Eli Lilly’s experimental once-daily pill Foundayo, also known as orforglipron, demonstrates comparable heart safety to insulin glargine and superior glucose control, marking a potential breakthrough in oral diabetes treatments amid safety and tolerability considerations.
Eli Lilly said its once-daily pill Foundayo, also known as orforglipron, matched insulin glargine on heart safety in the company’s largest and longest trial of the experimental treatment in type 2 diabetes, adding fresh momentum to a drug the manufacturer hopes could eventually become an oral alternative to injectable therapy. The findings from the ACHIEVE-4 study were published in The Lancet and presented at the European Association for the Study of Diabetes meeting in Milan, according to Lilly.
The study enrolled 2,749 adults with type 2 diabetes who were overweight or obese and at heightened cardiovascular risk, with many already living with established heart disease. Lilly said participants were randomised across 16 countries and followed for a median of about two years in an open-label design, meaning both patients and doctors knew which treatment was being used. The main question was not whether the pill would outperform insulin, but whether it would avoid meaningfully worse cardiovascular outcomes, a standard known as non-inferiority.
On that measure, the pill cleared the bar. Major adverse cardiovascular events, including cardiovascular death, heart attack, stroke and hospitalisation for unstable angina, occurred in 4.2% of people on Foundayo compared with 5.0% on insulin glargine. Lilly said the hazard ratio of 0.84 sat within the margin required to show the pill was not inferior, although the result did not establish that the drug was better than insulin for heart outcomes. A separate report summarising the trial said the findings were consistent with the company’s topline results shared in April.
The study also showed stronger glucose and weight results with the pill. According to Lilly, average HbA1c fell by 1.6 percentage points at 52 weeks among people taking Foundayo, compared with a 1.0-point drop in the insulin group. Weight fell by 8.8% on the pill, while it rose by 1.7% with insulin, and more than half of patients taking the oral drug reached an HbA1c of 6.5% or lower by 104 weeks. Independent summaries of the data also noted improvements in blood pressure, inflammation and kidney-related markers, although the trial was not designed to prove those as primary benefits.
The death figures drew attention, but they come with an important caveat. Lilly said 19 people in the Foundayo group died during the trial, compared with 43 in the insulin group, while deaths from cardiovascular causes were also lower. However, the company said those analyses were not adjusted for the full set of statistical comparisons, which means the numbers should be treated as a signal rather than proof of a survival benefit. Dr Klara Klein of the University of North Carolina School of Medicine said in Lilly’s announcement that the trial showed an association with a lower risk of major cardiovascular events and death, while the company’s diabetes chief, Thomas Seck, described the drug as delivering strong efficacy across the Phase 3 ACHIEVE programme.
Safety and tolerability remain a central issue. Gastrointestinal side effects such as nausea, vomiting and diarrhoea were common, affecting 62.1% of people on Foundayo versus 14.2% on insulin glargine, and 10.6% of users stopped treatment during the first year because of side effects. Lilly says the drug is already approved in the US for chronic weight management, under a label that includes a warning about the risk of thyroid tumours, including cancer, but it is not yet approved for type 2 diabetes. The company has said it plans to seek that approval, while a separate outcomes study, ATTAIN-OUTCOMES, is intended to determine whether the medicine can ultimately show a true cardiovascular benefit rather than simply cardiovascular safety.
Disclaimer: This content is for informational purposes only and is not intended to be a substitute for professional medical judgment, advice, diagnosis, or treatment.
