments. For China’s large diabetic population, treatment regimens that are convenient to administer and support early intensive glycemic control are significant for achieving long-term disease management and improving outcomes. Such regimens not only help preserve beta-cell function and maintain long-term glycemic control but also reduce the risk of complications, providing evidence for optimizing current treatment models. Additionally, data from the Chinese population study presented at the conference showed that orforglipron generally performed well in terms of safety, tolerability, pharmacokinetics, and pharmacodynamics, offering important references for its clinical application in the Chinese population.”

The ACHIEVE-3 study is the first and currently only Phase 3 clinical trial to compare two oral GLP-1 receptor agonists head-to-head. In this study, orforglipron 9 mg and 17.2 mg showed greater improvements in glycemic control and weight management compared to oral semaglutide 7 mg and 14 mg^[3]. At Week 52, orforglipron reduced A1C by 1.9% (9 mg) and 2.2% (17.2 mg), respectively, while oral semaglutide reduced it by 1.1% (7 mg) and 1.4% (14 mg); in the highest dose comparison, orforglipron showed a 57.1% greater relative reduction in A1C compared to oral semaglutide. Among participants receiving the highest dose of orforglipron, 37.1% achieved normoglycemia (A1C < 5.7%), compared to 12.5% in the oral semaglutide group. Meanwhile, orforglipron also demonstrated superior effects in weight management. Participants receiving orforglipron had mean body weight reductions of 6.6 kg (6.7%, 9 mg group) and 8.9 kg (9.2%, 17.2 mg group), respectively, while the oral semaglutide groups had mean reductions of 3.6 kg (3.7%, 7 mg group) and 5.0 kg (5.3%, 14 mg group). In the highest dose comparison, orforglipron achieved superior weight loss, with a 73.6% greater relative reduction in body weight compared to oral semaglutide.

ACHIEVE-3 Study Results^[4]

The ACHIEVE-2 study showed that, based on a baseline A1C of 8.1%, at Week 40, orforglipron achieved superior glycemic control compared to dapagliflozin, with a mean A1C reduction of up to 1.7%, compared to a 0.8% reduction in the dapagliflozin group. Among participants receiving the highest dose of orforglipron, up to 68.6% achieved A1C ≤ 6.5% (an important target for stricter glycemic control), compared to 21.6% in the dapagliflozin group. In terms of body weight, participants receiving orforglipron also observed greater reductions, with mean body weight reductions of 3.2 kg (3.5%, 2.5 mg group), 5.8 kg (6.3%, 9 mg group), and 6.8 kg (7.3%, 17.2 mg group), compared to a mean reduction of 2.7 kg (3.0%) in the dapagliflozin group.

In the ACHIEVE-5 study, when added to titrated insulin glargine, orforglipron demonstrated significant improvements in glycemic control and weight management compared to placebo. Based on a mean baseline A1C of 8.5%, at Week 40, orforglipron achieved a mean A1C reduction of up to 2.1%, compared to a 0.8% reduction in the placebo group. Among participants receiving the 9 mg dose of orforglipron, up to 69.1% achieved A1C ≤ 6.5%, compared to 11.1% in the placebo group. Meanwhile, participants receiving orforglipron had mean body weight reductions of 2.2 kg (2.7%, 2.5 mg group), 5.0 kg (5.8%, 9 mg group), and 5.2 kg (6.1%, 17.2 mg group), while the placebo group experienced a mean body weight increase of 0.5 kg (0.6%).

“Across the ACHIEVE clinical program, orforglipron consistently demonstrated positive treatment effects on glycemic control and weight management, further strengthening our confidence in its potential to improve patient outcomes,” said Dr. Thomas Seck, Senior Vice President of Product Development for Cardiometabolic Health at Eli Lilly. “ACHIEVE-3 is the first Phase 3 head-to-head trial comparing two oral GLP-1 receptor agonists, and the results showed that orforglipron was superior to oral semaglutide on key outcome measures most important to people with type 2 diabetes. For the millions of people with type 2 diabetes who prefer a convenient oral treatment option, orforglipron has the potential to become an important first-line therapeutic choice.”

Across the three studies, orforglipron demonstrated clinically meaningful improvements from baseline in several key cardiometabolic risk factors, including non-HDL cholesterol, HDL cholesterol, VLDL cholesterol, total cholesterol, systolic blood pressure, and triglycerides. Additionally, the overall safety, tolerability, and treatment discontinuation rates for orforglipron across the three studies were consistent with previous study results. The most common adverse events were gastrointestinal-related, including nausea, diarrhea, vomiting, dyspepsia, and decreased appetite. In the ACHIEVE-3 study, treatment discontinuation rates due to adverse events were 8.7% and 9.7% for the orforglipron 9 mg and 17.2 mg dose groups, respectively, compared to 4.5% and 4.9% for the oral semaglutide 7 mg and 14 mg dose groups; in the ACHIEVE-2 study, rates were 9.2%, 10.8%, and 12.4% for the orforglipron 2.5 mg, 9 mg, and 17.2 mg dose groups, respectively, compared to 1.2% for the dapagliflozin group; in the ACHIEVE-5 study, rates were 3.6%, 7.6%, and 9.6% for the orforglipron 2.5 mg, 9 mg, and 17.2 mg dose groups, respectively, compared to 3.6% for the placebo group.

Based on the published results from the ACHIEVE studies, including ACHIEVE-1, ACHIEVE-4, and the data announced today, Eli Lilly plans to submit a marketing application for orforglipron for the treatment of type 2 diabetes to the U.S. Food and Drug Administration (FDA) by the end of the second quarter, utilizing the FDA’s “Priority Review Voucher” pathway.

CMAT-35103

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