Lilly's GLP-1 diabetes pill beats Novo's Rybelsus in a head-to-head trial

Eli Lilly's closely watched GLP-1 pill orforglipron outperformed Novo Nordisk's oral diabetes drug Rybelsus in the first head-to-head, phase 3 trial, demonstrating greater blood sugar control and weight loss, the company announced today.

The results from the year-long Achieve-3 study, which enrolled 1,698 participants across six countries, show that patients who couldn't control their blood sugar with metformin fared significantly better on orforglipron across every key measure.

At the highest dose (36 mg), orforglipron reduced HbA1c by 2.2% from a baseline of 8.3%, compared to 1.4% with Rybelsus's highest dose (14 mg). The highest of orforglipron also drove an average weight loss of 19.7 lbs, nearly double the 11.0 lbs seen with Rybelsus.

More than 85% of patients taking orforlipron achieved an A1C below 7%, compared with 66% on Rybelsus, and 37% reached near-normal blood sugar levels below 5.7% -- triple the rate seen by patients taking Rybelsus.

Beyond glycemic control and weight loss, orforglipron patients also saw greater improvements across key cardiovascular risk markers -- including cholesterol, blood pressure and triglycerides -- compared to those who took Rybelsus.

Adding to its clinical appeal, orforglipron carries a simpler dosing profile than its rival. Unlike Rybelsus, which requires patients to take it on an empty stomach and wait at least 30 minutes before eating, orforglipron can be taken at any time without dietary restrictions.

"The results of Achieve-3 highlight the potential advantages of orforglipron over oral semaglutide for type 2 diabetes: greater A1C reduction, more weight loss, and the ability to take it without food or water timing restrictions -- that's a combination that could matter significantly to people managing their disease day in and day out," Kenneth Custer, Ph.D., executive vice president and president of Lilly Cardiometabolic Health, said in the company's press release.

But Lilly's drug appears to lead to higher rates of side effects than Novo's, indicating a tolerability gap. Around 10% of patients taking the highest dose of Lilly's drug quit the trial early due to gastrointestinal issues -- including nausea, diarrhea, and indigestion -- compared to 5% of those taking Rybelsus.

Achieve-3 is one of five global late-phase trials in Lilly's Achieve program, which has enrolled more than 6,000 people with type 2 diabetes since launching in 2023. Detailed results from the three remaining trials are expected later this year, the company says.

Lilly is slated to submit orforglipron for FDA approval for treating type 2 diabetes later this year, according to the company's release. The addition of a diabetes pill could strengthen Eli Lilly's dominance in the metabolic space, particularly in an oral market where Novo Nordisk currently holds the upper hand.

The company submitted orforglipron for regulatory approval for weight loss in adults with obesity and overweight in December, having been awarded a fast-track voucher the month before under the National Priority program. With global filings now in place and an FDA decision on obesity anticipated sometime in the second quarter, the company is prioritizing getting the drug to market as soon as possible, Custer noted.

Eli Lilly has already ramped up production of orforglipron pills at its Huntsville, Alabama, facility to ensure it can meet patient demand in anticipation of FDA approval.

Alivia Kaylor is a scientist and the senior site editor of Pharma Life Sciences.