Lilly's Oral Small-Molecule GLP-1RA Orforglipron Demonstrates Significant Efficacy in Phase 3 ACHIEVE-1 Trial, Presented at ADA 2025
Eli Lilly
Global Pharmaceutical R&D and Production Company
In all dose groups, the investigational drug orforglipron achieved an average reduction of 1.3% to 1.6% in A1C for adults with type 2 diabetes when administered orally once daily, with improvements observed as early as four weeks after starting the medication.
A key secondary endpoint of the ACHIEVE-1 study showed that the highest dose group of orforglipron achieved an average weight loss of 7.3 kg (7.9%) at Week 40.
Orforglipron's safety is consistent with the GLP-1RA class of drugs.
On June 21, 2025, Eli Lilly and Company announced detailed results from the Phase 3 clinical study ACHIEVE-1. This study evaluated the efficacy and safety of orforglipron compared to placebo in adult patients with type 2 diabetes whose blood glucose remained inadequately controlled despite dietary management and exercise. Orforglipron is the first oral small-molecule (non-peptide) glucagon-like peptide-1 receptor agonist (GLP-1RA) to successfully complete a Phase 3 study without restrictions on diet or water intake. At week 40, all three dose groups of orforglipron (3mg, 12mg, 36mg) achieved the primary endpoint of significantly reducing A1C. Additionally, the 12mg and 36mg dose groups of orforglipron demonstrated clinically and statistically significant weight loss compared to placebo. In this study, the overall safety profile of orforglipron was consistent with GLP-1RA class drugs, with gastrointestinal reactions being the most common adverse event. The study results were presented at the 85th Scientific Sessions of the American Diabetes Association (ADA) in 2025 and simultaneously published in The New England Journal of Medicine.
Statement:
1. Orforglipron is an investigational drug and has not been approved in China.
2. Eli Lilly does not recommend the use of any unapproved drugs/indications.
In the study, orforglipron met the primary endpoint, with a significant reduction in glycated hemoglobin (A1C) compared to the placebo group at 40 weeks. The A1C decreased by 1.3% to 1.6% from a baseline of 8.0% (using the efficacy estimand).1。For the key secondary endpoint, after receiving orforglipron treatment, up to 76.2% of patients achieved A1C <7%, meeting the American Diabetes Association (ADA) treatment target; 66% of patients reached A1C ≤6.5%; and 25.8% of patients achieved A1C <5.7%, which is considered a normal A1C value.2,3Improvement in A1C was observed as early as four weeks after the start of treatment, accompanied by a corresponding decrease in fasting blood glucose. Patients in the highest dose group experienced an average weight loss of 7.3 kg (7.9%). Participants had not yet reached a weight plateau by the end of the study, and ongoing long-term studies, such as the ATTAIN series, will provide comprehensive evaluations of the safety and efficacy of orforglipron in obesity treatment.
Principal Investigator, Senior Scientific Advisor at Velocity Clinical Research Center of Dallas Urban Medicine, and Clinical Professor of Medicine at the University of Texas Southwestern Medical Center, Dr. Julio RosenstockIndicates:
The ACHIEVE-1 study showed that this new oral small-molecule GLP-1RA drug can bring clinically significant reductions in A1C and weight for adult patients with type 2 diabetes within 40 weeks. Improvement in blood glucose was observed as early as 4 weeks into the treatment, demonstrating the potential of orforglipron as an effective oral GLP-1RA drug in the early treatment of type 2 diabetes. The results of this study support further research on orforglipron in broader populations and over longer durations.
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i The superiority test is corrected using a multiplicity adjustment method.
ii The full data list of key secondary endpoints can be found in the published article.
iii In all dose groups of orforglipron, the proportion of patients achieving A1C <5.7% and the weight loss endpoint in the 3mg orforglipron dose group were not controlled for Type I error.
Jeff Emmick, Ph.D., Senior Vice President of Product Development at Eli Lilly and CompanyIndicates:
This once-daily oral medication is convenient to take, with no restrictions on diet or water intake. For millions of type 2 diabetes patients who prefer oral medications over injectables, orforglipron is expected to offer a new treatment option. The recently announced positive results from the ACHIEVE-1 study indicate that orforglipron significantly reduces A1C and body weight, with a safety profile consistent with injectable GLP-1RA drugs. Additionally, data from four other global studies in the ACHIEVE program, as well as results from two ATTAIN studies focused on weight management, are highly anticipated. Meanwhile, we are working closely with regulatory authorities, hoping this once-daily oral GLP-1RA drug will soon benefit patients worldwide.
