Oral Semaglutide and the Future of GLP-1 Obesity Treatment, With Timothy Garvey, MD

As highly effective GLP-1-based therapies continue to transform obesity care, their growing use has sharpened attention on safety, patient selection, and the importance of active clinical oversight. While the US Food and Drug Administration (FDA) approval of oral semaglutide (Wegovy) expands access and choice, it also underscores the need for careful risk assessment and long-term management strategies as clinicians incorporate these agents into routine practice.

The December 22, 2025, approval was based on the results from the phase 3 OASIS 4 clinical trial, a 64-week medical study that included 307 adults with obesity or overweight with ≥ 1 weight-related comorbidity, without diabetes. In addition to the oral formulation’s proven efficacy for weight loss, OASIS 4 data showed the most common adverse reactions were similar to those previously seen in clinical trials with semaglutide injection 2.4 mg, including nausea, diarrhea, and vomiting.

In an interview with HCPLive, Timothy Garvey, MD, a professor of medicine and director of the Diabetes Research Center at the University of Alabama at Birmingham, emphasizes that established contraindications remain unchanged across GLP-1 formulations but notes that the therapy is not suitable for patients with contraindications like a history of medullary thyroid carcinoma or acute pancreatitis. He also highlights gallbladder disease as an important clinical consideration, noting that rapid or substantial weight loss, regardless of modality, is associated with increased gallstone risk, with GLP-1 therapies appearing to amplify this effect.

Beyond traditional safety concerns, Garvey calls attention to a more nuanced challenge emerging in real-world practice: excessive weight loss in highly responsive patients. While many individuals benefit substantially from GLP-1–induced weight reduction, some continue losing weight beyond a healthy threshold.

“Some patients just keep losing weight and losing weight, and they can feel tired and run down and listless, and their cognition can even be a little cloudy,” he said. “They don't socialize as well… Some of these patients will say ‘Dr Garvey, I'm losing too much weight. I have to slow down. My friends tell me I don't look good. I look older, I'm tired, I don't have the energy to get things done anymore.’ Other patients will have those same symptoms, but they're kind of enthralled or addicted to the weight loss, and they'll just want to keep losing weight and losing weight. They don't have a perspective on this, and this is where a healthcare professional comes in.”

Adherence considerations also differ between formulations. Oral semaglutide requires daily dosing under specific conditions to optimize absorption, including administration with water on an empty stomach before food intake. Garvey notes that while this regimen may appear burdensome, most patients adapt readily, particularly when oral therapy aligns with their preferences.

Looking ahead, Garvey frames oral semaglutide as part of a rapidly advancing therapeutic continuum. Dual- and triple-agonist agents targeting multiple metabolic pathways are already demonstrating weight loss approaching that of bariatric surgery in clinical trials. However, he cautions that greater potency does not equate to universal need. Increasingly, clinicians are finding success with submaximal dosing, emphasizing individualized treatment rather than maximal weight reduction.

Despite recent progress, Garvey stressed that long-term experience with these second-generation agents remains limited.

“We've only had these medicines since 2021, so we don't have long-term experience. We don't know what the long-term effects will be with bone loss and muscle loss and perhaps 10 years later, more falls and fractures. We just don't know,” Garvey said. “We need a longer term experience, and we need to develop evidence-based strategies for maintaining patients on these medications, promoting adherence, and make sure they take medicines for this chronic disease so they can maintain the health benefits and the weight loss. We're not there yet, so we still have a long way to go.”

Editors’ Note: Garvey reports relevant disclosures with Boehringer-Ingelheim, Novo Nordisk, Eli Lilly, Merck, Neurovalens, Fractyl Health, and others.

References

1. Brooks A. FDA Approves Semaglutide (Wegovy) Pill As First Oral GLP-1 for Weight Loss. December 22, 2025. Accessed December 24, 2025. https://www.hcplive.com/view/fda-approves-semaglutide-wegovy-pill-as-first-oral-glp-1-for-weight-loss

2. Kunzmann K. FDA Approves Semaglutide for Obesity Weight Management. June 4, 2021. Accessed December 24, 2025. https://www.hcplive.com/view/fda-approves-semaglutide-obesity-weight-management