- Design
- Phase 3, randomised, open-label, event-driven non-inferiority trial (ACHIEVE-4)
- Population
- 2,749 adults with type 2 diabetes and established cardiovascular or kidney disease
- Primary outcome
- Time to four-component MACE
- Effect
- 4.2% vs 5.0%; HR 0.84 (95% CI 0.59–1.20); non-inferiority met
ACHIEVE-4 was an open-label, event-driven phase 3 trial in 2,749 adults with type 2 diabetes, BMI 25 or more, HbA1c 7.0–10.5% and established cardiovascular or chronic kidney disease. Participants took once-daily oral orforglipron or titrated insulin glargine on top of up to three oral drugs.
Over a median 2 years, major adverse cardiovascular events occurred in 4.2% on orforglipron and 5.0% on glargine (HR 0.84, 95% CI 0.59 to 1.20), meeting the pre-set non-inferiority margin of 1.8. Severe or clinically significant hypoglycaemia was 6.8% against 19.2%. Gastrointestinal effects were 62.1% against 14.2% and drove discontinuations.
This is a safety trial: it shows orforglipron does not raise cardiovascular risk, not that it lowers it. The comparator was insulin, not placebo or an injectable GLP-1 agonist with proven benefit. Orforglipron's regulatory status should be checked locally before any prescribing decision.
- Orforglipron met cardiovascular safety against insulin glargine; it has not shown cardiovascular benefit.
- Hypoglycaemia was about a third as common as with glargine in this trial.
- Expect gastrointestinal effects in most patients; they were the main reason for stopping.
- Check local regulatory status before considering it; the trial alone does not establish availability.
Why it matters
An oral, non-peptide GLP-1 drug could widen access where injections are a barrier.
Don't overread it
Non-inferiority to insulin is a safety result; it does not show the cardiovascular benefit proven for some injectable GLP-1 agonists.
The statistics, in plain English
The hazard ratio of 0.84 points towards fewer events, but the interval runs from 0.59 to 1.20 and crosses 1, so no benefit is shown. Non-inferiority was declared because the upper limit, 1.20, sat well below the 1.8 margin.
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