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NEW ORLEANS — The oral nonpeptide GLP-1 receptor agonist orforglipron (Foundayo, Eli Lilly) showed greater A1c reduction and weight loss in people with type 2 diabetes (T2D) than both dapagliflozin and oral semaglutide (Rybelsus), although with a somewhat worse tolerability profile than semaglutide, new phase 3 clinical trial data from the ACHIEVE studies showed.

The drug also improved glycemic control in patients with T2D taking insulin glargine.

The findings from ACHIEVE-2, ACHIEVE-3, and ACHIEVE-5 were all presented at the American Diabetes Association (ADA) 2026 Scientific Sessions.

Nonpeptide drugs are easier to produce than the current GLP-1 agonist peptides, ACHIEVE-5 investigator Francesco Giorgino, MD, said in an interview with Medscape Medical News.

“Once it goes off patent, orforglipron will be easy to produce and relatively cheap, which is what we want for this class of drugs. I think that is the value of orforglipron and [whatever] follows in terms of nonpeptide agonists,” said Giorgino, professor of endocrinology and metabolism, chief of the Division of Endocrinology, and director of the Specialty School of Endocrinology and Metabolism at the University Hospital Policlinico Consorziale, University of Bari Aldo Moro, Bari, Italy.

Orforglipron, approved by the FDA on April 1, 2026, for weight management, is still under development for the treatment of T2D. Unlike oral semaglutide, it has no food or water restrictions.

Previous data from ACHIEVE-1 comparing orforglipron with placebo for both A1c reduction and weight loss were presented at the ADA meeting last year. And in April 2026, Eli Lilly released topline data for ACHIEVE-4, showing noninferiority in cardiovascular outcomes compared with insulin glargine.

ACHIEVE-2 was published in The Lancet concurrent with its presentation; ACHI EVE-3 was published in The Lancet on March 21, 2026; and ACHIEVE-5 was published in JAMA on June 7, 2026.

ACHIEVE-2: Orforglipron vs Dapagliflozin

In ACHIEVE-2, a total of 962 adults with T2D with A1c levels of 7.0%-10.5% (mean, 8.14%) while using metformin and a mean BMI of 32.6 were randomly assigned to receive 3 mg, 12 mg, or 36 mg orforglipron or 10 mg dapagliflozin.

Mean reductions from baseline in A1c at 40 weeks were 1.23, 1.50, and 1.56 percentage points for the 3-mg, 12-mg, and 36-mg doses of orforglipron, respectively, vs 0.81 with dapagliflozin (P < .0001 for all). All orforglipron doses produced A1c levels below 7% at week 40 (6.82%, 6.40%, and 6.41%, respectively, vs 7.38% for dapagliflozin).

The mean percent body weight loss at week 40 was 5.7% and 6.8% with the 12-mg and 36-mg orforglipron doses vs 2.4% for dapagliflozin (P < .0001 for all vs baseline).

Mild-to-moderate gastrointestinal events occurred in 47%, 46%, and 54% of participants receiving the three orforglipron doses, respectively, vs 12% of those receiving dapagliflozin. More participants discontinued orforglipron (15%, 18%, and 20%) than dapagliflozin (6%). There were no severe hypoglycemia episodes.

ACHIEVE-3: Orforglipron vs Oral Semaglutide

In ACHIEVE-3, 1698 participants with T2D with a mean baseline A1c of 8.3% while taking metformin were randomly assigned to receive either doses of 12 mg (n = 424) or 36 mg (n = 423) orforglipron or oral semaglutide in 7-mg (n = 426) or 14-mg (n = 425) doses.

For the treatment regimen estimand, mean A1c reductions at 52 weeks from baseline were 1.71 and 1.91 percentage points with the 12-mg and 36-mg orforglipron doses, respectively, compared with 1.23 and 1.47 percentage points with the 7-mg and 14-mg semaglutide doses, respectively.

Estimated treatment differences were -0.48% for 12 mg orforglipron vs 7 mg semaglutide (P < .0001), -0.44% for 36 mg orforglipron vs 14 mg semaglutide (P < .0001), -0.24% for 12 mg orforglipron vs 14 mg semaglutide (P = .0050), and -0.68% for 36 mg orforglipron vs 7 mg semaglutide (P < .0001).

The primary objective of noninferiority was met, and both orforglipron doses showed superiority to both semaglutide doses, including 12 mg orforglipron vs 14 mg semaglutide.

