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Trial · Interventional

CompletedPhase 3Results postedRegistry data

A Study of Orforglipron (LY3502970) Compared With Semaglutide in Participants With Type 2 Diabetes Inadequately Controlled With Metformin

Short name ACHIEVE-3

NCTNCT06045221 (opens ClinicalTrials.gov in a new tab)Other id18565Other idJ2A-MC-GZGUOther idU1111-1290-6014
Open at ClinicalTrials.govAsk about this trial

Overview

Status
Completed
Phase
Phase 3
Enrollment
1,698 participants (actual)
Sponsor
Eli Lilly and Company · Industry
Design
Randomized · Open label (no masking)
Countries
6 countries

United States, Argentina, China, Japan, Mexico, Puerto Rico

Start
22 Sept 2023
Primary completion
22 Aug 2025
Completion
22 Aug 2025
First posted
21 Sept 2023
Last update posted
15 Sept 2026
Conditions
Type 2 Diabetes

Timeline

1 trial · 1 completed · 1 with posted results

  • Completed
  • Ongoing
  • Not yet recruiting
  • Stopped
  • Estimated dates (est.)
  • Results posted
2023202420252026
  1. Ph 3

    ACHIEVE-3

    NCT06045221

    22 Sept 2023 to 22 Aug 2025

Registry summary

Text and fields below are the sponsor's entries at ClinicalTrials.gov, shown as posted.

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.

Interventions

  • OrforglipronDrug
  • SemaglutideDrug

Arms4

  • Experimental

    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.

  • Experimental

    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.

  • Active comparator

    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.

  • Active comparator

    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.

Primary outcomes1

Outcomes the sponsor listed as primary.

  1. 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]

    Time frame · Baseline, Week 52

    Registry description

    * HbA1c is the glycosylated fraction of hemoglobin A. It is measured to identify average plasma glucose concentration over prolonged periods of time. * LS mean was analysed by mixed model repeated measures (MMRM) model with Country + Baseline\*Time\*Treatment + Strata\*Time\*Treatment as variables. Strata is defined by joint levels of HbA1c level (\<=8.0%, \>8.0%).

Secondary outcomes(20)

  1. 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]

    Time frame · Baseline, Week 52

    Registry description

    * HbA1c is the glycosylated fraction of hemoglobin A. It is measured to identify average plasma glucose concentration over prolonged periods of time. * LS mean was analysed by mixed model repeated measures (MMRM) model with Country + Baseline\*Time\*Treatment + Strata\*Time\*Treatment as variables. Strata is defined by joint levels of HbA1c level (\<=8.0%, \>8.0%).

  2. Percentage of Participants Who Achieved HbA1c <7.0% [53 Millimoles/Mole (mmol/Mol)]

    Time frame · Week 52

    Registry description

    The reported values represent model-based group mean percentages estimated from a logistic regression model using imputed data, with estimates combined across multiple imputations using Rubin's rule. Logistic regression model variables: Country + Treatment\*Baseline + Treatment\*Strata (defined by baseline HbA1c level \[\<=8.0%, \>8.0%\]).

  3. Percentage of Participants Who Achieved HbA1c <=6.5% (48 mmol/Mol)

    Time frame · Week 52

    Registry description

    The reported values represent model-based group mean percentages estimated from a logistic regression model using imputed data, with estimates combined across multiple imputations using Rubin's rule. Logistic regression model variables: Country + Treatment\*Baseline + Treatment\*Strata (defined by baseline HbA1c level \[\<=8.0%, \>8.0%\]).

  4. Percentage of Participants Who Achieved HbA1c <5.7% (39 mmol/Mol)

    Time frame · Week 52

    Registry description

    The reported values represent model-based group mean percentages estimated from a logistic regression model using imputed data, with estimates combined across multiple imputations using Rubin's rule. Logistic regression model variables: Country + Treatment\*Baseline + Treatment\*Strata (defined by baseline HbA1c level \[\<=8.0%, \>8.0%\]).

  5. Percent Change From Baseline in Body Weight

    Time frame · Baseline, Week 52

    Registry description

    LS mean was analysed by MMRM model with Country + Baseline\*Time\*Treatment + Strata\*Time\*Treatment as variables. Strata is defined by joint levels of HbA1c level (\<=8.0%, \>8.0%).

  6. Change From Baseline in Body Weight

    Time frame · Baseline, Week 52

    Registry description

    LS mean was analysed by MMRM model with Country + Baseline\*Time\*Treatment + Strata\*Time\*Treatment as variables. Strata is defined by joint levels of HbA1c level (\<=8.0%, \>8.0%).

  7. Change From Baseline in Fasting Serum Glucose

    Time frame · Baseline, Week 52

    Registry description

    LS mean was analysed by MMRM model with Country + Baseline\*Time\*Treatment + Strata\*Time\*Treatment as variables. Strata is defined by joint levels of HbA1c level (\<=8.0%, \>8.0%).

