26 February 2026
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Head-to-head trial pitting Eli Lilly’s oral GLP-1 against oral semaglutide underscores efficacy of weight-loss pills
A new study found that Eli Lilly’s GLP-1 pill resulted in greater reductions in blood sugar levels and weight than oral semaglutide did, but fewer people stayed on it
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A clinical trial for diabetes pitting orforglipron, a diabetes and weight loss pill developed by Eli Lilly, against oral semaglutide, made by Novo Nordisk, suggests the former pill may have the benefit of reducing blood sugar and weight.
The results, which were published in Lancet Thursday, is “very encouraging” for the safety and efficacy of orforglipron in people with type 2 diabetes, said Daniel Drucker, an endocrinologist at the University of Toronto, adding that he is awaiting further clinical trial results of the drug in people with obesity. Drucker has previously consulted for Novo Nordisk, Eli Lilly and other companies that have developed drugs for weight loss.
“More options for people with these challenging diseases would be very helpful, especially if the new oral tablet medications are affordable,” he says.
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Orforglipron is a once-daily pill that acts on glucagon-like peptide 1 (GLP-1) receptors. The injectable GLP-1 agents Zepbound and Mounjaro are also made by Eli Lilly.
Oral semaglutide has been on the market to treat type 2 diabetes since 2019. That version of the drug has been sold as the once-daily pill Rybelsus by Novo Nordisk, which also makes the GLP-1 drugs Ozempic and Wegovy. In December 2025, the company’s Wegovy pill became the first oral GLP-1 drug to be approved by the US Food and Drug Administration to treat obesity. Now, orforglipron is close to becoming the next oral option to be approved in the US
The new study of 1,698 people compared the effects of taking 12 milligram and 36 mg doses of orforglipron with taking 7 mg and 14 mg of oral semaglutide. After 52 weeks, participants who took 36 milligrams of orforgliprone saw a key blood sugar marker decrease by nearly 2 percent, while those who received 14 milligrams of oral semaglutide saw levels drop by nearly 1.5 percent.
“I’m hoping that for people with type 2 diabetes, this can really help them be less dependent on insulin,” says Rozalina McCoy, an endocrinologist and internist at the University of Maryland School of Medicine. “With insulin, there is a risk of weight gain, of hypoglycaemia, and there is more treatment burden and the need for glucose monitoring.”
GLP-1 drugs have also been shown to have cardiovascular benefits, she adds, although further clinical trials are needed to assess orforgliprone’s effects on heart health.
Orforglipron also outperformed oral semaglutide in weight loss: 36-milligram doses of Eli Lilly’s drug resulted in an average 8 percent body weight reduction (nearly 20 pounds), compared with a 5 percent weight loss (11 pounds) in participants taking 14 mg of oral semaglutide.
Importantly, this study compared orforgliprine with oral semaglutide doses that were based on those currently available for Rybelsus, but the maximum effective dose offered for the recently approved Wegovy pill for obesity is 25 mg.
“We know that oral semaglutide can be taken at much higher doses than are currently approved for obesity,” says McCoy. It is difficult to know whether the higher doses of oral semaglutide will show different performance, she says.
A spokesperson for Eli Lilly said so Scientific American that the study used 7 mg and 14 mg doses of oral semaglutide because “they were the only approved doses for type 2 diabetes at the time this study was designed and conducted,” adding that “the results should be interpreted in the context of the doses studied.”
If approved by the FDA, orforglipron will be available in six dosages — 1 mg, 3 mg, 6 mg, 12 mg, 24 mg and 36 mg — the spokesperson said.
Orforglipron showed a higher incidence of unwanted side effects such as nausea, vomiting and other gastrointestinal problems compared to semaglutide. More people discontinued orforgliprone during the trial than those who stopped taking semaglutide as well.
“We can’t completely separate side effects from effectiveness,” says McCoy. “It’s not that one drug is worse than the others. I think it underscores the importance of (matching) treatment to the right patient and making sure that we as clinicians really counsel patients about what to expect and how they can reduce their risk of having these side effects.”
Both pills target GLP-1 receptors in the body to increase insulin secretion and satiety levels. Oral versions of these drugs must be given in much higher doses than injectable versions to withstand digestion. At the same time, how the active protein, or peptide, in GLP-1 drugs like oral semaglutide is absorbed through the gut can vary between people — causing differences in effectiveness and tolerability, McCoy says.
Orforglipron’s active ingredient is a non-peptide small molecule that is more easily absorbed in the intestine without being broken down in the stomach.
“It’s always been the dream to have a small molecule version of a GLP-1 drug because now not only can it be taken orally, but also small molecules are much easier to manufacture,” says McCoy. “The hope is that when they are easier to manufacture, they will be less expensive.”
Eli Lilly expects US federal regulators to make a decision on whether to approve orforgliprone for obesity as soon as this spring. The company also plans to submit the drug for evaluation for type 2 diabetes later this year.
