New oral GLP-1s are changing the weight loss game. Here is what you need to know before recommending or dispensing one.
In this episode, TRC Healthcare Associate Editor and Clinical Pharmacist Vickie Danaher, PharmD, discusses how orforglipron, the second oral GLP-1 agonist for weight loss, stacks up against oral semaglutide in terms of dosing, efficacy, safety, and more.
This is an excerpt from our May 2026 Pharmacy Essential Updates continuing education webinar series.
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CE Information:
TRC Healthcare offers CE credit for this podcast for pharmacist subscribers at our platinum level or higher and pharmacy technician subscribers. Log in to your Pharmacist’s Letter or Pharmacy Technician’s Letter account and look for the title of this podcast in the list of available CE courses. None of the speakers have anything to disclose.
Clinical Resources from Pharmacist’s Letter, Pharmacy Technician’s Letter, and Prescriber Insights:
- Article: Be Ready for the New Oral GLP-1 Agonist Orforglipron
- Chart: GLP-1 and GIP/GLP-1 Receptor Agonist Interactive Comparison Chart
- Chart: Comparison of Weight Loss Products
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Transcript:
This transcript is automatically generated.
00:00:04 Narrator
Welcome to Clinical Capsules from TRC HealthCare, your trusted source for practical, evidence-based updates.
00:00:12 Narrator
On this episode, associate editor and clinical pharmacist, Vicki Danaher, shares practical guidance on how Orforglopron, the second oral GLP-1 agonist for weight loss, stacks up against oral semaglutide in terms of dosing, efficacy, safety, cost, and more in an excerpt from our popular Pharmacy Essential Updates webinar series.
00:00:33 Narrator
This podcast offers continuing education credit for pharmacists and pharmacy technicians.
00:00:38 Narrator
Please log into your pharmacist’s letter or pharmacy technician’s letter account and look for the title of this podcast in the list of available CE courses.
00:00:46 Narrator
None of the speakers have anything to disclose.
00:00:49 Narrator
Catch new episodes of Clinical Capsules every second and fourth Tuesday, bringing concise, actionable insights from TRC experts straight to your ears.
00:00:58 Narrator
Let’s take a closer look.
00:01:06 Vickie Danaher
So let’s get started by looking at a really hot topic about new prescription orforglipron (Foundayo) for weight loss.
00:01:16 Vickie Danaher
And our article says you’ll get questions about orforglipron (Foundayo), the second oral GLP-1 receptor agonist approved for adults with overweight or obesity.
00:01:29 Vickie Danaher
And we know that this follows the approval of the first oral GLP-1 agonist for this indication, oral semaglutide or Wegovy pill.
00:01:38 Vickie Danaher
So now having oral orforglipron also available means that we’ll need to know how it stacks up to oral semaglutide in terms of things like efficacy, safety, and dosing to help individualize which med might be a better fit for a particular patient.
00:01:55 Vickie Danaher
So to get us thinking about this, let’s explore a patient scenario that many of us are likely to encounter in practice.
00:02:02 Vickie Danaher
Our patient today is Angela.
00:02:05 Vickie Danaher
She’s 46 years old, and she’s also at the pharmacy with questions about weight loss medications.
00:02:11 Vickie Danaher
Angela has obesity with a BMI of 34, and she also has hypertension or high blood pressure, for which she takes lisinopril 10 milligrams daily.
00:02:21 Vickie Danaher
For obesity, Angela says that she’s tried lifestyle changes, but that hasn’t been enough to help her keep the weight off.
00:02:29 Vickie Danaher
She also mentions that she’s not quite ready for weight loss injections, but she knows that there’s two newer oral GLP medications available in pills.
00:02:38 Vickie Danaher
So she asks you which one of these oral meds is better, either oral semaglutide or the new oral orforglipron.
00:02:48 Vickie Danaher
So what would you say back to Angela?
00:02:50 Vickie Danaher
Are there any things you’d want to ask her or know about her to help answer her question?
00:02:57 Vickie Danaher
Let’s start to dig into the specifics with orforglipron and how it compares to oral semaglutide.
00:03:04 Vickie Danaher
And in many ways, we can think of orforglipron as similar to oral semaglutide.
00:03:09 Vickie Danaher
Both are oral once daily GLP-1 agonists that work to slow gastric emptying.
00:03:15 Vickie Danaher
So food leaves the stomach more slowly.
00:03:18 Vickie Danaher
And they both reduce appetite by acting on receptors in the brain involved in hunger and satiety.
00:03:25 Vickie Danaher
But a big difference is that orforglipron is a non-peptide small molecule drug.
00:03:32 Vickie Danaher
And this molecular structure allows it to stay more stable and better absorbed throughout the gut.