  8. Change From Baseline in Daily Average 7-point Self-monitored Blood Glucose (SMBG)

    Time frame · Baseline, Week 52

    Registry description

    The SMBG data were collected at the following 7 time points: Morning Premeal - Fasting, Morning 2-hour Post meal, Midday Premeal, Midday 2-hour Post meal, Evening Premeal, Evening 2-hour Post meal and Bedtime. The daily average was calculated as the average of the 7 blood glucose values collected on a particular day. LS mean was analysed by MMRM model with Country + Baseline\*Time\*Treatment + Strata\*Time\*Treatment as variables. Strata is defined by joint levels of HbA1c level (\<=8.0%, \>8.0%).

  9. Percentage of Participants Who Achieved Weight Loss of >=5%

    Time frame · Week 52

    Registry description

    The reported values represent model-based group mean percentages estimated from a logistic regression model using imputed data, with estimates combined across multiple imputations using Rubin's rule. Logistic regression model variables: Country + Treatment\*Baseline + Treatment\*Strata (defined by baseline HbA1c level \[\<=8.0%, \>8.0%\]).

  10. Percentage of Participants Who Achieved Weight Loss of >=10%

    Time frame · Week 52

    Registry description

    The reported values represent model-based group mean percentages estimated from a logistic regression model using imputed data, with estimates combined across multiple imputations using Rubin's rule. Logistic regression model variables: Country + Treatment\*Baseline + Treatment\*Strata (defined by baseline HbA1c level \[\<=8.0%, \>8.0%\]).

  11. Percentage of Participants Who Achieved Weight Loss of >=15%

    Time frame · Week 52

    Registry description

    The reported values represent model-based group mean percentages estimated from a logistic regression model using imputed data, with estimates combined across multiple imputations using Rubin's rule. Logistic regression model variables: Country + Treatment\*Baseline + Treatment\*Strata (defined by baseline HbA1c level \[\<=8.0%, \>8.0%\]).

  12. Change From Baseline in Systolic Blood Pressure (SBP)

    Time frame · Baseline, Week 52

    Registry description

    LS mean was analysed by MMRM model with Country + Baseline\*Time\*Treatment + Strata\*Time\*Treatment as variables. Strata is defined by joint levels of HbA1c level (\<=8.0%, \>8.0%).

  13. Change From Baseline in Diastolic Blood Pressure (DBP)

    Time frame · Baseline, Week 52

    Registry description

    LS mean was analysed by MMRM model with Country + Baseline\*Time\*Treatment + Strata\*Time\*Treatment as variables. Strata is defined by joint levels of HbA1c level (\<=8.0%, \>8.0%).

  14. Percent Change From Baseline in Total Serum Cholesterol

    Time frame · Baseline, Week 52

    Registry description

    LS mean was analysed by MMRM model with Country + log(Baseline)\*Time\*Treatment + Strata\*Time\*Treatment as variables. Strata is defined by joint levels of HbA1c level (\<=8.0%, \>8.0%).

  15. Percent Change From Baseline in Serum Low Density Lipoprotein (LDL) Cholesterol

    Time frame · Baseline, Week 52

    Registry description

    LS mean was analysed by MMRM model with Country + log(Baseline)\*Time\*Treatment + Strata\*Time\*Treatment as variables. Strata is defined by joint levels of HbA1c level (\<=8.0%, \>8.0%).

  16. Percent Change From Baseline in Serum Non High Density Lipoprotein (Non-HDL) Cholesterol

    Time frame · Baseline, Week 52

    Registry description

    LS mean was analysed by MMRM model with Country + log(Baseline)\*Time\*Treatment + Strata\*Time\*Treatment as variables. Strata is defined by joint levels of HbA1c level (\<=8.0%, \>8.0%).

  17. Percent Change From Baseline in Serum Triglycerides

    Time frame · Baseline, Week 52

    Registry description

    LS mean was analysed by MMRM model with Country + log(Baseline)\*Time\*Treatment + Strata\*Time\*Treatment as variables. Strata is defined by joint levels of HbA1c level (\<=8.0%, \>8.0%).

  18. Percent Change From Baseline in Serum High Density Lipoprotein (HDL) Cholesterol

    Time frame · Baseline, Week 52

    Registry description

    LS mean was analysed by MMRM model with Country + log(Baseline)\*Time\*Treatment + Strata\*Time\*Treatment as variables. Strata is defined by joint levels of HbA1c level (\<=8.0%, \>8.0%).

  19. Percent Change From Baseline in Serum Very Low Density Lipoprotein (VLDL) Cholesterol

    Time frame · Baseline, Week 52

    Registry description

    LS mean was analysed by MMRM model with Country + log(Baseline)\*Time\*Treatment + Strata\*Time\*Treatment as variables. Strata is defined by joint levels of HbA1c level (\<=8.0%, \>8.0%).

