The availability now of two oral GLP-1s in addition to injectable options offers even greater opportunities for individualizing treatment for those with access, according to experts who shared their perspectives with Medscape Medical News.

The day after the FDA approved Eli Lilly's oral GLP-1 drug orforglipron (Foundayo) for obesity management, Novo Nordisk released findings of an indirect comparison showing greater weight loss and tolerability for oral semaglutide (Wegovy pill), which was FDA-approved in December 2025. However, experts who spoke with Medscape Medical News advised caution in interpreting those findings, while offering their perspectives on the current obesity management landscape. 

Although both are once-daily oral GLP-1 drugs, orforglipron and oral semaglutide differ in that the former is a small molecule (non-peptide) that can be taken at any time of day without restrictions on food or liquid intake. Oral semaglutide, in contrast, must be taken with water in the morning on an empty stomach, followed by a 30-minute wait before eating. 

"Discovery of a non-peptide 'small molecule' GLP-1 receptor agonist represents a true 'tour de force' from a technical point of view. The clinical efficacy data with orforglipron are impressive, similar in most to the best-in-class peptide drugs. From a manufacturing point of view, it may be feasible to scale up production in proportion to the magnitude of the public health need. In short, orforglipron has the potential to have a transformational impact on the treatment of obesity and type 2 diabetes." Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland School of Medicine, Baltimore, told Medscape Medical News. 

Donna H. Ryan, MD, professor emerita at Pennington Biomedical Research Center, New Orleans, told Medscape that orforglipron is the "new kid on the block" nonpeptide that is not degraded like proteins and is therefore metabolized in the liver. "This means there may be implications for using orforglipron with other medications. Orforglipron is metabolized by cytochrome P450 3A4, as is simvastatin. So the [orforglipron] label indicates the simvastatin dose should not exceed 20 mg when given concomitantly. … It's a good option for prescribers, but my advice is read the label about drug interactions carefully before prescribing."

And, she noted, "the weight loss with both of the oral agents looks good, albeit less than with injectable semaglutide and tirzepatide."

Sean Wharton, MD, medical director of the Wharton Medical Clinic, Toronto, who has led clinical trials on both oral GLP-1s, doesn't see major differences between the two oral GLP-1s on a practical level. "They both had pretty good trials showing weight change. They have similar side effect profiles to the other GLP-1s. They're both pills, so they don't need to be kept in the refrigerator [as do the injectables]."

As far as the need for fasting and the need to wait before eating with oral semaglutide, Wharton pointed out, "People in the trial did pretty well. They didn't have a major issue with that restriction." Moreover, he noted, "this molecule has been around a long time as Rybelsus for type 2 diabetes, so people know who to give it to and who not to give it to." 

However, he did point out that using oral semaglutide could be complicated for patients taking other medications that have similar fasting/food restrictions, such as levothyroxine or some psychiatric medications. So, for those patients, orforglipron might be a better option. 

On the other hand, Wharton also noted that unlike orforglipron, oral semaglutide is also indicated for reducing the risk of major adverse cardiovascular events in adults with established cardiovascular disease and either obesity or overweight and therefore might be preferable for those individuals. "If you're a believer that it's the semaglutide molecule that helps with coronary arteries, not just the weight loss and being in the trial, then oral semaglutide is that molecule," he commented. 

In considering the two orals, Wharton said, "I'm not worried about the weight change [or] the side effect profile. I'm worried about the patient's insurance, what the patient would like to take, whether they have type 2 diabetes, and whether they are taking other medications."

Novo Nordisk's Indirect Comparison: How Valid? 

Novo Nordisk's ORION study, to be presented at the Obesity Medicine Association's upcoming meeting, was an indirect comparison of data from the two pivotal trials: OASIS 4 for oral semaglutide 25 mg and ATTAIN-1 for orforglipron 36 mg (equivalent to the approved highest Foundayo dose of 17.2 mg). Analyses were adjusted for differences between trial populations, including baseline body weight, glycemic status, and sex.

