Eli Lilly and Company has announced positive topline results from the Phase 3 ACHIEVE-2 and ACHIEVE-5 trials evaluating orforglipron for the treatment of type 2 diabetes.

Orforglipron is an investigational, once-daily small molecule (non-peptide) oral glucagon-like peptide-1 (GLP-1) receptor agonist that can be taken any time of the day without restrictions on food and water intake. The molecule was discovered by Chugai Pharmaceutical and licensed to Lilly in 2018, with preclinical pharmacology data jointly published by both companies.

Lilly is running Phase 3 studies of orforglipron for type 2 diabetes as well as for weight management in adults with obesity or overweight with at least one weight-related comorbidity. The molecule is also being investigated as a potential treatment for obstructive sleep apnea, hypertension, and osteoarthritis pain in adults with obesity. 

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

In both trials, orforglipron (3 mg, 12 mg, 36 mg) met the primary and all key secondary endpoints at 40 weeks for both the efficacy and treatment-regimen estimands, delivering significant A1C reduction and weight loss as well as improvements in multiple cardiovascular risk factors, all consistent with previously disclosed studies in type 2 diabetes.

"Orforglipron has now demonstrated superiority over two active comparators in clinical trials for type 2 diabetes," said Jeff Emmick, senior vice president of product development, Lilly Cardiometabolic Health.

He explained, "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."

The ACHIEVE Phase 3 global clinical development programme has enrolled more than 6,000 people with type 2 diabetes across five global registration trials, which began in 2023. Results of ACHIEVE-4—the final global registration trial—are expected in the first quarter of 2026

Lilly plans to submit orforglipron for the treatment of type 2 diabetes to global regulatory agencies in 2026, while submission for the treatment of obesity is anticipated by the end of this year.