Obesity is a growing global health challenge. Many people now use GLP-1 receptor agonists, medicines that help reduce body weight by curbing appetite, slowing digestion, and improving metabolism. These drugs are usually given by injection, which can be inconvenient or uncomfortable. An oral GLP-1 pill offers a simpler option, and recent trials show strong promise. Still, experts say challenges remain before such pills can become widely used.
What Recent Trials Reveal About the Pill
In the OASIS-4 Phase 3 trial, researchers tested oral semaglutide 25 mg in 307 adults with obesity or overweight, but without diabetes. Over 64 weeks, participants lost an average of 16.6% of their body weight, while the placebo group lost about 2.7%. More than a third of participants achieved at least 20% weight loss. Even with imperfect adherence, people still lost about 13.6% of body weight, showing the drug’s strong effect. Nearly 30% achieved a 20% loss despite not following every instruction.
Another trial, OASIS-1, tested a higher dose of 50 mg oral semaglutide in adults with obesity or overweight. Over 68 weeks, this group lost 15.1% of their body weight, compared to only ~2% in the placebo. In participants with full adherence, the loss rose to ~17.4%.
Meanwhile, Eli Lilly is developing orforglipron, a non-peptide oral GLP-1 pill. In a study of nearly 1,700 adults with diabetes, the highest dose (36 mg) led to ~9.2% weight loss, outperforming oral semaglutide 14 mg (~5.3%). Orforglipron also lowered blood sugar more effectively. These results show that oral GLP-1 pills are starting to rival injections, especially when given at higher doses and over long periods.
How the Pill Works and Why It Is Hard to Make
GLP-1 drugs mimic a natural hormone that regulates hunger, slows stomach emptying, and controls blood sugar. The challenge is that GLP-1 molecules are fragile. Stomach acid and digestive enzymes break them down, and the intestine blocks large molecules from entering the bloodstream.
To solve this, researchers use different scientific strategies. Some modify the peptide chemically so that it resists breakdown inside the stomach. Others create protective coatings that release the drug only in parts of the gut where absorption is more likely. Some even add absorption enhancers that help the drug cross the gut lining into the bloodstream.
A study published in Scientific Reports described how a modified GLP-1 candidate, MEDI7219, showed stability and oral activity in animal models. While early-stage, it highlights how carefully engineered peptides and delivery systems can make oral GLP-1 therapies possible.
Safety and Side Effects
The main challenge with oral GLP-1 pills, as with injections, is side effects. In OASIS-4, the most common problems were gastrointestinal issues such as nausea and vomiting. Nearly half of the participants reported nausea, though most cases were mild or moderate. About 6.9% of participants discontinued treatment due to side effects.
Similar findings appeared in studies of orforglipron, where nausea, vomiting, and stomach discomfort were reported, especially at higher doses. While these symptoms are not new to GLP-1 therapy, they remain an obstacle to long-term adherence. The safety profiles, however, look broadly similar to injectable GLP-1 drugs.
Still, long-term risks are not fully known. Researchers want to learn how these pills might affect the heart, pancreas, gallbladder, or other systems over the years of use. The need for larger, longer studies remains.
Why an Oral Pill Could Be a Game-Changer
If oral GLP-1 pills are approved, they could significantly change obesity treatment. Many people dislike injections and would prefer a daily pill, which could make patients more likely to stay consistent with treatment. Pills also make treatment more accessible in places with limited healthcare infrastructure, as they do not require special training or equipment.
Unlike injections that often need refrigeration, pills are easier to store and transport, lowering barriers to distribution. As The Washington Post reported, patient preference plays a big role; people are generally more open to trying a pill than a shot. This could broaden the reach of obesity medicines to millions who might otherwise refuse injections.
The Challenges That Remain
Despite the excitement, experts emphasize that important hurdles must still be solved. One challenge is bioavailability. To be effective, pills often require higher doses, which can raise costs and increase side effects. Another issue is adherence. While clinical trials provide motivation and close monitoring, real-world patients may skip doses, take them incorrectly, or stop when they feel sick.
Side effect tolerance is another obstacle. Nausea and vomiting, though common, may cause patients to discontinue therapy. Long-term safety is still being studied, as it remains unclear how pills affect diverse populations over multiple years.
The path to regulatory approval is also critical. The FDA is currently reviewing Novo Nordisk’s application for oral Wegovy. Approval could be a milestone, but questions about cost and insurance coverage remain. If pills are too expensive, many patients will not benefit, even if the science is sound.
What Experts Say
Industry leaders have expressed optimism. Martin Holst Lange, Chief Scientific Officer at Novo Nordisk, said the OASIS-4 trial showed “compelling efficacy for an oral weight management medication with 16.6% weight loss and a safety and tolerability profile consistent with injectable Wegovy®”.
From Eli Lilly, Kenneth Custer highlighted orforglipron’s promise, calling it “the most promising approach to creating an effective small-molecule GLP-1.” He pointed out that it showed superior results compared to oral semaglutide in a head-to-head diabetes study.
What Comes Next
The near future will be decisive. The FDA’s ruling on oral semaglutide 25 mg could open the door for the first widely available oral GLP-1 pill. Results from orforglipron’s obesity trials are also expected soon, which could reshape competition in this market. At the same time, real-world studies will reveal how well people tolerate and adhere to pills outside of clinical settings. Finally, debates about pricing and insurance coverage will decide how widely these new treatments can be used.
Conclusion
The move from injections to pills in GLP-1 therapy could transform obesity treatment. Trials show that oral semaglutide and orforglipron can deliver significant weight loss, sometimes approaching injection results. Yet success will depend on solving challenges like side effects, dosing, bioavailability, and affordability.
If these barriers are overcome, oral GLP-1 pills could give millions of people an easier, more acceptable way to manage obesity. For now, they remain a powerful option on the horizon, one that could make effective obesity care more accessible worldwide.
