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Saturday, June 21, 2025

Lilly Novel Oral GLP-1 Agent Cuts A1c, Weight in Early Diabetes

 An investigational, oral small-molecule GLP-1 receptor agonist improved glycated hemoglobin levels in adults with early-stage type 2 diabetes, a phase III randomized trial found.

Among 559 participants in ACHIEVE-1, all doses of orforglipron monotherapy were superior to placebo for HbA1c reduction over 40 weeks (P<0.001 for all comparisons), reported Julio Rosenstock, MD, of Velocity Clinical Research at Medical City in Dallas:

  • 3-mg dose: -1.24 percentage points change from baseline (95% CI -1.44 to -1.04)
  • 12-mg dose: -1.47 percentage points (95% CI -1.67 to -1.27)
  • 36-mg dose: -1.48 percentage points (95% CI -1.66 to -1.29)
  • Placebo: -0.41 percentage points (95% CI -0.60 to -0.22)

Baseline HbA1c started at 8% and dropped to 6.5-6.7% with all doses of orforglipron by week 40. The drop was quick too, with noticeable reductions within 4 weeks. "Patients like to see rapid effects," said Rosenstock at the American Diabetes Associationopens in a new tab or window (ADA) annual meeting. The findings were simultaneously published in the New England Journal of Medicineopens in a new tab or window.

"Oral small-molecule non-peptide GLP-1 receptor agonists such as orforglipron ... have the potential to be widely accepted as much [earlier] therapy for type 2 diabetes," he added. "I think these drugs have the potential to be first-line therapy in people with type 2 diabetes."

Participants, whose baseline BMI had to be at least 23, also lost some weight with orforglipron. They had a 4.5% reduction in body weight with the 3-mg dose, 5.8% reduction with the 12-mg dose, and 7.6% reduction with the 36-mg dose compared with a 1.7% drop with placebo. These reductions corresponded to weight reductions of -4.2 kg (9.3 lbs), -5.2 kg (11.5 lbs), -7.2 kg (15.9 lbs), and -1.5 kg (3.3 lbs), respectively.

To put these metabolic improvements into perspective, 14-mg daily oral semaglutide (Rybelsus) yielded a 1.5% HbA1c reduction and a 4.9 kg (10.8 lbs) weight loss after 26 weeks in the PIONEER-1 trialopens in a new tab or window. In SUSTAIN-1opens in a new tab or window, 1-mg once-weekly injectable semaglutide (Ozempic) yielded a 1.55% HbA1c reduction and 4.6 kg (10.1 lbs) body weight reduction in patients with type 2 diabetes.

In comparison, orforglipron's glycated hemoglobin reduction was similar to semaglutide's but body weight reduction was a bit more. Rosenstock pointed out that this is simply based on a comparison of clinical trial data, and the drugs have yet to go head-to-head in a clinical trial.

One upside to orforglipron is that it doesn't carry the same timed restriction on intake of food, water, or other medications like oral semaglutide does, added Rosenstock, arguably making it a more convenient option.

Orforglipron acts as a selective, high-affinity, partial agonist of the GLP-1 receptor that favors biased activation toward G protein over β-arrestin recruitment at the GLP-1 receptor.

Running in parallel with ACHIEVE is the ATTAIN clinical program testing orforglipron in obesity. A 2023 phase II trialopens in a new tab or window presented at ADA found people with obesity on orforglipron -- tested in 12, 24, 36, or 45 mg once-daily doses -- lost between 8.6-12.6% of body weight within 26 weeks.

As for the multicenter ACHIEVE-1, 559 adults were recruited from China, India, Japan, Mexico, and the U.S. and randomized 1:1:1:1 to one of the four trial arms. All had to have treatment-naïve type 2 diabetes only managed with diet and exercise and an HbA1c of at least 7% but no higher than 9.5%.

Those on orforglipron adhered to the following dose-escalation regimen: 1 mg starting dose, and the dose increased every 4 weeks (to 3 mg, 6 mg, 12 mg, 24 mg, and 36 mg, as applicable) until the assigned maintenance dose was reached.

By week 40, orforglipron-treated adults also had significant reductions in fasting serum glucose of 31 mg/dL with the 3-mg and 12-mg doses, and 35 mg/dL with the 36-mg dose compared with 11 mg/dL with placebo.

As expected with a GLP-1 agent, the most common adverse events (AEs) were mild-to-moderate gastrointestinal AEs, most of which occurred during dose escalation.

No episodes of severe hypoglycemia were reported. Permanent discontinuation due to AEs occurred in 4-8% of orforglipron participants and 1% of participants receiving placebo.

Developer Eli Lilly saidopens in a new tab or window it expects to submit orforglipron for weight management for regulatory approval by the end of this year, with the submission for the treatment of type 2 diabetes expected in 2026.

Disclosures

ACHIEVE-1 was funded by Eli Lilly. Some co-authors are company employees.

Rosenstock disclosed relationships with Eli Lilly, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Biomea Fusion, Boehringer Ingelheim, Corcept Therapeutics, Hanmi Pharmaceutical Co, Novartis, Novo Nordisk, Oramed, Pfizer, Regeneron, Regor Pharmaceutical, Roche, Sanofi, Structure Therapeutics, Terns, and Zealand.

Co-authors disclosed multiple relationships with industry including Eli Lilly.

Primary Source

New England Journal of Medicine

Source Reference: opens in a new tab or windowRosenstock J, et al "Orforglipron, an oral small-molecule GLP-1 receptor agonist, in early type 2 diabetes" N Engl J Med 2025; DOI: 10.1056/NEJMoa2505669.

https://www.medpagetoday.com/meetingcoverage/ada/116186

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