Narrator - Dr. Abel  00:00
Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions.

Narrator - ?  00:11
This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy.

Narrator - Dr. Abel  00:17
This podcast contains general information for educational purposes only. This is not professional advice and should not be used in lieu of obtaining advice from a qualified health care provider.

Narrator - ?  00:27
And now on to the show.

Dr. Sean Kane  00:31
Welcome to HelixTalk episode 186 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is breaking the bank or breaking the scale controversy surrounding compounded GLP one receptor agonists for weight loss.

Dr. Khyati Patel  00:47
Dr. Kane, I'm super excited for this topic. I think there's been a lot of conversations going around. Not only how popular these drugs are, but the routes people are taking to be able to afford the drug, to have the access to the drug. There's been a lot of people weighing on, you know, whether we should only use the FDA approved marketed drugs from the manufacturers or all these compounding practices are ethical, legal, whatever. So I'm very excited to dive into this detail. Yeah.

Dr. Sean Kane  01:14
And as an alert for the listeners, this episode is going to be a little bit longer than normal. We have quite a few more references than normal. We had to do a lot more leg work in the background to kind of understand the legal implications of compounded GOP ones, also the clinical implications and some other things as well. But we're going to start with kind of a probably pretty typical clinical scenario. So we've got EP. This is a 40 year old patient that comes into Dr. Patel will say, your clinic, asking about the new GLP one receptor agonists for weight loss.

Dr. Khyati Patel  01:44
And this patient is, you know, five foot six inches tall, weighs about 190 pounds. If you calculate the BMI, it's 30.7 as a definition for obesity. BMI of, you know, 30 or higher, it's considered obese. This patient was asking about ozempic at a for weight loss of the past visit. She doesn't have diabetes, doesn't have pre diabetes, and so that stops the buck with the insurance company. The insurance won't cover it. When she's looking at the cash price, it's like 1000s of dollars, right? So $1,000 for our ozempic, which is the diabetes version, and then about 1300 for the weight loss version, which is brand name. We go we so there's like two different brand names. We'll dive into that a little bit too. And this is cost prohibitive for her. She has tried diet and exercise, but that hasn't really gone or led her anywhere.

Dr. Sean Kane  02:38
I think the listeners probably know this. But the $1,000 to $1,300 that's per month, that's not like per year or anything, that's a really prohibitive cost for the vast majority of patients. So today, she's coming back to your clinic that was, we'll say, a month or two ago, and she's bringing up Facebook ads or Instagram reels or whatever that she's seen, and she's seen ozempic and similar drugs to ozempic, these GLP one receptor agonists for way cheaper, and the ads are saying you don't need insurance for it. She wants to know more about what are these? Are they safe? Are they effective? Is she an appropriate candidate for these compounded products that she's seen ads for? Right?

Dr. Khyati Patel  03:20
And this is where we're going to dive into the details of what are these compounded GOP ones, whether they're safe, they're, you know, legal, or not. So let's, let's look into those.

Dr. Sean Kane  03:30
So at a very 30,000 foot view, what's going on here is that we have a number of companies, we're talking like 50 plus companies out there, that are offering a telemedicine opportunity for patients. And if you are deemed a candidate for that telemedicine visit, they will prescribe you a compounded GLP one, and the cost of this is way, way cheaper than the kind of FDA version of ozempic, Wegovy, Mounjaro, Zepbound. So these are compounded versions that are much cheaper, and it's kind of a package deal, so you get the prescriber visit, plus the medication, and you know exactly how much it would cost if you were prescribed it, because it's transparent, because there's no insurance coverage for this, right?

Dr. Khyati Patel  04:13
And we're gonna, for this episode, focused on the compounder GLP ones. This is sort of the safety concern that's brought up by FDA, and similar to what our patient is asking, hopefully our listeners can also benefit from knowing, you know, what are some of these concerns and what's the legal aspect behind it?

Dr. Sean Kane  04:32
And for the AVID HelixTalk listener, we actually covered some of these medications in previous HelixTalk episodes. So in 142 we talked about laraglutide or saxenda. We talked about semaglutide or Wegovy. And then in Episode 153 the GLP gip receptor agonist that we talked about towards appetite or Mounjaro are now Zepbound. So we've covered these a little bit, but not in the context of, you know, the compounded versions, and especially a bigger focus on weight loss. As opposed to the diabetes indication.

Dr. Khyati Patel  05:02
Yeah, and when we talk about compounded GLP ones, we're talking the compounded version of semaglutide or tirzepatide, because that's what most compounding pharmacies are making. So for the purpose of this episode, these two are the agents that we're going to kind of focus on. We want to acknowledge that the six Sunday or larachotide is FDA approved for weight loss, and it also, you know, kind of help. The liragotide, by itself, also helps with diabetes patients. However, kind of looking at the entire landscape of weight loss therapies, there are some other FDA approved medications out there. They don't stand a chance in comparison to how much weight loss the GLP ones provides. But we do have naltrexone, Bupropion combination with the brand name of contrav, phentermine by itself, Apex P or lomara. We have phantom in Topiramate combination goes by casemia. And then we have the oralostat, whether it be over the counter version, Ally versus the prescription version, as mentioned, these are not as effective as the GLP ones, and that's why GOP ones for weight loss are becoming more popular, because they provide more bang for the buck.

Dr. Sean Kane  06:15
And I'd even add on to that, the side effect profile some of these other therapies is much worse than the GLP ones. And although the GLP ones do have their side effects, and it's a pretty like noticeable side effect profile, the main thing is gi oriented, of nausea, changes in your bowel habits, versus some of these other ones, they recommend wearing dark pants in case you have an accident, for example, with orlistat or phentermine, you feel like you just took a line of cocaine like you are so amped up that you're sweaty things like that. Your blood pressure goes up with Topiramate. It's like your head is in a cloud. You have word finding difficulties. All of these have, like, really unique side effects, and they're not as effective as these GLP ones. So it's really not that surprising that we're seeing a lot of people really interested in these really effective, less toxic therapies compared to what has been on the market for

Dr. Khyati Patel  07:05
decades, right? And some of these newer agents in GLP one categories, have quite a few studies done, right? Long term studies as well. So we have longer term data as well in terms of both efficacy and safety.

Dr. Sean Kane  07:18
So we'll start with semaglutide, and for the longest time, Dr. Patel, I pronounced it semaglutide, and I have a really hard time going back and forth. But the manufacturer calls it semaglutide, and this is manufactured by Novo Nordisk. And we'll get back to Novo Nordisk later in the episode about how the company is kind of responding to some of the concerns about compounded GLP ones. But this is a GLP one receptor agonist. Dr. Patel, can you kind of share what does that mean? So, GLP one, in your body, you've got it. Everyone's got it. Humans have it, yeah. What does that receptor do? And then how is semaglutide different in terms of it's not just a GLP one, it's doing stuff to last a little bit longer in the body.

Dr. Khyati Patel  07:58
So, GLP one, it falls under an umbrella hormone category called incretin hormone. We're going to talk about tears, appetite, which is a GLP one and GIP. Gip is also another anchor 10 hormone. In the case of semaglutide, it's just a pure GLP one. It's very similar to our body's GLP one. So when we eat food from the wall of our stomach this GLP, one hormone is released. Its job is to go to the pancreas and tell the pancreas, Hey, make insulin. The food is here. It also suppresses glucagon secretion from the alpha cells. It improves satiety two ways. It improves the gut and brain communication, but also it increases the gastric emptying, so you're staying fuller for a longer period of time, so you're not, you know, eating as much, or eating in between the meals, like snacks and stuff. So you're cutting out calories this way. And this semaglutide is, again, very similar to our body's GLP one. But if you imagine, this is taken once a week, and the reason it is we are able to be able to take it once a week is because the half life is a little bit long. It binds to our albumin, so has kind of less affinity for that DPP four enzyme that kind of eats up, or chews up the GLP ones. And so it's like stays for longer in our body, and it works longer. So we're able to take it once a week.

Dr. Sean Kane  09:19
And if you were to talk to a patient who takes these GLP ones, they'll commonly talk about how the food, noise, like the the inner feeling in your brain, of like, Oh, I wonder what I'm going to eat next, goes away or is diminished. They sometimes forget to eat a meal, just because they don't feel this pang of hunger all of the time, which is what they might be used to when they're trying to diet, for example. And then also they either don't desire to overeat, so there's this, not this craving to have a food competition with yourself of eating an entire pizza, or they recognize that if they were to over indulge, that they're going to feel really miserable afterwards, and then becomes kind of the self fulfilling thing that they associate that over indulgence with a bad. Thing, as opposed to that feeling of, Wow, I just ate an entire pizza, and it tasted so good, right?

