Indirect Comparison Finds Lilly's Oral Orforglipron 17.2 mg Beats Oral Semaglutide 25 mg on Weight and A1C in Type 2 Diabetes
核心洞察
An indirect treatment comparison presented at EASD found orforglipron 17.2 mg produced 1.5% greater weight loss than oral semaglutide 25 mg at 52 weeks.
The same analysis showed orforglipron 17.2 mg lowered A1C by 0.3% more than oral semaglutide 25 mg, with consistent results across statistical methods.
The comparison drew on data from the Phase 3 ACHIEVE-3 trial of orforglipron and the PIONEER PLUS trial of oral semaglutide 25 mg and 50 mg.
Eli Lilly and Company reported that its once-daily oral GLP-1 receptor agonist Foundayo (orforglipron) 17.2 mg was associated with significantly greater weight loss and better blood sugar control than oral semaglutide 25 mg in adults with type 2 diabetes (搜索), based on a new indirect treatment comparison. The results were presented at the 62nd Annual Meeting of the European Association for the Study of Diabetes (EASD) in Milan, Italy.
The analysis drew on data from the Phase 3 ACHIEVE-3 trial of orforglipron and the Phase 3b PIONEER PLUS trial of oral semaglutide. At 52 weeks, participants taking orforglipron 17.2 mg lost 1.5% more of their body weight on average than those taking oral semaglutide 25 mg (95% CI -2.7%, -0.2%). Orforglipron also lowered A1C by 0.3% more than oral semaglutide 25 mg (95% CI -0.6%, -0.1%). The analysis was covariate-adjusted for gender, age, baseline A1C and baseline weight.
Analyses using different statistical methods produced consistent results, with orforglipron 17.2 mg showing 1.5% to 2.4% greater weight loss and 0.3% to 0.6% greater A1C reduction compared with oral semaglutide 25 mg.
"For someone managing type 2 diabetes (搜索), the choice between treatments is a decision that impacts their life every day," said Deborah Horn, D.O., director of the Center for Obesity (搜索) Medicine at McGovern Medical School at UTHealth Houston. "Having data to help us compare available medications provides clinicians the opportunity to make informed treatment choices that fit each patient's needs."
Rachel Batterham, OBE, MBBS, Ph.D., FRCP, senior vice president of medical innovation and external engagement at Lilly Cardiometabolic Health, noted the limits of the approach. "Head-to-head trials ultimately provide the best comparison of two medicines, but when we don't yet have those data, then other approaches can provide informative data points," she said. "Results from this indirect treatment comparison suggest that Foundayo may deliver A1C and weight lowering that is similar to the 25 mg dose of oral semaglutide. These results, paired with simple administration free of fasting or water restrictions, are what make Foundayo a potentially foundational therapy for adults managing type 2 diabetes (搜索) around the world."
What ACHIEVE-3 Showed Against Approved Doses
The new analysis builds on the head-to-head ACHIEVE-3 study, in which orforglipron 9 mg and 17.2 mg delivered greater A1C and weight reductions than oral semaglutide 14 mg. ACHIEVE-3 (NCT06045221) is a Phase 3, 52-week, randomized, open-label trial evaluating orforglipron compared with oral semaglutide (Rybelsus) in adults with type 2 diabetes (搜索) inadequately controlled with metformin. The trial randomized 1,698 participants across the U.S., Argentina, China, Japan, Mexico and Puerto Rico to receive 9 mg or 17.2 mg orforglipron or 7 mg or 14 mg oral semaglutide in a 1:1:1:1 ratio. Its primary objective was to demonstrate that orforglipron is non-inferior in A1C reduction from baseline after 52 weeks compared with oral semaglutide when comparing the lower and higher doses.
In ACHIEVE-3, orforglipron lowered A1C by an average of 1.9% (9 mg) and 2.2% (17.2 mg) compared with 1.1% (7 mg) and 1.4% (14 mg) with oral semaglutide at 52 weeks. Participants lost an average of 14.6 lbs (6.7%) on the 9 mg dose and 19.7 lbs (9.2%) on the 17.2 mg dose, compared with 7.9 lbs (3.7%) and 11.0 lbs (5.3%) with oral semaglutide 7 mg and 14 mg, respectively. The ACHIEVE Phase 3 global development program enrolled more than 6,000 people with type 2 diabetes (搜索) across five registration trials.
A 25 mg once-daily dose of oral semaglutide is not approved in the United States for the treatment of type 2 diabetes (搜索). Novo Nordisk has submitted an application to the FDA seeking approval of that dose.
Dosing, Administration and Development History
Foundayo is FDA-approved for adults with obesity (搜索), or some adults with overweight who also have weight-related medical problems, to reduce excess body weight and maintain weight reduction long term, alongside a reduced-calorie diet and increased physical activity. It is a once-daily small molecule (non-peptide) oral glucagon-like peptide-1 receptor (搜索) agonist that can be taken any time of the day without restrictions on food and water intake. Orforglipron was discovered by Chugai Pharmaceutical Co., Ltd. and licensed by Lilly in 2018. It is being studied as a potential treatment for type 2 diabetes (搜索), obstructive sleep apnea (搜索), osteoarthritis knee pain, hypertension, peripheral artery disease and stress urinary incontinence.
Foundayo is available as 0.8 mg, 2.5 mg, 5.5 mg, 9 mg, 14.5 mg and 17.2 mg oral tablets and should not be used with other GLP-1 receptor agonist medicines. Its label carries warnings for thyroid C-cell tumors, including thyroid cancer, and it is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or with Multiple Endocrine Neoplasia syndrome type 2. Other labeled risks include pancreatitis, severe stomach problems, dehydration leading to kidney problems, hypoglycemia when used with insulin or sulfonylureas, serious allergic reactions, vision changes in patients with type 2 diabetes (搜索), gallbladder problems, and food or liquid entering the lungs during procedures using anesthesia or deep sedation. The most common side effects are nausea, constipation, diarrhea, vomiting, indigestion, abdominal pain, headache, swollen belly, fatigue, belching, heartburn, gas and hair loss.
Lilly noted that all data referenced in the analysis are based on the efficacy estimand. In ACHIEVE-3, the efficacy estimand represents treatment efficacy had all randomized participants remained on study intervention, with possible dose interruptions or modifications, for 52 weeks without initiating additional antihyperglycemic medications for more than 14 days. In PIONEER PLUS, the corresponding estimand is termed the trial product estimand in the manuscript.