In the ACHIEVE-1 study, the overall safety profile of orforglipron was consistent with GLP-1RA class drugs. The most common adverse events in patients receiving orforglipron (3mg, 12mg, and 36mg) were as follows: diarrhea (19%, 21%, and 26%) vs. 9% in the placebo group; nausea (13%, 18%, and 16%) vs. 2% in the placebo group; dyspepsia (11%, 20%, and 15%) vs. 7% in the placebo group; constipation (8%, 17%, and 14%) vs. 4% in the placebo group; vomiting (5%, 7%, and 14%) vs. 1% in the placebo group. These gastrointestinal adverse reactions were generally mild to moderate and primarily occurred during the dose escalation period. The overall treatment discontinuation rates due to adverse events were 6% in the 3mg group, 4% in the 12mg group, 8% in the 36mg group, and 1% in the placebo group. No liver safety signals were observed.
Eli Lilly is expected to release top-line results from two studies by the end of this year: the ACHIEVE-2 study comparing orforglipron with dapagliflozin, and the ACHIEVE-3 study evaluating orforglipron against oral semaglutide. Both studies target adult patients with type 2 diabetes whose blood sugar remains inadequately controlled despite metformin treatment. Top-line results from the ATTAIN-1 and ATTAIN-2 studies assessing orforglipron for weight management are also anticipated to be released in the third quarter of this year. Eli Lilly plans to submit a marketing application for orforglipron for weight management to global regulatory authorities by the end of this year, with an additional application for the treatment of type 2 diabetes expected in 2026.
Orforglipron is an investigational, once-daily oral small molecule (non-peptide) glucagon-like peptide-1 receptor agonist (GLP-1 RA). The medication can be taken at any time of the day without restrictions on diet or water intake.5The drug was discovered by Chugai Pharmaceutical Co., Ltd. and licensed to Eli Lilly and Company for development in 2018. Chugai Pharmaceutical Co., Ltd. and Eli Lilly and Company jointly published the preclinical pharmacology data of this molecule.6Currently, Eli Lilly and Company is conducting Phase 3 trials of orforglipron for the treatment of type 2 diabetes and for weight management in overweight adults with obesity or at least one weight-related comorbidity. In addition, Eli Lilly and Company is also investigating orforglipron as a potential therapy for obstructive sleep apnea and hypertension in adults with obesity.
ACHIEVE-1 (NCT05971940) is a 40-week, randomized, double-blind, placebo-controlled Phase 3 study designed to compare the efficacy and safety of orforglipron 3mg, 12mg, and 36mg as monotherapy versus placebo in adult patients with type 2 diabetes whose blood glucose levels are inadequately controlled by diet and exercise. The study randomized 559 patients in the United States, China, India, Japan, and Mexico, assigning them in a 1:1:1:1 ratio to receive 3mg, 12mg, or 36mg of orforglipron or placebo. The objective of the study is to demonstrate that treatment with orforglipron (3mg, 12mg, 36mg) for 40 weeks results in a significant reduction in glycated hemoglobin (A1C) levels compared to placebo in patients with type 2 diabetes who have not used any diabetes medications in the 90 days prior to the first visit and have never received insulin therapy. Eligible patients had an A1C range of ≥7.0% to ≤9.5% and a body mass index (BMI) ≥23 kg/m². All patients receiving orforglipron started at a dose of 1mg once daily, with dose escalation every 4 weeks until reaching the final randomized maintenance dose: 3mg (starting from 1mg), 12mg (starting from 1mg, increased to 3mg, then to 6mg), or 36mg (starting from 1mg, increased to 3mg, then to 6mg, 12mg, and 24mg). Flexible dose adjustments were prohibited during the clinical study.
The ACHIEVE Phase 3 global clinical development program for Orforglipron has enrolled more than 6,000 patients with type 2 diabetes in five global registration trials. The program was initiated in 2023, with results expected to be released this year and in 2026.
References
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Eli Lilly and Company is a pharmaceutical company dedicated to improving human health through scientific innovation and benefiting patients worldwide. As a leader in the healthcare industry, Eli Lilly and Company has nearly 150 years of history. Today, our medicines have helped tens of millions of people globally. Harnessing the power of biotechnology, chemistry, and genomic medicine, our scientists are actively advancing new medical breakthroughs to address severe global health challenges. We are redefining therapies for diabetes and obesity, reducing the long-term impact of obesity on the body; supporting prevention and treatment efforts for Alzheimer's disease; providing solutions for a range of immune diseases that threaten human health; and transforming difficult-to-treat cancers into manageable conditions. Every step Eli Lilly and Company takes toward a healthier world is driven by our belief in "making life better for millions of patients." This includes innovative clinical trials aimed at addressing multiple global challenges while ensuring the accessibility and affordability of medicines. For more information about Eli Lilly and Company, please visit: www.lilly.com.cn.
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