Dr. Khyati Patel  10:05
And some people, you know, if they do try to overeat, that nausea and vomiting comes in too, and so that's like a deterrent from them eating more than they should. And I've also heard from patients saying that certain foods that they used to go after that they used to over indulge. They just don't have an appetite for it. They're not doing it, whether it be Coke, whether it be, you know, sugary, rich food, like cake or pastries and stuff. They're they like, oh, I don't. I don't have an appetite for it anymore.

Dr. Sean Kane  10:32
And it's interesting Dr. Patel, because it's not that the food doesn't taste good to that patient, like It tastes like it always tastes. It's just that the signal in the brain that says, Hey, big dopamine hit is just different. And we'll actually talk about this later, that there's early research being done about this GOP ones for alcohol use disorders, that breaking that dopamine hit of ingesting something may be a future avenue for these medications as well. Yeah.

Dr. Khyati Patel  10:59
Actually, recent study came out for people people with alcoholism, and they actually found abstinence wasn't reached in lot of patients, as they expected, but the amount of alcohol they drank while they were taking these agents definitely went down. So you're absolutely right about how it breaks that dopamine reward pathway

Dr. Sean Kane  11:17
before we move on to the next one that we're about to talk about. I did want to highlight the acronym of GLP one. So glucagon like peptide one. You know, intuitively you would think that it acts like glucagon, because it's glucagon like but it's actually the opposite, where it's shutting down glucagon, it's increasing insulin release. The reason for that name, that is kind of a trivia fact, is that chemically, it is similar to glucagon, but some of the changes that have been made to that peptide in your body that every human has. It actually has the opposite effect of glucagon. So it's kind of a misnomer, that it's glucagon like in structure, but the opposite in terms of its function in the human body.

Dr. Khyati Patel  11:51
Yeah, that's pretty interesting caveat behind it. And then we have this semaglutide. Brand names are ozempic, which is marketed or approved by FDA for diabetes indication. And then we also have Wegovy, which is slightly bit a higher dose, and that one is FDA approved for the indication of obesity management or weight loss. Both of these are available as pen for sub q injection. The difference is ozempic is a multi dose pen versus vigobi is like that one single dose pen. You use it, throw it next time you're going to use a new pen.

Dr. Sean Kane  12:25
And obviously these have different brand names. That means the package inserts for these are going to be different. So if you look at the wegovy package insert, which is, again, for weight loss, it's not going to talk about its benefits, necessarily, for diabetes or a 1c reduction. So you will see differences in the package inserts as well. But interestingly enough, the dosing is really, really similar. So both for weight loss and for diabetes, you start at point five milligrams per week, and you usually do that for four weeks, and then you kind of go up on your dose. And then for ozempic with diabetes, the labeled maximum dose is two milligrams per week, and the labeled maximum dose for wegovy is a little bit higher for weight loss, which is 2.4 milligrams per week.

Dr. Khyati Patel  13:04
Yeah. And I think in the obesity studies too, they kind of had a marker for therapy failure. So if patient was at 1.7 milligrams per week dose, and they didn't receive about 5% of body weight loss for at least 12 weeks, then that therapy was considered to be failure. And then, you know, you can't move on to the higher dose while there is this titration set up for Wegovy. Uh, how you go? Some patients may not be able to tolerate the higher dose, so it's okay for clinicians to keep patients on the maximum tolerated dose as long as they're getting the weight loss benefit. So Dr. Kane, you know, why can't somebody just use ozempic and say they have diabetes, right? There's a backdoor entry to have the insurance approve it if they're not going to approve it big ove, for example, for weight loss. And I think the biggest answer now we know, as insurance companies are getting smarter, they know people are using this back door. What happened last year? We had a severe shortage of ozempic because people started getting ozempic for weight loss. They weren't really patients with diabetes or even risk factors such as pre diabetes, they just were using it for weight loss. So we had massive shortage, and that's where the insurance company said we got to do something about it. We got to protect our diabetes. Protect our diabetes patients who need this medicine for diabetes. And so they started asking actually, for diagnosis on the prescription, and if it didn't meet the right diagnosis, they will not approve the drug.

Dr. Sean Kane  14:35
Then obviously a physician or a prescriber can't lie about that. That would be insurance fraud. So if you're saying it's for diabetes, but they don't have diabetes, you could get in trouble for that. So it is a way to make sure that prescribers, when the patient is filling it through third party insurance, that they're kind of playing by wegovy versus ozempic In terms of the correct indication there, right?

Dr. Khyati Patel  14:56
And if a patient is a cash paying patients, yeah, sure. You could use, you know, whatever, at the end of the day, they are still paying that out of the pocket.

Dr. Sean Kane  15:04
And then there is an oral version of semaglutide. This one's for diabetes. Can you tell us a little

Dr. Khyati Patel  15:10
bit about this one? So, yeah, this oral version of semaglutide is brand name is ribel says, so it's a pill comes in a different milligram, so they look much higher than our ozempic milligrams, because the bioavailability is pretty, pretty bad. When it was compared to ozempic in clinical trials and stuff, it didn't produce as much agency reduction or weight loss, and also didn't have that macro, vascular benefits that we saw with the subcutaneous version of somagotite. So there is a little bit of caveat over there, patients were switching to ribel says when there was this ozempic shortage for diabetes reasons. In my practice, I haven't really seen people using ribel Sis for weight loss. However, there are some similar molecules coming out in the pipeline. We will see what indications they are being approved for.

Dr. Sean Kane  16:00
So potentially for patients who have, like, profound needle phobia that they want to be on a GLP one, they could consider something like this, but it's not as effective. So if they can tolerate the needle, it's probably better to not use this molecule. Then, yeah, absolutely. And then we go V so we covered ozempic for diabetes. Wegovy is semaglutide for weight loss, and this is FDA approved as an adjunct to diet and exercise. And the way it was studied, and how it was FDA approved is that patients need to have a BMI of 30 or greater, which constitutes obesity, or they can be in the overweight category with a BMI of 27 or higher, but they also have to have a weight related comorbid condition, which would be an example of like hypertension, diabetes, dyslipidemia, or have a previous cardiovascular event. Interestingly, wegovy is also approved for kids. So if a child is 12 years or older and their BMI is above the 95th percentile, they've also been studied, and it's FDA approved for that population as

Dr. Khyati Patel  16:59
well, right? I think we're seeing the obesity instances in, you know, this pediatric population increasing, and so it's good to see that there is this validated therapy out there for those patients. Well, the other one is tirzapatite, as we mentioned earlier. This is a dual anchored hormone medication includes both gi p, which is glucose dependent insulinotropic polypeptide. It's a mouthful of a name, plus a GLP one. So it's a designer medication. This one is made by Eli Lilly, and basically the mechanism for the GLP one portion is similar to what we discussed earlier. The G, i, p has a very, again similar activity as the GLP one. This one also likes to bind to albumin, and therefore also has a long half life. So tirzepatide, just like the ozampic or we Goby, is going to be given once a week.

Dr. Sean Kane  17:53
And then we have two versions of this. We have munjaro for diabetes, bound for weight loss. The dose and the dose titration are identical for both indications, which is kind of interesting. So you start at 2.5 milligrams per week, and you can titrate up to a maximum of 15 milligrams per week. But Dr, tell, as you mentioned, if a patient is doing great weight loss wise on two and a half, they don't need to go up at all, right? So it's based on the patient response,

Dr. Khyati Patel  18:17
yeah, that's absolutely true. So you could, you know, titrate the dose based on patient's tolerance. The usually that 2.5 milligram dose is the starting dose, so the landing or the maintenance doses, consider those higher doses thereafter. But again, there is essentially no reason why patient can't take Mounjaro, which is an FDA Food indication for diabetes. However, again, as I mentioned, the insurance companies are now dictating that we put the indication, and so they will deny Mounjaro claim if it is given for weight loss, if patient is cash paying, then you can use either or,

Dr. Sean Kane  18:57
and just like with ozempic and govi, this is available as a sub q injection pen, except this time we have a single dose pen for sub q injection for both forms, the diabetes version and the weight loss version. Then interestingly, there's also a vial. So kind of interesting that the manufacturer FDA approved pens. Why would a patient ever use a vial? Dr. Patel,

Dr. Khyati Patel  19:19
yeah, so this vial form is only available through Lily's program called Lily direct. This is very similar to those telehealth program that you mentioned. Lilly figured out, you know, why not connect the patient to the right medication? So these vials you're not going to see at common pharmacies, but if a patient is connected to a prescriber and then the therapy thereafter, and there are cash paying patients, they will be able to get this vial version of medication. Yeah, we're gonna go into the detail of, you know, what doses are available per the vial and what the cost looks like. It's a little bit more affordable than what the you know, the Z bound single shot pens there are, yeah,

Dr. Sean Kane  19:59
but of course, it's. Little bit less convenient for a patient, because they're going to have to have a syringe, pull drug from the vial into the syringe, inject it themselves, not as easy as a pen, that is a single dose pen that they just give to themselves.

