Phase 3 · Orforglipron

ACHIEVE-2 trial results

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

Change From Baseline in HbA1c [Noninferiority Analysis] (percentage of HbA1c), Baseline, Week 40. Orforglipron 3 mg: -1.32; Orforglipron 12 mg: -1.74; Orforglipron 36 mg: -1.73; Dapagliflozin 10 mg: -0.76.

Participants
962
Status
completed
Completed
2025-09-26
Sponsor
Eli Lilly and Company

As posted on ClinicalTrials.gov (NCT06192108), updated at source Oct 16, 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-2 measured first

Change From Baseline in HbA1c [Noninferiority Analysis]percentage of HbA1c · Baseline, Week 40 · least squares mean
Orforglipron 3 mgn=240Orforglipron 12 mgn=241Orforglipron 36 mgn=241Dapagliflozin 10 mgn=240
-1.32(0.074)-1.74(0.062)-1.73(0.079)-0.76(0.076)
Side effects by arm

Side effects in ACHIEVE-2

Percent of participants affected, Baseline Up to Week 42. The most common events the registry lists.

EventOrforglipron 3 mgOrforglipron 12 mgOrforglipron 36 mgDapagliflozin 10 mg
Any serious event3.3%5.8%4.1%4.6%
Nausea19.6%17.8%22.4%1.7%
Diarrhoea18.3%16.6%19.9%5%
Diabetic retinopathy12.1%12.4%11.2%15.4%
Vomiting7.9%8.3%12%1.7%
Constipation7.9%8.3%10.4%0.8%
Dyspepsia6.3%5%10.4%0.8%
Abdominal distension5%5.4%8.3%1.3%
Decreased appetite5%3.3%8.3%0%
Nasopharyngitis7.1%5.8%6.6%4.2%
Hyperglycaemia5.8%2.5%1.2%6.3%
Lipase increased5.4%6.2%5.8%2.9%
Gastrooesophageal reflux disease2.9%2.5%5.8%0.4%
Eructation5.4%4.1%5%0%
Vulvovaginal mycotic infection0%0%0.8%5.3%
Urinary tract infection3.3%1.2%2.1%5%
Headache2.1%3.7%5%1.3%
Cataract2.5%1.7%0.8%4.6%
Upper respiratory tract infection2.1%4.6%2.9%2.9%
Gastritis2.5%4.1%2.5%0%
Fatigue2.1%1.2%4.1%0.4%
Abdominal pain3.8%3.7%2.5%0%
Flatulence2.5%3.7%2.9%0%
Retinopathy hypertensive0.8%2.9%1.2%3.3%
Influenza2.9%2.1%3.3%2.1%
Hyperuricaemia1.7%2.9%2.1%1.3%
Secondary outcomes

