The oral GLP-1 receptor agonist orforglipron met its cardiovascular safety goal in a phase III trial of adults with type 2 diabetes and elevated cardiovascular risk. Results from ACHIEVE-4, presented at the European Association for the Study of Diabetes annual meeting and published in The Lancet, showed the drug was noninferior to insulin glargine on a composite of major adverse cardiovascular events over a median of two years (4.2% vs 5.0%; HR 0.84, 95% CI 0.59-1.20).
The trial also found sustained improvements in blood sugar control and body weight over 104 weeks, along with a reduction in albuminuria and a slower decline in kidney function compared with insulin glargine. However, gastrointestinal adverse events were far more common with orforglipron (62.1% vs 14.2%) and were the main reason for discontinuation. The study was open-label and not statistically powered to show cardiovascular superiority.
Orforglipron, already FDA-approved for obesity, is a non-peptide small molecule that can be taken once daily without fasting or water restrictions, which may make it easier to manufacture and use than existing peptide-based GLP-1 drugs. But those established drugs have already demonstrated cardiovascular benefit and approval for that indication. The ongoing ATTAIN-Outcomes trial, expected to complete in 2031, is designed to test whether orforglipron reduces cardiovascular events compared with placebo.