Dr. Khyati Patel  20:11
Correct and this vial aspect of Zepbound or tirzepatide is really important, because when we talk about other compounded GLP ones. They're also available in vial, but I want to differentiate that these two vials are not the same. The Zepbound or tirzepatide vial that's coming from Eli Lilly is the FDA approved product, versus we are going to soon dive into these compounded version of GLP ones, which are not FDA approved, but they are formulated in a vial, syringe dosage form.

Dr. Sean Kane  20:42
That's great point. So you know, we're not going to cover the efficacy in great depth, but we do have two meta analyzes posted in our references, and we're going to very briefly summarize how effective are GLP ones, specifically semaglutide and trazepatide for both diabetes and for weight loss.

Dr. Khyati Patel  20:59
Yeah, and this weight loss efficacy is actually dose dependent, and that's why you see the spectrum of doses that are out there. At lower doses, the weight loss was lower. Higher doses, you produce more weight loss. We have couple of meta analysis and systematic reviews in the show note cited, so take a look at those. But kind of looking at them in patients with diabetes, these drugs produce anywhere between five to 20 pound of weight loss, between somagotide point five milligrams to zapatite 15 milligrams, and

Dr. Sean Kane  21:29
then for obese patients who do not have diabetes, which typically these patients have more weight to lose. Their baseline weights in the studies are around 105 kilos. Their BMI are in the mid 30s, their weight loss is somewhere between 13 and 20% weight loss, which correlates to roughly about 30 to 55, or even 60 pounds of weight, which is a clinically meaningful difference for a patient who's more than 200 pounds losing between 30 and 60 pounds. It's actually quite a

Dr. Khyati Patel  22:01
bit, right? And if you look at these not meta analyzes, but individual drug trials, you would notice that there were quite a few people who achieved like, 20% or more weight loss, not as many as who achieved 510, or 15% but there were some people who achieved 20% or more weight loss, which is, which is incredible. You don't do you don't get to see that with some of the other FDA approved therapies we mentioned earlier. We won't

Dr. Sean Kane  22:25
get too much into it, but it's at least worth noting that, generally speaking, when a patient stops their GLP one, there is weight gain that is associated with that. The manufacturers say, Well, this is a chronic condition, just like you have a statin that you take every day, their vision would be that you continue taking your GLP one, maybe at a lower dose or a more maintenance phase, but it is worth noting that the weight can, and usually does, come back to some degree if you stop the medication. Yeah.

Dr. Khyati Patel  22:51
And in the show note, we also have documented one trial that just came out, which was a three year use of terzapatide. So that's the longest trial we have seen with any GLP one or incretin molecule for weight loss, and it has shown efficacy and sustained safety as well.

Dr. Sean Kane  23:09
So Dr. Mattel, the next section we're going to talk about, I think, is probably the most exciting area of GLP ones. You know, when these came to market, they were marketed for diabetes, and we recognized, hey, they produce weight loss. And then the manufacturer said, Hey, let's go for the weight loss indication. At this point, we have a ton of different trials looking at the use of GLP ones and people who don't have diabetes, and sometimes people who also don't even have profound obesity, so not morbidly obese patients. And we're seeing a wide variety of clinical benefits beyond just Hey, you look cosmetically better because you've lost weight, right?

Dr. Khyati Patel  23:45
And these additional benefits come in the form of those macro vascular benefits, right? We've seen ascvd risk reduction, prevention of those cardiovascular related outcomes and deaths. We've seen renal outcomes as well, so improvement in progression to CKD or microorbinure, and kind of those major adverse kidney events kind of related to diabetes, but we have studies in pre diabetes patients, so this three year trial that I just mentioned, it was actually done in that patient population to see if they would progress to diabetes, and they actually showed that there is lower risk of progression to diabetes when we are using GLP ones in the pre diabetes patient population.

Dr. Sean Kane  24:28
We've also seen trials recently for non alcoholic steatohepatitis, which is a form of cirrhosis not caused by alcohol, and that was either a resolution or delay in that cirrhosis. We've seen it in sleep apnea patients, where their sleep apnea gets better, which is commonly associated with obesity, obese patients with knee arthritis, they have better physical functioning and less pain, with the weight reduction associated with GLP ones, and then also obese patients that have prior cardiovascular disease. By giving this medication to those patients, it actually reduces the risk. Future cardiovascular events, just like a statin does, right?

Dr. Khyati Patel  25:03
And in patients who have you know that preserved ejection fraction heart failure, we have seen improvement in quality of life with somagotide. We have seen reduction in cardiovascular death and worsening heart failure events with the tirzahpatide. And then going back to what you said about knee arthritis, Dr. Kane, our rheumatologists love this drug too. So not just the you know, OA, but from ra perspective, we've seen that the inflammatory markers in these patients with weight loss have gone down, and there's been improvement in arthritis, psoriasis as well as lupus related markers.

Dr. Sean Kane  25:36
And then we already mentioned alcohol use disorder that breaking that dopamine rush. We've seen early evidence of that as well, and I'm sure that we're just scratching the surface in the next five years, this is a gold mine for everyone. It's a win for patients, because they're getting clinically relevant benefit out of these medications, and for the drug manufacturers, there's plenty for everyone. It's not like one medication is winning out. We have just two that we're talking about in this episode, but there's more in the pipeline. You bet there's more, right?

Dr. Khyati Patel  26:04
Oh yeah, there is. And we're, you know, we're looking at a blockbuster drug here, just like the statins were in the late 1990s we're gonna rip a lot of benefit out of these molecules for the long, long term. That's possible. Well, Dr. Kane, you and I are missed out the boat. We don't have any stocks or investment in the any of these drug companies. However, the listeners, you know there is more coming, so think about it.

Dr. Sean Kane  26:29
And you know, Dr. Patel, in addition to the fact that these, this one drug class, can potentially be used in so many different indications, the other thing I really love about the story of these GLP ones is that it really emphasizes that obesity is not just a cosmetic problem, that it is a chronic condition that impacts a variety of different health things. I feel like we've always known this, that the more obese you are, the more adipose tissue you have. You're high risk of other chronic conditions. But now we have evidence that by giving you this medication, whether it's the anti inflammatory properties or literally just the weight loss, that that is benefiting not just you cosmetically, but all of these wide variety of clinical benefits that are associated with obesity. Yeah, and I

Dr. Khyati Patel  27:13
think we need to get to that point where we're not associating obesity as a choice, right? And then removing that stigma that there are so many reasons why a patient can be obese, it could be hormonal issues. You know, more less satiety hormone, more hunger hormone. There is more than 100 genes actually found responsible for causing obesity. How are we going to fix that? Right? So it's not just the patient not adhering to lifestyle or diet recommendation. Yes, some of those social determinants of health as to food availability, access to, you know, exercise equipment, or safe neighborhoods where they can do walks and stuff, all of that really impacts it. However, it's it's not fair to blame the patient. And I think we are realizing that closer as we go, some insurance companies are paying for these drugs, and when I see like, $15 copay on this, I get really happy, but it's very far and few, but we know we have a long way

Dr. Sean Kane  28:13
to go. And you know there is a stigma associated with taking a medication for weight loss that is not present with many other conditions, and again, the stigma comes from, oh, that person's just lazy or they can't control their eating habits. And that's actually not the case, just like it's not cheating for someone to take an anti hypertensive to control their blood pressure when they could just eat less salt and exercise more and lose weight, like that. We don't criticize them for taking an antihypertensive, or someone who has depression, we don't tell them just get over it. We give them a medication to treat their chronic condition that we have a medication that's effective for why don't we have that same approach for obesity? Right?

Dr. Khyati Patel  28:52
I mean, think about alcohol use disorder or tobacco use disorders, right? First, we used to think that this is up to the patient. They can quit it without needing any help. But we now know there is so much physiological dependence, and that comes with the food too. There is lot of those relationships with those hormones and the brain, the way that communication works, and we need those medications to help patients on a chronic basis.

Dr. Sean Kane  29:16
So Dr. Patel, clearly you and I are fans of GLP one receptor agonists, but we of course, have to talk about the downside, and in addition to cost, the other big downside is the side effect profile of these medications. So what do we know in terms of the risks associated with taking a GLP one

Dr. Khyati Patel  29:31
the most common complaint we hear regarding GLP ones is the gastrointestinal side effects, that's nausea and vomiting. We kind of talked about how these drugs work. If you try to over indulge or overeat, that's when the nausea and vomiting comes. Really when you're sitting and taking the GLP one not eating, you shouldn't really have nausea and vomiting, but this is how the medication actually works, anorexia, obviously, because it's actually beneficial in our case, for. Weight loss, but it also changes the bowel patterns, because you have that, you know, prolonged gastric emptying. So some patients may face diarrhea or constipation. People may also complain of abdominal pain or cramping. And then, unusually, I've also heard people complaining of belching or burping.

