Oral orforglipron lowered HbA1c and body weight across phase 3 comparisons in type 2 diabetes, ACHIEVE trials show
Presenter: Francesco Giorgino, MD, PhD, University of Bari Aldo Moro, Bari, Italy
From Pen to Pill: The Orforglipron ACHIEVE Clinical Trial Program. June 8, 2026.
Orforglipron, an oral glucagon-like peptide 1 (GLP-1) receptor agonist, improved glycemic control and reduced body weight in adults with type 2 diabetes across three phase-3 trials presented at the American Diabetes Association 2026 Scientific Sessions.
The three trials, ACHIEVE-2, ACHIEVE-3, and ACHIEVE-5, respectively set the drug against dapagliflozin, oral semaglutide, and placebo on a background of titrated insulin glargine.
Results of these comparative studies showed changes in hemoglobin A1c and body weight that favored orforglipron, a nonpeptide, small-molecule GLP-1 receptor agonist approved in April 2026, which is taken as a daily pill without restrictions on food or water.
New and effective oral options for diabetes treatment are needed, particularly for the many adults with type 2 diabetes who delay or avoid injectable therapies altogether due to fear of needles, complexity of injection schedules, or inconvenience, according to a news release describing the ACHIEVE study results.
ACHIEVE-5, which tested orforglipron as an add-on for adults whose long-standing diabetes remained inadequately controlled on basal insulin, was chosen as an ADA Presidents' Select abstract.
“ACHIEVE-5 results are encouraging because they suggest a once-daily oral GLP-1 option like orforglipron could help improve blood glucose control for people with type 2 diabetes who are already managing complex treatment routines, including basal insulin,” said Francesco Giorgino, MD, PhD, lead author of ACHIEVE-5.
Because type 2 diabetes is progressive, many patients eventually need insulin, but fear of hypoglycemia and weight gain can limit how far basal insulin is intensified, the ACHIEVE-5 authors wrote in a publication of the results simultaneously appearing in JAMA.
Adding a GLP-1 receptor agonist is an alternative that targets postprandial as well as fasting glucose, improves glycemic control, lowers body weight, and poses a relatively lower risk of hypoglycemia, they noted.
ACHIEVE-5
ACHIEVE-5 (NCT06109311) was a 40-week, randomized, double-blind, placebo-controlled phase 3 trial conducted at 72 sites in the United States, Brazil, China, Japan, and Romania.
It randomized 546 adults in a 1:1:1:1 ratio to once-daily orforglipron at 3 mg, 12 mg, or 36 mg, or to placebo, each added to titrated insulin glargine, with or without metformin and a sodium-glucose cotransporter 2 (SGLT-2) inhibitor. Participants had a median age of 61 years, a median diabetes duration of 14.6 years, a mean hemoglobin A1c of 8.50%, and a mean body mass index of 30.8 kg/m2.
The primary endpoint was the change in hemoglobin A1c from baseline to week 40 for the 12-mg and 36-mg doses.
At week 40, hemoglobin A1c had fallen by 1.88% with the 12-mg dose, 1.82% with the 36-mg dose, and 1.58% with the 3-mg dose, compared with 0.79% with placebo (P < .001 for all estimated treatment differences versus placebo).
A hemoglobin A1c below 7.0% was reached by 57% of participants receiving orforglipron 3 mg, 70% of those receiving 12 mg, and 65% of those receiving 36 mg, versus 25% with placebo.
Mean body weight decreased by 2.6% in participants receiving orforglipron 3 mg, 4.8% in those receiving 12 mg, and 5.4% in those receiving 36 mg, compared with 0.2% with placebo, and up to 48% of participants lost at least 5% of their body weight.
Orforglipron did not raise the rate of clinically significant hypoglycemia relative to placebo, according to the report, and the most common adverse events were gastrointestinal and mostly mild to moderate.
