Patients and researchers at CU Anschutz are part of a trial testing orforglipron - a daily, non-peptide pill that could reshape how GLP-1 therapies are delivered
The takeaway:
Orforglipron is an FDA-approved non-peptide oral GLP-1 pill, offering a potential alternative to injectable weight-loss drugs. Demand for GLP-1 medications has surged in recent years, but cost and injectable delivery have limited access for many patients. A CU Anschutz researcher is overseeing a clinical trial for orforglipron, and a patient shares her experience in the trial.
Every morning for two years, Julia Swaney has popped a pill, hoping it would quiet the "food noise" she's struggled with since she was a teen.
The pill she takes has had no effects, other than making her burp. It hasn't reduced her appetite or helped her lose weight.
"It's disappointing," Swaney said. For her, weight loss would mean being better able to keep up with her grandkids. But she remains committed.
As a participant in the ATTAIN-1 clinical trial at CU Anschutz, Swaney is playing an essential role in determining the safety and efficacy of orforglipron, a first-of-its-kind oral GLP-1. The Food and Drug Administration (FDA) approved orforglipron for weight loss in April, based on results from the first part of the randomized, double-blinded placebo-controlled clinical trial.
"We're excited about the initial results," said Neda Rasouli, MD, professor of medicine in the Division of Endocrinology/Metabolism/Diabetes and the study's lead at CU Anschutz Diabetes and Endocrinology Clinical Trial Program. "In the first 72 weeks of the study, all doses tested led to meaningful weight loss, ranging from patients losing 7.8% of their body weight at the lowest dose to 12.4% at the highest dose, with the placebo group seeing little to no weight changes."
Since the trial is double-blinded, Rasouli doesn't know if Swaney is one of the 30% of patients receiving the placebo. But she said it's possible Swaney - who hasn't experienced the typical side effects of a GLP-1 - is either taking the placebo or is a "non-responder." In GLP-1 clinical trials, Rasouli estimates about 5-10% of people don't respond. In real world use, she estimates as many as 20% of people don't respond to GLP-1 treatment.
"Either way, the importance of her contribution - and all those who participate in and stay with clinical trials - cannot be understated," Rasouli said.
Key points:
Orforglipron, a once-daily non-peptide oral GLP-1 pill, has shown weight loss results similar to peptide-based GLP-1 medications in early clinical trial data.
Not all patients respond to GLP-1 medications in the same way, and researchers are still working to understand why some people experience little or no effect.
Participants in placebo-controlled clinical trials play a critical role in advancing new treatments, even when they do not see personal benefits.
Researchers hope that non-peptide oral GLP-1 medications like orforglipron will be easier to produce, more affordable and more accessible to patients.
How an oral GLP-1 could change obesity treatment
Orforglipron is a new type of GLP-1 medication - a once-daily pill designed to help people lose weight without injections. It's the first non-peptide GLP-1 agonist to receive FDA approval, after trials showed its safety and efficacy are similar to other GLP-1s approved for chronic weight management in adults with obesity.
"Because orforglipron is non-peptide, it's easier to produce and manufacture, which can hopefully keep costs down so we can treat more people with obesity," Rasouli said.
Oral GLP-1 drugs that are peptide-based, such as semaglutide (oral Wegovy), must be taken on an empty stomach, with patients waiting at least 30 minutes before eating or drinking. Orforglipron doesn't have those restrictions, making it appealing to both doctors and patients. She said even the most motivated people have a hard time adhering to the directions on the label, and many people don't want to use injectables for the rest of their lives.
More than 3,000 patients at 138 locations worldwide are participating in the ATTAIN-1 trial. The trial ended after 70 weeks for patients who did not qualify as having pre-diabetes (i.e., their blood glucose levels were higher than normal but did not require medication). Because Swaney was identified as a participant with pre-diabetes, she was asked to continue with the study for 190 weeks to determine whether the medication had any impact on the development of diabetes.
As a retired nurse, Swaney appreciates the team at CU Anschutz that oversees her care.
