Lilly’s oral GLP-1 drug orforglipron cuts A1C and body weight in type 2 diabetes Phase 3 trial

Eli Lilly and Company (NYSE: LLY) has released detailed results from its Phase 3 clinical trial ACHIEVE-1, demonstrating that orforglipron—a once-daily oral glucagon-like peptide-1 (GLP-1) receptor agonist—achieved statistically superior reductions in blood glucose and weight compared to placebo in adults with type 2 diabetes. Presented at the 85th Scientific Sessions of the American Diabetes Association and simultaneously published in The New England Journal of Medicine, the study results position orforglipron as a potential first-in-class oral, non-peptide GLP-1 drug capable of offering the benefits of injectable therapies in a pill form.

Orforglipron is part of Lilly’s broader strategy to expand its diabetes and obesity treatment portfolio with convenient, patient-friendly alternatives. This innovation may represent a game-changing option for patients unable or unwilling to use injectable GLP-1 treatments such as semaglutide or liraglutide.

What are the latest Phase 3 trial results showing about orforglipron’s A1C and weight loss effects?

In the randomized, double-blind, placebo-controlled trial ACHIEVE-1, involving 559 adults with type 2 diabetes inadequately controlled through diet and exercise, orforglipron significantly lowered glycated hemoglobin (A1C) levels from a baseline of 8.0%. Over a 40-week period, all three doses—3 mg, 12 mg, and 36 mg—achieved average A1C reductions between 1.3% and 1.6%, compared to only 0.1% for placebo. The onset of glycemic improvement was observed as early as four weeks, and participants also experienced reductions in fasting serum glucose.

The trial also delivered positive weight loss outcomes, which served as a key secondary endpoint. Participants on the highest dose of orforglipron lost an average of 16.0 pounds (7.9% of baseline weight), while lower doses produced clinically meaningful reductions ranging from 9.7 to 12.2 pounds. Importantly, the study did not observe a weight loss plateau during the 40-week period, suggesting sustained benefits over longer durations may be possible, pending further trial readouts.

How does orforglipron compare to injectable GLP-1 receptor agonists in terms of safety and tolerability?

Safety data from the ACHIEVE-1 trial show that orforglipron has a safety profile consistent with that of injectable GLP-1 drugs, a class known for mild-to-moderate gastrointestinal side effects. The most frequently reported adverse events included diarrhea, nausea, dyspepsia, constipation, and vomiting. Rates of these side effects increased slightly with dosage but remained within expected ranges:

Diarrhea occurred in 19% to 26% of orforglipron participants across doses compared to 9% for placebo. Nausea ranged from 13% to 18% versus 2% for placebo. Notably, treatment discontinuation due to side effects was relatively low: 6% at the 3 mg dose, 4% at 12 mg, and 8% at 36 mg, compared to 1% in the placebo group. No hepatic safety concerns were observed during the trial period.

According to Dr. Julio Rosenstock, clinical lead for the trial, the rapid onset of glycemic improvement and consistent weight loss suggest that orforglipron holds promise as a viable oral alternative to currently marketed injectable GLP-1 therapies.

Why is orforglipron significant in the context of diabetes treatment innovation?

As the first oral small-molecule GLP-1 receptor agonist to complete a Phase 3 trial with positive outcomes, orforglipron is poised to fill a crucial treatment gap for patients who are unwilling or unable to adopt injectable therapies. Its unique formulation allows for administration without food or water restrictions, adding convenience that could significantly enhance patient adherence and engagement.

Orforglipron was originally discovered by Chugai Pharmaceutical Co., Ltd. and licensed to Lilly in 2018. It represents a novel approach to GLP-1 therapy through a non-peptide route, differentiating it from peptide-based drugs such as Novo Nordisk’s oral semaglutide, which still retains absorption challenges and food restrictions.

Institutional investors and analysts see the oral delivery mechanism as a potential competitive advantage, particularly in markets where injection-based treatment compliance remains low. This sentiment is expected to strengthen pending positive outcomes from upcoming comparator trials against oral semaglutide and dapagliflozin.

What does the ACHIEVE-1 trial design reveal about orforglipron’s potential across global populations?

ACHIEVE-1 enrolled a diverse cohort from the United States, China, India, Japan, and Mexico. Participants were treatment-naïve for antidiabetic medications and met inclusion criteria of HbA1c between 7.0% and 9.5% and a BMI of at least 23 kg/m². All patients started treatment at a 1 mg dose, which was titrated stepwise over four-week intervals to their assigned maintenance dose of 3 mg, 12 mg, or 36 mg. Flexible dosing was not permitted, providing a uniform basis for assessing efficacy and safety.

The global nature of this trial, alongside its consistent dosing regimen and adherence to ADA targets, supports the generalizability of orforglipron’s clinical benefits across different ethnic and demographic groups. Analysts have pointed to this design as a strength in Lilly’s regulatory filings and market expansion efforts, particularly in Asia-Pacific regions where injection hesitancy is prevalent.

What are analysts expecting from future trials and regulatory milestones for orforglipron?

Lilly has four additional global trials underway under its ACHIEVE clinical program. ACHIEVE-2 is comparing orforglipron to the SGLT2 inhibitor dapagliflozin, while ACHIEVE-3 is assessing efficacy relative to oral semaglutide. Both trials target patients with inadequate glycemic control despite metformin therapy.

In parallel, Lilly is conducting ATTAIN-1 and ATTAIN-2 trials, evaluating orforglipron as a weight-loss therapy in patients with obesity or overweight conditions. These trials are expected to produce data in the third quarter of 2025. The American drugmaker anticipates submitting orforglipron for obesity-related indications by the end of 2025, with a diabetes filing expected in 2026.

Institutional sentiment remains broadly positive, given orforglipron’s potential to expand the total addressable market for GLP-1 therapies. Market watchers note that Lilly’s current obesity drug, tirzepatide, already faces high demand, and orforglipron could provide a complementary offering.

How does orforglipron fit into Lilly’s broader diabetes and obesity strategy?

Eli Lilly and Company has positioned orforglipron as part of its long-term commitment to reshaping diabetes care through patient-centric innovation. Alongside injectable options such as Mounjaro (tirzepatide), orforglipron complements Lilly’s pipeline by providing a flexible oral treatment for early-stage patients or those seeking non-injectable alternatives.

In a statement, Dr. Jeff Emmick, senior vice president of product development at Lilly, highlighted that the once-daily convenience of orforglipron without intake restrictions could make it a preferred first-line therapy. The company is focused on ensuring global access and accelerating time-to-market for its innovative treatments through strong trial design and early regulatory engagement.

As analysts await data from head-to-head studies and obesity-focused trials later this year, orforglipron’s demonstrated efficacy in A1C and weight reduction combined with its safety profile and convenience could place it at the forefront of the next generation of diabetes therapeutics.