Oral orforglipron matched insulin glargine for cardiovascular safety

Design

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

Population

2,749 adults with type 2 diabetes, BMI 25 or more, and cardiovascular or kidney disease

Primary outcome

Four-point MACE (CV death, MI, stroke, unstable angina admission)

Effect

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

ACHIEVE-4 randomised 2,749 adults with type 2 diabetes, a BMI of 25 or more and established cardiovascular or chronic kidney disease to once-daily oral orforglipron, a non-peptide GLP-1 receptor agonist, or titrated insulin glargine. It was open-label and designed to show non-inferiority, with a margin of 1.8 for the hazard ratio. Published in The Lancet on 30 September.

Over a median of two years, four-point MACE occurred in 4.2% on orforglipron and 5.0% on glargine (HR 0.84, 95% CI 0.59–1.20), meeting non-inferiority. Severe or clinically significant hypoglycaemia was much less common with orforglipron (6.8% vs 19.2%), but gastrointestinal adverse events affected 62.1% against 14.2% and were the main reason for stopping.

This is a safety result. It does not show cardiovascular benefit, and the comparator was insulin rather than placebo or an injectable GLP-1 agonist with proven outcome benefit. For patients with established disease, semaglutide and others with outcome data remain the drugs with demonstrated benefit.

• Orforglipron showed cardiovascular safety, not benefit, against insulin glargine.
• Expect gastrointestinal effects in most patients; plan slow titration and early review.
• Hypoglycaemia was about a third as common as with glargine.
• For established cardiovascular disease, GLP-1 agonists with proven outcome benefit remain first choice.
• Orforglipron's regulatory status in India is not established; check before discussing it as an option.

Why it matters

An oral non-peptide GLP-1 option may widen access, but safety non-inferiority is a lower bar than benefit.

Don't overread it

A non-inferiority margin of 1.8 is wide; the result rules out a large excess of harm, not a small one.

The statistics, in plain English

The hazard ratio of 0.84 has an interval from 0.59 to 1.20, so the data are compatible with anything from a 41% reduction to a 20% increase in events. That is enough to exclude the pre-set harm threshold of 1.8, which is what non-inferiority means here, but not enough to claim benefit.

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