Dr. Sean Kane  30:21
And like you said, a lot of these side effects are magnified if you are doing the wrong thing from a dietary perspective. Online, there are some somewhat funny stories of patients that talk about they were on one of these medications for six months, and they kind of had stopped drinking alcohol, and then they have five beers in one night, and they have a hangover for multiple days, and they have all sorts of bad nausea, vomiting, diarrhea, things like that. So these can be magnified based on the choices of what you eat and drink and things like that as well.

Dr. Khyati Patel  30:51
Yeah, and that that goes along as a very important counseling point for the patient, for them to be able to tolerate the medication as long as they can. And as we

Dr. Sean Kane  31:00
talked about, these are dose dependent side effects. Dependent side effects, so using true zapitite As an example, the two and a half milligram dose is actually generally a sub therapeutic dose, but that you start on that one so that the patient can develop some tolerance to these side effects, and then they're able to then tolerate the higher doses. So that's why we generally have this titration, as opposed to just starting at the maximum dose.

Dr. Khyati Patel  31:22
Yeah. And as we talked about, you know, certain patients will get to their desired weight loss goal without getting to that Max dose. So always look at your patient, you know, look at their goals. Always balance out that efficacy and safety profile. You don't have to push them to the max.

Dr. Sean Kane  31:38
And then, you know, other side effects that we see would be fatigue, maybe some dizziness, and it's kind of unclear whether this is caused by the drug itself or caused by the lower caloric intake than what the patient is used to. So if I didn't eat for a day, I'm going to be fatigued and maybe dizzy, or if I'm having way less calories than my body is used to, those are commonly cited side effects. But again, it may not be a drug effect. It's more about what the drug makes you do, which is eat fewer calories.

Dr. Khyati Patel  32:05
And this one came up as a surprise to me. Dr. Kane, I haven't really heard it from our patients, but tears appetite may also cause hair loss in women. It's not seen to be a bigger effect in men. Again, this could be related to the caloric intake, or it could be the drug effect we don't really know yet, and this has not been mentioned in the somatic pi and then

Dr. Sean Kane  32:28
there are some rare but serious side effects, and these would be the ones that would be the scarier side effects that someone might read about and choose not to take one of these medications. One would be cholecystitis. So this is gallstones, and we actually see cholecystitis commonly in patients who lose a lot of weight really fast. So bariatric surgery would be an example. Or someone who goes on like a crash diet and they end up being successful and losing weight, that can happen. We also have a potential risk of acute pancreatitis. This is extremely rare, so this is inflammation of the pancreas. We've seen this signal all the way back to Exenatide, which was one of the very first GLP one receptor agonists on the market. But again, this is extremely rare and very uncommon, but a patient should know that if they have intense abdominal pain, that it could be this and that they would need to hold that GLP one and get checked out.

Dr. Khyati Patel  33:17
Yeah, absolutely. And then we've seen some C cell thyroid tumors in the rodent models, not in the animal models, but that warning kind of has trickled down into these PIs. If the patient has any family or personal history of medullary third carcinoma, or they have the multiple endocrine neoplasia syndrome, again, mouthful, type two syndrome that this medications will be contraindicated in them. So always, you know, kind of rule out or rule in your patients, not only based on indication, but also contraindication.

Dr. Sean Kane  33:50
And then, of course, because we're injecting stuff, we can see typical injection site reactions like a little bit of rash or itchiness or redness or tenderness at the site of injection. Yeah, actually,

Dr. Khyati Patel  34:01
have seen a couple of them in my practice so far. But again, these are not very common. They're they're not dose specific. However, if a patient has a reaction to one GLP, one injection site, reaction to one GLP, one product, doesn't mean that they'll have it with the other so you could, if the patient is not able to tolerate that reaction, we could always try another product, if the insurance again covers it.

Dr. Sean Kane  34:27
So Dr. Patel in general, I would say that we have a pretty big upside, and we do have a downside of the side effects that we just covered. But I would say for most patients, the upside is going to outweigh the downside, but then we have to talk about cost, which is the biggest barrier and the biggest sticking point to these medications.

Dr. Khyati Patel  34:44
Yeah, everybody wants this therapy. And let's talk about some of the reasons as to why we're seeing the cost going up. Dr. Kane, you mentioned earlier, depending on the product, without insurance, this can range anywhere between 1000 to $1,300 per month. And again, we're not gonna we're gonna treat obesity as a chronic condition. So you can imagine that this cause kind of adds up,

Dr. Sean Kane  35:07
and that is independent of your dose. So whether you're at the smallest dose or the biggest dose, you're gonna pay the same amount. And as you mentioned, Dr. Patel, if you have diabetes, most insurance providers do pay for this, but if you're using it for weight loss, even though we recognize that weight loss is associated with these other chronic conditions, we have evidence that by taking this medication, it helps those other chronic conditions. At this point, it's generally not covered.

Dr. Khyati Patel  35:31
Yeah, and those patients who do have commercial coverage, we do have the coupons card. These are copay system cards. They say that the you know it's going to be as little as $25 per month. But again, there are stipulations. You can't have CMS based insurance, or no Medicare, no Medicaid. You have to have a commercial insurance like UnitedHealthcare or BCBS, and that there is some coverage by the insurance. If the drug is in the exclusion criteria, then you cannot use the copay card.

Dr. Sean Kane  36:04
I think that's a really big barrier, because if you think about it, if the insurance company says we don't cover GOP ones for weight loss, you cannot use one of these coupon cards, because that is the stipulation in the coupon card, is that the insurance company is putting some money towards that medication.

Dr. Khyati Patel  36:20
The other options we have is for Wegovy through Novo Nordisk. There is a program which costs the medication $650 per month for those patients who are uninsured or paying out of pocket.

Dr. Sean Kane  36:33
Then we already mentioned. Lilly has a lily direct program for Zep. Found this is where you get the vial, not the pen, directly from Lilly. It's their version of like a telemedicine visit, plus the prescription that gets sent to you. So no insurance happens here. It's cash pay only for the starting dose. It's $399 for the next highest dose, at five milligrams, it's $549 and they do supply other doses because they're FDA approved vials of seven and a half, 1012, and a half and 15 milligrams. I couldn't find the prices. I'm assuming they're higher. I don't know, but they're definitely going to be at least $549 if not higher for those higher doses.

Dr. Khyati Patel  37:12
And so why are they so expensive? Dr. Kane, right? I think one thing I can think about is supply and demand chain. Right? There is so much demand and not enough supply, so obviously that raises the cost of the good.

Dr. Sean Kane  37:24
Yeah, these are relatively new. You know, semaglutide came out in 2017 so it's actually getting a little bit older, but trazepatide was 2022 as you mentioned, supply and demand. Also, there is no generic versions of these. So I looked, and I think the earliest anyone anticipates a generic semaglutide would be early 2030s, so we're not going to see it in the next handful of years that we have a generic, cheaper, FDA approved version of these medications.

Dr. Khyati Patel  37:51
And I bet there are good lawyers, patent lawyers, oh, my god, spending it years after years. I think we're going to see that. Another thing I've seen, at least when there was a lot of shortage going on, is that there is this celebritization of the drug itself. You know, not to name any celebrities particularly, but for example, Oprah endorsed it, right? And there's so many followers. And so there is, like, this craze, you know, social media, or this, like, influencer based demand that also rises up, and that's where we are seeing the shortages.

Dr. Sean Kane  38:25
Dr. Patel earlier, when we mentioned the coupon cards, you mentioned you can't have a CMS oriented insurance coverage, so you can't be Medicare, Medicaid. Why? Why is it? And this is actually true basically, with all coupon cards, that if you have Medicare Medicaid, you cannot get the manufacturer rebate coupon to reduce your co pay.

Dr. Khyati Patel  38:44
Well, there is this word called anti kickback statutes, and that means these drug companies cannot provide anything off of value or savings to encourage or reward patients for using a particular drug that is paid for by federal healthcare. So this is kind of just like everybody's equal. We're not favoring one drug versus the other.

Dr. Sean Kane  39:08
And then the other kicker is that, literally, by law, even if a patient wanted to get these medications, they're willing to pay whatever the co pay is. By law, Medicare and Medicaid cannot currently cover anti obesity drugs. This is a head scratcher, so I went through literally the Social Security Act to figure out what on earth is going on here at activist health. So Part D, which is the Medicare version of prescription drug coverage. They actually have a clause that says that coverage for Medicare patients excludes agents when used for anorexia, weight loss or weight gain.

Dr. Khyati Patel  39:45
Very interesting, even vague gain agents are not covered.

