Expert Q&A: How Orforglipron Could Transform Obesity Treatment

As research on oral glucagon-like peptide-1 (GLP-1) therapies accelerates, orforglipron—a once-daily pill currently in late-stage clinical trials—could mark a turning point in obesity care. With promising weight-loss efficacy, easier dosing, and the potential to expand access for patients hesitant about injections, oral GLP-1s may reshape how clinicians approach long-term obesity management. In this Q&A, expert Katherine H. Saunders, MD, with Weill Cornell Medicine, discusses the latest data, real-world considerations, and what an effective oral option could mean for patients and providers alike.

Katherine H. Saunders, MD

Q: The ATTAIN-1 phase 3 trial of orforglipron reported mean weight loss of approximately 12.4% at 72 weeks on the highest dose in adults without diabetes. From a clinician’s perspective, how clinically meaningful is that magnitude of loss, and in which patient profiles would you expect the greatest benefit?

A: This magnitude of weight loss is clinically meaningful for a large percentage of patients, as it is associated with improvement or resolution of many already established weight-related health complications as well as prevention of many new weight-related health complications. We expect the greatest health benefits in individuals who continue their medication long-term, since obesity is a chronic disease that requires long-term care.

Q: How do you compare orforglipron’s efficacy, tolerability, and discontinuation rates (≈5–10% due to adverse events) to the injectable GLP-1s patients already know (e.g., semaglutide, tirzepatide)? What tradeoffs matter most in real-world decision-making?

A: Orforglipron’s profile is comparable to injectable semaglutide and tirzepatide. Once we decide that a patient is a good candidate for obesity medication, there are many factors that guide our choice of agent. Unfortunately, cost and coverage play a huge role these days. The addition of another oral medication to our obesity armamentarium would be a huge win since many patients prefer oral to injectable.

Q: One practical differentiator is administration: unlike oral semaglutide, orforglipron can be taken without strict fasting or water limits. How might this simpler dosing affect adherence and outcomes in everyday practice?

A: Simpler dosing would likely improve adherence and persistence, which are essential considerations when it comes to long-term management of the chronic disease of obesity.

Q: Zooming out, what does the current oral anti-obesity landscape look like today? Which options are available and effective now (e.g., phentermine/topiramate, naltrexone/bupropion, orlistat), and where might an oral GLP-1 fit among these choices?

A: Phentermine/topiramate and naltrexone/bupropion (Contrave) are 2 of the critical tools in our obesity armamentarium. Since obesity is a heterogeneous disease, different people respond differently to different medications, and patients often need more than one medication to achieve health goals. The more medications we have, the more patients we can treat effectively. An oral GLP-1 would be a welcome addition.

Q: Many eligible patients still aren’t aware that prescription weight-management pills exist—let alone how they differ. Where are the awareness gaps (patients, primary care, payers), and what communication would you like to see to close them?

A: There are gigantic knowledge gaps and a tremendous amount of misinformation when it comes to obesity and medical obesity treatment. These gaps are everywhere, and they lead to widespread weight bias, stigma, discrimination, undertreatment and poor health outcomes. I would love to see more communication that obesity is a serious, complex, chronic disease that is impossible for most people to treat effectively without medical treatment. I would also like to see more communication that obesity is treatable, and a range of safe and effective treatment options exist.

Q: If an oral GLP-1 like orforglipron gains approval, how do you anticipate coverage and access will work—formulary placement under the pharmacy benefit, prior authorization/step therapy with older oral agents, or GLP-1-class requirements similar to injectables? What could speed responsible uptake vs. create bottlenecks?

A: I anticipate that small molecule oral GLP-1s like orforglipron would be less expensive to manufacture, so the list prices would be lower than those of the injectable GLP-1s. There are many bottlenecks with our current system, so I would love to see new processes that facilitate widespread and responsible uptake.

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Q: What safety and monitoring considerations will you prioritize with oral GLP-1s (e.g., gastrointestinal tolerability, dehydration/constipation management, rare risks), and how will you counsel patients to minimize discontinuations?

A: The key to successful medical obesity treatment is to optimize effectiveness, safety and long-term adherence. It’s critical to assess the risk/benefit profile of any medication for each individual patient and set them up for success with education, counseling, personalized dose titration and ongoing monitoring and support.

When we start an oral GLP-1 medication, we counsel patients on how to modify eating behavior and food choices to maximize tolerability and minimize side effects. Most adverse events can be avoided by selecting appropriate patients, individualizing treatment and providing clear guidance on when to notify the care team well before side effects progress to adverse events.

Q: For needle-averse or injection-fatigued patients, how big a shift could an effective pill represent—both for initial treatment and for long-term maintenance after weight loss with injectables?

A: A huge shift!

Q: Beyond the scale, what metabolic or cardiovascular markers (HbA1_C in those with prediabetes, lipids, blood pressure, inflammation) are you watching most closely in oral GLP-1 programs, and what has the early signal suggested so far?

A: We’re watching all of those metabolic and cardiovascular markers because health improvements matter much more than magnitude of weight loss (although the 2 are related, of course). Early signals are promising!

Q: Looking ahead to regulatory timelines and real-world deployment, what would you need—data, labeling, patient selection guidance, supply confidence—to feel comfortable making an oral GLP-1 a first- or second-line option in your practice within the broader GLP-1 ecosystem?

A: All of that!