Phase 3 · Orforglipron

ACHIEVE-3 trial results

A Phase 3, Randomized, Open-Label Study to Investigate the Efficacy and Safety of Once Daily Oral LY3502970 Compared With Oral Semaglutide in Adult Participants With Type 2 Diabetes and Inadequate Glycemic Control With Metformin (ACHIEVE-3)

Change From Baseline in Hemoglobin A1c (HbA1c) [Non-inferiority of 36 mg Orforglipron Versus 14 mg Semaglutide and 12 mg Orforglipron Versus 7 mg Semaglutide] (Percentage of HbA1c), Baseline, Week 52. 12 mg Orforglipron: -1.91; 36 mg Orforglipron: -2.16; 7 mg Semaglutide: -1.11; 14 mg Semaglutide: -1.45.

Participants
1,698
Status
completed
Completed
2025-08-22
Sponsor
Eli Lilly and Company

As posted on ClinicalTrials.gov (NCT06045221), updated at source Sep 15, 2026. Read again whenever the registry updates it. Registry figures can differ from a published paper, which may use another analysis.

Primary outcome

What ACHIEVE-3 measured first

Change From Baseline in Hemoglobin A1c (HbA1c) [Non-inferiority of 36 mg Orforglipron Versus 14 mg Semaglutide and 12 mg Orforglipron Versus 7 mg Semaglutide]Percentage of HbA1c · Baseline, Week 52 · least squares mean
12 mg Orforglipronn=32636 mg Orforglipronn=3227 mg Semaglutiden=32514 mg Semaglutiden=351
-1.91(0.058)-2.16(0.051)-1.11(0.063)-1.45(0.061)
Side effects by arm

Side effects in ACHIEVE-3

Percent of participants affected, Baseline to end of safety follow-up (up to 57 weeks). The most common events the registry lists.

Event12 mg Orforglipron36 mg Orforglipron7 mg Semaglutide14 mg Semaglutide
Any serious event5%9.5%4.5%5.6%
Nausea26.4%27.4%13.1%21.2%
Diarrhoea21.7%23.4%13.1%18.1%
Vomiting17%16.5%7.7%10.4%
Hyperglycaemia5.9%4.7%16.2%8%
Diabetic retinopathy13.4%14.2%12.7%13.6%
Constipation13.2%13%7.7%8.9%
Dyspepsia11.3%10.4%4.2%7.8%
Eructation9.9%7.6%4%3.3%
Abdominal distension5.7%8%2.6%3.3%
Decreased appetite7.1%6.9%4.9%6.4%
Gastrooesophageal reflux disease5.7%6.1%2.8%4.2%
Hypertension2.8%3.5%4.7%6.1%
Abdominal pain5%5.4%3.1%3.3%
Flatulence5.2%2.8%3.5%1.6%
Headache5.2%3.8%4.5%4.5%
Secondary outcomes