Dr. Sean Kane  39:48
Yeah, right. Interestingly, they also exclude a variety of other things like fertility treatment, drugs for cosmetic purposes or hair growth, symptomatic relief of cough and cold. So sorry if you want to get guafinessin with CO. Being covered vitamins and minerals, except for prenatal vitamins and fluoride preparations. And really interestingly, adect Patel, way back when this act first came out, they also excluded smoking cessation aids, which is a huge head scratcher, barbiturates, which maybe at the time, were more common, not super common. Now and then, benzodiazepines, and all three of those smoking cessation barbiturates and benzos, those have all now been revoked where they originally were not allowed to be covered, and now they are covered because they updated the law. And they actually haven't updated the law currently for, let's say, weight loss, right?

Dr. Khyati Patel  40:34
And I think you know, as we said, this tide change is going to occur where they're going to accept obesity as a chronic medications. And I think we're already seeing some changes, right? So there's this in 2025 I believe CMS is proposing to revise this and include the drugs for obesity, recognizing that obesity is a chronic condition, and it's not just a lifestyle choice. But again, they're also saying this will not go to people who are overweight, just those who are obese. So you're going to be bound by your numbers for BMI, because being an overweight is it's not considered a disease. So there's going to be a lot of caveats over here,

Dr. Sean Kane  41:14
yeah, and at this point, so the CMS proposal for covering weight loss medications for obese patients. This came out at the end of November. There's a 60 day public comment period, and then it will then be either accepted or not accepted, probably in January. So new administration, and we'll kind of see where things go. I have no clue, but it's at least encouraging to see that obesity is being recognized by CMS as a chronic health condition that should be covered, just like smoking cessation or insomnia or any other condition out there, right?

Dr. Khyati Patel  41:49
And I know the answer to you know, handling any public health crisis is not just more medications or more preventative measures. We need to also look at the root causes of obesity, why that is happening. So we need to continue our efforts there. But those people who are already affected by this condition, we need to also get them help. Now.

Dr. Sean Kane  42:11
The last thing about cost, you would think that the cost in America, the US, would be similar to the cost in Canada, similar to the cost in the UK. That's actually not the case. And this is, again, kind of a head scratcher of how did this end up happening? I don't know, but what is the typical cost if you were to get this in any other country in the world, aside from the US?

Dr. Khyati Patel  42:31
And I'm not surprised, Dr. Kane, if you just compare any other drugs cost in United States versus any other countries, it's usually cheaper elsewhere. And that's that actually promotes patients, or incentivize patients to get the medications through these international or foreign sources, which, again, not FDA approved. So the typical

Dr. Sean Kane  42:51
cost we're seeing in Canada is 150 to $300 a month. And other countries, it varies on which GLP one you're looking at, what dose, what country, somewhere between 104 $100 per month in these other countries, and we're talking US dollars here

Dr. Khyati Patel  43:05
that is so much cheaper compared to what they're selling it cash price in the United States.

Dr. Sean Kane  43:10
Yeah. And kind of interesting. There was at least one province in Canada that actually made a law that said that if you're not a Canadian citizen, that they will not fill GOP ones for non citizens because they wanted to have enough supply for the citizens in that province.

Dr. Khyati Patel  43:25
Very interesting that they had to do it because they probably saw more demand coming through.

Dr. Sean Kane  43:29
Okay, so let's circle back to our patients. Our patient wanted to have a GLP. One couldn't afford it. Insurance wouldn't cover it. They saw a Facebook or an Instagram ad for these compounded products. How did these services work? Yeah.

Dr. Khyati Patel  43:43
So first of all, you know, the provider has to quote, unquote, assess the patient whether they are fit for this therapies or not. So there will be a telemedicine visit with the provider. Obviously, the provider must have the prescriptive authority to be able to prescribe the drugs. And you know, interestingly enough, when we think about telemedicine, you're always thinking about this video visit doesn't even have to be that face to face conversation, so as long as you know the provider part of things are met, the visit can be initiated, and then next comes the prescription part of it.

Dr. Sean Kane  44:18
We should also mention that nine times out of 10. This is not run through insurance, so some of the insurance rules about telemedicine billing don't apply here. So if Blue Cross Blue Shield says that you need to have a video based call, or it must last longer than X number of minutes, or whatever, any of those rules don't apply because this is typically a cash paying patient, and they aren't bound to any format of telemedicine or anything like that.

Dr. Khyati Patel  44:45
Yeah, so let's say patient sees this provider. They are candidate for GLP one the provider is going to send the prescription to this compounded pharmacy they contract with, and the pharmacy supposedly is regulated by the State Board of Pharmacy. Plus the FDA

Dr. Sean Kane  45:01
and we will talk about some instances outside of the normal legal pathway. But in this context, for right now, we're talking about the legal pathway for compounded GLP ones, which is where you have an authorized prescriber sending that prescription to a registered and regulated pharmacy in a state in the US, yeah,

Dr. Khyati Patel  45:21
so there's legal, registered pharmacy. Then compounds the GLP, one product, ships it to the patient. Again, it's available as a vial, syringe. So they're gonna pack all the additional supplies, such as the u1 100 insulin syringes, the alcohol wipes, you know, instructions on how to use it, sharps, container, all of that stuff. They're gonna

Dr. Sean Kane  45:40
have a phone number and things like that, so you can call the phone. Call the pharmacy, so it's not like the patient can't have a relationship with the pharmacist or the pharmacy, although I would say that's probably somewhat unusual. So this is all done in alignment what we're talking about right now with FDA regulations. This is all legal, and the main reason that these services exist is that they're cheaper, so depending on the dose and the provider and the pharmacy that you're looking at, we're looking at somewhere between semaglutide 180 to $350 a month. Tricepotide 300 to $500 a month. So a little bit more. The cost also varies based on if they charge you for the visit itself, and how often you have to have a visit if there's like an initial startup fee. There's a bunch of other nuances here, but you're definitely paying at least half of whatever you'd normally pay if you bought cash version of these FDA approved medications, right?

Dr. Khyati Patel  46:32
And so kind of diving more detail into when we say a compounded drug, what exactly is a compounded drug, right? So we kind of have to go back to the Federal Food, Drug and Cosmetic Act of the two different sections of 503 A and 503 B, and this is where the different compounding regulations kind of come in play.

Dr. Sean Kane  46:54
And Dr. Patel, this is something I learned in school, and honestly I hadn't touched in a really long time. And we do have references and things like that. But in this context, compounding is basically where an individual is kind of mixing, combining or altering ingredients to come up with a tailored product. So this is very different than manufacturing, where manufacturing you're making it for any patient. It's not patient specific. The intent of compounding is that you're making a tailored thing for a patient, and you're doing that because there isn't kind of a current product available that meets the needs of that patient.

Dr. Khyati Patel  47:25
So basically, the 503 A and 503 B, these are basically the entities that are allowed to compound. So 503 A's usually are state licensed pharmacies, federal facilities or licensed physicians. They don't have to have a special registration. Whereas, versus 503 B are kind of these out sourcing facilities, they need to have a special registration with the FDA, because it's compounding. They have to follow the good manufacturing practices. We call them the cGMP requirements. They also have to have special reporting plus labeling requirement. And this regulation was actually written, if you all remember, in response to the debacle that happened with the New England compounding pharmacy, which led to fungal meningitis, meningitis outbreak in 2012 and so we needed to tighten up these regulations. And so those that are under 503 b has to follow these rules.

Dr. Sean Kane  48:23
So Dr. Patel, kind of the way I think of it is 503 A is, in general, your typical pharmacy that's kind of doing a little bit of compounding here and there. The 503 B, they have way higher regulations, and they're typically doing way more compounding. That's kind of what they're doing, is that they're kind of preparing these products. They're still patient specific products, but they do it more in bulk, and then, because of that, they have more regulations around them, right?

Dr. Khyati Patel  48:45
I think that's a very simplified way of summarizing the two differences. Yeah, absolutely. Dr. Kane, that's the definition of compounding. Who can and cannot do it, but what drug ingredients can really be compounded?

Dr. Sean Kane  48:59
Yeah, so the fdnc Act actually is pretty specific about what you can actually mix together. You can't just do whatever you want. So one is that the drug has to be made by someone who is registered with the FDA, and that person or that entity has to be able to provide a valid certificate of analysis. So in other words, the active ingredient has to be made by a facility that is registered and kind of proves that they have a high quality product. I can't just make trirzepatide in my kitchen sink and call it a day. It has to be done by a facility that meets certain requirements, right?

Dr. Khyati Patel  49:33
And it seems like it needs to be the certificate of analysis, so additional testing needs to be done on this ingredient as well. Additionally, the drug needs to be listed in the US Pharmacopeia USP, commonly known as or national formulary, be an FDA approved drug or listed by FDA as an acceptable for compounding.

