Q&A: Understanding Adherence, Side Effects, and Patient Choice With Oral Semaglutide

In this Q&A, Richard Frank, MD, MHSA, discusses key considerations when choosing between oral and injectable semaglutide (Wegovy; Novo Nordisk), emphasizing that clinical efficacy, safety, and side effect profiles are largely similar between the 2 formulations. He explains that differences in real-world adherence are driven less by tolerability and more by how the medications are taken, with the daily, highly structured requirements of the oral formulation posing potential barriers to long-term persistence compared with the once-weekly injectable option. Frank highlights the importance of shared decision-making, noting that patient preference, lifestyle, and expectations should guide therapy selection, and underscores the critical role pharmacists play in educating patients on proper administration, managing side effects, and setting realistic expectations for long-term, chronic weight management therapy.

Pharmacy Times: How do the clinical outcomes of the newly approved oral semaglutide for weight management compare with injectable GLP-1 therapies in terms of weight loss efficacy and durability?

Richard Frank, MD, MHSA: Absolutely. So I think there were 2 major trials, one for the oral Wegovy and then the other for the injectable Wegovy. I’m using Wegovy simply because I don’t want to confuse it with Ozempic, which is designated for diabetes.

The OASIS 4 trial (NCT05564117) for oral Wegovy at the maximum dose of 25 milligrams daily led to approximately a mean weight reduction of about 13.6%, or rounded up to 14%. Roughly 79% of participants achieved 5% or more weight reduction. That’s an important cut point because it’s what the CDC and typically other professional organizations argue is a clinically significant weight reduction.

In the STEP trial (NCT03548935) for injectable Wegovy, which is a bit older—by a couple of years now—the maximum dose of 2.4 mg led to roughly a 14.9% weight reduction, so rounded up to 15%, with 86% of participants achieving a 5% or more weight reduction.

So, on the whole, clinically, these are about equivalent drugs in terms of weight reduction, and that’s probably the most important point. Both of these outcomes were observed after more than a year of persistency, so it really gives you a sense of long-term outcomes.

It turns out that there was even an extension on the STEP trial around injectable Wegovy, and I think the maximum mean reduction got up as high as 15.2%. So these drugs roughly deliver approximately 15% weight reduction.

Pharmacy Times: What side effect profile should clinicians and pharmacists be most aware of with oral semaglutides, and how does it differ—if at all—from injectable formulations?

Frank: So both of these drugs have a high incidence of GI side effects—gastrointestinal side effects—with nausea, vomiting, and diarrhea being the most common.

It turns out that initially we thought the oral agent would deliver a higher incidence of gastrointestinal side effects. It’s probably about the same, at roughly 3/4 of patients.

Now, the vast majority of patients—almost 95% of them—who are experiencing gastrointestinal side effects have mild to moderate symptoms, and so rarely does it lead to discontinuation of the drug. For both the oral and the injectable, discontinuation rates as a result of GI side effects are only about 7%, or less than 10%.

So in general, the same rough side effect profile and the same discontinuation rates due to side effects. We’ll talk a bit in a moment about the overall discontinuation rates.

There’s this weird thing that with oral Wegovy, it tends to have more skin sensation changes. Roughly about 5% of patients have skin sensation or dysesthesia with oral Wegovy, whereas injectable is only about 2.5%. So that’s the one side effect difference between the two drugs.

I suppose also that gastrointestinal side effects due to dyspepsia, or heartburn, tend to be a bit more common in the oral agent than the injectable. Overall, though, they look very similar in terms of the side effect profile.

Pharmacy Times: Early data suggest higher discontinuation rates with oral GLP-1 therapies compared with injectables. From your perspective, what are the primary drivers of this trend—tolerability, adherence challenges, patient expectations, or something else?

Frank: So I think you would have thought that adherence would be higher with pills than injectables. I think clinicians just naturally think patients don’t want to inject themselves. But you’re right, Danielle—the discontinuation rates for oral agents are roughly 3 times as common at 64 to 68 weeks, so roughly 15 months.

