BACKGROUND: Orforglipron is a novel non-peptide (GLP-1) receptor agonist designed for daily oral administration without food or water restrictions. This study aimed to compare the efficacy and safety of orforglipron with oral semaglutide in individuals with type 2 diabetes inadequately controlled with metformin.
METHODS: In this 52-week, randomised, open-label, active-controlled, multicentre, multinational, phase 3 study, we enrolled adults (=18 years) with type 2 diabetes inadequately controlled with metformin (=1500 mg per day), glycated haemoglobin (HbA1c) between 7·0% and 10·5% (53-91 mmol/mol), and BMI at least 25 kg/m2 from 131 medical research centres and hospitals in Argentina, China, Japan, Mexico, and the USA. Participants were randomly assigned (1:1:1:1) to orforglipron (12 mg or 36 mg) or semaglutide (7 mg or 14 mg); all groups had an up to 4-week lead-in period and 52-week treatment period, with the drugs administered orally once per day. The primary objective of the study was to assess non-inferiority of orforglipron 36 mg versus semaglutide 14 mg and orforglipron 12 mg versus semaglutide 7 mg for mean change at week 52 from baseline in HbA1c (with a non-inferiority margin of 0·3%) in the intention-to-treat population. Hierarchical analysis for superiority was prespecified after attainment of non-inferiority. The treatment regimen estimand, based on data from all randomly assigned participants regardless of intercurrent events, was the primary estimand; the efficacy estimand was considered supportive. The safety endpoints used data from all participants who received at least one dose of the study drug. This trial was registered on ClinicalTrials.gov (NCT06045221) and is completed.
FINDINGS: From Sept 22, 2023, to Aug 22, 2025, 1698 participants were recruited and randomly assigned to orforglipron (n=424 on 12 mg and n=423 on 36 mg) or semaglutide (n=426 on 7 mg and n=425 on 14 mg). For the treatment regimen estimand, mean changes at week 52 from a baseline HbA1c of 8·3% were -1·71% (SE 0·07) with orforglipron 12 mg, -1·91% (0·08) with orforglipron 36 mg, -1·23% (0·05) with semaglutide 7 mg, and -1·47% (0·06) with semaglutide 14 mg. Estimated treatment differences were -0·48% (95% CI -0·65 to -0·31; p<0·0001) for orforglipron 12 mg versus semaglutide 7 mg; -0·44% (-0·62 to -0·26; p<0·0001) for orforglipron 36 mg versus semaglutide 14 mg; -0·24% (95% CI -0·41 to -0·072; p=0·0050) for orforglipron 12 mg versus semaglutide 14 mg; and -0·68% (-0·85 to -0·50; p<0·0001) for orforglipron 36 mg versus semaglutide 7 mg. The primary objective of non-inferiority was met and both orforglipron doses showed superiority to both semaglutide doses, including orforglipron 12 mg versus semaglutide 14 mg. The most frequent adverse events were gastrointestinal events (orforglipron: 249 [59%] of 424 on 12 mg and 245 [58%] of 423 on 36 mg; semaglutide: 157 [37%] of 426 on 7 mg and 193 [45%] of 425 on 14 mg), most of which were mild to moderate in severity. More participants in the orforglipron groups (37 [9%] on 12 mg and 41 [10%] on 36 mg) discontinued study treatment due to adverse events than in the semaglutide groups (19 (4%) on 7 mg and 21 (5%) on 14 mg), and mean increase in pulse rate was greater in the orforglipron groups (12 mg 3·7 bpm; 36 mg 4·7 bpm) than in the semaglutide groups (7 mg 1·0 bpm; 14 mg 1·5 bpm). Four deaths occurred during the study: one in the orforglipron 12 mg group, one in the orforglipron 36 mg group, and two in the semaglutide 7 mg group.
INTERPRETATION: In individuals with type 2 diabetes inadequately controlled with metformin, orforglipron 12 mg and 36 mg was non-inferior and superior to semaglutide 7 mg and 14 mg with respect to the mean change in HbA1c from baseline to 52 weeks. Although the safety profiles of both orforglipron and semaglutide were generally consistent with the GLP-1 receptor agonist class, the incidence of gastrointestinal events, discontinuations due to adverse events, and mean increase in pulse rate were higher with orforglipron than oral semaglutide.
FUNDING: Eli Lilly.
| Discipline Area | Score |
|---|---|
| Family Medicine (FM)/General Practice (GP) |  |
| General Internal Medicine-Primary Care(US) | |
| Internal Medicine | |
| Endocrine | Coming Soon... |
Orforglipron seems superior to semaglutide but has nearly double the withdrawals due to AEs.
A new useful oral med is good. It's a little more effective than its comparator but has a few more side effects.
The intervention drug is not on the market. I am not sure that I understand the proposed advantage.
Although the newer oral agent, orfoglipron, is more effective at glycemic control (an additional 0.5% lower A1c over semaglutide), the main reason we see a desire for and use of these products is weight loss. The oral agents yield only about half of the weight loss benefit as injectable agents.
Head-to-head comparisons to active comparators are uncommon and well appreciated! Demonstrating the superiority of orforglipron vs oral semaglutide is remarkable. The practice implications of these findings do need to be tempered by higher side effect / discontinuation rates among patients taking orforglipron. This is all as expected based on the underlying mechanisms governing the absorption of these agents. What never ceases to surprise me is that the semaglutide oral arm demonstrates as much efficacy as it does, given the burden of meal time restrictions. Great trial to serve as the introduction of a new molecule that will be an important addition to diabetes pharmacotherapy.