Orforglipron highlights superior blood sugar control and weight loss compared to oral semaglutide in head to head type 2 diabetes trial
Posted on March 2, 2026
Eli Lilly has recently announced their new detailed results from ACHIEVE-3, the first head-to-head Phase 3 trial evaluating the safety and efficacy of orforglipron, a small molecule oral GLP-1 without food or water restrictions, compared with oral semaglutide in adults with type 2 diabetes inadequately controlled with metformin. This trial enrolled 1,698 participants across four treatment arms: orforglipron 12 mg and 36 mg, and oral semaglutide 7 mg and 14 mg.
“ACHIEVE-3 gives us the first head-to-head comparison between two oral GLP-1 receptor agonist therapies in adults with type 2 diabetes, and the differences were clinically meaningful,” said Dr. Julio Rosenstock, clinical professor of medicine at the University of Texas Southwestern Medical Center and lead investigator. “Orforglipron 12 mg and 36 mg doses outperformed oral semaglutide 7 mg and 14 mg diabetes-related doses on every key endpoint we measured, including A1C and weight loss, with improvements appearing as early as four weeks and sustained throughout the study.”
| ACHIEVE-3 Full Results | |||||
| Oral Semaglutide 7 mg |
Oral Semaglutide 14 mg |
Orforglipron 12 mg |
Orforglipron 36 mg |
||
| Primary Endpoint | |||||
| Change in A1C from baseline of 8.3% at week 52 |
Efficacy estimand | -1.1 % | -1.4 % | -1.9% | -2.2% |
| Treatment‑ regimen estimand |
-1.2 % | -1.5 % | -1.7% | -1.9% | |
| Secondary Endpoints | |||||
| Change in weight from baseline of 97.0 kg (213.9 lbs) at week 52iv |
Efficacy estimand |
-3.7%
(-3.6 kg; -7.9 lbs) |
-5.3%
(-5.0 kg; -11.0 lbs) |
-6.7%
(-6.6 kg; -14.6 lbs) |
-9.2%
(-8.9 kg; -19.7 lbs) |
| Treatment‑ regimen estimand |
-3.9%
(-3.8 kg; -8.4 lbs) |
-5.3%
(-5.2 kg; -11.5 lbs) |
-6.1%
(-6.2 kg; -13.7 lbs) |
-8.2%
(-8.1 kg; -17.8 lbs) |
|
| Percentage of
participants achieving A1C |
Efficacy estimand |
54.6 % | 66.1 % | 80.0% | 85.4% |
| Treatment‑ regimen estimand |
53.9 % | 63.8 % | 72.2% | 75.8% | |
| Percentage of
participants achieving A1C |
Efficacy estimand |
40.9 % | 50.9 % | 71.8% | 76.8% |
| Treatment‑ regimen estimand |
38.4 % | 48.3 % | 62.7% | 67.7% | |
| Percentage of
participants achieving A1C |
Efficacy estimand |
7.8 % | 12.5 % | 25.4% | 37.1% |
| Treatment- regimen estimand |
7.4 % | 11.7 % | 21.4% | 31.4% | |
Note that Orforglipron showed clinically meaningful improvements from baseline across key cardiovascular risk factors, including non-HDL cholesterol, HDL cholesterol, VLDL cholesterol, total cholesterol, systolic blood pressure and triglycerides.
“The results of ACHIEVE-3 highlight the potential advantages of orforglipron over oral semaglutide for type 2 diabetes: greater A1C reduction, more weight loss, and the ability to take it without food or water timing restrictions — that’s a combination that could matter significantly to people managing their disease day in and day out,” said Kenneth Custer, Ph.D., executive vice president and president of Lilly Cardiometabolic Health. “With global submissions underway and FDA action on obesity expected next quarter, we’re focused on making this option available as quickly as possible.”
Related Topics and Keywords
Lilly's oral GLP-1, orforglipron, type 2 diabetes
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