Head-to-head trial of Eli Lilly’s oral GLP-1 against oral semaglutide underlines efficacy of weight-loss pills
A new trial found that Eli Lilly’s GLP-1 pill resulted in greater reductions in blood sugar levels and weight than oral semaglutide, but fewer people stuck to it
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A diagnostic tests for diabetes Orforglipron, a diabetes and weight-loss pill developed by Eli Lilly, pits against oral semaglutide, made by Novo Nordisk, and suggests that the former pill may be effective in reducing blood sugar and weight.
The results, which were published in Knife University of Toronto endocrinologist Daniel Drucker says Thursday he is “very encouraging” for the safety and efficacy of orforgliprone in people with type 2 diabetes, adding that he awaits further clinical trial results of the drug in people with obesity. Drucker has previously consulted for Novo Nordisk, Eli Lilly and other companies developing weight loss drugs.
“More options for people with these challenging diseases would be very helpful, especially if the cost of new oral tablet drugs is reasonable,” he says.
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Orforgaliprone is a once-a-day pill that acts on glucagon-like peptide 1 (GLP-1) receptors. The injectable GLP-1 drugs Zepbound and Monjaro are also made by Eli Lilly.
Oral semaglutide has been on the market since 2019 for the treatment of type 2 diabetes. That version of the drug is sold as the once-daily pill Ribelsus by Novo Nordisk, which also makes the GLP-1 drugs Ozempic and Vegovy. In December 2025, the company’s Wegovi pill became the first oral GLP-1 drug to be approved by the US Food and Drug Administration for the treatment of obesity. Now orforglipron is moving closer to becoming the next oral option to be approved in the US
The new trial of 1,698 people compared the effects of taking 12 mg and 36 mg doses of orforgaliprone with those of taking 7 mg and 14 mg of oral semaglutide. After 52 weeks, participants who took 36 milligrams of orforgaliprone saw about a 2 percent drop in the key blood sugar marker, while those who took 14 milligrams of oral semaglutide saw their levels drop by about 1.5 percent.
“I’m hoping that for people with type 2 diabetes, it can really help them be less dependent on insulin,” says Rosalina McCoy, M.D., an endocrinologist and internist at the University of Maryland School of Medicine. “With insulin, there is a risk of weight gain, hypoglycemia, and the treatment burden is higher and glucose monitoring is required.”
She adds that cardiovascular benefits have also been observed with GLP-1 drugs, although further clinical trials are needed to assess the effects of orforgaliprone on cardiovascular health.
Orforgaliprone also outperformed oral semaglutide in terms of weight loss: A 36-milligram dose of Eli Lilly’s drug resulted in an average 8 percent body weight loss (about 20 pounds), compared to a 5 percent weight loss (11 pounds) in participants taking 14 milligrams of oral semaglutide.
Importantly, this trial compared orforgliprin with an oral semaglutide dose, which was based on the dose currently available for ribalsus, but the maximum effective dose given for the recently approved Vegovy pill for obesity is 25 mg.
“We know that oral semaglutide can be taken at much higher doses than is currently accepted for obesity,” says McCoy. It’s hard to know whether higher doses of oral semaglutide will show different performance, she says.
Eli Lilly spokesperson said scientific American The trial used 7 mg and 14 mg doses of oral semaglutide because “at the time this trial was designed and executed, they were the only approved doses for type 2 diabetes,” adding that “the results should be interpreted in the context of the doses studied.”
If approved by the FDA, orforgaliprone will be available in six dosages — 1 mg, 3 mg, 6 mg, 12 mg, 24 mg and 36 mg, the spokesperson said.
Orforgaliprone showed higher rates of adverse side effects such as nausea, vomiting, and other gastrointestinal issues compared to semaglutide. More people stopped taking orforgaliprone during the trial than those who stopped taking semaglutide.
“We can’t completely separate side effects from effectiveness,” says McCoy. “It’s not that one drug is worse than the other. I think it emphasizes the importance of (matching) treatment to the right patient and making sure that we, as physicians, really counsel patients on what they should expect and how to minimize the risk of those side effects.”
Both pills target GLP-1 receptors in the body to increase insulin secretion and satiety levels. Oral versions of these drugs need to be given in much higher doses than injectable versions to withstand digestion. Also, how the active protein or peptide in GLP-1 drugs such as oral semaglutide is absorbed through the gut can vary between people — leading to differences in effectiveness and tolerability, McCoy says.
The active ingredient of orforgliprone is a nonapeptide small molecule that is more easily absorbed in the intestine without being broken down in the stomach.
“It’s always been a dream to have a small molecule version of a GLP-1 drug because now not only can it be taken orally, but small molecules are also much easier to produce,” says McCoy. “The hope is that as they become easier to produce, they will become more affordable.”
Eli Lilly expects U.S. federal regulators to decide this spring on whether to approve orforgliprone for obesity. The company also plans to submit the drug for review for type 2 diabetes later this year.
