Oral GLP-1 Orforglipron Hits Target in Phase 3 Diabetes Trial

Topline results from the ACHIEVE-1 trial show that oral orforglipron, a once-daily glucagon-like peptide-1 (GLP-1) receptor agonist, is effective and safe for adults with type 2 diabetes (T2D) inadequately controlled by diet and exercise.1

Announced by Eli Lilly and Company on April 17, 2025, orforglipron achieved statistically significant reductions in hemoglobin A1c and body weight in the Phase 3 trial, while its safety profile remained consistent with the primarily injectable therapies from the drug class.

“ACHIEVE-1 is the first of seven Phase 3 studies examining the safety and efficacy of orforglipron across people with diabetes and obesity,” said David A. Ricks, chair and chief executive officer of Lilly. “We are pleased to see that our latest incretin medicine meets our expectations for safety and tolerability, glucose control and weight loss, and we look forward to additional data readouts later this year.”1

ACHIEVE-1 was a 40-week, randomized, double-blind, placebo-controlled trial measuring the efficacy and safety of orforglipron 3 mg, 12 mg and 36 mg as monotherapy against placebo, randomizing 559 participants in a 1:1:1:1 ratio. The trial intended to determine the superiority of orforglipron in A1c reduction from baseline after 40 weeks in individuals with T2D who are naive to insulin therapy and have not taken anti-diabetic medications in ≥90 days before the initial study visit.

Analyses showed the daily oral GLP-1 met the primary endpoint, lowering A1c by an average of 1.3–1.6% from a baseline of 8.0% using the efficacy estimand. A key secondary endpoint found more than 65% of individuals on the highest dose of orforglipron achieved A1c ≤6.5%, below the American Diabetes Association’s (ADA) threshold for diabetes.

Individuals also experienced an average weight loss of 16.0 lbs (7.9%) at the highest dose of orforglipron. Lily noted the participants did not reach a weight plateau when the study ended, suggesting full weight reduction has not been attained.

Further analysis for the treatment-regimen estimand showed statistically significant A1c reductions across each dose of orforglipron, with 12 mg and 36 mg doses also showing statistically significant reductions in body weight.

Data from ACHIEVE-1 showed orforglipron achieved reductions in A1c of 1.2-1.5% versus 0.4% for placebo, and percent weight reductions of 4.5-7.6% versus 1.7% for placebo across each dose. Weight reduction ranged from 4.2-7.2 kg versus 1.5 kg for placebo.

Safety remained consistent with the established profile of GLP-1s, with the most commonly reported adverse events being gastrointestinal-related and generally mild to moderate in severity. Based on dose, the most common adverse events for orforglipron were diarrhea (19-26%), nausea (13-18%), dyspepsia (10-20%), constipation (8-17%), and vomiting (5-14%).

No hepatic safety signals were identified in ACHIEVE-1, but treatment discontinuation rates due to adverse events were 6% (3 mg), 4% (12 mg), and 8% (36 mg) for orforglipron versus 1% with placebo

Lilly indicated orforglipron marked the first oral small molecule GLP-1 RA taken without food and water restrictions to successfully complete a Phase 3 trial. The company will present results from ACHIEVE-1 at the ADA’s 85th Scientific Sessions and share further results from the Phase 3 clinical trial program later this year, including data evaluating orforglipron for weight management.

In the phase 2 weight management trial, presented at the ADA's 83rd Scientific Sessions, use of orforglipron was associated with a mean reduction in body weight up to 14.7% at 36 weeks.2

Lilly also announced its intention to submit orforglipron for weight management to global regulatory agencies by the end of 2025, with further submission for the treatment of T2D expected in 2026. Pending approval, the company indicated its confidence in launching orforglipron worldwide without supply constraints.1

Recent shortages have affected other blockbuster weight loss products, including semaglutide injection (Ozempic) and semaglutide injection 2.4 mg (Wegovy). The US Food and Drug Administration (FDA) deemed the shortage over in February 2025.3

“As a convenient once-daily pill, orforglipron may provide a new option and, if approved, could be readily manufactured and launched at scale for use by people around the world,” Ricks added.1

References

1. 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. April 17, 2025. Accessed April 17, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-demonstrated-statistically.

2. Campbell P. Orforglipron shows promise as weight loss, diabetes agent in phase 2 trials. HCP Live. June 24, 2023. Accessed April 17, 2025. https://www.hcplive.com/view/orforglipron-shows-promise-as-weight-loss-diabetes-agent-in-phase-2-trials.

3. Iapoce C. FDA announces end to shortage of semaglutide products (Ozempic, Wegovy). HCP Live. February 21, 2025. Accessed April 17, 2025. https://www.hcplive.com/view/fda-announces-end-to-shortage-of-semaglutide-products-ozempic-wegovy-.