00:03:38 Vickie Danaher
Stomach acid doesn’t break it down, so it can be taken at any time of day with or without food.
00:03:45 Vickie Danaher
On the other hand, oral semaglutide is a peptide that can be broken down by stomach acid.
00:03:51 Vickie Danaher
So to keep it from being destroyed in the stomach, patients have to follow pretty strict dosing requirements.
00:03:57 Vickie Danaher
They’ll need to take oral semaglutide with no more than 4 ounces of water at least 30 minutes before the first food, beverage, or oral medications of the day.
00:04:09 Vickie Danaher
Now, before we get into orforglipron’s efficacy and dosing, I want to address the point of confusion that came up for our editors as we were really researching and digging into this topic.
00:04:18 Vickie Danaher
So if you read the studies, you may notice that the approved dosages and dosage forms of orforglipron are different than what was used in the clinical trials.
00:04:29 Vickie Danaher
The clinical trials studied an investigational capsule formulation of orforglipron with doses ranging from 1 milligram up to 36 milligrams.
00:04:41 Vickie Danaher
However, the approved and marketed products, so what we’re actually going to see in our pharmacies, is an orforglipron tablet with strengths ranging from 0.8 milligrams to 17.2 milligrams.
00:04:55 Vickie Danaher
Now the manufacturer says that each tablet strength available corresponds to an equivalent capsule strength that was studied.
00:05:02 Vickie Danaher
For example, the 0.8 milligram tablet that’s available corresponds to the 1 milligram capsule that was studied, and the 17.2 milligram tablet that’s available corresponds to the 36 milligram capsule that was studied in the trials.
00:05:20 Vickie Danaher
And unpublished manufacturer data show that at each equivalent dose pair, the tablets and the capsules provide comparable systemic exposure.
00:05:29 Vickie Danaher
So meaning that they deliver essentially the same blood levels of the drug.
00:05:35 Vickie Danaher
This was a deliberate strategy by the manufacturer to move from the capsule used in trials to a tablet that could be more easily manufactured at scale without changing the pharmacokinetic profile.
00:05:49 Vickie Danaher
So if you’re reading the clinical trial data or seeing this in parts of the package insert and you notice that the capsule doses don’t seem to match the tablet versions on the shelf, that’s why.
00:06:04 Vickie Danaher
Okay, so now that we’ve cleared up the formulation issue, let’s talk about how well orforglipron actually works for obesity.
00:06:12 Vickie Danaher
So in terms of efficacy, be aware that oral orforglipron 17.2 milligram tablet daily for 72 weeks leads to about 9% more weight loss than with placebo.
00:06:24 Vickie Danaher
So this comes out to be about 20, 21 pounds or so for a 227 pound patient.
00:06:31 Vickie Danaher
And we can explain that this efficacy seems in the same ballpark as oral semaglutide 25 milligrams daily, which leads to about 11% more weight loss than with placebo.
00:06:42 Vickie Danaher
So generally speaking, efficacy seems pretty similar if we think about 9% more weight loss than placebo versus 11% more weight loss than with placebo, with oral semaglutide potentially having a very slight edge.
00:06:56 Vickie Danaher
But keep in mind that there aren’t any published head-to-head trials for these two medications in obesity.
00:07:02 Vickie Danaher
So any comparisons that we see are based on cross-trial data.
00:07:07 Vickie Danaher
And we know that we need to interpret these cautiously, given differences in study population, designs, and study duration.
00:07:15 Vickie Danaher
When considering GLP-1 meds for weight loss, we’ll also want to tailor the selection based on things like cost and access, the patient’s other comorbidities, and other medication benefits.
00:07:27 Vickie Danaher
For example, oral semaglutide for obesity is also approved to reduce the risk of cardiovascular events, such as stroke or heart attacks, in patients with CV disease and obesity.
00:07:38 Vickie Danaher
And then we know that other GLP-1 agonist medications, like semaglutide or tirzepatide, come in different products approved for type 2 diabetes based on their blood glucose-lowering benefits.
00:07:54 Vickie Danaher
But be aware that orforglipron is not yet approved for type 2 diabetes.
00:08:00 Vickie Danaher
However, one 17.2 milligram tablet daily lowers A1C about 1% more than placebo and about 0.4% more than oral semaglutide 14 milligrams daily.
00:08:14 Vickie Danaher
And the manufacturer does plan to submit this drug for a diabetes indication later on this year.
00:08:22 Vickie Danaher
So I anticipate hearing more about orforglipron for this use, as well as other things it’s being studied for, including cardiovascular risk reduction and osteoarthritis.
00:08:35 Vickie Danaher
When it comes to dosing, like the other GLP-1 agonists, orforglipron is started low and titrated monthly to improve tolerability.
00:08:44 Vickie Danaher
And to help facilitate this, the med is available in six different strengths.
