ACHIEVE-4: oral orforglipron was non-inferior to insulin glargine for cardiovascular events, with far less hypoglycaemia

Design

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

Population

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

Primary outcome

Four-point MACE

Effect

4.2% vs 5.0%; HR 0.84 (0.59–1.20); severe hypoglycaemia 6.8% vs 19.2%

ACHIEVE-4, an event-driven, open-label phase 3 trial at 317 sites in 16 countries, published in The Lancet on 30 September, randomised 2,749 adults with type 2 diabetes, HbA1c 7.0–10.5%, BMI 25 or more and established cardiovascular or chronic kidney disease to once-daily oral orforglipron or titrated insulin glargine. Mean age was 63; 86% had cardiovascular disease and 38% chronic kidney disease.

Over a median of two years, four-point major adverse cardiovascular events occurred in 4.2% on orforglipron and 5.0% on glargine (HR 0.84, 95% CI 0.59–1.20), meeting the prespecified non-inferiority margin. Clinically significant or severe hypoglycaemia occurred in 6.8% against 19.2%. Gastrointestinal adverse events were far more common with orforglipron (62% vs 14%) and were the main reason for stopping. Deaths were 1.4% against 3.2%, almost all judged unrelated to treatment.

The trial establishes cardiovascular safety, not benefit: the confidence interval includes both a 41% reduction and a 20% increase. Kidney outcomes are not reported in the abstract. For nephrologists, the relevance is a non-injectable alternative to insulin intensification in diabetic kidney disease, where hypoglycaemia is a particular hazard. The trial was industry funded, and orforglipron's approval and availability in India are not established.

• In type 2 diabetes with CKD, hypoglycaemia risk is a strong reason to prefer non-insulin intensification where possible.
• Orforglipron showed cardiovascular safety against insulin, not superiority; injectable GLP-1 agonists with proven benefit remain preferred where available.
• Expect gastrointestinal effects in most patients on oral GLP-1 agonists; titrate slowly and watch for dehydration and acute kidney injury.
• Continue SGLT2 inhibitors for kidney protection alongside any GLP-1-based therapy.
• Check the regulatory status of orforglipron in India before considering it.

Why it matters

It offers a once-daily tablet that avoids most of insulin's hypoglycaemia in people with CKD, without cardiovascular cost.

Don't overread it

This is a safety trial against insulin; it does not show orforglipron reduces cardiovascular or kidney events.

The statistics, in plain English

Non-inferiority means the upper bound of the hazard ratio's interval (1.20) fell below the preset limit of 1.8, so a large increase in cardiovascular events was excluded. The interval still includes no difference, so benefit is not shown.

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