ACHIEVE-2
ACHIEVE-2 (NCT06192108) compared orforglipron with the SGLT-2 inhibitor dapagliflozin in 962 adults whose diabetes was inadequately controlled on metformin, in a 40-week, randomized, open-label phase 3 trial. Participants received once-daily orforglipron at 3 mg, 12 mg, or 36 mg, or dapagliflozin 10 mg.
At week 40, hemoglobin A1c had fallen by 1.23% with orforglipron 3 mg, 1.50% with 12 mg, and 1.56% with 36 mg, versus 0.81% with dapagliflozin, meeting both noninferiority and superiority criteria for every dose (P < .0001), according to study results simultaneously published in The Lancet.
Orforglipron also produced greater body weight loss, ranging from 6.3% to 7.3%, compared with 3.0% with dapagliflozin, the report showed, and as many as 80% of orforglipron-treated participants reached a hemoglobin A1c below 7.0%.
“Although we know that incretin therapy is more effective than the SGLT-2 inhibitor class in regard to A1C and weight control, we were surprised by the magnitude of the effect in this study,” said Michelle D. Welch, MD, lead author of ACHIEVE-2.
“As many patients and providers are reluctant to start injectable medications, orforglipron can deliver impactful improvements in blood glucose control and weight goals in a simple daily oral medication,” Dr. Welch added.
ACHIEVE-3
ACHIEVE-3 (NCT06045221), a 52-week, randomized, open-label phase 3 trial, also simultaneously published in The Lancet, tested orforglipron head-to-head against oral semaglutide in 1,698 adults whose diabetes was inadequately controlled on metformin. Participants received orforglipron at 12 mg or 36 mg, or oral semaglutide at 7 mg or 14 mg.
From a baseline of 8.3%, hemoglobin A1c levels fell by 1.91% with orforglipron 36 mg compared with 1.47% with semaglutide 14 mg. Both orforglipron doses were superior to both semaglutide doses, according to the investigators.
Body weight fell by 8.2% with orforglipron 36 mg versus 5.3% with semaglutide 14 mg, although orforglipron was associated with more gastrointestinal symptoms and a slightly greater increase in heart rate, the authors reported.
“The findings support orforglipron as a potential new oral GLP-1 [receptor agonist] effective option, when approved, for people living with type 2 diabetes to address key known barriers associated with current injection therapy or administration recommendations,” said Julio Rosenstock, MD, lead author of ACHIEVE-3.
Longer-term data will be needed to determine how the findings translate into broader clinical practice, and the ACHIEVE-4 trial and a dedicated cardiovascular outcomes trial are assessing the cardiovascular safety of orforglipron, the authors noted.
Disclosures
All three trials were sponsored and funded by Eli Lilly and Company, the drug's developer. Several authors are employees of or hold stock in the company. Full author disclosures were provided in abstracts posted on the ADA Scientific Sessions website.
References
Giorgino F, D'Souza S, Ludwig L, et al. Orforglipron added to titrated insulin glargine in type 2 diabetes: the ACHIEVE-5 randomized clinical trial. JAMA Jun 7. doi:10.1001/jama.2026.9512
Welch M, Forst T, Jia W, et al; ACHIEVE-2 Trial Investigators. Orforglipron compared with dapagliflozin in adults with type 2 diabetes and inadequate glycaemic control with metformin (ACHIEVE-2): a multicentre, randomised, non-inferiority, open-label, phase 3 trial. Lancet 2006 Jun 8. doi:10.1016/S0140-6736(26)00800-7
Rosenstock J, Yabe D, Cox D, et al; ACHIEVE-3 Investigators. 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
American Diabetes Association. ACHIEVE trials demonstrate comparative benefits of novel, small-molecule oral GLP-1 RA, expanding oral treatment options for patient population in need of alternative solutions [press release]. June 8, 2026. https://www.prnewswire.com/news-releases/achieve-trials-demonstrate-comparative-benefits-of-novel-small-molecule-oral-glp-1-ra-expanding-oral-treatment-options-for-patient-population-in-need-of-alternative-solutions-302793432.html Accessed June 8, 2026.