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

doi:10.1016/s0140-6736(26)01865-9

Cardiometabolic & kidneyRandomised controlled trial

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

LancetPublished 30 Sep 2026

Randomised controlled trial
phase 3
event-driven
multicentre
open-label
non-inferiority
active comparator
parallel-group

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Authors' 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

Primary result

MACE-4

Hazard ratio

0.84

95% CI 0.59–1.20

P < 0.0001 for non-inferiority

Events by treatment group

Orforglipron4.2%57 of 1358

Insulin glargine5.0%67 of 1343

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

Orforglipron1.4%

Insulin glargine3.2%

Deaths: 62 deaths in total

Deaths

All deaths except one (insulin glargine) deemed unrelated to treatment

Safety

Gastrointestinal adverse events

Orforglipron62.1%

Insulin glargine14.2%

Clinically significant or severe hypoglycaemia (glucose <3 mmol/L [54 mg/dL])

Orforglipron6.8%

Insulin glargine19.2%

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:10.1016/s0140-6736(26)01865-9

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Summarised from the published abstract; every number is checked against it