Lilly’s Oral GLP-1 Candidate Outperforms Semaglutide in Trial

Eli Lilly and Company report that its investigational oral GLP-1 receptor agonist, orforglipron, delivered greater blood sugar reduction and weight loss than oral semaglutide in a 52-week head-to-head Phase 3 trial in adults with type 2 diabetes.

Eli Lilly and Company reports that its oral GLP-1 receptor agonist, orforglipron, achieved statistically significant improvements across primary and key secondary endpoints in the ACHIEVE-3 study. The findings, published in The Lancet, position Lilly’s once-daily pill as a potential competitor in the expanding global market for oral cardiometabolic therapies.

“ACHIEVE-3 gives us the first head-to-head comparison between two oral GLP-1 receptor agonist therapies in adults with type 2 diabetes, and the differences were clinically meaningful,” says Julio Rosenstock, Clinical Professor Of Medicine, University of Texas Southwestern Medical Center, and lead investigator of the study. He noted that both 12mg and 36mg doses of orforglipron outperformed 7mg and 14mg doses of oral semaglutide on A1C and weight endpoints, with improvements emerging as early as four weeks and sustained through week 52.

Kenneth Custer, Executive Vice President and President, Lilly Cardiometabolic Health, says the combination of greater A1C reduction, higher weight loss, and administration without food or water timing restrictions could be relevant for patients managing chronic disease. He adds that regulatory submissions are underway globally, with potential US regulatory action for obesity expected in the second quarter of 2026.

Head-to-Head Data in ACHIEVE-3

ACHIEVE-3 enrolled 1,698 adults with type 2 diabetes inadequately controlled with metformin across the United States, Argentina, China, Japan, Mexico, and Puerto Rico. Participants were randomized in a 1:1:1:1 ratio to receive orforglipron 12mg or 36mg, or oral semaglutide 7mg or 14mg, over 52 weeks.

The primary endpoint was change in A1C from a baseline of 8.3% at week 52. Using the efficacy estimand, A1C declined by 2.2% in the orforglipron 36mg group, compared with 1.4% in the oral semaglutide 14mg group. At the lower doses, A1C fell by 1.9% with orforglipron 12mg versus 1.1% with semaglutide 7mg.

Weight change was a key secondary endpoint. From a baseline of 97kg, participants receiving orforglipron 36mg lost 9.2% of body weight, or 8.9kg, compared with 5.3%, or 5.0kg, among those on semaglutide 14mg. The relative difference represented a 73.6% greater weight reduction at the highest dose.

The proportion of patients reaching glycemic targets also differed. In the efficacy analysis, 85.4% of participants in the 36mg orforglipron arm achieved A1C below 7%, compared with 66.1% in the semaglutide 14mg arm. For A1C of 6.5% or lower, rates were 76.8% and 50.9%, respectively. A subset achieved A1C below 5.7%.

Orforglipron also showed changes from baseline in non-HDL cholesterol, HDL cholesterol, very low-density lipoprotein cholesterol, total cholesterol, systolic blood pressure, and triglycerides.

The safety profile was consistent with the GLP-1 class. The most common adverse events were gastrointestinal, including nausea, diarrhea, vomiting, dyspepsia, and decreased appetite. Discontinuation rates due to adverse events were 8.7% and 9.7% for the 12mg and 36mg orforglipron groups, compared with 4.5% and 4.9% for semaglutide 7mg and 14mg.

Orforglipron is a once-daily small-molecule, non-peptide GLP-1 receptor agonist discovered by Chugai Pharmaceutical and licensed by Lilly in 2018. Unlike oral semaglutide, it can be taken without restrictions related to food or water intake.

Lilly’s broader ACHIEVE clinical development program has enrolled more than 6,000 people with type 2 diabetes across five global registration trials that began in 2023. Additional registrational results are anticipated later this year. The company has submitted orforglipron to regulators in more than 40 countries and plans a US submission for type 2 diabetes later in 2026.

Oral GLP-1 Competition Intensifies

The data arrive amid accelerating competition in oral cardiometabolic treatments. In December 2025, the US Food and Drug Administration approved an oral formulation of semaglutide for weight management under the Wegovy brand from Novo Nordisk. The once-daily pill marked the first oral GLP-1 medicine authorized in the United States for obesity, based on Phase 3 data showing double-digit percentage weight loss over 64 weeks.

Other drugmakers are advancing oral or next-generation metabolic therapies. Hanmi Pharmaceutical signed a distribution agreement with Mexico-based Laboratorios Sanfer to introduce efpeglenatide and related diabetes treatments to the Mexican market, reflecting rising demand in a country where obesity and diabetes prevalence remain among the highest in the OECD.

The World Health Organization (WHO) issued its first guideline endorsing GLP-1 therapies for long-term obesity management in 2025, while cautioning that fewer than 10% of eligible patients may have access globally by 2030 due to pricing and system constraints.

Against this backdrop, Lilly’s metabolic portfolio has influenced capital markets. In November 2025, Eli Lilly and Company became the first pharmaceutical manufacturer to reach a market valuation of US$1 trillion, reflecting investor focus on obesity and diabetes treatments and pipeline expansion. Analysts have linked part of that valuation to expectations around oral candidates such as orforglipron.

Mexico as Strategic Market

Mexico represents a priority market within Lilly’s Latin America strategy, says the company. According to Phelippe Philippsen, Country Manager, Lilly Mexico, the company aims to increase the number of patients it serves by a factor of five and reach US$2 billion in revenue in the country by 2030. He says 2026 would be a pivotal year, with plans to launch two to three new indications or products over the next five years and expand clinical research investment.

From 2019 to 2024, Lilly’s investment in clinical trials in Mexico grew fivefold, Philippsen says, adding that collaboration with public authorities includes new access models and engagement aligned with national health strategies. He also cites digital initiatives, including AI-powered medical education tools and the Lilly 360 platform, designed to expand outreach to physicians beyond traditional sales models.

Mexico’s epidemiological profile underscores the commercial and public health relevance of GLP-1 therapies. Data from ENSANUT Continua 2020–2023 indicates that more than one-third of Mexican adults live with obesity, and a significant share of the population has type 2 diabetes. These conditions are closely linked to cardiovascular risk, which remains a leading cause of mortality.

As regulators review submissions for oral GLP-1 agents across indications, stakeholders including payers, providers, and employers are assessing the implications for access, adherence, and long-term disease burden. Outcome data, regulatory timelines, and pricing strategies are expected to shape adoption.

For Lilly, the ACHIEVE-3 results provide comparative evidence in a market segment that is shifting toward oral administration. Whether the data translate into regulatory approvals and broad reimbursement will determine how rapidly the therapy moves from clinical development into routine cardiometabolic care.