Cardiovascular safety of orforglipron versus insulin glargine in adults with type 2 diabetes at increased cardiovascular risk (ACHIEVE-4): a phase 3, event-driven, randomised, open-label, non-inferiority, active comparator trial
Primary result · MACE-4Result — go to the resultHazard ratio 0.84 95% CI 0.59–1.20Authors' conclusion
In people with type 2 diabetes at increased cardiovascular risk, the cardiovascular safety of orforglipron was confirmed by demonstrating non-inferiority to insulin glargine for MACE-4.
Study context
- Population
- Adults with T2DM at increased CV risk (established CVD or CKD), HbA1c 7.0%–10.5%, BMI ≥25 kg/m², on up to three glucose-lowering drugs
- Participants
- 2,749 adults
- Comparison
- Oral orforglipron vs insulin glargine
- Orforglipronn = 1,371
- Insulin glarginen = 1,378reference
- Primary endpoint
- Time to major adverse cardiovascular events (MACE-4):
- CV death
- Non-fatal MI
- Non-fatal stroke
- Hospitalisation for unstable angina
- Follow-up
- Median 2 years
Methodological detailsphase 3, event-driven, multicentre, open-label, non-inferiority, active comparator, parallel-group
- Phase 3
- Event-driven
- Multicentre
- Open-label
- Non-inferiority
- Active comparator
- Parallel-group
Primary result
MACE-4
Hazard ratio
0.84
95% CI 0.59–1.20
P < 0.0001 for non-inferiority
Events by treatment group
Orforglipron vs Insulin glargine
HR 0.84 (95% CI 0.59–1.20); P for non-inferiority < 0.0001
As reported in the abstract
Further findings
Deaths
- Deaths: 62 deaths in total
Deaths
- All deaths except one (insulin glargine) deemed unrelated to treatment
Safety
Gastrointestinal adverse events
Clinically significant or severe hypoglycaemia (glucose <3 mmol/L [54 mg/dL])
- Gastrointestinal adverse events: n 1371 vs 1355
- Clinically significant or severe hypoglycaemia (glucose <3 mmol/L [54 mg/dL]): n 1371 vs 1355
Original publication
Cardiovascular safety of orforglipron versus insulin glargine in adults with type 2 diabetes at increased cardiovascular risk (ACHIEVE-4): a phase 3, event-driven, randomised, open-label, non-inferiority, active comparator trial. Lancet. Published 30 September 2026. doi:10.
Summarised from the published abstract; every number is checked against it