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.
Klara R Klein, Carol Wysham, Katherine R Tuttle et al.
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In 30 seconds
ACHIEVE-4 was a phase 3, event-driven, multicentre, randomised, open-label, active-comparator non-inferiority trial comparing once-daily oral orforglipron with titrated insulin glargine in adults with type 2 diabetes, overweight or obesity, and increased cardiovascular risk. Over a median follow-up of 2 years, MACE-4 occurred in 4·2% of participants receiving orforglipron and 5·0% receiving insulin glargine. Orforglipron met the prespecified non-inferiority criterion (HR 0·84; 95% CI 0·59-1·20; p<0·0001 for non-inferiority). Gastrointestinal adverse events were more frequent, while clinically significant or severe hypoglycaemia was less frequent, with orforglipron.
Key findings
- MACE-4 occurred in 57 (4·2%) of 1358 orforglipron participants and 67 (5·0%) of 1343 insulin glargine participants; HR 0·84; 95% CI 0·59-1·20.
- Gastrointestinal adverse events affected 851 (62·1%) of 1371 participants receiving orforglipron and 193 (14·2%) of 1355 receiving insulin glargine.
- Clinically significant or severe hypoglycaemia occurred in 93 (6·8%) of 1371 orforglipron participants versus 260 (19·2%) of 1355 insulin glargine participants.
Why it matters
The trial provides cardiovascular safety evidence for an oral, non-peptide GLP-1 receptor agonist in people with type 2 diabetes at increased cardiovascular risk, a population in which the abstract notes this safety had not previously been studied. The differing adverse-event profiles are also relevant when weighing this option against insulin glargine, although the study establishes non-inferiority rather than cardiovascular superiority.
What to keep in mind
The trial was open-label and compared orforglipron with insulin glargine; its non-inferiority design establishes cardiovascular safety against this comparator, not superiority or benefit versus placebo.