00:08:49 Vickie Danaher
So we’ll want to watch oral orforglipron dosing closely and help ensure appropriate titration.
00:08:59 Vickie Danaher
Most patients getting orforglipron for weight loss will start with one 0.8 milligram tablet for 30 days and then increase every month to 2.5 milligrams and then to 5.5 milligrams once daily, which is the lowest designated therapeutic dose.
00:09:19 Vickie Danaher
From there, the dose may be increased to the next dosage levels, so 9 milligrams, 14.5 milligrams, or 17.2 milligrams once daily after at least 30 days on each strength.
00:09:32 Vickie Danaher
This would be based on the patient’s treatment response and tolerability.
00:09:38 Vickie Danaher
So this is a key area for us in the pharmacy, and especially for pharmacy technicians to be checking strengths closely during order entry and pulling meds from the pharmacy shelves, verifying that the patient is picking up the correct dosage based on the titration schedule, and also ensuring that the lower doses get stopped as patients step up dosing to avoid duplication.
00:10:00 Vickie Danaher
Now let’s talk about side effects and key safety considerations with orforglipron.
00:10:07 Vickie Danaher
And we can explain to our patients like Angela in our case that overall the side effects of orforglipron are pretty similar to what we see with the other GLP-1 receptor agonists.
00:10:17 Vickie Danaher
The most common issues are stomach-related things like nausea, diarrhea, abdominal discomfort, and sometimes vomiting, especially during dose titration.
00:10:27 Vickie Danaher
But studies suggest that there may be a somewhat higher discontinuation rate with orforglipron compared with oral semaglutide, potentially due to these GI side effects.
00:10:38 Vickie Danaher
So that’s something to keep in mind and another reason to make sure that patients start low and go slow with the dose titration to improve tolerability.
00:10:48 Vickie Danaher
In terms of serious safety concerns, orforglipron carries the same precautions and warnings as other GLP-1 agonists, so rare risks of thyroid tumors, pancreatitis, and gallbladder disease, for example.
00:11:02 Vickie Danaher
Also take note that orforglipron has no human data in pregnancy or lactation, and based on animal studies, fetal risk is possible.
00:11:13 Vickie Danaher
So females of childbearing age should use effective contraception during treatment with orforglipron.
00:11:20 Vickie Danaher
Also point out that the effect of orforglipron on the absorption of oral contraceptives hasn’t been studied.
00:11:27 Vickie Danaher
And we know that from some other GLP-1 agonists that possible reduced absorption and efficacy of oral contraceptives could occur due to the GLP-1’s effect on delaying gastric emptying.
00:11:40 Vickie Danaher
So orforglipron labeling recommends a non-oral method of contraception, such as the ring, patch, or an intrauterine device, or using a barrier method like condoms, for 30 days after starting orforglipron and 30 days after each dose increase.
00:11:59 Vickie Danaher
In terms of other interactions, there’s also a few other bigger ones to stay alert for with orforglipron as well.
00:12:06 Vickie Danaher
For example, orforglipron shouldn’t be used with strong CYP3A4 inducers, such as carbamazepine, since this may reduce orforglipron drug levels and effectiveness.
00:12:22 Vickie Danaher
On the other hand, CYP3A4 inhibitors increase orforglipron exposure, which may increase the risk of adverse reactions.
00:12:31 Vickie Danaher
So for these, the maximum dosage of orforglipron is 9 milligrams once daily when used with a strong CYP3A4 inhibitor like clarithromycin.
00:12:45 Vickie Danaher
Patients on simvastatin should also not take more than 20 milligrams once daily of this cholesterol medication if also taking orforglipron.
00:12:55 Vickie Danaher
Use with simvastatin increased exposure of the active metabolite of simvastatin acid twofold, whether orforglipron was co-administered or dosing was staggered by two hours.
00:13:08 Vickie Danaher
So this has the potential to increase statin adverse effects.
00:13:12 Vickie Danaher
However, no clinically relevant changes were observed for orforglipron when used with rosuvastatin or atorvastatin.
00:13:20 Vickie Danaher
And then, of course, the big question and what GLP-1 agonist a patient will get often boils down to cost.
00:13:29 Vickie Danaher
And like we often see prior auths with the other GLP-1 agonists for obesity, we should expect prior auths for orforglipron too.
00:13:37 Vickie Danaher
Orforglipron costs about $650 per month, which is about half the cost of oral semaglutide tablets.
00:13:45 Vickie Danaher
But patients may be able to get these prescriptions for less with manufacturer savings or direct-to-consumer programs.
00:13:52 Vickie Danaher
So really, the choice of products will also need to factor in the patient’s particular coverage benefits and how much they’re willing to spend for these medications.
