Orforglipron's highest dose showed greater weight loss than one oral semaglutide dose in an indirect comparison

Why it matters

Orforglipron is a once-daily small molecule (non-peptide) oral glucagon-like peptide-1 receptor agonist that can be taken any time of the day without restrictions on food and water intake. No head-to-head trial has yet compared its highest dose with the oral semaglutide dose used as the comparator here, which is the middle of the three doses studied in PIONEER PLUS. Lilly therefore drew on data from two separate trials, ACHIEVE-3 and PIONEER PLUS, with adjustment for covariates. Rachel Batterham, OBE, MBBS, Ph.D., FRCP, senior vice president of medical innovation and external engagement, Lilly Cardiometabolic Health, set out both the limit and her own reading of the result: "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", adding that "Results from this indirect treatment comparison suggest that Foundayo may deliver A1C and weight lowering that is similar to the [comparator] dose of oral semaglutide." The comparator itself matters too: that once-daily dose of oral semaglutide is not approved in the United States for the treatment of type 2 diabetes, and Novo Nordisk has submitted an application to the FDA seeking approval of that dose.

The details

• The analysis was an indirect treatment comparison using data from ACHIEVE-3 and PIONEER PLUS, in adults with type 2 diabetes and a BMI of 25 or more.
• The comparator was a dose of oral semaglutide that is the middle of the three doses studied in PIONEER PLUS, and it was not one of the two oral semaglutide doses used in ACHIEVE-3.
• At 52 weeks, participants in the highest orforglipron dose group lost 1.5% more of their body weight than the comparator oral semaglutide group (95% CI -2.7%, -0.2%).
• At the same time point, the highest orforglipron dose group lowered A1C by 0.3% more than the comparator oral semaglutide group (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, showing 1.5% to 2.4% greater weight loss and 0.3% to 0.6% greater A1C reduction for the highest orforglipron dose group compared with the comparator oral semaglutide group.
• The results were presented at the 62nd Annual Meeting of the European Association for the Study of Diabetes (EASD) in Milan, Italy.
• ACHIEVE-3 (NCT06045221), the underlying head-to-head trial, is a Phase 3, 52-week, randomized, open-label trial of orforglipron compared with oral semaglutide (Rybelsus) in adults with type 2 diabetes inadequately controlled with metformin. It randomized 1,698 participants across the U.S., Argentina, China, Japan, Mexico and Puerto Rico into four groups in a 1:1:1:1 ratio: two orforglipron dose groups and two oral semaglutide dose groups.
• Its primary objective was to show that orforglipron is non-inferior in A1C reduction from baseline after 52 weeks compared with oral semaglutide, comparing the lower and higher doses.
• In ACHIEVE-3, A1C fell by an average of 1.9% in the lower orforglipron dose group and 2.2% in the higher orforglipron dose group at 52 weeks, compared with 1.1% in the lower and 1.4% in the higher of the two oral semaglutide dose groups of that trial, both of which are different doses from the comparator used in the indirect comparison.
• Body weight fell by an average of 6.7% in the lower orforglipron dose group and 9.2% in the higher orforglipron dose group, compared with 3.7% in the lower and 5.3% in the higher of the two oral semaglutide dose groups of ACHIEVE-3, again different doses from the indirect comparison's comparator.
• All data in the release are based on the efficacy estimand. In ACHIEVE-3, that estimand represents treatment efficacy had all randomized participants remained on study intervention (with possible dose interruptions and/or dose modifications) for 52 weeks without initiating additional antihyperglycemic medications.
• Deborah Horn, D.O., director of the Center for Obesity Medicine at McGovern Medical School at UTHealth Houston, said: "Having data to help us compare available medications provides clinicians the opportunity to make informed treatment choices that fit each patient's needs."

What it does not change

This is an indirect treatment comparison across two separate trials, not a head-to-head trial of the two compared doses, a point Batterham states in the release itself, where she also reads the result as orforglipron possibly delivering A1C and weight lowering similar to that comparator dose. The underlying ACHIEVE-3 trial was open-label, and its primary objective was non-inferiority in A1C reduction, not superiority. The result is also not a regulatory decision: Foundayo is FDA-approved for adults with obesity, 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, while orforglipron is still being studied as a potential treatment for type 2 diabetes. On the other side of the comparison, that once-daily dose of oral semaglutide is not approved in the United States for the treatment of type 2 diabetes.

What's next

Novo Nordisk has submitted an application to the FDA seeking approval of the oral semaglutide dose used as the comparator. On Lilly's side, the ACHIEVE Phase 3 global clinical development program for orforglipron enrolled more than 6,000 people with type 2 diabetes across five global registration trials. Orforglipron is also being studied as a potential treatment for type 2 diabetes, obstructive sleep apnea, osteoarthritis knee pain, hypertension, peripheral artery disease and stress urinary incontinence.

What we don't know yet

The release reports efficacy outcomes (weight and A1C) from the indirect comparison and gives no side-by-side tolerability or safety comparison between the two compared doses. It gives no results past 52 weeks, and no filing or decision date for orforglipron in type 2 diabetes. The abstract behind the comparison, by Cheng and colleagues, is listed in the references without a journal or publication date, so the full methods are not visible from the release. The figures also depend on the efficacy estimand, which represents what would have happened had all randomized participants remained on study intervention, rather than what every participant actually experienced.