GLP-1 drugs, like semaglutide and tirzepatide, have transformed how obesity is treated. Now, a new oral GLP-1 drug has shown promising results for weight loss. Adults who took the highest dose lost an average of 12.1% of their body weight over 36 weeks. The experimental drug, called aleniglipron, is a once-daily pill being developed for people with overweight or obesity. Unlike commonly used GLP-1 medicines that are given as injections, aleniglipron is a small-molecule drug that can be taken orally.

The study, published in Nature Medicine, found that people taking 45 mg of aleniglipron lost 9% of their starting body weight on average after 36 weeks. Those taking 90 mg lost 10.7%, while the 120 mg group lost 12.1%. In comparison, the placebo group experienced only a 0.5% reduction in body weight. Researchers said the results support further development of the drug, although larger and longer Phase 3 trials are still needed.

What Is Aleniglipron?

Aleniglipron is an experimental GLP-1 receptor agonist, but it differs from several existing GLP-1 medicines because it is a small molecule rather than a peptide-based drug. GLP-1 is a hormone that's naturally produced in the body and it plays an important role in appetite, digestion and blood sugar regulation.

GLP-1 medicines work by activating GLP-1 receptors. This can increase feelings of fullness, reduce appetite and slow the movement of food through the stomach. The medicines can also stimulate insulin release when blood sugar levels rise. Together, these effects can help people eat less and lose weight.

Robert Kushner, MD, '82 GME, professor emeritus of Medicine in the Division of Endocrinology, Metabolism and Molecular Medicine, and a co-author of the study, said, "The difference with aleniglipron is it's a small molecule, which means it's chemically made and could be taken with or without food. Most medications we take, whether it's aspirin or blood pressure medicine, are small molecules. They're chemicals that you make structurally, and because of that you can potentially combine them with other medications."

What Did The Study Find?

The Phase 2b trial included 230 adults with overweight or obesity. Participants had an average age of about 50 years and were treated at 38 medical centres in the United States.

They were randomly assigned to receive either aleniglipron or a placebo. The active-treatment groups received daily doses of 45 mg, 90 mg or 120 mg. The dose was gradually increased every four weeks rather than starting participants immediately on the highest dose. Treatment continued for 36 weeks.

The weight-loss results increased with the dose:

  • 45 mg: Average weight loss of 9%
  • 90 mg: Average weight loss of 10.7%
  • 120 mg: Average weight loss of 12.1%
  • Placebo: Average weight loss of 0.5%

The highest-dose group therefore achieved the largest reduction in body weight. The researchers also reported that weight loss continued during the 36-week treatment period rather than clearly reaching a plateau.

What Are The Side Effects?

As with other medicines that affect the GLP-1 pathway, gastrointestinal side effects were among the most common problems reported in the trial. These included symptoms such as nausea and other digestive complaints.

The researchers described the gastrointestinal side effects as generally mild to moderate. They also became less frequent as treatment continued. Overall, 10.4% of participants stopped treatment, while researchers reported no cases of drug-induced liver injury.

However, the study was not large or long enough to establish the complete safety profile of aleniglipron. More participants will need to be followed for a longer period in later-stage trials.

Why Is An Oral GLP-1 Pill Important?

GLP-1 medicines have changed the treatment of obesity, but injections can be a barrier for some people. A daily pill could make treatment easier for people who are uncomfortable with injections.

Aleniglipron may also have advantages in terms of storage and manufacturing. Unlike some injectable GLP-1 medicines that require specific storage conditions, an oral small-molecule drug could potentially be easier to distribute. Its ability to be taken with or without food may also make daily treatment simpler.

While the findings are encouraging, aleniglipron is still an investigational drug. The current study was a Phase 2b trial, meaning researchers are still evaluating the medicine before larger Phase 3 studies. For now, the results suggest that oral GLP-1 medicines could become an important option in the treatment of obesity.

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