Orforglipron Edges Oral Semaglutide 25 mg in T2D, Indirect Comparison Finds

Orforglipron (Foundayo; Eli Lilly and Company) 17.2 mg was associated with modestly greater weight loss and hemoglobin A1c (A1C) reduction than oral semaglutide 25 mg (Wegovy pill; Novo Nordisk) in adults with type 2 diabetes (T2D), according to an indirect treatment comparison (ITC) presented at the 62nd Annual Meeting of the European Association for the Study of Diabetes (EASD) in Milan, Italy.¹

The differences were small: 1.5 percentage points of body weight and 0.3 percentage points of A1C, according to a news release from Eli Lilly. They also come from cross-trial modeling rather than a randomized head-to-head study, a distinction pharmacists should keep in mind.¹

Previous comparisons have occurred in different populations. For example, a separate indirect treatment comparison announced in April 2026 by Novo Nordisk suggested that oral semaglutide could provide greater weight loss versus orforglipron in a weight management population. The wealth of comparisons between the products outlines the fierce competition in the GLP-1 space between the biopharmaceutical giants Eli Lilly and Novo Nordisk.

How the Comparison Was Built

The Lilly-funded analysis drew on 2 separate phase 3 trials. ACHIEVE-3 (NCT06045221) randomly assigned 1698 adults with T2D inadequately controlled on metformin to orforglipron or oral semaglutide 7 mg or 14 mg for 52 weeks. PIONEER PLUS (NCT04707469), funded by Novo Nordisk, compared oral semaglutide 14 mg, 25 mg, and 50 mg.^1,3,4

At 52 weeks, orforglipron 17.2 mg was associated with 1.5% greater weight loss (95% CI, -2.7% to -0.2%) and a 0.3% greater A1C reduction (95% CI, -0.6% to -0.1%) than oral semaglutide 25 mg. The analysis was adjusted for gender, age, baseline A1C, and baseline weight. Lilly reported that alternative statistical methods produced consistent results, ranging from 1.5% to 2.4% greater weight loss and 0.3% to 0.6% greater A1C reduction. All figures reflect the efficacy estimand, which estimates the treatment effect had all participants remained on the study drug.¹

The source trials differed in ways that matter for any cross-trial comparison. ACHIEVE-3 was open-label and enrolled adults on metformin with a mean baseline A1C of 8.3%. PIONEER PLUS was double-blind and enrolled adults on 1 to 3 oral glucose-lowering drugs with a mean baseline A1C of 9.0%.^3,4

"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," Rachel Batterham, OBE, MBBS, PhD, FRCP, senior vice president of medical innovation and external engagement at Lilly Cardiometabolic Health, said in the release.¹

What ACHIEVE-3 Showed Directly

The ITC builds on ACHIEVE-3, which compared orforglipron directly with oral semaglutide at doses up to 14 mg. The published trial used investigational capsule doses of 12 mg and 36 mg, which correspond to the marketed 9-mg and 17.2-mg tablets. Using the treatment-regimen estimand, A1C fell 1.91% with the 36-mg dose vs 1.47% with semaglutide 14 mg (estimated treatment difference, -0.44%; 95% CI, -0.62 to -0.26). Both orforglipron doses were superior to both semaglutide doses.^2,5

Tolerability is where the counseling burden lands. Gastrointestinal adverse events occurred in 59% and 58% of participants taking the 2 orforglipron doses vs 37% and 45% of those taking semaglutide 7 mg and 14 mg. Discontinuation due to adverse events was roughly double with orforglipron (9% and 10% vs 4% and 5%). Mean pulse rate rose by 3.7 and 4.7 beats per minute with orforglipron vs 1.0 and 1.5 beats per minute with semaglutide.³

Richard Frank, MD, MHSA, chief medical officer at Vida Health, noted this trade-off in a previous interview with Pharmacy Times, saying that orforglipron "does have a significantly higher incidence of GI [gastrointestinal] [adverse] effects, so some patients may not be able to tolerate it.”⁶

Practical Considerations for Pharmacists

Neither regimen in the ITC is currently approved in the US for T2D. The FDA approved orforglipron in April 2026 for adults with obesity or overweight with weight-related medical problems, and it is still being studied for T2D. Lilly noted that a 25-mg once-daily dose of oral semaglutide is not approved in the US for T2D and that Novo Nordisk has submitted an application seeking that approval. The 25-mg semaglutide pill is, however, part of the US Wegovy portfolio for weight management, so pharmacists may see the same dose prescribed under a different indication.^1,7,8

Orforglipron can be taken any time of day without food or water restrictions. Oral semaglutide for weight management must be taken in the morning on an empty stomach with no more than 4 oz of water, followed by a 30-minute wait before eating or drinking.^1,7

Pharmacists should also screen for interactions. The maximum orforglipron dose is 9 mg with a strong CYP3A4 inhibitor, and use with strong CYP3A4 inducers should be avoided. Patients using oral contraceptives may need a backup method for 30 days after starting orforglipron and after each dose increase.^1,9

Beyond selection, Frank said pharmacists can help patients get the most out of these therapies by "understanding how to titrate them, understanding how to dose optimize them, understanding how to navigate the [adverse] effects associated with them, and encouraging patients to engage in a lifestyle intervention, either virtually through telemedicine or in person."⁶

REFERENCES

1. Lilly's Foundayo (orforglipron) 17.2 mg showed greater weight loss and A1C reduction than oral semaglutide 25 mg among adults with type 2 diabetes in a new indirect treatment comparison. News release. Eli Lilly and Company. September 29, 2026. Accessed September 29, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-foundayo-orforglipron-172-mg-showed-greater-weight-loss

2. Halpern L. Oral semaglutide demonstrates greater weight loss vs orforglipron in indirect comparison. Pharmacy Times. Published April 6, 2026. Accessed September 30, 2026. https://www.pharmacytimes.com/view/oral-semaglutide-demonstrates-greater-weight-loss-versus-orforglipron-in-indirect-comparison

3. Rosenstock J, Yabe D, Cox D, et al. Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial. Lancet. 2026;407(10534):1147-1160. doi:10.1016/S0140-6736(26)00202-3

4. Aroda VR, Aberle J, Bardtrum L, et al. Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial. Lancet. 2023;402(10403):693-704. doi:10.1016/S0140-6736(23)01127-3

5. US Department of Veterans Affairs. Orforglipron (Foundayo) for chronic weight management: national drug monograph. May 2026. Accessed September 29, 2026. https://www.va.gov/formularyadvisor/DOC_PDF/MON_Orforglipron_FOUNDAYO_monograph_May_2026.pdf

6. Frank R, Valletti D. Could orforglipron change obesity treatment forever? Pharmacy Times. May 5, 2026. Accessed September 30, 2026. https://www.pharmacytimes.com/view/could-orforglipron-change-obesity-treatment-forever-

7. Brooks A. Foundayo (orforglipron) for weight loss. diaTribe. April 20, 2026. Accessed September 29, 2026. https://diatribe.org/diabetes-medications/new-oral-drug-foundayo-weight-loss

8. Hohmann E. Higher-dose semaglutide approved under new FDA accelerated review process. AJMC. Published March 20, 2026. Accessed September 29, 2026. https://www.ajmc.com/view/higher-dose-semaglutide-approved-under-new-fda-accelerated-review-process

9. Lilly Medical. What is the approved dosing for Foundayo (orforglipron) for weight management? Accessed September 29, 2026. https://medical.lilly.com/us/products/answers/what-is-the-approved-dosing-for-foundayo-orforglipron-for-weight-management-320858