The discontinuation rates are roughly 3 times as common in the oral agent as the injectable. And so it’s probably not the side effect profile, because as we just discussed, that’s about the same. So we think it’s in the way that patients have to take the medication.

A pill is a daily thing to do. There are a lot of expectations around taking the pill. You have to take the pill on an empty stomach. You can’t have anything to eat or drink for 30 minutes. The drug has to stay in its original container. I haven’t seen the original container yet, so I don’t know how bulky or inconvenient it might be.

So there are a lot of expectations around taking the pill every single day with the oral agent. With an injectable, it’s once a week. And I suspect many patients might take it the day before or the day after, in the evening, at night, or in the morning. It’s not quite as rigorous and constrained as the oral agent.

So we think that’s going to be the reason why patients discontinue. But as you know, both agents have a relatively high discontinuation rate in the second year. As patients achieve their weight loss goals, they tend to want to come off these drugs. So that’s not surprising on the whole. But oral agents do have a higher discontinuation rate than the injectable.

Pharmacy Times: How might the dosing complexity and administration requirements of oral semaglutide influence adherence, particularly compared with once-weekly injectable options?

Frank: I think that’s what we’re just thinking about. So when I think about taking the oral agent, it’s got to be done on an empty stomach first thing in the morning. The patient has to wait 30 minutes. They shouldn’t take it with other drugs.

So many of us who are on prescriptions sort of brush our teeth, pop our pills, and go on and have our coffee. That’s not what you do with oral semaglutide. You’ve got to take the drug on an empty stomach, take it with nothing else, and wait 30 minutes before you get your coffee.

So that, in and of itself, might be a huge barrier to persistency.

Pharmacy Times: What role do you see pharmacists playing in improving persistence and appropriate use of oral weight loss therapies, especially given the discontinuation patterns seen with oral GLP-1 agents?

Frank: Whenever I think about clinical care teams, I always think of pharmacists being important participants on the care team and participating in helping patients to understand what are reasonable expectations about these drugs, what are reasonable expectations around the side effects of these drugs, and what they need to do to take these drugs and have the highest level of efficacy.

So for an outpatient pharmacist who might be filling this prescription, having a couple minutes’ conversation with a patient—assuming they have the time—to talk about how to take the medications appropriately, keep them in their original packaging, what the side effect profile is expected to be, how to move through those side effects, and then really explaining to the patient that for many patients these are lifelong medications, and that stopping and starting them is not likely to deliver either the expected cosmetic result, i.e., the weight reduction, or even the improvements in health, because we’re likely to see cycling in weight if patients stop and start these medications.

So I think the most important thing for the pharmacist when managing these medications and talking to their patients is really explaining how this is treating a common, chronic medical problem—obesity—with a chronic medication that really needs to be taken consistent with the label.

Pharmacy Times: As oral weight loss therapies enter the market, what considerations should health care teams, including pharmacists, keep in mind when selecting between oral and injectable GLP-1 options for individual patients?

Frank: I think it’s really about patient preference, because at this point what we see is that the clinical side effect profile, the safety profile, and even the clinical outcome look similar between the injectable and the oral.

Now, I think if it’s presented too quickly to the patient—“Hey, I can give you a pill, or you can take an injection once a week”—many patients may land on the pill because it seems easier. But as we’ve discussed so far today, I think it really behooves the clinician, the prescriber, and the patient to have a few minutes to discuss what it looks like to take this particular pill versus the injection and all of the complexity around the pill and then really determine what works for the patient.

Now, the fortunate thing is a patient can start out on the injection and then migrate to the pill if the injection becomes problematic. Or, in the reverse, the patient can start on the pill and then migrate to the injection if it becomes problematic. So it’s not as though the patient locks themselves in permanently around a particular route of administration.

But I do think it’s important for the clinician to talk to the patient about what they can expect.