The most frequent events were gastrointestinal, occurring in 59% and 58% of the two orforglipron doses vs 37% and 45% for the semaglutide doses. Most were mild to moderate in severity.

More participants in the orforglipron groups discontinued the study treatment due to adverse events (9% and 10% for the two orforglipron doses vs 4% and 5% for the two semaglutide doses). The mean increase in pulse rate was also greater with orforglipron than with semaglutide (3.7 and 4.7 beats/min vs 1.0 and 1.5 beats/min).

There were four study deaths: two with orforglipron and two with semaglutide.

ACHIEVE-5: Orforglipron Added to Glargine

A total of 546 adults with T2D with a mean baseline A1c of 8.5% and BMI of 30.8 taking insulin glargine, with or without metformin and/or an SGLT2 inhibitor, were randomly assigned to receive either once-daily 3 mg, 12 mg, or 36 mg orforglipron or placebo, along with titrated insulin glargine.

At week 40, mean reductions from baseline in A1c were 1.58, 1.88, and 1.82 percentage points for the three orforglipron doses, respectively, vs 0.79 with placebo. All three doses were superior to placebo (P < .001 for all).

Mean percentage body weight reductions from baseline were 2.6%, 4.8%, and 5.4% for the three orforglipron doses, respectively, vs 0.2% for placebo.

The most frequent adverse events with orforglipron were gastrointestinal, mostly mild to moderate. Orforglipron did not increase the risk for clinically significant hypoglycemia vs placebo.

Where Does Orforglipron Fit?

Discussant Alice Y.Y. Cheng, MD, an endocrinologist at Trillium Health Partners and Unity Health Toronto and an associate professor at the University of Toronto in Toronto, Ontario, Canada, said orforglipron “fits anywhere you would currently use a GLP-1 agonist.”

She added that the new data support the recent push to use GLP-1 receptor agonists or SGLT2 inhibitors “earlier in the management of [T2D], perhaps even at diagnosis, and I think orforglipron offers an ability to make that happen more realistically.”

Even though the injectable therapies are very easy, “I have patients who still don’t want to take an injection, so the ability to take a pill is very welcome,” she said. “The ability to take a pill without food or water restriction is welcome, and then to also know that you’re going to get strong glucose and weight efficacy from it is also very much welcome, and if it’s at a lower cost, then it’s super welcome.”

However, Cheng stressed “that this does not replace SGLT2 inhibitors. Yes, there was a head-to-head study vs dapagliflozin, but we know SGLT2 inhibitors have a very strong role to play for organ protection, so it’s not a competition, it’s a friendship.”

She also called orforglipron “an excellent option for anybody who does not need to lose that much weight. It’s ironic that we would consider an 8% weight loss to be not that much weight if we think about where we used to be 5-10 years ago.”

For cardiovascular benefit, oral semaglutide is the only oral agent with study data thus far, she noted.

Addition to Armamentarium

Daniel J. Rubin, MD, professor of medicine at the Lewis Katz School of Medicine at Temple University in Philadelphia, told Medscape Medical News, “I think orforglipron will be an important addition to the armamentarium. I don’t think it’s really the right answer for everyone, but the more options we have, the better we can individualize therapy for our patients.”

There are people who respond well to one medication and not another, or they have more side effects with one than the other, he explained. “I think it’s great to see more data coming out on it. The more we know, the better for us and our patients.”

Giorgino reported being on advisory panels of, being a consultant for, and/or receiving research support from Abbott, Eli Lilly, Novo Nordisk, AstraZeneca, Medtronic, Roche Diabetes Care, LifeScan, Sanofi, Boehringer Ingelheim, and International GmbH. 

Cheng reported serving as an advisory, consultant, and/or speaker for Abbott Diabetes; Amgen Canada; Aspen Pharmacare; Astellas Pharma Inc.; AstraZeneca; Bausch Health, Canada; Bayer AG; Boehringer Ingelheim; Biomea Fusion; International GmbH; Dexcom, Inc.; Eisai Co., Ltd.; Eli Lilly & Co.; Gan & Lee Pharmaceuticals; Insulet Corporation; HLS Therapeutics Inc.; Merck & Co., Inc.; Novo Nordisk; Sanofi; Sandoz International GmbH; and Vertex Pharmaceuticals, Inc. 

Rubin reported having no disclosures.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and diaTribe. She is on X @MiriamETucker and BlueSky @miriametucker.bsky.social.