00:14:02 Vickie Danaher
Keeping all this in mind, let’s now circle back to our patient, Angela, and think about how we’d actually approach the conversation with her in practice.
00:14:11 Vickie Danaher
To help decide whether oral semaglutide or orforglipron might be a better fit, there’s a few key things we’d want to ask because there’s no one-size-fits-all here.
00:14:21 Vickie Danaher
One big question that I saw many of you chatted in is about her routine and adherence.
00:14:26 Vickie Danaher
So can Angela reliably take a medication first thing in the morning on an empty stomach with strict timing?
00:14:32 Vickie Danaher
Or would something with more flexible dosing better fit her day and her schedule?
00:14:38 Vickie Danaher
We’d also want to ask about other medications that she’s taking.
00:14:41 Vickie Danaher
For example, we know that she gets lisinopril from our pharmacy.
00:14:45 Vickie Danaher
But is she on any drugs that could interact, like strong CYP3A4 inhibitors or inducers or oral contraceptives?
00:14:53 Vickie Danaher
Those details could sway the decision here as well.
00:14:57 Vickie Danaher
And then definitely cost and access matter too.
00:15:00 Vickie Danaher
So does she have insurance coverage for either option?
00:15:03 Vickie Danaher
Do they require prior authorization?
00:15:06 Vickie Danaher
Or is she going to purchase the medication out of pocket and is she aware of the cost?
00:15:10 Vickie Danaher
And then finally, what are her expectations of therapy?
00:15:14 Vickie Danaher
We want to make sure that this aligns with what these medications can deliver and what she’s willing and able to stick with long-term.
00:15:24 Vickie Danaher
So when you put all that together, the goal isn’t to say that one medication is universally better, but to help match the option to each patient’s preferences, routine, risk factors, and values.
00:15:36 Vickie Danaher
For example, orforglipron may be better for patients who want or need simpler or more flexible dosing, or those who struggle with fasting requirements or morning routines, since it can be taken at any time of day with or without food.
00:15:50 Vickie Danaher
Whereas, again, oral semaglutide must be taken on an empty stomach with a very small amount of water, and then patients must wait 30 minutes before the first food, beverage, or other meds of the day.
00:16:03 Vickie Danaher
On the other hand, oral semaglutide may be a better fit for those patients who can reliably follow the strict dosing instructions and who want to squeeze out the maximum amount of weight loss possible, since semaglutide might have slightly better efficacy.
00:16:16 Vickie Danaher
Although, again, the efficacy with orforglipron is in the same general ballpark.
00:16:22 Vickie Danaher
For now, we’d also want to suggest oral semaglutide in patients who have cardiovascular disease, since semaglutide has the benefit of reducing the risk of MACE or major adverse cardiovascular events like CV death, heart attack, or stroke, but orforglipron doesn’t yet have this indication.
00:16:42 Vickie Danaher
And oral semaglutide would also be the option to lean towards if a patient takes strong CYP3A4 interacting drugs, since it has fewer interactions compared to orforglipron.
00:16:55 Vickie Danaher
Let’s wrap things up here with a few more practice pearls that we can bring back to our pharmacies.
00:17:00 Vickie Danaher
And a big one that we’ll need to continue doing is paying close attention to products and strengths.
00:17:04 Vickie Danaher
Since like I mentioned earlier, orforglipron comes in six different strengths.
00:17:10 Vickie Danaher
Also make sure to keep and dispense orforglipron tablets in its original container at room temperature and tell patients to store them the same way at home, since the tablets are sensitive to light.
00:17:25 Vickie Danaher
If a dose of orforglipron is missed, instruct patients to take the dose as soon as possible and not to double up on the next dose.
00:17:34 Vickie Danaher
Continue to emphasize and encourage increased physical activity, having a well-balanced, nutritious diet with protein and staying hydrated, and last but not least, taking steps to help promote adherence and set patients up for success.
00:17:47 Vickie Danaher
We know that patients will often need to stay on the medication long-term to maintain weight loss.
00:17:56 Vickie Danaher
As more and more GLP-1 options continue to enter the picture, remember that you can turn to our interactive GLP-1 receptor agonist comparison chart available on our Pharmacist’s Letter and Pharmacy Technician’s Letter website.
00:18:09 Vickie Danaher
It lets you quickly line up products by things like indications, dosing, titration schedules, and clinical outcomes.
00:18:15 Vickie Danaher
So it’s especially useful when you’re comparing options, thinking through a potential switch, or just double checking whether something makes sense.
00:18:25 Vickie Danaher
And stepping back a bit further, if you’re thinking beyond just GLP-1s, we also have a broader comparison of weight loss products chart that looks at how all the approved options for obesity and overweight stack up.
00:18:41 Narrator
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00:18:51 Narrator
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00:18:58 Narrator
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