Lilly's orforglipron outperforms oral semaglutide in ACHIEVE-3 trial, delivering superior A1C reductions and weight loss.

Lilly's oral GLP-1 medication, orforglipron, outperformed oral semaglutide in a head-to-head trial for type 2 diabetes treatment. For the primary endpoint, orforglipron lowered A1C by 2.2% vs. 1.4% with oral semaglutide at the highest doses. Participants taking the highest dose of orforglipron lost an average of 19.7 lbs vs. 11.0 lbs with oral semaglutide, a 73.6% relative improvement. The safety and tolerability of orforglipron were consistent with previous trials.

Novo Nordisk's oral GLP-1 receptor agonist, Rybelsus® (oral semaglutide), has received a significant boost with the European Medicines Agency's (EMA) approval to reflect its proven cardiovascular benefits. This approval is based on the results from the SOUL clinical trial, where oral semaglutide demonstrated a 14% reduction in cardiovascular death, heart attack, and stroke compared to placebo when added to standard care in adults with type 2 diabetes at high cardiovascular risk EU approval makes Novo Nordisk’s oral semaglutide the first and only oral GLP-1 RA to reduce cardiovascular death, heart attack and stroke^[1].

The SOUL trial, a phase 3b study, involved 9,650 participants with type 2 diabetes and established cardiovascular disease and/or chronic kidney disease (CKD). The primary outcome was the time-to-first occurrence of major adverse cardiovascular events (MACE), a composite of cardiovascular death, heart attack, and stroke. The trial showed a superior reduction in MACE of 14% for those treated with oral semaglutide compared to placebo EU approval makes Novo Nordisk’s oral semaglutide the first and only oral GLP-1 RA to reduce cardiovascular death, heart attack and stroke^[1].

In addition to the cardiovascular benefits, new results from the SOUL trial will be presented at the European Association for the Study of Diabetes (EASD) 2025 Annual Meeting, highlighting that oral semaglutide significantly reduced hospitalizations related to serious adverse events compared to placebo . These findings are consistent regardless of body mass index (BMI) and body weight of participants .

In the US, a decision is expected later this year for a label extension for the cardiovascular indication for Rybelsus®. Novo Nordisk has also submitted an application for a once-daily 25 mg oral formulation of semaglutide (Wegovy® in a pill) in adults living with obesity or overweight and cardiovascular disease, with a decision expected at the turn of this year .

Rybelsus® is the first and only oral GLP-1 RA approved for the treatment of type 2 diabetes, following its launch in 2019. It is supported by a strong clinical and real-world evidence base, demonstrating superior blood glucose reduction and body weight reduction versus multiple comparators, as well as an established safety profile in people with type 2 diabetes [^5-8].

References
EU approval makes Novo Nordisk’s oral semaglutide the first and only oral GLP-1 RA to reduce cardiovascular death, heart attack and stroke^[1] McGuire DK, et al. N Engl J Med. 2025;392(20):2001-2012. https://www.nejm.org/doi/full/10.1056/NEJMoa2504029
Buse JB, et al. Oral presentation presented at the European Association for the Study of Diabetes (EASD) 2025; 15-19 Sep 2025; Vienna, Austria.
Inzucchi SE, et al. Oral presentation presented at the European Association for the Study of Diabetes (EASD) 2025; 15–19 Sep 2025; Vienna, Austria.
Novo Nordisk Data on File. LEA portal Product Planning, 25th Aug 2025.
Rosenstock J, et al. JAMA. 2019;321(15):1466-1480. https://jamanetwork.com/journals/jama/fullarticle/2732942
Rodbard HW, et al. Diabetes Care. 2019;42(12):2272-2281. https://care.diabetesjournals.org/content/42/12/2272
Pratley R, et al. Lancet. 2019;394(10192):39-50. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30365-3/fulltext
Husain M, et al. N Engl J Med. 2019;381(9):841-851. https://www.nejm.org/doi/full/10.1056/NEJMoa1900339