Dr. Sean Kane  49:53
So I can't take four leaf clovers and grind them up and call them something different that doesn't exist and compound. Net. These have to be things that are recognized as drugs, and these different reputable sources of what constitutes a drug that has some evidence behind it, right?

Dr. Khyati Patel  50:09
And once the drugs are pulled from the market by FDA, they cannot be compounded. So obviously this needs to be, you know, FDA approved in current used drugs. You cannot bring back Vioxx, for example,

Dr. Sean Kane  50:22
we laugh about it. Dr. Patel, but I could actually see patients that loved Vioxx, which was Cox, two specific NSAID, I could see patients going down this pathway if they really had a good response to Vioxx, but the FDA says, No, if we pull it from the market, you can't just start compounding it as like a back door, right?

Dr. Khyati Patel  50:38
And there's usually a reason for the drug to be pulled from the market. In this case, it was a safety issue, yeah.

Dr. Sean Kane  50:44
Another thing is that the drug cannot be on an FDA list of products that, quote, present demonstratable difficulty for compounding. There's literally a list by the FDA called the DGC list, the demonstratable difficulties for compounding list. And this is actually really important, Dr. Patel, because Novo Nordisk, the maker of semaglutide, this is their pathway, legally that they're trying to restrict compounding right now, we have a link to this, but they've actually petitioned the FDA to consider semaglutide to be a difficult to compound product. And if they kind of win that, and it gets on this list, that would mean that all compounding pharmacies can't use semaglutide as an ingredient because it's on this list of too difficult to compound.

Dr. Khyati Patel  51:27
One more is that drug cannot be on the biologic, biological drug list. So they shouldn't be under that bla pathway or for the new drug application. So again, it cannot be a monoclonal antibody, for example.

Dr. Sean Kane  51:41
Then lastly, and probably most importantly, the drug cannot essentially be a copy of a commercially available product, unless this is the big thing, unless it's either very rarely done, or the drug is on an FDA shortage list, and that's the big one that is driving a lot of this.

Dr. Khyati Patel  51:59
And this is the crack in the door where things are kind of filtering through and allowing compounding of these. GLP, one products, exactly so again, not being a commercially available copy. You know, some pharmacies are adding additives to it to call it different than what's commercially available. Or the fact that these drugs, some of them, have been on shortage lists for the FDA, and

Dr. Sean Kane  52:22
there are some limitations to compounding. So for 503 a pharmacies, they can't have more than 5% of their prescriptions be out of state. Historically, there is some nuance around this that they could get around, that that seems to be not as big of a deal now. And then for 503 B, outsourcing facilities, there is no limitation. So that is also the pathway that some of these pharmacies are taking, is via 503, B, and then there's no limit on how much they can disperse out of state. From a compounding perspective, right?

Dr. Khyati Patel  52:49
Kind of make that semi bulk facility? Exactly so. Dr. Gaine, we kind of mentioned that the drug cannot be an essential copy of what's FDA approved and what's out in the market, when would be the compounded product essentially be a copy.

Dr. Sean Kane  53:05
So we have a link to literally an FDA document, kind of outlining procedures for this in our show notes. There are some exceptions, but basically they consider a copy if you have the same active pharmaceutical ingredient or API with a same or similar dosage strength and the same route of administration. So kind of same drug dose route, if those are all identical, that may be, with a couple exceptions, that may be essentially a copy, and that would violate that clause.

Dr. Khyati Patel  53:33
And as a rule of thumb, the FDA does not consider it copy if the competent product will produce a significant difference for the patient. So a good example would be a compounded product doesn't have to have an inactive ingredient that a patient is allergic to, but the compounded product may have the same active pharmaceutical ingredients, dose and route, but not having the allergic or problematic inactive ingredient, it makes the difference for that individual patient, and that's why we can say this is individualized and compounded for that given patient.

Dr. Sean Kane  54:09
And then the other thing is similar dosage strength. They actually quantify this in the FDA regulation, so they say a similar dosage strength is within 10% and then they have a caveat that it also can't be easily substituted with commercially available products. So the example they give is, you can't make a 50 milligram version of a thing where 25 milligram tablets are commercially available because the patient patient can just take 225 milligram tablets, assuming that that isn't the case. If your dose is more than 10% different than whatever the commercially available doses, they don't consider that a similar strength anymore.

Dr. Khyati Patel  54:44
We talked about, you know, compounded product, how that works? What are some of the rules and regulations from the FDA when we specifically talk about the GLP one products compounded? Are these pharmacies? Are they doing it legally, or are they considered legal?

Dr. Sean Kane  55:00
So again, we will talk about some examples later, where there are online sources where people are getting these medications in an illegal fashion, but the legal version of this, where you have a prescriber, a legal, registered pharmacy, and it gets shipped to the patient, this is legal, and they're either doing it through drug shortage, because these medications kind of are currently on the drug shortage list, or they're producing, not essentially a copy. So one or both of those are their mechanism of legally producing semaglutide, or tricepotide, compounded for patients at a reduced cost. So let's

Dr. Khyati Patel  55:34
talk about the drug shortage piece of things, right. There is a nice website on the FDA. There is about 100 products on the FDA drug shortage list. And this changes all the time, depending on the manufacturer availability or the shortage drops or resolves, the FDA will update the list. So as of right now, to zapatite shortage is listed as resolved on this FDA shortage list. Versus somago tide is still showing in shortage. Both of these shortage had started in 2022 but for some reason, the moonjaro or the tis appetite or zip bound shortage has been resolved. And there's been some controversy about how FDA just came around and lifted this shortage or resolved this shortage without notifying people. And there are a lot of people who are upset.

Dr. Sean Kane  56:20
Dr. Tubb, when you say upset, what you're really referring to is people are suing.

Speaker 1  56:23
That's right. That's one way to show how upset you are.

Dr. Sean Kane  56:27
And so I'm not going to get into the legal aspects of this, because, honestly, it's not my area. But what I can tell you is the outsourcing facilities association of a sued the FDA, and basically their argument was, you just took tracepatite off the shortage list without any opportunity for comment. It just kind of magically happened all in one night, without any notice. And if you think about it, these compounding outsourcing pharmacies, they've prepared infrastructure for at least two years to provide compounded products. So this infrastructure existed because there was a shortage. And their argument is that there was no due process that you know, there was no opportunity to argue actually it should still be on shortage. There's no transparency of how it was determined that it was or wasn't on shortage. So I understand that viewpoint, but in typical American fashion, we have a lawsuit to kind of figure things out. And what the FDA has said right now is that until that until that kind of gets settled, they're going to allow compounding pharmacies to continue making tears appetite. But at some point, something is going to change, either it stays on the list or it doesn't, once this lawsuit is resolved, and then we'll kind of see where things are at that point, right?

Dr. Khyati Patel  57:36
And the other mechanism, Dr. Kane you mentioned, was not have being essentially a copy. And so how are they getting around by not making essentially the same copy?

Dr. Sean Kane  57:46
So remember, Dr. Patel, from a dose perspective, more than 10% different is considered different. So using tersepetite as an example, you can get a pen of two and a half or five milligram, single dose pen. But what if Dr. Patel your dose needs to be four or six milligrams?

Speaker 1  58:04
Ah, so you can put that in the vial Exactly.

Dr. Sean Kane  58:07
So these compounding pharmacies are providing dilutions where you could customize your dose at four or six milligrams. That is different than two and a half and five using that 10% rule, theoretically, you are no longer essentially a copy, and that would be allowed under the law. Interesting.

Dr. Khyati Patel  58:24
And then I've also seen where people are adding, or compounding pharmacies are adding other ingredients, such as some B vitamins, like B 12 or b6 or b3 I've seen l carnitine or like glycine. Supposedly, there's claims that you know these vitamins, B vitamins can provide you anti fatigue. You know, in fact, when GLP ones can lead to that, there's some unsupported claim that l carnitine can also help with the weight loss. Obviously, it doesn't stand a chance in front of the GLP one.

Dr. Sean Kane  58:58
Yeah. And you know, the counter argument to these products is from a stability standpoint, from an efficacy and safety standpoint. We don't have data on combining vitamin B 12 in the same vial as terzepatide, and whether that impacts a drug molecule, how it gets injected, the side effect profile, any of that stuff. So there is a realistic argument that adding any of these drugs, these are drugs right that have been approved. We know about the drugs, but we don't know as much about the stability data and what effects they have clinically. There is a counter argument that maybe this is not the best practice, but this is another pathway for compounding pharmacies to make a product right.

Dr. Khyati Patel  59:37
And as we discussed Dr. Kane earlier, this business of compounded GLP one is getting so popular to the point where facilities have employed resources and kind of locked themselves into making these products for a longer period of time because the demand was just so much with the shortage. But FDA has kind of released a couple of warnings in. The recent times related to this trend, we do have links to both of those warnings in the show note, but FDA wants people to know that these compounded products are not FDA approved.

