Oral orforglipron met its cardiovascular safety bar against insulin glargine

Design

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

Population

2,749 adults with type 2 diabetes and established cardiovascular or kidney disease

Primary outcome

Four-component major adverse cardiovascular events

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, overweight or obesity and established cardiovascular or chronic kidney disease to once-daily oral orforglipron, a small-molecule GLP-1 receptor agonist, or titrated insulin glargine. The trial was open-label and event-driven, published in The Lancet on 30 September 2026.

Over a median two years, major cardiovascular events occurred in 4.2% on orforglipron and 5.0% on glargine (HR 0.84), meeting the prespecified non-inferiority margin. Severe or clinically significant hypoglycaemia was far less common with orforglipron (6.8% versus 19.2%). Gastrointestinal adverse events affected 62% on orforglipron against 14% on glargine and were the main reason for stopping.

This is a safety trial: it shows orforglipron does not raise cardiovascular risk, not that it lowers it as some injectable GLP-1 agonists do. The comparison with insulin also means the deaths and hypoglycaemia figures partly reflect insulin's own risks. An oral agent without the fasting rules of oral semaglutide would matter for adherence, but approval status varies by country and its position with CDSCO is not known.

• Read this as cardiovascular safety, not cardiovascular benefit; no placebo-controlled outcome trial has reported.
• Expect gastrointestinal effects in most patients starting an oral GLP-1 agonist, and titrate slowly.
• Prefer agents with proven cardiovascular benefit for patients with established heart disease until outcome data arrive.
• Note the lower hypoglycaemia risk compared with basal insulin when weighing options in older patients.

Why it matters

An oral GLP-1 agonist without fasting rules is coming, and its heart safety is the first box it had to tick.

Don't overread it

A non-inferiority result against insulin does not show cardiovascular benefit.

The statistics, in plain English

Non-inferiority means the upper end of the confidence interval (1.20) stayed below a margin set in advance (1.8). The point estimate of 0.84 leans towards benefit, but the interval includes no difference, so no reduction in events can be claimed.

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