Oral GLP-1 Drug Orforglipron Is Non-Inferior to Insulin for Cardiovascular Safety in Phase 3

Phase 3 results showing that orforglipron, an oral, non-peptide, small-molecule GLP-1 receptor agonist, met cardiovascular safety criteria compared with insulin glargine in patients with type 2 diabetes at high cardiovascular risk were published in The Lancet. This is the ACHIEVE-4 trial, reported by researchers including those at the University of North Carolina School of Medicine in the United States.

317 sites in 16 countries, median follow-up of 2 years

A total of 2,749 adults with cardiovascular disease or chronic kidney disease, an HbA1c of 7.0 to 10.5% and a body mass index of 25 or higher were assigned 1 to 1 to take orforglipron once daily or to receive insulin glargine injections. It was an open-label, non-inferiority design, and the primary outcome was a four-component major adverse cardiovascular event (MACE-4) combining cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalisation for unstable angina.

Over a median of 2 years, MACE-4 occurred in 4.2% of the orforglipron group and 5.0% of the insulin group (hazard ratio 0.84, 95% confidence interval 0.59 to 1.20). The prespecified non-inferiority criterion was met, but superiority was not shown. Gastrointestinal adverse events were much more common in the orforglipron group, 62.1% versus 14.2%, and were the main reason for stopping treatment. In contrast, clinically significant hypoglycaemia was less frequent, 6.8% versus 19.2%.

The non-inferiority margin was wide

This is the first large-scale evaluation of the cardiovascular safety of an oral non-peptide GLP-1 class drug. However, it was a safety trial with a wide non-inferiority upper limit set at a hazard ratio of 1.8, and because the comparator was insulin rather than placebo, a separate trial is needed to know whether the drug has cardiovascular protective effects. The open-label design and developer support are also points to consider when interpreting the results.