Dr. Sean Kane  1:00:12
And while I do agree with this statement, I do think it might send the wrong signal to patients, saying that the thing in the vial, the drug, is not FDA approved. What isn't FDA approved is the compounded product, and the way it's compounded, it's not evaluated, just like a manufactured product is. So yes, it hasn't been evaluated for efficacy and safety in that particular formulation from that compounding pharmacy. But you are using, in this case, FDA approved semaglutide or tirzepatide. It's more the process of preparing the vial versus the active ingredient not being FDA approved, right?

Dr. Khyati Patel  1:00:46
And another thing to consider is, you know, the process is important, meaning the provider who's signing the prescription needs to have that prescriptive authority. Those pharmacies who's compounding it needs to be registered. You know, obviously the ingredients, the raw ingredients that our pharmacies are using, needs to come from registered manufacturers. As long as these requirements are put in place, compounded products are okay to use.

Dr. Sean Kane  1:01:14
And the other big warning that's come out, that is probably the biggest reason that I have a lot of hesitation for compounded GLP ones is dosing errors. And the reason for this is that if you get the manufactured version of these GLP ones, you're going to get a pen, an injection, a pen for injection. And it's pretty easy to give those medications, and it's harder to have a dosing error with those with these compounded products, you get a vial, and you get a u1 100 insulin syringe, and u1 100 means that one ml is going to be 100 units on the syringe itself. And what really bothers me is that when providers pharmacies are describing the dose, they describe it in units. And it's a problem because when we think about like insulin units, that's a unit of weight, meaning five units of insulin. Whether the dilution is high or low, you're getting five units, right. But with these products now, we're using the word units as a volume, not a weight based approach, and that becomes problematic, because as soon as a vial concentration changes, your dose in terms of the number of units or the amount of MLS that you're pulling up, is going to be different. And that causes a ton of confusion, let alone the fact that patients that, let's say that they don't have diabetes, they may be really unfamiliar with reading, literally just reading a u1 100 syringe and knowing how much to inject based on that syringe, right?

Dr. Khyati Patel  1:02:36
And the caveat goes further, where some of these compounding pharmacies or online pharmacies, they're not educating patients on how to use the vial, syringe method, or how many units to draw up. It's not very clear. And this is where the dosing errors are happening. And this is what FDA actually is more concerned. There's actually some cases reported where patients have injected 50 units instead of five units, you know, with the way the concentration was on the vial versus what the patient was asked to inject.

Dr. Sean Kane  1:03:07
And even from a prescriber standpoint, so not even getting to the patient, but the prescriber confusing the dilution of the vial and then how they describe the dose to the pharmacy, basically mixing up milligrams, units and MLS, and the prescription is written incorrectly at the get go because of this confusion of how we're describing the units. Because if you look up in a drug information resource for tursepatite, it will never say inject point three units. It's going to say inject 2.5 milligrams. And you have to know, how do you convert milligrams to units when you're writing that compounded product?

Dr. Khyati Patel  1:03:39
And to be honest, Dr. Kane patients are shopping from coupon to coupon when it comes to this type of services, and so their provider may change. Their pharmacy may change from month to month, and the pharmacies are not going to be the same. So there is this transition issue where they're going to get the right dose when they're upping the dose, are they going to understand how many units to inject. This is where all the dosing errors come in.

Dr. Sean Kane  1:04:03
And Dr. till at this point, we've really covered the FDA warnings regarding the legal, regulated use of compounded GLP ones. Next, we're going to move a little bit into some of the warnings about the not so legal, not regulated versions that definitely patients need to be aware of are not appropriate. So one warning is with a new GLP, one that isn't on the market right now, called retatch ride. This is not FDA approved. It is illegal, literally illegal, for a compounding pharmacy to make this because this is not an FDA approved drug. It's not out there yet. So if you're seeing this, even if it causes weight loss, that's great, but you can't use this legally because it's not an FDA approved drug.

Dr. Khyati Patel  1:04:44
Yeah, we've also heard that the raw ingredient so mangut, some pharmacies are using the salt format, a form of it, like sodium or acetate. Again, this is not FDA approved. This is illegal. And my

Dr. Sean Kane  1:04:57
understanding Dr. Patel is that the salt forms were. Thing that happened more in 2022 2023 at this point, that isn't happening anymore, but if it was to happen, that is not considered within the realm of this legal compounding area. Yeah.

Dr. Khyati Patel  1:05:10
And there's some concerns of counterfeit products, where we are concerned about purity of the product due to the manufacturing processes, or compounding processes where product is contaminated or concentration, where what it says on the vial is not what's inside the vial. So again, this is considered misbranding or counterfeit product, and in certain cases, there's been these services where patients have paid up front for the provider visit and the pharmacy, and then the pharmacy has not delivered the medication, so patients haven't received the product they paid for.

Dr. Sean Kane  1:05:47
And Dr. Patel, I think this is probably the most common area that a patient is likely to encounter in terms of getting into big trouble beyond the dosing error, it said they're going to like a med spa is the main one that I've read about where a med spa is providing a syringe, and you don't know anything about that syringe. It wasn't prepared by a pharmacy. It wasn't prescribed by a provider. This has kind of been being given to you that is way outside of the legal realm of what we're talking about with compounded GLP ones. I think the number one thing here is to recognize you need to have a provider visit with a prescribing provider, and it has to go to a registered pharmacy, and that registered pharmacy is using active ingredients that are coming from sources that are approved as manufacturers of that product by the FDA, and that they've done testing that whole thing is really where it's okay. Outside of that, that's where we really get into trouble with some of these counterfeit products, products that don't have what they say in them, and things like that. Yeah.

Dr. Khyati Patel  1:06:48
I mean, there's been some cases of oral or sublingual GLP. One products, again, these are not FDA approved. And then, you know, that goes one, one point ahead. We described the dosing issue, the counterfeit products or not FDA approved, you know, ingredients and stuff. But FDA also warns patients to list some of the side effects they have experienced using the compounded GLP ones. There's been already some reports of these, ADRs. Most of these are similar to FDA approved GLP one, ADR, such as, you know, GI issues, or acute pancreatitis or gallstone, as we talked about earlier. But there are some reports of fainting, headache and dehydrations which are not the typical GLP one, FDA approved GLP one side effects

Dr. Sean Kane  1:07:38
and Dr. Patel, if I was a betting person, I would bet that some of these more severe side effects are a result of improper prescribing the dose, or the patient improperly giving themselves the dose, where there's a dosing error somewhere in that pathway. Again, it's really easy to mess up the dosing, and if you mess it up, these are generally dose dependent side effects, and if you give yourself a 10 fold increase in the dose, you're going to be pretty miserable for a long period of time, because these drugs last a long period

Dr. Khyati Patel  1:08:05
of time. Yeah, and you know that that's, that's very a good connection, but Dr. Kane, at the end of the day, if we were to summarize, you know, we talked a lot at length about, you know, how they are compounded, what are some of the rules and regulation and the issues that we have seen thus far? But people still want to use these products, right? Because it's attractive cost. What are some of the pros and cons? If you can weigh it out in a quick manner,

Dr. Sean Kane  1:08:27
yeah, so big pro is going to be if there's a shortage, this is a way that you can get these medications. So if you have diabetes and you want this, this is how you could get it if, literally, your pharmacy that you typically go to doesn't have it. Keep it in mind that some glutite is still on the FDA shortage list. Tricepotide, technically is not, but it's kind of in legal limbo right now.

Dr. Khyati Patel  1:08:48
And also, you know, if your insurance doesn't cover it, then compounded versions are definitely, as we discussed earlier, much, much less expensive.

Dr. Sean Kane  1:08:56
And it is going to be really interesting to see if the new CMS rule about weight loss drugs goes through in probably January ish in terms of will Medicare, Medicaid eventually cover these because that's a huge patient population of typically 65 years and older, that Medicare population that are prone to osteoarthritis, prone to diabetes, cardiovascular disease, this is kind of the population we'd like to give GLP ones to. So that is going to be interesting. And then it'll be interesting if the third party insurance companies like Blue Cross, Blue Shield, end up doing the same thing and deciding to cover it because of the other health benefits associated with giving this medication. Right?

Dr. Khyati Patel  1:09:33
Usually we see commercial insurance as following the suit. So hopefully that happens, and then this efficacy is readily apparent to the patient when they're using competent product, like, if the drug doesn't work, patient will notice it that they are not losing the weight, and they'll be able to, you know, notify their provider

Dr. Sean Kane  1:09:51
and that. So that's kind of a big deal, because one of the biggest criticisms of these compounded products is, what if they don't work because you added B 12 and B 12 inactivates the ingredient. Yeah. Well, if you're losing weight, you're losing weight, and you can tell so the efficacy is readily apparent. And then the last thing from a pro side is that it isn't just about weight loss that especially in obese patients, there are a wide variety of health benefits. We'll talk about our patient at the end. But if you're basically deciding between no GLP one, no weight loss, no nothing versus a compounded GLP one, probably the GLP one wins out there, as opposed to doing nothing. In terms of, if you have someone who is indicated for the medication, it makes sense to give them the medication.

