ACHIEVE-1: Oral GLP-1 Agonist Orforglipron Shows Strong HbA1c, Weight Reductions

Results of the ACHIEVE-1 trial suggest orforglipron could be the next game-changing GLP-1 receptor agonist to make waves in healthcare.

An oral, small molecule, nonpeptide GLP-1 receptor agonist from Eli Lilly and Company, the ACHIEVE-1 trial demonstrated orforglipron was associated with significant improvements in glycemic control, body weight, and other biomarkers among patients with type 2 diabetes, even among those with overweight or obesity.1

"The ACHIEVE-1 trial demonstrated that orforglipron, a novel oral small-molecule GLP-1, achieved clinically meaningful reductions in A1C and body weight over 40 weeks in adults with type 2 diabetes," said lead investigator Julio Rosenstock, MD senior scientific advisor for Velocity Clinical Research at Medical City Dallas, clinical professor of medicine, University of Texas Southwestern Medical Center.2 "The early onset of glycemic improvement, observed as soon as four weeks, reinforces the therapeutic potential of orforglipron as an effective, oral GLP-1 therapy for early type 2 diabetes treatment. These findings support further investigation in broader populations and longer-duration studies."

The revelations of GLP-1 receptor agonist therapies have captivated the medical community for nearly a decade and gripped public consciousness in recent years. A leader in this surge has been Eli Lilly and Company, with tirzepatide becoming one of the popular agents for type 2 diabetes and obesity management since its initial approval in 2022. According to reports, the diabetes formulation of tirzepatide (Mounjaro) brought in $3.84 billion in Q1 2025 while the weight loss formulation (Zepbound) brought in $2.31 billion.3

In April 2025, Eli Lilly and Company announced topline results from the ACHEIVE-1 trial of orforglipron in type 2 diabetes and full results were presented at the 85th Scientific Sessions of the American Diabetes Association (ADA 2025).1,2,4

A phase 3 trial, the study leveraged a 40-week, randomized, double-blind, placebo-controlled design and sought to evaluate the efficacy and safety of orforglipron 3 mg, 12 mg, and 36 mg as monotherapy against placebo. For inclusion in the trial, patients needed to have type 2 diabetes treated only with diet and exercise, an HbA1c of at least 7% but no greater than 9.5%, and a BMI of at least 23.0 kg/m2.1

The trial randomized 559 participants in a 1:1:1:1 ratio to the aforementioned treatment groups for 40 weeks, with the primary endpoint of interest being the change from baseline to week 40 in HbA1c. Secondary endpoints of interest included percent change in body weight from baseline to week 40 as well as changes in other biomarkers, including fasting serum glucose and triglycerides.1

At baseline, the study population had a mean duration of type 2 diabetes of 4.4 years, a mean HbA1c of 8.0%, mean body weight of 90.2 kg. Investigators noted 48.1% of the participants were women and 38.3% had previously received a glucose-lowering agent. Investigators also pointed out, 94.1% of participants completed the trial and 90.2% continued to receive orforglipron or placebo throughout the 40-week trial period.1

Trial results demonstrated all 3 doses of orforglipron significantly reduced HbA1c at 40 weeks relative to placebo. The orforglipron 3 mg group achieved a mean HbA1c reduction of 1.24 percentage points from baseline, while the 12 mg and 36 mg groups saw reductions of 1.47 and 1.48 percentage points, respectively. In contrast, the placebo group experienced only a 0.41 percentage point reduction.1

The estimated differences relative to placebo were –0.83 percentage points for 3 mg (95% CI, –1.10 to –0.56), –1.06 for 12 mg (95% CI, –1.33 to –0.79), and –1.07 for 36 mg (95% CI, –1.33 to –0.81), with all comparisons reaching statistical significance (P < 0.001). At week 40, mean A1C levels across the orforglipron groups ranged from 6.5% to 6.7%, which investigators purport indicates substantial glycemic control.1

Secondary outcome analysis suggested participants on orforglipron also experienced significant dose-dependent reductions in body weight. Among the 3 mg group, participants lost an average of 4.5% of their baseline weight, while the 12 mg and 36 mg groups lost 5.8% and 7.6%, respectively. In contrast, the placebo group lost only 1.7%. Investigators also pointed out significant reductions were observed from baseline to week 40 for fasting serum glucose, triglyceride levels, and non-HDL-cholesterol.1

Safety data suggested the most common adverse events were mild-to-moderate gastrointestinal events and most of these occurred during dose escalation. Investigators noted there were no episodes of severe hypoglycemia reported during the trial and permanent discontinuation of orforglipron or placebo due to adverse events occurred in 4.4% to 7.8% of participants receiving orforglipron and 1.4% of participants receiving placebo.1

"This convenient once-daily pill with no restrictions on food and water intake could be an option for millions of people with type 2 diabetes who prefer oral medications over injectables," said Jeff Emmick, M.D., Ph.D., senior vice president of product development at Lilly.2 "The positive ACHIEVE-1 results position orforglipron as a potential treatment option with meaningful A1C and weight reduction, and a safety profile similar to injectable GLP-1 therapies."

References:

1. Rosenstock J, Hsia S, Nevarez Ruiz L. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes. The New England Journal of Medicine. Published online June 21, 2025. doi: 10.1056/NEJMoa2505669
2. Eli Lilly and Company. Lilly’s oral GLP-1, orforglipron, showed compelling efficacy and a safety profile consistent with injectable GLP-1 medicines, in complete Phase 3 results published in The New England Journal of Medicine | Eli Lilly and Company. Eli Lilly and Company. Published June 21, 2025. Accessed June 21, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-showed-compelling-efficacy-and
3. Armstrong A. Lilly’s Revenue Leaps 45% Thanks to Zepbound, Mounjaro, Of Course. BioSpace. Published May 1, 2025. Accessed June 21, 2025. https://www.biospace.com/business/lillys-revenue-leaps-45-thanks-to-zepbound-mounjaro-of-course
4. Eli Lilly and Company. Lilly’s oral GLP-1, orforglipron, demonstrated statistically significant efficacy results and a safety profile consistent with injectable GLP-1 medicines in successful Phase 3 trial | Eli Lilly and Company. Eli Lilly and Company. Published April 17, 2025. Accessed June 21, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-demonstrated-statistically