  20. Change From Baseline in Short Form 36 Version 2 (SF-36-v2) Acute Form (Physical Component and Mental Component Scores)

    Time frame · Baseline, Week 52

    Registry description

    The SF-36v2 is a participant-reported measure designed to assess health status using 36 items across 8 domains: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. The physical functioning domain assesses limitations due to health "now," whereas the remaining domains assess functioning "in the past week." Each domain is scored individually, and information from these 8 domains is aggregated into 2 health component summary scores, the physical component summary and mental component summary. Items are answered on Likert scales of varying lengths (3-point, 5-point, or 6-point scales). Scoring of each domain and both summary scores are norm based and presented in the form of T-scores, with a mean of 50 and a standard deviation of 10. Higher scores indicate better levels of function and/or better health. Range cannot be specified in norm-based scores.

Posted results

Values are shown as posted at ClinicalTrials.gov, with their units. PepBank has not converted, pooled or compared them.

Primary outcome results

Primary outcomeLeast squares mean· Baseline, Week 52

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]

GroupValue (Percentage of HbA1c)Spread
12 mg Orforglipron-1.910.058
36 mg Orforglipron-2.160.051
7 mg Semaglutide-1.110.063
14 mg Semaglutide-1.450.061
Secondary and other outcome results(7)
Secondary outcomeLeast squares mean· Baseline, Week 52

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]

GroupValue (Percentage of HbA1c)Spread
12 mg Orforglipron-1.910.058
36 mg Orforglipron-2.160.051
7 mg Semaglutide-1.110.063
14 mg Semaglutide-1.450.061
Secondary outcomeMean· Week 52

Percentage of Participants Who Achieved HbA1c <7.0% [53 Millimoles/Mole (mmol/Mol)]

GroupValue (percentage of participants)Spread
12 mg Orforglipron80.041.97
36 mg Orforglipron85.411.80
7 mg Semaglutide54.632.45
14 mg Semaglutide66.122.27
Secondary outcomeMean· Week 52

Percentage of Participants Who Achieved HbA1c <=6.5% (48 mmol/Mol)

GroupValue (percentage of participants)Spread
12 mg Orforglipron71.762.26
36 mg Orforglipron76.822.14
7 mg Semaglutide40.872.38
14 mg Semaglutide50.882.42
Secondary outcomeMean· Week 52

Percentage of Participants Who Achieved HbA1c <5.7% (39 mmol/Mol)

GroupValue (percentage of participants)Spread
12 mg Orforglipron25.442.24
36 mg Orforglipron37.092.56
7 mg Semaglutide7.841.27
14 mg Semaglutide12.541.64
Secondary outcomeLeast squares mean· Baseline, Week 52

Percent Change From Baseline in Body Weight

GroupValue (Percent change)Spread
12 mg Orforglipron-6.70.34
36 mg Orforglipron-9.20.40
7 mg Semaglutide-3.70.27
14 mg Semaglutide-5.30.30
Secondary outcomeLeast squares mean· Baseline, Week 52

Change From Baseline in Body Weight

GroupValue (kilogram (kg))Spread
12 mg Orforglipron-6.60.34
36 mg Orforglipron-8.90.39
7 mg Semaglutide-3.60.26
14 mg Semaglutide-5.00.29
Secondary outcomeLeast squares mean· Baseline, Week 52

Change From Baseline in Fasting Serum Glucose

GroupValue (milligram per deciliter (mg/dL))Spread
12 mg Orforglipron-55.21.77
36 mg Orforglipron-60.11.55
7 mg Semaglutide-28.92.49
14 mg Semaglutide-40.22.33

Adverse events, as posted

Adverse events as posted: participants affected out of participants at risk, by group
GroupDeathsSerious eventsOther events
12 mg OrforglipronParticipants 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.1 / 42421 / 424278 / 424
36 mg OrforglipronParticipants 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.1 / 42340 / 423278 / 423
7 mg SemaglutideParticipants 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.2 / 42619 / 426225 / 426
14 mg SemaglutideParticipants 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.0 / 42524 / 425249 / 425

Each cell reads participants affected / participants at risk, as the registry posted them.

Registry data comes from ClinicalTrials.gov. Study results come from studies, not from the registry. How PepBank works

Studies1

Studies that cite this trial.

Studies with results

1 study on this page

Indexing hint: Randomized controlled trial · 2026

33 results

Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial.

Rosenstock et al. 2026Lancet (London, England)cited by 22

PMID 41765029DOI 10.1016/s0140-6736(26)00202-3PUB-41765029

Full text at the publisher33 results
Publisher pageSee results (33)

Eligibility

Who could join, as posted.

Sex
All
Age
from 18 Years
Healthy volunteers
Not accepted
Inclusion and exclusion criteria, as posted
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.

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