Short summary: The ACHIEVE-2 trial compared three doses of the oral GLP-1 medicine orforglipron with dapagliflozin in 962 adults with type 2 diabetes whose blood sugar was not adequately controlled with metformin. After 40 weeks, HbA1c fell more with orforglipron, but gastrointestinal side effects and treatment discontinuation were more common. The study does not answer every long-term heart or kidney question.
What was studied
ACHIEVE-2 was a phase 3, multicentre, randomised, open-label trial. It included adults with type 2 diabetes who were taking metformin but still had an HbA1c between 7.0% and 10.5%. Participants were assigned to once-daily orforglipron at 3 mg, 12 mg, or 36 mg, or to dapagliflozin 10 mg.
Orforglipron is an oral, non-peptide GLP-1 receptor agonist being studied as a tablet option. Dapagliflozin is an oral SGLT2 inhibitor. These medicines work in different ways, so the trial was a comparison between treatment approaches, not a test of whether one medicine is right for every person.
What the trial found
At week 40, all three orforglipron doses were non-inferior to dapagliflozin for lowering HbA1c and produced larger average reductions in the trial’s primary analysis:
- Orforglipron 3 mg: HbA1c fell by 1.23 percentage points.
- Orforglipron 12 mg: HbA1c fell by 1.50 percentage points.
- Orforglipron 36 mg: HbA1c fell by 1.56 percentage points.
- Dapagliflozin 10 mg: HbA1c fell by 0.81 percentage points.
Body weight also fell more on orforglipron than on dapagliflozin in the study. The size of the difference varied by dose. These results show what happened on average in this selected trial group, not what every person will experience.
Side effects and tolerability
Gastrointestinal side effects were common with orforglipron. They occurred in about 47% of people receiving 3 mg, 46% receiving 12 mg, and 54% receiving 36 mg, compared with 12% in the dapagliflozin group. The most common problems were gastrointestinal symptoms typical of GLP-1 treatment, such as nausea, fullness, vomiting, diarrhoea, or constipation.
Discontinuation because of side effects was also more frequent with orforglipron than with dapagliflozin. No severe hypoglycaemia episodes were reported in the treatment groups during the trial. That result should not be interpreted as a guarantee that a medicine cannot cause low blood sugar in other circumstances, especially when medicines are combined.
What this does not prove
- This was a 40-week study, so it does not establish long-term cardiovascular or kidney outcomes.
- The trial was open label, which can influence some treatment experiences and reporting, although the primary HbA1c measurements were prespecified.
- The results apply most directly to adults with type 2 diabetes using metformin who met the study criteria.
- A phase 3 result does not by itself mean that a medicine is approved or available in every country. Regulatory decisions, prescribing information, and access can differ by location.
- The study was funded by Eli Lilly and Company, the developer of orforglipron. That does not invalidate the results, but it is important context when reading the findings.
What this may mean for patients
The study suggests that an oral GLP-1 treatment can lower HbA1c and body weight more than dapagliflozin over 40 weeks in adults who were not at their blood sugar goal on metformin. It also highlights a practical trade-off: stronger average glucose and weight effects came with more gastrointestinal symptoms and more treatment discontinuation.
Medication choice should also consider kidney function, heart failure or cardiovascular disease, weight goals, side effects, cost, availability, and personal preferences. Dapagliflozin and other SGLT2 medicines have evidence and uses that are not captured by this one HbA1c comparison. A lower HbA1c result in one trial does not automatically make one medicine the best choice for a particular person.
Questions to ask your diabetes team
- What is the main treatment goal for me right now: HbA1c, weight, heart protection, kidney protection, or several goals together?
- How might this medicine affect nausea, appetite, bowel symptoms, hydration, or daily routines?
- How would my other medicines need to be reviewed if my glucose improves?
- What should I do if I cannot eat or drink normally because of side effects?
- Is the medicine approved and available where I live, and what would it cost?
Do not start, stop, or change diabetes medicine because of a news article. Discuss treatment decisions with the clinician who knows your medical history, glucose pattern, kidney function, and other medicines.
Bottom line
In ACHIEVE-2, orforglipron lowered HbA1c more than dapagliflozin after 40 weeks in adults with type 2 diabetes taking metformin, and weight loss also favoured orforglipron. Gastrointestinal side effects and discontinuation were more common. The results are important, but they are not a complete treatment guide and do not establish long-term heart or kidney outcomes.
Source and evidence summary
- Primary study: ACHIEVE-2, a multicentre, randomised, open-label phase 3 trial. PubMed PMID 42259339.
- Journal DOI: 10.1016/S0140-6736(26)00800-7.
- Trial registration: ClinicalTrials.gov NCT06192108.