Orforglipron GLP-1 Pill Matches Injectable Semaglutide in Type 2 Diabetes Trial

A large new clinical trial involving more than 1,600 participants has found that the GLP-1 pill orforglipron performs similarly to injectable semaglutide in people with type 2 diabetes.

In a 72-week experiment conducted at 136 sites across 10 countries, researchers led by University of Texas obesity-medicine specialist Deborah Horn found that people taking the drug's highest dose lost an average of 9.6 percent of their body weight.

This result is comparable with the approximately 10 to 15 percent reduction in body mass typically recorded among people with diabetes using injectable semaglutide over a similar timeframe.

"Overall," the researchers write in their paper, "the findings indicate that orforglipron could address the unmet need for oral therapy by achieving outcomes similar to those of injectable GLP-1 receptor agonists, potentially shifting treatment paradigms."

How GLP-1 medicines affect appetite and blood sugar

GLP-1 medicines harness the body's natural post-meal appetite-reducing processes. After eating, the gut releases a hormone known as glucagon-like peptide-1 (GLP-1), which activates receptors in several organs. Activating these receptors reduces appetite, prompts the pancreas to produce more insulin and release less glucagon, and slows digestion, allowing blood sugar to rise more gradually.

GLP-1 medicines are synthetic versions of this hormone. By activating the same biological pathways, they can help people with diabetes control blood sugar and, more recently, support weight loss.

At present, the drug can only be delivered by injection because its peptides are broken down too rapidly by stomach acid, preventing oral doses from being used.

Orforglipron as an oral GLP-1 alternative

Unlike GLP-1 medicines, orforglipron is not a peptide, although it activates the same receptor as GLP-1. It is also absorbed through the digestive tract in the manner of a more conventional medicine. Early evidence of its effectiveness has been encouraging: an earlier clinical trial of 3,127 people with obesity but without diabetes reported an average body-weight reduction of 12.4 percent.

The latest study examined how the drug performs in people with type 2 diabetes. All 1,613 participants had been diagnosed with the condition and were considered either overweight or obese. Their mean age was 57, while their average weight was 101 kilograms.

Participants were divided into four groups. A control group received a placebo containing no active drug ingredients, while the remaining three groups received 6, 12, or 36 milligrams of orforglipron. For 72 weeks, every participant took their allocated tablet each day while following a diet reduced by 500 kcal from their baseline intake.

Neither the participants nor the researchers knew which tablet any individual was receiving. This method, called double-blinding, helps reduce bias in the interpretation of results.

Weight-loss results from the orforglipron trial

The findings were highly clear-cut. On average, the group taking 36 milligrams, the highest dose, lost 9.6 percent of their body weight, or roughly 9.6 kilograms. Average weight loss was 7 percent in the 12-milligram group and 5.1 percent in the 6-milligram group. By comparison, the placebo group lost an average of 2.5 percent.

Notably, 26 percent of those receiving the highest dose lost more than 15 percent of their body weight.

Other health measures also improved. Compared with the placebo, all orforglipron doses produced significant improvements in blood-sugar markers, while indicators related to the heart, inflammation and blood pressure also improved. Its adverse effects resembled those associated with injectable GLP-1 medicines: nausea, diarrhoea, vomiting and constipation. Given how the drug operates, these effects were unsurprising.

It is somewhat less effective than a weekly 15-milligram injection of the GLP-1 medicine tirzepatide, which in an earlier clinical trial produced an average 14.7 percent body-weight reduction among participants with diabetes. However, for some people, the convenience, comfort and accessibility of a tablet may justify the modestly lower effectiveness.

"We know it is harder for individuals with diabetes to lose weight. It is exciting to have an oral medication that provides double-digit weight loss, which on average was 23 pounds," Horn says.

"Once FDA approved, orforglipron is scheduled to be available in 2026 at a significantly decreased cost compared to current injectables. This could position it to be the 'metformin' of obesity and become widely covered by insurance plans, opening the door to treatment for all."

The study was funded by pharmaceutical company Eli Lilly and published in The Lancet.