Could Orforglipron Change Obesity Treatment Forever?

In this Q&A with Pharmacy Times, Richard Frank, MD, chief medical officer at Vida, discusses how emerging oral GLP-1 therapies may shift the obesity treatment landscape by offering a more convenient alternative to injectables, potentially improving patient adherence and earlier initiation of care. He highlights key differences in efficacy, tolerability, and real-world use, while emphasizing the importance of individualized treatment selection. Frank also explores how expanded therapeutic options could enhance access and flexibility for patients and providers.

Pharmacy Times: With the approval of orforglipron (Foundayo; Eli Lilly and Company) as a nonpeptide oral glucagon-like peptide-1 (GLP-1) receptor agonist, how do you see this shifting the treatment landscape for obesity and cardiometabolic disease compared with existing options?

Richard Frank, MD: I think it is an innovation. Eli Lilly has come up with a nonpeptide small molecule that is readily absorbable without food, water, or fasting restrictions. It is an update to what we've seen with oral semaglutide from Novo Nordisk. It does deliver approximately 11% mean body weight reduction and improvements in waist circumference, systolic blood pressure, and triglycerides. So, overall, it's an enhancement to what we see on the marketplace.

Pharmacy Times: Orforglipron does not require the same fasting and administration constraints as oral semaglutide—how meaningful is this difference in real-world use and patient uptake?

Frank: I think it does make a difference for patients who are uncomfortable with an injection or don't have access to cold storage. A pill is a significant improvement. As you know, oral semaglutide requires a 30-minute fast. You can only have it with a little bit of water. It needs to be taken first thing in the morning before any other medications. So, it's an administrative challenge for patients. Orforglipron is just an easier pill to take. Having said that, it does have a significantly higher incidence of GI [gastrointestinal] [adverse] effects, so some patients may not be able to tolerate it.

Pharmacy Times: As more convenient oral options become available, do you anticipate earlier initiation of GLP-1 therapy in the treatment paradigm, particularly for patients who may have previously avoided injectables?

Frank: I think I do. First off, as you pointed out, some patients just have a needle phobia or a discomfort with needles, and the fact that they can take a pill is just easier. Additionally, I think some primary care physicians may have a slightly unspoken bias about not prescribing injectable medications, whereas a pill just feels more comfortable in their daily workflow. They're accustomed to ordering prescriptions for pills as opposed to injectable medications. I think it's easier as an entry point for patients who may be seeking treatment for obesity. Somehow, it seems psychologically easier to start with a pill, and if the pill fails, then escalate to an injectable.

And then, actually, in some practices, including ours, we sometimes wean from injectables and move to oral medications for long-term management in patients who have achieved their weight loss goals. Lastly, in some areas, it's a challenge around cold chain infrastructure, meaning the injectables have to be refrigerated and pills do not. So, if there's any difficulty around maintaining a low temperature point and storage, the pill becomes easier.

Pharmacy Times: How should clinicians think about sequencing therapy now? Does an oral agent like orforglipron serve as an entry point before injectables or as an alternative for specific patient populations?

Frank: It can be seen either way. For some patients who really have an objective to lose quite a bit of weight, using an injectable is still the most potent solution. So, we'll go the injectable route. Semaglutide [Ozempic, Wegovy; Novo Nordisk] has roughly a 15% weight reduction. For patients who might try injectable tirzepatide [Zepbound; Eli Lilly and Company], you're looking at around 20% weight reduction. The orals are a bit lower potency. Oral semaglutide is somewhere below 15%, and orforglipron is around 11%. So, the injectables are definitely more potent for patients who are comfortable with them.

But to your point, a patient could start with an oral, see how they do, and if they fail, move to an injectable. And then, as I said earlier, some patients may wean from an injectable to an oral agent over the long haul, and those drugs are slightly cheaper on a direct-to-consumer basis.

Pharmacy Times: From a health system perspective, what impact could oral GLP-1 agents have on access, affordability, and overall utilization compared with injectable therapies?

Frank: I think ultimately, treating obesity is a complex disease. It's behavioral, it's genetic, and it's environmental. Ideally, patients are receiving a behavioral intervention, a comprehensive lifestyle intervention, along with pharmacotherapy. But for patients who are reliant on pharmacotherapy to achieve their weight loss goals, the more choices we have, the better. An oral agent, as we've shared through this brief interview, just makes it easier for those patients who either aren't comfortable with injectables, don't have a mechanism to store injectables, or have a doctor who may not be comfortable prescribing injectables. It just gives us more options, and the more options, the better, is really how I think about it.

Pharmacy Times: Given that long-term outcomes depend on addressing underlying cardiometabolic risk, how can pharmacists help ensure that GLP-1 therapies—whether oral or injectable—are part of a broader, sustainable treatment strategy rather than a standalone solution?

Frank: Absolutely. So, as we just said, having a comprehensive lifestyle intervention that includes coaching, medical nutrition therapy from registered dietitians, and a behavioral intervention not only helps patients develop lifelong habits to sustain weight reduction, should they ever choose to come off these agents, but it also helps patients who may plateau on these drugs.

Additionally, we know that patients who are on antiobesity medications plus a behavioral intervention have greater weight reduction than patients who are on either intervention alone. So as we think about how health systems and pharmacists can assist patients in navigating these medications and really getting the most out of them, understanding how to titrate them, understanding how to dose optimize them, understanding how to navigate the [adverse] effects associated with them, and encouraging patients to engage in a lifestyle intervention, either virtually through telemedicine or in person, I think these are all elements that pharmacists can assist patients with in really getting the most out of these drugs and creating the greatest and most sustainable risk reduction possible when navigating obesity.