The oral non-peptide GLP-1 receptor agonist orforglipron reduced HbA1c by up to 2.1% and body weight by up to 10.1 kg over 26 weeks in people with type 2 diabetes, outperforming both placebo and injectable dulaglutide.
Up to -2.10% HbA1c reductionOrforglipron achieved HbA1c reductions nearly double those of the injectable GLP-1 drug dulaglutide (-1.10%) and far exceeding placebo (-0.43%) over 26 weeks.
What the researchers found
At week 26, orforglipron at doses of 12 mg or greater produced statistically superior HbA1c reductions compared to placebo. The maximum HbA1c reduction was -2.10% (placebo-adjusted: -1.67%), compared to -0.43% with placebo and -1.10% with injectable dulaglutide 1.5 mg weekly.
Weight loss with orforglipron reached up to -10.1 kg (placebo-adjusted: -7.9 kg), compared to -2.2 kg with placebo and -3.9 kg with dulaglutide.
Gastrointestinal adverse events occurred in 44-70% of orforglipron-treated patients (vs. 18% placebo, 34% dulaglutide) but were mostly mild to moderate. Clinically significant hypoglycemia was rare (3 orforglipron patients, 1 dulaglutide). No severe hypoglycemia occurred. The study completion rate was 92%, with 79% completing the full 26 weeks of treatment.
Why it matters
This study represents a potential paradigm shift in GLP-1 therapy. Current oral GLP-1 options (like oral semaglutide) are still peptide-based and require strict fasting before dosing. Orforglipron is a non-peptide molecule that can be taken without food or water restrictions, while delivering blood sugar and weight loss results that exceeded an injectable GLP-1 drug. If confirmed in phase 3 trials, this could make GLP-1 therapy far more accessible and convenient for millions of diabetes patients.
How the study worked
This was a 26-week, phase 2, double-blind, randomized, multicentre study across 45 centres in the USA, Hungary, Poland, and Slovakia. 383 adults with type 2 diabetes (HbA1c 7.0-10.5%, BMI ≥23) on diet/exercise with or without metformin were randomized to placebo, dulaglutide 1.5 mg weekly, or one of six orforglipron dose groups (3, 12, 24, 36, or 45 mg daily, with two different escalation regimens for the 36 and 45 mg doses). Participants were masked to treatment. The primary endpoint was mean HbA1c change from baseline at week 26.
What this study cannot tell us
This is a phase 2 dose-finding study with a relatively small sample size (383 participants) and short duration (26 weeks). Long-term safety and efficacy data are needed. The gastrointestinal adverse event rate was high (up to 70%), which could affect real-world adherence. Only 79% completed the full treatment course. The study population was primarily from the US and Eastern Europe, limiting global generalizability. The study was sponsored by Eli Lilly, the drug's manufacturer.
How to read the evidence
This is a well-designed phase 2 randomized controlled trial published in The Lancet with an active comparator (dulaglutide), placebo control, and double-blinding. The evidence is strong for the dose range studied but is still preliminary — phase 3 confirmation with larger populations and longer follow-up is required for regulatory approval.
When this study was published
Published in 2023, this landmark study helped advance orforglipron into phase 3 clinical trials. By 2026, additional data from larger trials may be available, potentially including regulatory decisions.
The bigger picture
The GLP-1 receptor agonist market has exploded, with drugs like semaglutide (Ozempic/Wegovy) transforming diabetes and obesity treatment. However, most GLP-1 drugs require injections, and even oral semaglutide needs strict fasting. A non-peptide oral GLP-1 agonist that can be taken with food and water would remove major barriers to treatment adherence. Orforglipron, developed by Eli Lilly, is one of the most advanced oral non-peptide GLP-1 candidates and these phase 2 results from The Lancet helped propel it into large-scale phase 3 testing.
Questions still open
- Will the high gastrointestinal side effect rates seen at higher doses be manageable in long-term use, or will they limit practical dosing?
- How will orforglipron compare to oral semaglutide in head-to-head trials?
- Can orforglipron achieve comparable cardiovascular outcome benefits to injectable GLP-1 receptor agonists that have been proven to reduce heart attacks and strokes?
Common questions
How is orforglipron different from oral semaglutide (Rybelsus)?
Why were the side effects so common with orforglipron?
Read the original research
Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study.
Lancet (London, England), 402(10400), 472-483
Citation
Frias, Juan P; Hsia, Stanley; Eyde, Sarah; Liu, Rong; Ma, Xiaosu; Konig, Manige; Kazda, Christof; Mather, Kieren J; Haupt, Axel; Pratt, Edward; Robins, Deborah. (2023). Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study.. Lancet (London, England), 402(10400), 472-483. https://doi.org/10.1016/S0140-6736(23)01302-8