Eli Lilly and Company (LLY) announced detailed results from three Phase 3 trials, dubbed ACHIEVE-2, ACHIEVE-3, and ACHIEVE-5, evaluating Orforglipron, or Foundayo, in participants with type 2 diabetes.
Orforglipron demonstrated strong reductions in HbA1C (A1C) and weight loss across studies, but was also associated with higher discontinuation rates due to gastrointestinal side effects.
Orforglipron
Orforglipron or Foundayo is an once-daily small molecule (non-peptide) oral glucagon-like peptide-1 or GLP-1 receptor agonist. Orforglipron was discovered by Chugai Pharmaceutical Co., Ltd. and licensed by Lilly in 2018.
In April 2026, Foundayo was approved by the FDA for use in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain long-term weight reduction in adults with obesity or overweight in the presence of at least one weight-related comorbid condition.
Trial details
ACHIEVE-2: A Phase 3, 40-week, randomised, active-controlled, open-label study comparing the efficacy and safety of Orforglipron 2.5 mg, 9 mg and 17.2 mg to dapagliflozin 10 mg in 962 participants with type 2 diabetes and inadequate glycemic control with metformin.
The objective of the study was to demonstrate that Foundayo is non-inferior to Dapagliflozin in reducing A1C from baseline after 40 weeks.
ACHIEVE-3: A Phase 3, 52-week, randomised, open-label trial evaluating the efficacy and safety of Orforglipron in 1,698 participants across the U.S., Argentina, China, Japan, Mexico and Puerto Rico to receive either 9 mg or 17.2 mg Orforglipron compared with 7 mg or 14 mg of oral semaglutide in adults with type 2 diabetes inadequately controlled with metformin.
The primary objective of the study was to demonstrate that Orforglipron is non-inferior to oral semaglutide for A1C reduction from baseline after 52 weeks, when comparing the lower and higher doses. ACHIEVE-5: A Phase 3, 40-week, randomised, double-blind, placebo-controlled study assessing the efficacy and safety of Orforglipron 2.5 mg, 9 mg and 17.2 mg in 546 participants with type 2 diabetes and inadequate glycemic control with insulin glargine, with or without metformin and/or SGLT-2 inhibitors.
The primary goal of the study was to demonstrate a reduction in A1C from baseline after 40 weeks with Orforglipron compared with placebo. Study participants had an A1C greater than or equal to 7.0% and less than or equal to 10.5% and a BMI greater than or equal to 23 kg/m2.
Key findings
ACHIEVE-2
In ACHIEVE-2, Orforglipron delivered superior results, lowering A1C by an average of 1.7% at 40 weeks, compared with 0.8% with dapagliflozin, from an average baseline of 8.1%.
ACHIEVE-3
In ACHIEVE-3, Orforglipron lowered A1C by an average of 1.9% at 9 mg and 2.2% at 17.2 mg compared to 1.1% at 7 mg and 1.4% at 14 mg with oral semaglutide at 52 weeks.In Achieve 3 Orforglipron, 17.2 mg achieved a 57.1% greater relative reduction in A1C and a 73.6% greater relative weight loss compared to oral semaglutide 14 mg.
ACHIEVE-5
Orforglipron lowered A1C by up to an average of 2.1% at 40 weeks, compared with 0.8% with placebo at 40 weeks , demonstrating significant improvements.
In ACHIEVE-2 and ACHIEVE-5, Orforglipron delivered significant improvements in blood sugar and weight, with up to 68.6% and 69.1% of participants reaching an A1C goal of less than or equal to 6.5%, respectively.
In addition, the company noted that across all three trials, Orforglipron showed clinical improvements from baseline in key cardiovascular risk factors.
Safety Concerns and Treatment Discontinuations
According to the firm, across the three trials, the most common adverse events were gastrointestinal, including nausea, diarrhoea, vomiting, dyspepsia and decreased appetite.
In ACHIEVE-3, treatment discontinuation rates due to adverse events were 8.7% and 9.7% with Orforglipron 9 mg and 17.2 mg, vs 4.5% and 4.9% with oral Semaglutide.
In ACHIEVE-2, treatment discontinuations were observed at 2.5 mg, 9 mg, and 17.2 mg of Orforglipron, at 9.2%, 10.8%, and 12.4%, respectively, compared with 1.2% with Dapagliflozin.
In ACHIEVE-5, 3.6%, 7.6%, and 9.6% treatment discontinuations with 2.5 mg, 9 mg, and 17.2 mg of Orforglipron were recorded compared to 3.6% with placebo.
The data were presented at the American Diabetes Association (ADA) 86th Scientific Sessions.
Based on the results, Lilly plans to submit Orforglipron for the treatment of type 2 diabetes to the U.S. FDA by the end of the second quarter of 2026.
LLY has traded between $623.78 and $1,182.73 over the last year. The stock closed Monday's trade at $1149.15, up 1.57%.
In the pre-market, LLY is up 1.05% to $1,160.08.
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