Oral orforglipron was non-inferior to insulin glargine for cardiovascular events

Design

Phase 3, event-driven, randomised, open-label, active-comparator non-inferiority trial

Population

2,749 adults with type 2 diabetes, BMI ≥25 and established cardiovascular or chronic kidney disease

Primary outcome

Time to 4-component MACE

Effect

4.2% vs 5.0%; HR 0.84 (95% CI 0.59–1.20), non-inferior (margin 1.8)

ACHIEVE-4 randomised 2,749 adults with type 2 diabetes, overweight or obesity and established cardiovascular or chronic kidney disease to once-daily oral orforglipron or titrated insulin glargine. Orforglipron is a small-molecule GLP-1 receptor agonist, taken as a capsule without the fasting rules oral semaglutide needs. Mean age was 63 and mean HbA1c 8.2%.

Over a median of two years, major cardiovascular events (cardiovascular death, myocardial infarction, stroke or unstable angina admission) occurred in 4.2% on orforglipron and 5.0% on glargine (HR 0.84, 95% CI 0.59–1.20). That met the prespecified non-inferiority margin of 1.8, which is a generous margin. Severe or clinically significant hypoglycaemia was 6.8% against 19.2%. Gastrointestinal adverse events affected 62% against 14%, and were the commonest reason for stopping.

This is a safety trial, not a benefit trial: it shows the drug does not raise cardiovascular risk compared with insulin, not that it lowers it. The comparison with insulin rather than placebo, and the open-label design, limit what can be said beyond that. For a clinician it matters because an oral incretin without injection or strict dosing rules could widen access, if and when it is approved and priced.

• Orforglipron met a cardiovascular safety bar against insulin glargine; it has not shown cardiovascular benefit.
• For patients with established cardiovascular disease, peptide GLP-1 receptor agonists with proven outcome benefit remain the evidence-based choice.
• Severe hypoglycaemia was about a third as common as with glargine in this trial.
• Expect gastrointestinal effects in most patients starting it; they drove discontinuation.
• Its regulatory status in India is not known; check before discussing it as an option.

Why it matters

An oral incretin with no fasting rules could reach patients who will not inject, if its safety holds.

Don't overread it

Non-inferiority to insulin is not superiority; the hazard ratio's interval includes no difference.

The statistics, in plain English

The hazard ratio of 0.84 has a 95% interval of 0.59 to 1.20. Because it crosses 1.0, the trial cannot say orforglipron lowered events; because its upper end is below 1.8, it rules out a large increase. The 1.8 margin is the conventional cardiovascular safety threshold, but it would still allow a meaningful harm to go undetected.

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