"The study has been so thorough," Swaney said. "Everyone seems concerned with my health and wellbeing, beyond getting the data they need."
"Obesity is a disease. It's not just a lack of willpower. It's not simply people who don't pay attention to their health and well-being. There is dysregulation in the body's wiring system, in the appetite center and metabolism, that leads some people to become obese." - Neda Rasouli. MD
Why lifestyle changes alone fall short in obesity treatment
Over the years, Swaney has tried to lose weight on her own. She's had some success but nothing long-term. Now that she's 65, weight loss isn't about the vanity of being a certain size or looking a certain way. She just wants to be able to do the things she likes to do and take care of the people who count on her. She doesn't want to be "disabled" by her weight.
"I've always been hyper-aware of what I'm eating and whether I feel like I'm in control of my eating habits," she said. She is well-educated about nutrition and understands the "common sense" aspects of weight loss.
But, long-term changes are hard to maintain, for all people with obesity, Rasouli said. Our metabolisms "push back" when weight loss occurs, resisting big changes and working to return to a usual weight.
Swaney believes that maintaining better habits would lead to long-term weight loss, even without a GLP-1. Yet Rasouli said the evidence suggests otherwise, with long-term studies showing that lifestyle changes alone result in only 5% of people keeping the weight off long term.
"Obesity is a disease. It's not just a lack of willpower. It's not simply people who don't pay attention to their health and well-being. There is dysregulation in the body's wiring system, in the appetite center and metabolism, that leads some people to become obese." Rasouli said.
Stopping the voice that says 'eat more and more'
"People who haven't struggled with their weight don't realize how constant the 'food noise' can be," Rasouli said. In her practice, she's seen the remarkable impact GLP-1s can have on eliminating food noise and changing appetites and metabolisms.
"These medications are changing that 'wiring' - the physiology - and it's helping so many people to lose weight."
But not everyone who tries a GLP-1 responds the same. Rasouli said it's important to remember that reported weight losses are averages. So if a GLP-1 reports a 13% average weight loss, some people lost 20% or more while some lost 5% or less.
It's a pattern Rasouli sees in her clinical practice. She had just talked to a patient who was on the strongest injectable GLP-1 who was frustrated because she hadn't lost weight.
"There's still a big gap in our understanding," Rasouli said. "We don't know who responds best or why." She adds that it's still unknown if these drugs will become less effective over time - and if they can be affordable enough to reach all the people who need them.
It's what makes the non-peptide, oral orforglipron so exciting.
"We should admire her contribution to science. Without patients willing to participate and complete the studies - especially those who may be on placebo - we wouldn't have the evidence needed for FDA approval. And if we learn she's a non-responder, that's just as valuable. It helps us understand why treatments don't work the same for everyone." - Neda Rasouli. MD
"With effective, accessible medications, we can keep attacking the medical problem of obesity," she said. According to the manufacturer's website, orforglipron costs about $100 to $150 less per month than Zepbound for non-insurance, direct-pay patients, making it roughly 20% to 50% cheaper depending on dose.
Rasouli and Swaney won't know until the trial ends whether Swaney has been taking the active drug or a placebo - or whether she simply isn't responding to the treatment.
Swaney's commitment to seeing the study through deserves recognition, Rasouli said.
"We should admire her contribution to science. Without patients willing to participate and complete the studies - especially those who may be on placebo - we wouldn't have the evidence needed for FDA approval. And if we learn she's a non-responder, that's just as valuable. It helps us understand why treatments don't work the same for everyone."
Until the study ends in early 2027, Swaney will keep taking the pill every morning. She's seen what GLP-1s can do for others and knows they're not always used in the healthiest ways. If she chooses to use one after the study, she's determined to do so responsibly.
"I'd hoped this would be the magic thing that finally worked," she said. "But it's been a good dose of reality."
Now, Swaney is focused on something harder to measure: understanding the emotional urges to eat and what it will take to manage them, with or without medication.