What else it measured

Change From Baseline in HbA1c [Superiority Analysis]percentage of HbA1c · Baseline, Week 40 · least squares mean
Orforglipron 3 mgn=240Orforglipron 12 mgn=241Orforglipron 36 mgn=241Dapagliflozin 10 mgn=240
-1.32(0.074)-1.74(0.062)-1.73(0.079)-0.76(0.076)
Percentage of Participants With an HbA1c Target Value of < 7.0% (53 mmol/Mol)percentage of participants · Week 40 · number
Orforglipron 3 mgn=240Orforglipron 12 mgn=241Orforglipron 36 mgn=241Dapagliflozin 10 mgn=240
63.2580.0977.9437.03
Percentage of Participants With an HbA1c Target Value of ≤6.5% (48 mmol/Mol)percentage of participants · Week 40 · number
Orforglipron 3 mgn=240Orforglipron 12 mgn=241Orforglipron 36 mgn=241Dapagliflozin 10 mgn=240
54.6266.6968.6221.59
Percent Change From Baseline in Body Weightpercent change · Baseline, Week 40 · least squares mean
Orforglipron 3 mgn=240Orforglipron 12 mgn=241Orforglipron 36 mgn=241Dapagliflozin 10 mgn=240
-3.5(0.38)-6.3(0.40)-7.3(0.49)-3.0(0.27)
Change From Baseline in Body Weightkilogram (kg) · Baseline, Week 40 · least squares mean
Orforglipron 3 mgn=240Orforglipron 12 mgn=241Orforglipron 36 mgn=241Dapagliflozin 10 mgn=240
-3.2(0.33)-5.8(0.37)-6.8(0.46)-2.7(0.25)
Percent Change From Baseline in Non-High-Density Lipoprotein (Non-HDL) Cholesterolpercent change · Baseline, Week 40 · geometric least squares mean
Orforglipron 3 mgn=233Orforglipron 12 mgn=235Orforglipron 36 mgn=237Dapagliflozin 10 mgn=234
-2.80(1.634)-8.17(1.597)-4.99(1.774)0.06(1.766)
Percent Change From Baseline in Triglyceridespercent change · Baseline, Week 40 · geometric least squares mean
Orforglipron 3 mgn=230Orforglipron 12 mgn=232Orforglipron 36 mgn=234Dapagliflozin 10 mgn=232
-9.87(2.499)-12.74(2.704)-14.76(2.447)-4.00(2.594)
Change From Baseline in Systolic Blood Pressure (SBP)millimeters of mercury (mmHg) · Baseline, Week 40 · least squares mean
Orforglipron 3 mgn=240Orforglipron 12 mgn=241Orforglipron 36 mgn=241Dapagliflozin 10 mgn=240
-2.8(0.65)-5.1(0.69)-5.8(0.68)-3.8(0.59)
Change From Baseline in Fasting Serum Glucose (FSG)milligram per deciliter (mg/dL) · Baseline, Week 40 · least squares mean
Orforglipron 3 mgn=229Orforglipron 12 mgn=230Orforglipron 36 mgn=235Dapagliflozin 10 mgn=231
-32.3(2.55)-43.1(2.39)-43.9(2.44)-22.5(2.91)
Percentage of Participants With ≥ 5% Body Weight Reductionpercentage of participants · Week 40 · number
Orforglipron 3 mgn=240Orforglipron 12 mgn=241Orforglipron 36 mgn=241Dapagliflozin 10 mgn=240
38.5755.8961.2627.91
Percentage of Participants With ≥ 10% Body Weight Reductionpercentage of participants · Week 40 · number
Orforglipron 3 mgn=240Orforglipron 12 mgn=241Orforglipron 36 mgn=241Dapagliflozin 10 mgn=240
14.1529.7433.605.68
Percentage of Participants With ≥ 15% Body Weight Reductionpercentage of participants · Week 40 · number
Orforglipron 3 mgn=240Orforglipron 12 mgn=241Orforglipron 36 mgn=241Dapagliflozin 10 mgn=240
3.188.9317.461.06
The trial

How ACHIEVE-2 was run

The main purpose of this study is to assess the safety and efficacy of orforglipron compared with dapagliflozin in improving blood sugar control in participants with type 2 diabetes (T2D) with inadequate glycemic control using metformin. The study will last approximately 46 weeks.

  • Orforglipron 3 mg: Participants received orforglipron, administered orally once daily (QD), starting at a dose of 1 milligram (mg) and escalated at week 4 to a dose of 3 mg, which was then maintained up to week 40.
  • Orforglipron 12 mg: Participants received orforglipron, administered orally QD, starting at a dose of 1 mg and escalated every 4 weeks (to 3 mg at week 4 and 6 mg at week 8) until reaching a dose of 12 mg at week 12, which was then maintained up to week 40.
  • Orforglipron 36 mg: Participants received orforglipron, administered orally QD, starting at a dose of 1 mg and escalated every 4 weeks (to 3 mg at week 4, 6 mg at week 8, 12 mg at week 12, and 24 mg at week 16) until reaching a dose of 36 mg at week 20, which was then maintained up to week 40.
  • Dapagliflozin 10 mg: Participants received dapagliflozin, administered orally QD, at a fixed dose of 10 mg starting at randomization, which was maintained up to week 40.
Who could join the trial

Inclusion Criteria: * Have a clinical diagnosis of T2D based on the World Health Organization classification or other locally applicable diagnostic standards. * Have HbA1c ≥7.0% (53 mmol/mol) to ≤10.5% (91 mmol/mol) at screening. * Have been on stable diabetes treatment with metformin ≥1500 milligram per day (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. * Have a body mass index (BMI) ≥23.0 kilogram/square meter (kg/m²) at screening. Exclusion Criteria: * Have Type 1 Diabetes (T1D) * Are currently receiving or planning to receive treatment for diabetic retinopathy and/or macular edema * Have an estimated glomerular filtration rate (eGFR) \<45 milliliter per minute (mL/min)/1.73 square meter (m2) * Have acute or chronic hepatitis * Have had chronic or acute pancreatitis any time. * Have been treated with any antihyperglycemic medication (other than metformin) within the 90 days prior to screening.

Published papers

Papers from ACHIEVE-2

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

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