Orforglipron has demonstrated cardiovascular (CV) safety in adults with type 2 diabetes (T2D) and obesity or overweight who are at high cardio-renal risk, as shown in the phase III ACHIEVE-4 study.
Findings from the trial presented at EASD 2026 showed that orforglipron met noninferiority criteria vs insulin glargine for major adverse cardiovascular events (MACE) over a median 2-year follow-up (4.2 percent vs 5 percent; hazard ratio [HR], 0.84; p<0.0001 for noninferiority).
Over 104 weeks, orforglipron sustained improvements in HbA1c and weight reduction compared with insulin glargine. At week 52, patients taking orforglipron had a reduction in albuminuria (median change in the urinary albumin-to-creatinine ratio, -24.2 percent vs 0 percent).
In addition, those treated with orforglipron had a slower decline in estimated glomerular filtration rate, as measured by cystatin C (estimated treatment difference, 2.8 mL/min/1.73 m2).
Safety reaffirmed
Study author Dr Klara Klein of the University of North Carolina School of Medicine in Chapel Hill, North Carolina, US said the ACHIEVE-4 study “reaffirmed the safety of orforglipron” while demonstrating clinically meaningful improvements in glucose control and weight.
“Combined with the convenience of a shelf-stable, once-daily oral medication that can be taken without fasting or water restrictions, these results highlight orforglipron’s potential to expand global access to effective diabetes treatment,” she added.
Other glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated CV benefits and have received FDA approval for CV protection. Klein noted that ACHIEVE-4 was not powered to demonstrate superiority in CV outcomes.
However, she believed that the CV benefit is largely a class effect. “This is a new small molecule. We can’t say definitively until we have a trial demonstrating this. That’s coming soon,” she said during a press conference.
Multicountry trial
ACHIEVE-4 was conducted across 16 countries from 2023 to 2024. Participants (n=2,749) had an HbA1c of 7–10.5 percent, and a BMI of ≥25 kg/m². Nearly two in three had been taking two or more glucose-lowering drugs, including metformin (88 percent), an SGLT-2 inhibitor (53.3 percent), or a sulfonylurea (36.2 percent), for at least 3 months before enrolment. The median age was 63.1 years, and 62.5 percent were male. At baseline, 85.9 percent had established cardiovascular disease and 37.6 percent had chronic kidney disease. [Lancet 2026;doi:10.1016/S0140-6736(26)01865-9]
Participants were randomly assigned in a 1:1 ratio to receive either once-daily oral orforglipron at the maximum tolerated dose or once-daily titrated insulin glargine injections.
CV death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina were included in the MACE endpoint.
Clinically significant or severe hypoglycaemia (glucose <3 mmol/L), a secondary endpoint, was less common with orforglipron than with insulin glargine (6.8 percent vs 19.2 percent). Treatment-emergent adverse events (TEAEs), including supraventricular tachyarrhythmias and atrial fibrillation or atrial flutter, were reported in 3.2 percent and 2.7 percent of participants, respectively.
As expected, gastrointestinal adverse events were more common with orforglipron (62.1 percent vs 14.2 percent), while all-cause mortality was lower (1.4 percent vs 3.2 percent)
“The safety profile was consistent with that established for orforglipron in the previous ACHIEVE and ATTAIN studies which evaluated glycaemic control and weight management, respectively,” said Klein.
Orforglipron is a non-peptide GLP-1 RA approved by the US FDA to treat obesity. Unlike other GLP-1 medications, its non-peptide structure simplifies manufacturing and offers greater convenience, as it can be taken without food or water restrictions.