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Higher Oral Semaglutide Doses Improve Blood Sugar Regulation and Weight Loss

Orange and white capsules spilling out of a plastic pill bottle on an orange background.
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Diabetes is a progressive disease that affects one’s ability to control blood sugar levels. For many patients, the condition becomes more severe over time and blood sugar levels grow more difficult to manage. Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide, have granted patients more control in lowering of blood sugar.

John Buse, MD, PhD, the Verne S. Caviness Distinguished Professor of Medicine in the Division of Endocrinology and Metabolism, and an international team of researchers have presented new findings about new higher-dose formulations of oral semaglutide. Their study, which was published in The Lancet, found that once-daily oral semaglutide taken at 25 milligrams (mg) and 50 mg did a better job in lowering blood sugar levels and promoting weight loss than the lowest dose of 14 mg.

“Low doses of GLP-1 receptor agonists are really powerful for reducing A1C, or the average glucose in the blood,” said Buse, who is also co-director of the NC Translational and Clinical Sciences Institute. “Whereas, the higher doses that are really good for weight reduction. On average, patients lost eight kilograms (17.5 lbs) at 50 milligrams, which is nearly twice as much weight loss that we saw with the lowest dose.”

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The new study is in line with other studies, which are pushing for the use of oral GLP-1 receptor agonists as a treatment for obesity.

In total, 1,606 participants, who were on average male and of 58.2 years of age, participated in the phase three program for regulatory approval. The participants were randomized into three groups and were asked to take oral semaglutide once a day. Each group took a different dosage of semaglutide, either a 14 mg dosage, a 25 mg dosage, or a 50 mg dosage, for 52 weeks.

Blood sugar levels are measured through a percentage, called A1C. According to the American Diabetes Association, most adults with diabetes need to have an A1C that is less than 7% to be considered healthy. All of the participants in the trial had an A1C between 8.0% and 10.5%. Researchers found that those who received the 25 mg and 50 mg doses of oral semaglutide were more likely to reach the A1C target of <7.0%, compared with those who took 14 mg.

Semaglutide also causes weight loss by suppressing appetite. At the end of the 52 weeks, the participants who took 50 mg of oral semaglutide had lost, on average, 17.5 pounds. Those who took 25 mg and 14 mg lost about 14.8 pounds and 10 pounds, respectively.

Over the course of the trial, researchers took note of side effects. The most common side effect was nausea, owing to the effect that the drug has on the fullness of the stomach. Some of the participants, particularly those who took the higher doses of 25 mg and 50 mg, experienced vomiting, diarrhea, and/or constipation.

Reference: Aroda VR, Aberle J, Bardtrum L, et al. Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial. The Lancet. 2023:S0140673623011273. doi: 10.1016/S0140-6736(23)01127-3

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