Diabetes Dialogue: Results of ATTAIN-1 and STEP UP Phase 3 Trials

Welcome back to Diabetes Dialogue: Technology, Therapeutics, & Real-World Perspectives!

In this episode, cohosts Diana Isaacs, PharmD, an endocrine clinical pharmacist, director of Education and Training in Diabetes Technology, and codirector of Endocrine Disorders in Pregnancy at the Cleveland Clinic, and Natalie Bellini, DNP, program director of Diabetes Technology at University Hospital Diabetes and Metabolic Care Center, discuss the recently published results of the ATTAIN-1 and STEP UP clinical trials, both of which were presented at the European Association for the Study of Diabetes (EASD) 2025 Conference.

The hosts highlight the success of orforglipron, a non-peptide oral GLP-1 receptor agonist, in patients with obesity or overweight with a weight-related medical problem and without diabetes. The size of the study, as well as the various doses of orforglipron included, were also discussed as key factors in ATTAIN-1’s importance. Additionally, orforglipron is intended solely for weight loss, and can be taken orally, revolutionizing the standard GLP-1 RA field. Isaacs and Bellini also comment on the significant weight loss over the 72-week trial duration, with a 6mg orforglipron dose resulting in 7.5% weight loss on average, a 12mg dose resulting in 8.4% weight loss, and 36mg showing an 11.2% average loss, compared to 2.1% with placebo. Orforglipron also exhibited few adverse effects while leading to significant weight drops in the majority of patients enrolled in the study.¹

Orforglipron’s status as an oral medication as opposed to an injection will likely make it more enticing to patients and clinicians alike, as it will reduce treatment burden across the board. Isaacs and Bellini also highlight the ease with which the medication can be taken, as injections are more time-consuming than a daily pill. Bellini noted the benefit of additional alternate therapies, as patients experiencing gastrointestinal effects with semaglutide or tirzepatide now may have another potential route to receiving the same treatment.¹

The hosts then addressed the phase 3 STEP UP trial, which investigated semaglutide 7.2 mg in adults with obesity. Isaacs notes this being a significantly higher dose of semaglutide than what is currently approved by the US Food and Drug Administration (FDA). Of the 1407 patients treated in STEP UP, mean body weight change was higher among the semaglutide 7.2 cohort than those receiving semaglutide 2.4. The 7.2 cohort exhibited an 18.7% body weight reduction versus 15.6% with 2.4. Bellini notes the significantly better outcomes in weight loss as a result of this dose versus the approved 2.4 mg amount. Additionally, she discusses semaglutide’s cardiovascular risk reduction indication, presenting the treatment as an alternative to poorly-tolerated GLP-1 RAs in patients with cardiovascular conditions.²

The hosts closed out the episode by discussing their hopes for a gradual reduction in GLP-1 RA cost, allowing for more ease of access among underserved populations. Bellini mentions the potential for superior cardiovascular health improvements in patients taking semaglutide 7.2. With both of these medications moving further down the pipeline, the potential for more GLP-1 RAs entering the market may trigger a greater overhaul of the endocrinology industry’s approach to weight loss drugs.

References

1. Eli Lilly. Lilly’s oral GLP-1, orforglipron, delivers weight loss of up to an average of 27.3 lbs in first of two pivotal Phase 3 trials in adults with obesity. Lilly Investors. August 7, 2025. Accessed September 24, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-delivers-weight-loss-average-273

2. Wharton S, Freitas P, Hjelmesæth J, et al. Once-weekly semaglutide 7.2 mg in adults with obesity (STEP UP): a randomized, controlled, phase 3b trial. The Lancet, 0(0). September 14, 2025. Accessed September 24, 2025. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(25)00226-8/abstract