VIENNA — Adults with obesity but without diabetes who took the investigational, oral GLP-1 receptor agonist orforglipron for 72 weeks lost significantly more weight than those on placebo, according to results of the ATTAIN-1 trial, the first completed phase 3 trial of the novel agent in this population.

The findings may mark an important advance in the obesity treatment landscape, said study lead, Sean Wharton, MD, from McMaster University, Hamilton, Ontario, Canada, who presented the results at the European Association for the Study of Diabetes (EASD) 2025 Annual Meeting. 

As an oral therapy, orforglipron could offer broader access and appeal to patients who prefer pills over injections. And, unlike current injectable GLP-1 agents, the drug does not require special storage, distribution, or restrictions around food and liquid intake, Wharton explained.

“This could mean an expansion of obesity interventions to groups currently excluded due to the cost of and lack of access to injectable medications,” he noted. 

For patients, what drug they take and the form they take it in “depends on what they can access, what’s available in the pharmacy, what they can afford, and maybe, what their friend is taking, and what they think will work well,” he added.

The findings of the study were simultaneously published in The New England Journal of Medicine. 

A Once-Daily Oral Treatment

Orforglipron is a small-molecule, nonpeptide oral GLP-1 receptor agonist, said Wharton, who explained that they didn’t know if they could stimulate the GLP-1 receptor without a large peptide analogue.

“The answer is yes,” he said. “This nonpeptide, small molecule activates the receptor, can be taken without food or water restrictions, and is not affected by time of day. Its small chemical structure gives it 79% bioavailability, and with a terminal half-life of 29-49 hours, it’s suitable for once-daily dosing.”

The trial enrolled 3127 participants from nine countries across four continents with obesity (BMI ≥ 30) or overweight (BMI ≥ 27) and at least one weight-related comorbidity but excluded individuals with type 1 or 2 diabetes, although 36% had prediabetes.

Of the study participants, 56.5% were White, 28.6% were Asian, and 8.6% were Black individuals; more than 35% were men, and the mean age was 45. Participants were randomized in a 3:3:3:4 ratio to receive 6 mg, 12 mg, or 36 mg orforglipron or placebo, respectively. All participants received professional guidance on a healthy diet (without caloric restriction) and physical activity. Treatment continued for 72 weeks.

The primary endpoint was mean percent change in body weight from baseline to week 72, assessed using the treatment-regimen estimand (the intention-to-treat population). Other measures included mean changes in waist circumference, systolic blood pressure, non-HDL cholesterol, and triglycerides.

Dose-Dependent Body Weight Reductions

Study completion rates ranged from 80% to > 87% across groups, with a rate of 87.5% at the highest dose (36 mg), which “is a very good result for weight management trials,” Wharton noted.

At week 72, the primary endpoints were -2.1%, -7.5%, -8.4%, and -11.2% with placebo and 6 mg, 12 mg, and 36 mg of orforglipron, respectively (P <  .001).

Turning to metabolic outcomes, mean changes in systolic blood pressure were -1.4 and -5.7 mm Hg in the placebo and pooled orforglipron groups, respectively (P < .001 for both). Among lipids, triglycerides decreased by 14.8% with pooled orforglipron compared to 3.8% with placebo, and non-HDL cholesterol decreased by 6.7% and 1.9%, respectively. 

“These were significantly different, and all remaining parameters also moved in the right direction,” Wharton reported.

Rates of adverse events and serious adverse events were similar across groups, though discontinuations due to adverse events increased with dose (2.7%, 5.3%, 7.9%, and 10.3% for placebo and the three drug doses, respectively). Gastrointestinal events were the most common, were generally mild to moderate, and occurred mainly during dose escalation. “There was no hepatic safety signal. Overall tolerability and safety were in line with expectations for GLP-1 therapies in obesity,” said Wharton.

In their publication, the authors noted that the highly diverse, large population from nine countries on four continents was a key strength of the trial.

More Information on Adverse Effects Needed

Asked to comment on the study by Medscape Medical News, Rasmus Sandsdal, MD, from the University of Copenhagen, Copenhagen, Denmark, said, “This new flurry of drugs coming out” raises questions “from the patient’s perspective about what’s the right fit for them.”

“It’s good to have a choice between injection and pill because some people will naturally think a pill is more comfortable,” he added. “But it is once daily.”

Sandsdal explained that he thought some patients who have “become familiar with the once-weekly injection” might find it less invasive compared to having to take a daily medication, which can come with a certain “illness” stigma.

He’s also previously noticed that the heart rate increase has been pronounced with some small-molecule GLP-1 drugs. “I’d like to see more specific details on the side effects because results were not as detailed here,” he said. “Future findings may tell us more about these small molecules which may have propensity to bind to off-targets.”

And “it will be interesting to see if they confer similar reductions in cardiovascular events as seen with established incretin therapies as big trials have also shown around a 20% reduction in MACE (major adverse cardiovascular events),” Sandsdal commented. 

Wharton highlighted that access to care was key. “I see this changing the way people live with obesity,” he told Medscape Medical News, "not because of the weight change or the cardiovascular benefits” but because people who desperately need it will have access to care they didn’t have before.

Wharton disclosed receiving honoraria, serving on advisory boards, and conducting research for Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Amgen, Bausch Health, Metsera, AbbVie, AstraZeneca, Pfizer. The study was sponsored by Eli Lilly, the manufacturer of orforglipron. Sandsdal reported receiving funds from the Danish Diabetes and Endocrine Academy, which is funded by the Novo Nordisk Foundation.