Mean weight loss was significantly greater with oral semaglutide 25 mg, with a mean difference of 3.2 percentage points, regardless of whether participants stayed on treatment, and 3.0 percentage points if all stayed on treatment. Treatment discontinuation due to any adverse event was about four times higher and discontinuation due to gastrointestinal adverse events was about 14 times higher with orforglipron. 

Wharton pointed out that the two trials, both of which he led, "were dramatically different" in that ATTAIN-1 enrolled a total of 3127 individuals in 138 locations in 13 countries around the world, while OASIS 4 enrolled just 205 participants, from four countries. "Could that give you different results? I don't know, but the bottom line is that they're not comparable." 

Indeed, obesity consultant Theodore K. Kyle, RPh, founder and CEO of ConscienHealth, Pittsburgh, told Medscape Medical News that "we have no actual direct comparisons, and indirect comparisons can be very misleading."

Taylor commented, "It is challenging to compare data between two different studies. Nevertheless, I find it plausible that a longer-acting drug like semaglutide could have better tolerability at any given amount of weight loss." 

What About Pills vs Injectables? 

As of now, the more-potent dual GLP-1/glucose-dependent insulinotropic peptide (GIP) agonist tirzepatide (Zepbound), as well as other dual and triple receptor agonist incretin drugs in later development, are injections given once weekly rather than daily, as the orals are. That may or may not be important to people, Wharton said, noting that "maybe for some people, it's easier to remember to take a pill every day." 

But he added that injectables do work better for those with higher BMIs. "There is greater weight loss. … If somebody has a BMI of 45 or 50, I'm not going prescribe a pill for them. If they have access to both, I'm going to prescribe a bigger gun." 

For those with lower BMIs who could benefit from either, Wharton said that "right now, for those paying out of pocket, the starting price for the pills is a little bit better than the starting price for the injectables, so that might be a little bit of advantage for those patients." (Both oral GLP-1s are available for as little as $25 per month for those with commercial insurance, or self-pay starting at $149 per month for the lowest dose, according to the respective companies.) 

Kyle noted that "drug prices are very fluid and not very transparent. The one thing that is true is that there is a lot of downward pressure on pricing. This [orforglipron] approval brings even more competition into the marketplace and will add to the pricing pressure. In the end, this is a good thing because it gives people choices. One size does not fit all in obesity care, and thus, people have to figure out what works best for them."

Taylor has reported receiving payments from the National Institute of Diabetes and Digestive and Kidney Diseases for an inventor's share of a patent covering metreleptin as a treatment for generalized lipodystrophy. He was employed by Eli Lilly in 2000-2002. Ryan reports current or past consulting/advisor/speaker fees from AbbVie, Altimmune, Amgen, AstraZeneca, Biohaven, Boehringer Ingelheim, Calibrate, Carmot, Regeneron, Roche, Currax, Cin Rx, eMed, Epitomee, Fractyl, Kailera, Lilly, Nestle, Novo Nordisk, Pfizer, PPD, Rhythm, Souffle Therapeutics, Source Bio, Structure Therapeutics, Tenvie, Viking, Zealand, Weight Watchers, and Regor; fees for data monitoring committees from Rhythm, Cin Rx, and Lilly; and stock options from Epitomee, Calibrate, Roman, and Scientific Intake. Wharton serves on advisory boards for, or receives honoraria from, AbbVie, Amgen, Astra Zeneca, Bausch Health Canada, Boehringer Ingelheim, Eli Lilly, i2o Therapeutics, Merck, Metsera, NGX, Novo Nordisk, and Regeneron. He has conducted clinical trials or other research for Amgen, Astra Zeneca, Bausch Health Canada, Boehringer Ingelheim, Eli Lilly, Merck, Roche, Novo Nordisk, and Pfizer. Kyle has been a consultant for Boehringer Ingelheim, Emerald Lake Safety, Novo Nordisk, Nutrisystem, and Roman Health Ventures. 

Miriam E. Tucker is a freelance journalist based in the Washington, DC area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR's Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker and BlueSky @miriametucker.bsky.social.