, 2025-04-18 11:59:00
Orforglipron, Eli Lilly’s investigational oral glucagon-like peptide 1 receptor agonist (GLP-1 RA), achieved positive phase 3 results for both A1c and weight loss, according to top-line data released by the company.
The findings came from Lilly’s ACHIEVE-1, the first of seven phase 3 trials examining the safety and efficacy of orforglipron in over 6000 patients with diabetes and obesity. Full results will be presented on June 2025 at the American Diabetes Association (ADA) 85th Scientific Sessions and will be published in a peer-reviewed journal.
Orforglipron is a once-daily nonpeptide small molecule that can be taken any time of day without restrictions on meals or water intake. This contrasts with the currently approved oral GLP-1 RA semaglutide (Rybelsus, Novo Nordisk), a peptide which ideally should be taken fasting and with no food or water for at least 30 minutes after ingestion to prevent degradation.
Asked to comment on the new top-line data, independent consultant Charles M. Alexander, MD, told Medscape Medical News that the results are “Great news for Lilly. A pill taken daily is going to be much easier for patients compared to injections, even once-weekly injections. A1c and weight loss were at least as good as semaglutide phase 3 type 2 diabetes data, if not a little bit better.”
However, Alexander added, “We need a head-to-head study to really understand both comparative efficacy and safety. What is the price going to be? The presentation at ADA and the publication…will help fill in the gaps not included in the top-line results.”
In a statement from the UK Science Media Centre, Naveed Sattar, MD, professor of cardiometabolic medicine/honorary consultant, University of Glasgow, Glasgow, Scotland, said, “These are important results. Having new oral agents that lower glucose but also meaningfully lower weight well beyond levels seen with most existing diabetes therapies is critical to future type 2 diabetes care.”
Sattar added, “Of course, one caveat is that we do not know the effects of this newer therapy on cardiovascular outcomes, but this will be forthcoming in future trials. It is also good to hear about the safety profile of these new oral GLP-1 RA drugs — especially the liver results — and it will be good to see the data in a full publication in due course.”
Top-Line Data Show Statistical Significance for A1c, Weight Loss
In ACHIEVE-1, 559 patients with type 2 diabetes were randomized to one of three orforglipron doses (3, 12, or 36 mg) or placebo for 40 weeks.
Percentage point reductions in A1c from baseline average 8.0% ranged from 1.3 with the 3-mg dose to 1.6 for the 12-mg dose vs 0.1 with placebo. All the A1c reductions were statistically significant. More than 65% of those taking the 36-mg dose achieved an A1c level of 6.5% or below.
Weight reduction, a secondary endpoint, ranged from 4.7% with the 3-mg dose to 7.9% with the 36-mg dose vs 1.6% with placebo. Absolute weight losses were 4.4 kg to 7.3 kg vs 1.3 kg, respectively. The results for 12-mg and 36-mg doses were statistically significant.
“Given that participants had not yet reached a weight plateau at the time the study ended, it appears that full weight reduction was not yet attained,” according to Lilly.
Adverse Events: Slight Differences From Injectable GLP-1 RAs?
As with other GLP-1 RA medications, the most common adverse events were gastrointestinal. Diarrhea was reported in 19% of patients with the 3-mg dose, 21% with the 12-mg dose, and 26% with the 36-mg dose vs 9% with placebo. Nausea was reported in 13%, 18%, and 16% vs 2%, respectively, and vomiting in 5%, 7%, and 14% vs 1%, respectively.
Treatment discontinuations due to adverse events occurred in 6%, 4%, and 8% vs 1%, respectively. There were no hepatic safety signals.
Alexander noted, “The adverse event profile was GI [gastrointestinal]–related like semaglutide but somewhat different with diarrhea leading the list. Vomiting was not as frequently reported as with semaglutide.”
As of now, there is no information about pricing for orforglipron. But a nonpeptide GLP-1 RA could be mass produced and, therefore, potentially more widely accessible than the injectables, a phase 2 study investigator told Medscape Medical News after presenting those data at the 2023 ADA meeting.
According to the Lilly statement, “If approved, the company is confident in its ability to launch orforglipron worldwide without supply constraints.”
More results from ACHIEVE-1 phase 3 clinical trials will be released later in 2025, along with findings from the ATTAIN phase 3 clinical trial program evaluating orforglipron for weight management. “Lilly expects to submit orforglipron for weight management to global regulatory agencies by the end of this year, with the submission for the treatment of type 2 diabetes anticipated in 2026,” the company said.
Alexander is a volunteer consultant to the diaTribe Foundation with the title of scientific and medical advisor. Sattar has consulted for and/or received speaker honoraria from Abbott, AbbVie, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, GlaxoSmithKline, Hanmi Pharmaceutical, Janssen, Menarini-Ricerche, Merck Sharp & Dohme, Metsera, Novartis, Novo Nordisk, Pfizer, Sanofi, and Roche and received grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche. He does not own stock in any medical areas.
Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape Medical News, with other work appearing in The Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.