What else it measured

Change From Baseline in Hemoglobin A1c (HbA1c) [Non-inferiority of 12 mg Orforglipron Versus 14 mg Semaglutide, Superiority of 12 mg and 36 mg Orforglipron Versus 7 mg and 14 mg Semaglutide]Percentage of HbA1c · Baseline, Week 52 · least squares mean
12 mg Orforglipronn=32636 mg Orforglipronn=3227 mg Semaglutiden=32514 mg Semaglutiden=351
-1.91(0.058)-2.16(0.051)-1.11(0.063)-1.45(0.061)
Percentage of Participants Who Achieved HbA1c <7.0% [53 Millimoles/Mole (mmol/Mol)]percentage of participants · Week 52 · mean
12 mg Orforglipronn=42436 mg Orforglipronn=4237 mg Semaglutiden=42614 mg Semaglutiden=425
80.04(1.97)85.41(1.80)54.63(2.45)66.12(2.27)
Percentage of Participants Who Achieved HbA1c <=6.5% (48 mmol/Mol)percentage of participants · Week 52 · mean
12 mg Orforglipronn=42436 mg Orforglipronn=4237 mg Semaglutiden=42614 mg Semaglutiden=425
71.76(2.26)76.82(2.14)40.87(2.38)50.88(2.42)
Percentage of Participants Who Achieved HbA1c <5.7% (39 mmol/Mol)percentage of participants · Week 52 · mean
12 mg Orforglipronn=42436 mg Orforglipronn=4237 mg Semaglutiden=42614 mg Semaglutiden=425
25.44(2.24)37.09(2.56)7.84(1.27)12.54(1.64)
Percent Change From Baseline in Body WeightPercent change · Baseline, Week 52 · least squares mean
12 mg Orforglipronn=33136 mg Orforglipronn=3237 mg Semaglutiden=32514 mg Semaglutiden=356
-6.7(0.34)-9.2(0.40)-3.7(0.27)-5.3(0.30)
Change From Baseline in Body Weightkilogram (kg) · Baseline, Week 52 · least squares mean
12 mg Orforglipronn=33136 mg Orforglipronn=3237 mg Semaglutiden=32514 mg Semaglutiden=356
-6.6(0.34)-8.9(0.39)-3.6(0.26)-5.0(0.29)
Change From Baseline in Fasting Serum Glucosemilligram per deciliter (mg/dL) · Baseline, Week 52 · least squares mean
12 mg Orforglipronn=32636 mg Orforglipronn=3217 mg Semaglutiden=32614 mg Semaglutiden=353
-55.2(1.77)-60.1(1.55)-28.9(2.49)-40.2(2.33)
Change From Baseline in Daily Average 7-point Self-monitored Blood Glucose (SMBG)milligram per deciliter (mg/dL) · Baseline, Week 52 · least squares mean
12 mg Orforglipronn=26236 mg Orforglipronn=2447 mg Semaglutiden=25414 mg Semaglutiden=278
-69.4(1.60)-74.9(1.40)-51.2(2.10)-61.4(1.48)
Percentage of Participants Who Achieved Weight Loss of >=5%percentage of participants · Week 52 · mean
12 mg Orforglipronn=42436 mg Orforglipronn=4237 mg Semaglutiden=42614 mg Semaglutiden=425
59.18(2.55)69.49(2.39)36.89(2.53)49.39(2.57)
Percentage of Participants Who Achieved Weight Loss of >=10%percentage of participants · Week 52 · mean
12 mg Orforglipronn=42436 mg Orforglipronn=4237 mg Semaglutiden=42614 mg Semaglutiden=425
28.23(2.34)43.46(2.54)13.18(1.84)20.95(2.08)
Percentage of Participants Who Achieved Weight Loss of >=15%percentage of participants · Week 52 · mean
12 mg Orforglipronn=42436 mg Orforglipronn=4237 mg Semaglutiden=42614 mg Semaglutiden=425
11.99(1.65)23.21(2.17)4.99(1.19)6.45(1.25)
Change From Baseline in Systolic Blood Pressure (SBP)millimeters of mercury (mmHg) · Baseline, Week 52 · least squares mean
12 mg Orforglipronn=33136 mg Orforglipronn=3237 mg Semaglutiden=32514 mg Semaglutiden=356
-4.5(0.55)-5.4(0.65)-2.0(0.58)-2.7(0.59)
The trial

How ACHIEVE-3 was run

The main purpose of this study is to assess efficacy and safety of orforglipron compared with oral semaglutide in participants with Type 2 diabetes and inadequate glycemic control with metformin.The study will last around 61 weeks.

  • 12 mg Orforglipron: Participants initiated treatment with a 1 mg once-daily oral dose of orforglipron and increased the dose every 4 weeks until the targeted dose of 12 mg once-daily was reached, after which this dose was to be continued for the remainder of the 52-week treatment period.
  • 36 mg Orforglipron: Participants initiated treatment with a 1 mg once-daily oral dose of orforglipron and increased the dose every 4 weeks until the targeted dose of 36 mg once-daily was reached, after which this dose was to be continued for the remainder of the 52-week treatment period.
  • 7 mg Semaglutide: Participants initiated treatment with a 3 mg once-daily oral dose of semaglutide and increased the dose every 4 weeks until the targeted dose of 7 mg once-daily was reached, after which this dose was to be continued for the remainder of the 52-week treatment period.
  • 14 mg Semaglutide: Participants initiated treatment with a 3 mg once-daily oral dose of semaglutide and increased the dose every 4 weeks until the targeted dose of 14 mg once-daily was reached, after which this dose was to be continued for the remainder of the 52-week treatment period.
Who could join the trial

Inclusion Criteria: * Have Type 2 Diabetes * Have HbA1c ≥7.0% (53 mmol/mol) to ≤10.5% (91 mmol/mol), as determined by the central laboratory at screening. * Have been on stable diabetes treatment with metformin ≥1500 milligram (mg)/day during the 90 days prior to screening and maintained through randomization. * Are of stable body weight (±5%) for at least 90 days prior to screening and agree to not initiate an intensive diet or exercise program during the study with the intent of reducing body weight, other than the lifestyle and/or dietary measures for diabetes treatment Exclusion Criteria: * Have Type 1 Diabetes * Are currently receiving or planning to receive treatment for diabetic retinopathy and/or macular edema, for example, laser photocoagulation or intravitreal injections of anti-vascular endothelial growth factor inhibitors. * Have a history of ketoacidosis or hyperosmolar state or coma within the last 6 months prior to screening, or between screening and randomization. * Have a New York Heart Association functional classification IV congestive heart failure. * Have an estimated glomerular filtration rate (eGFR) \<45 milliliter/minute (mL/min)/1.73 square meter (m²) or lower than the country-specific threshold for discontinuing metformin therapy per local label as determined by the central laboratory at screening. * Have a serum calcitonin level of ≥35 nanogram/Liter (ng/L), as determined by the central laboratory at screening. * Have a history of an active or untreated malignancy or are in remission from a clinically significant malignancy for less than 5 years.

Published papers

Papers from ACHIEVE-3

Trial averages do not predict what one person will experience. Results are shown as the registry posts them, without interpretation.

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