GLP-1 in a pill for weight loss - pinning down where we're at

While we now have several injectable GLP-1 based treatments available for weight management around the world [liraglutide (Saxenda), semaglutide (Wegovy), tirzepatide (Zepbound/Mounjaro)], there are no GLP-1s currently available in a pill format for obesity treatment.

But that is likely soon to change, backed by a whirlwind of data that have come out around orforglipron and oral semaglutide this week.

Background:

Semaglutide in a pill has been available as a treatment for type 2 diabetes for several years (called Rybelsus), at a dose of 7mg or 14mg daily. Semaglutide is a hormone-based treatment that is 94% identical to the GLP-1 hormone that our own body makes. It is the same semaglutide that you get in the injectable formats (Ozempic/Wegovy). In the pill format, it’s not as potent as the injectables, but it works well for many people to treat their diabetes and provide weight loss. It has to be taken in a fasting state with maximum 120mL (half a cup) of water in order to be absorbed.
Orforglipron is a non-peptide small molecule that stimulates the GLP-1 receptors. It is not hormone-based. An advantage of this approach is that it’s more easily absorbed, so you can take this pill with or without food or liquid.

OK. Now let’s get into three key study results that have been released this week:

In the ATTAIN-1 trial, published in the New England Journal of Medicine, 3,127 people with obesity were randomized to receive orforglipron 6mg, 12mg, or 36mg daily, or placebo. At 72 weeks, the weight loss seen was -7.5%, -8.4%, and -11.2% with 6mg, 12mg, and 36mg respectively, vs -2.1% with placebo. Almost one in five patients in the orforglipron 36mg group lost at least 20% of their weight. Metabolic health parameters (eg blood pressure, cholesterol, glucose) improved. The most common side effects were gastrointestinal (as known for the GLP-1 class) , and resulted in 3.5% to 7% of orforglipron groups stopping treatment vs 0.4% in the placebo group. There was no signal for liver safety concerns, as has been seen with other non-peptide small molecule GLP1s that have discontinued clinical development.

In the OASIS 4 study, published the very next day, in the same journal – and same lead author, Dr Sean Wharton! – 205 people with obesity were randomized to receive either oral semaglutide 25mg daily vs placebo. At 64 weeks, weight loss was -13.6% with semaglutide vs -2.2% with placebo. Almost one third of the oral semaglutide group had a weight reduction of at least 20%. Metabolic parameters improved (though blood pressure did not differ between groups). Again, GI side effects were most common, leading to treatment discontinuation in 3.4% of the semaglutide group vs 2% of the placebo group. (Note that oral semaglutide has also been studied as an obesity treatment at 50mg daily in the OASIS 1 study, as blogged previously.)

And in the midst of these publications, there was also a press release of topline results of the ACHIEVE-3 head to head trial of orforglipron vs oral semaglutide in people with type 2 diabetes (not yet published). In this study, 1,698 people with type 2 diabetes on metformin were randomized to receive orforglipron 12mg, 36mg, or oral semaglutide 7mg or 14mg daily. At 52 weeks, A1c (diabetes report card) reduction was superior with orforglipron, decreasing by -1.9% with the highest orforglipron dose (36mg), vs -1.5% with the highest oral semaglutide dose (14mg). Weight loss was also superior with orforglipron, at -8.2% with 36mg, vs -5.3% with oral sema 14mg. Gastrointestinal were again the most commonly reported side effects, with treatment discontinuation rate (for any reason) of 9.7% with orforglipron 36mg vs 4.9% with oral sema 14mg. Note that the 25mg dose of oral semaglutide tested in the PIONEER PLUS study (disclosure: I was an author on this publication) was not included in the ACHIEVE-3 trial. While we should not draw comparisons across trials, A1c reduction with oral sema 25mg in PIONEER PLUS was -1.8%, and weight loss was -6.7kg (-6.9%).

So what does all of this mean for people living with elevated weight? Well, some people may prefer a daily pill over a weekly injection. Pills are much easier to ship around the world, as they are smaller packages and don’t require refrigeration as the injectables do. It is speculated that orforglipron will come into the market at a competitive price as it is a non-peptide, thus easier to produce. As we highlight in our 2025 Canadian Obesity Pharmacotherapy Clinical Practice Guidelines (disclosure: I am the lead author), improvement in weight-related health issues should be a key factor in choosing the best treatment. Orforglipron is being studied for osteoarthritis, sleep apnea, and hypertension. While oral semaglutide 14mg has been proven to reduce cardiovascular events in people with type 2 diabetes (as blogged here), we may have to look to semaglutide’s injectable (Ozempic/Wegovy) data and decide whether we think that semaglutide in pill form would confer similar benefits. So, while it might seem complicated, I suspect that a lower price point and ease of transport of any oral GLP1s that come to market will be a key driver in uptake, as this will allow access for people who are not currently able to access/afford injectables. In Canada (and China), injectable semaglutide will be generic (Health Canada approved) in 2026, and the pricing of injectables will play into this picture as well.

BOTTOM LINE: GLP-1 treatments in pill format for obesity are likely to become available soon (expected in 2026). They are effective to improve weight and metabolic health. Ease of transport of pills, and potentially a lower price point, should increase access to more people around the world. Oral GLP-1s will provide an additional option to empower people to choose the best option in partnership with their health care team, to align with their health needs and preferences.

Disclaimer: I am/have been an investigator in clinical trials of orforglipron, semaglutide, tirzepatide, and liraglutide. I receive honoraria as a continuing medical education speaker and consultant from the makers of orforglipron and tirzepatide (Eli Lilly), and semaglutide and liraglutide (Novo Nordisk).

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