Eli Lilly’s Oral Diabetes Drug Shows Promise in Phase 3 Trial

Eli Lilly reports positive topline results from a Phase 3 clinical trial of orforglipron, its investigational once-daily oral medication for adults with type 2 diabetes who are not achieving glycemic control with diet and exercise alone.

Orforglipron, a non-peptide GLP-1 receptor agonist, is the first in its class to complete a Phase 3 study and demonstrated significant improvements in blood glucose control and weight reduction compared to placebo, reports Eli Lilly. According to Eli Lilly, the treatment could provide an alternative for patients seeking a non-injectable therapy without dietary restrictions, pending regulatory approval.

The ACHIEVE-1 study is the first of seven global trials evaluating orforglipron in people with diabetes and obesity. The study randomized 559 adults across the United States, China, India, Japan, and Mexico to receive daily doses of 3mg, 12mg or 36mg of orforglipron or a placebo for 40 weeks. Participants had a starting A1C between 7.0% and 9.5% and a body mass index (BMI) of 23kg/m² or higher. None had taken anti-diabetic medications for at least 90 days prior to enrollment.

In the trial, orforglipron met its primary endpoint by lowering A1C by an average of 1.3% to 1.6% depending on dose, compared to a 0.1% reduction in the placebo group. The most pronounced A1C reductions were seen with the 12mg and 36mg doses. Additionally, over 65% of participants receiving the highest dose achieved an A1C at or below 6.5%, which falls within the American Diabetes Association's target range.

The therapy also showed benefits in weight reduction. At the highest dose, participants lost an average of 16 pounds, or 7.9% of their starting body weight. Weight loss did not plateau by the end of the study period, suggesting potential for further loss with continued treatment.

Eli Lilly reports that the overall safety profile of orforglipron was in line with the GLP-1 class. The most common side effects were gastrointestinal, including diarrhea, nausea, dyspepsia, constipation, and vomiting. Adverse events were generally mild to moderate. Discontinuation due to side effects ranged from 4% to 8% across dosage levels, compared to 1% with placebo. No liver safety issues were observed.

The results will be presented at the American Diabetes Association’s 85th Scientific Sessions and published in a peer-reviewed journal. Eli Lilly plans to submit orforglipron for weight management to global regulators by the end of 2025 and for type 2 diabetes treatment by 2026.

Orforglipron was discovered by Chugai Pharmaceutical and licensed by Eli Lilly in 2018. The company is conducting a broader Phase 3 program for orforglipron, including the ACHIEVE and ATTAIN trials, which in total have enrolled more than 6,000 participants. The drug is also being studied for potential use in weight-related conditions such as obstructive sleep apnea and hypertension.

If approved, Eli Lilly says it is prepared to scale up manufacturing and global distribution without supply constraints. This capability could allow the company to meet growing demand for diabetes and obesity treatments as the global burden of type 2 diabetes is projected to reach 760 million adults by 2050.