Dr. Khyati Patel  1:10:32
And then, if you look at the some of the cons Dr. Kane, you know, as we discussed earlier, some concerns laid out by the FDA is these dosing errors happening just because it's that vile insulin syringe delivery method, even providers are confusing the units to mLs, and then it's easier that these errors are happening by the patients too.

Dr. Sean Kane  1:10:53
Then we're also worried about compounding errors and just being truthful, from a 503 a or 503 B, pharmacy, we are worried more about an error happening in terms of how it's prepared, that the concentration is different than what is intended versus a manufacturer, but the bigger deal is going to be counterfeit products, or products that aren't intended through this legal pathway that we've talked about, that are getting around, that that are at a higher risk for The Product basically not being what you think it is.

Dr. Khyati Patel  1:11:23
And then there is some concern about the active pharmaceutical injury, and this is where that Novo Nordisk, and you know, their concerns with the FDA kind of comes into play, that maybe if they're not using the approved API, then there is concerns about the stability of the product, but also the immunogenicity of the product.

Dr. Sean Kane  1:11:44
And there is some data with these compounded products that there may be a higher risk that your body basically attacks the drug molecule and activates it, then you don't get the benefit. And then finally, contamination. So whether this is bacterial contamination or other contaminants like trace metals or something like that, unlike with the New England issue back in 2012 with the fungal meningitis in 2012 one, they're injecting it into your spine. And two, they actually could not put preservatives in the injection, because it goes in your spine. So when you give a subq injection with preservatives, it's way safer than a spinal injection. But of course, we still are worried about the potential for contamination of the product. That is, of course, a risk.

Dr. Khyati Patel  1:12:26
And Dr. Kane, you know, FDA has been weighing on this for a long time. It looks like manufacturers are also weighing on this. But just recently, American Diabetes Association also put out their statement and recommendation. We do have the link for this particular statement in the show notes they come out and very strongly say that compounded GLP ones products are not recommended. Providers should not use them. Their second recommendation is to switch to an FDA approved medication instead. We listed them earlier. We know they're not as effective as GLP ones, but they're suggesting providers do that. And they're saying, once the shortage comes off or the product becomes available again, you know, weigh out the possibilities, you know, make transition plans to put patient back on those, you know, approved medications. And Dr. Patel, I think

Dr. Sean Kane  1:13:15
it's really important to note that this is from the American Diabetes Association, so this is for the diabetes indication and insurance coverage is currently different whether you have diabetes versus if you're using it for weight loss. So these recommendations are in the context in general, that these are more covered medications for that particular indication versus an obesity where it's typically not covered, right?

Dr. Khyati Patel  1:13:37
And they have done, actually, a really nice job of acknowledging that, you know, there might be some patients and providers who still want to go for the compounded drug use, and they have a list of things to make sure that you're doing as a provider, your due diligence, but also as a patient, your due diligence to make sure that you're going through these safe pathways, as we talked about, Right? So some examples will be letting your healthcare provider know that you want to use this compounded product, or you're starting it before getting them, making sure that patient gets the dosing and admin guidelines from this dispensing pharmacy so they're not just left in the unknown, making sure that they're not using product without proper labeling and knowing what exactly is in the product itself. And then even going one Lange further, and making sure that the pharmacy where the product is coming from either it's registered with the FDA, if it's 503 B, or licensed by the State Board of Pharmacy if it's 503 A, making sure that they're not purchasing from just any online pharmacy that's not registered or licensed, and then last, but not the least, you know, FDA still urges patients to report any side effects coming from the compounded GLP one products to the FDA Med Watch website, there's some additional review and warning signs for these unsafe online pharmacies or just. Computers and the table three of the statement. So if you're interested, definitely use the show notes link to review those further.

Dr. Sean Kane  1:15:07
So Dr. Patel, we're rounding off our pretty extensive episode on compounded GLP ones. We've talked about efficacy, safety, legal side of this. The whole thing, at the end of the day, we're going to go back to our patient of EP so she was our 40 year old patient with a BMI of 30.7 so categorized as obese. She's asking about compounded GLP ones. She's tried that an exercise that did not help her. Her insurance will not cover her GLP ones because she does not have diabetes or pre diabetes, and she cannot afford 1000 plus dollars per month to pay cash price. She also does not have any other conditions where maybe you could kind of edge in a GLP one. So diabetes as an example. So this is just for weight loss. So what are our realistic options for this patient?

Dr. Khyati Patel  1:15:56
That's a great question. Dr. Kane, and I think if I put it in the priority, I would go first with the Lilly direct program, whereas that bound whiles are available, as we discussed earlier, the starting dose is $399 and then the five milligram dose cost $549 is still expensive, but not that 1000 or $1,300 as we were kind of comparing earlier.

Dr. Sean Kane  1:16:18
And maybe the price will go down over time. But the big benefit here is that this is from the manufacturer directly that has been through the entire FDA approval process that manufacturers have to go through, which is more robust than, let's say, a 503 a pharmacy a second option could be a compounded GLP one, so talking to the patient about the risks and benefits, we went through the pro and con list of doing this again, the big deal things are going To be you need to make sure that the dose is properly prescribed and the patient understands how to actually deliver that dose to them, especially as the vial concentrations may differ between different pharmacies, or as they go up on their dose. Needs to come through a licensed or registered pharmacy, 503 a or 503 B, we talked about that, and then the proper dosing and administration instructions not only need to be verbally provided to the patient, but has to be written down so the patient can refer to it a week or two into therapy, where they'll make sure that they're giving themselves the right dose.

Dr. Khyati Patel  1:17:13
As we said, the compounded GLP ones do bring down the cost. So cost is going to be about 180 to $350 for this imaginary type, and the 300 to $500 for the Titus appetite per month, which is, you know, significant cost savings there.

Dr. Sean Kane  1:17:28
So at this point, if we're not going to use one of those two options, we kind of are stuck with diet and exercise until something changes. Could be cost of medications go down, other GLP ones into the market, and we have more competition, but whatever we do, the current approach is not working for the patient. So that might be referring to a dietitian, considering a personal trainer, gym membership program, things like that.

Dr. Khyati Patel  1:17:53
There is other weight loss systems out there. Example includes Noom or certain variable sensors that help you kind of keep up with your lifestyle, behavior changes such as libre lingo or nutritions that patient can use meanwhile

Dr. Sean Kane  1:18:07
as well. And this sounds terrible, Dr. Patel, but for this particular patient, the realistic scenario is going to be that she doesn't lose weight, she develops an obesity related complication, and now, instead of preventing her from having diabetes, she gets diabetes, and now she can afford the GLP one because it's covered by insurance. So time may be the thing that changes as well, in terms of her ability to have it covered, because now she has a new indication, because her obesity was not properly managed, because she couldn't, she couldn't afford the therapy, and

Dr. Khyati Patel  1:18:36
that's incredibly sad, right? Like we have to wait until a buck, you know, ball rolls down the road, which is not very desirable outcome. I mean, there's lots of complications that come with diabetes, additional costs that come with diabetes. Why don't we stop things in the beginning?

Dr. Sean Kane  1:18:54
And then finally, I don't think this is a very good option, but we did cover a variety of other FDA approved weight loss drugs that are currently on the market, but again, many of these medications have pretty bad side effect profiles, and they're not nearly as effective as GLP ones. So this could be part of the conversation, but if it was me, at least, I wouldn't really realistically entertain these other options very much. So that kind of concludes this very long but detailed and comprehensive episode on compounded GLP ones. As we mentioned, we have a variety of references in our show notes. This is also kind of a topic that is changing every day, so a week or month or a year from this episode, it's very likely that CMS coverage may change, or one of these medications will be on or off the FDA shortage list, or it might be on the difficult to compound list, or whatever it is, stuff is going to change, but at least today, the references are going to provide you with accurate, up to date information on kind of all of the different aspects of these compounded GLP ones. So for the listener, if you want to get pinged, whenever we have new episodes, we have a mailing list you can subscribe at HelixTalk.com We're also on x. At HelixTalk, and we love the five star reviews in Apple podcasts or wherever you're listening to us, so other listeners are more likely to hear today's episode. So with that, I'm Dr. Kane

Dr. Khyati Patel  1:20:09
and I'm Dr. Patel again. Thank you for sticking with us through this long episode, and as always, study hard.

Narrator - Dr. Abel  1:20:16
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