NovoNordisk's GLP-1 semaglutide drug, Rybelsus pill FDA approved to reduce heart attacks, strokes, cardiovascular death in type 2 diabetics.

Hi, thanks for watching episode #128 of the Doctor Podcast Show and I'm your host, Doctor Robert Sichert. Please subscribe and follow Doctor Podcast. I'd really appreciate it and it'll help us get more great guests for the Doctor Podcast Show in the future. Please also like, repost and share this important episode. Today's show topic is something that you hear about every day on TV and it's all over the Internet and that is the subject of GLP one or semiglutide drugs like Ozempic with Govi and Rebelsis.

They're extremely effective for weight loss and treating diabetes. But today we're going to discuss a new, very important use for Rebelsis that was just approved by the FDA recently. We'll also discuss a new study on semaglutide that was just published in one of the top medical journals in the world. And it's something you need to know to discuss all of that. We have one of the world's leading experts on these drugs, and our expert today is Doctor John Beuse. Dr. Beuse, A distinguished professor of medicine at the University of North Carolina at Chapel Hill.

He's a leading expert in diabetes and cardiovascular disease and has been instrumental in advancing the understanding and treatment of type 2 diabetes. Doctor Buse served as the Co chair of the sole clinical trial that's SOUL sole clinical trial, which investigated the cardiovascular benefits of Rebelsis, which is an oral form of the GLP one or semaglutide drugs and that's in adults with type 2 diabetes and who also have cardiovascular or heart disease and or chronic kidney disease. His work has significantly contributed to the evidence base for new therapeutic options, including the recent FDA approval expanding the use of Rudelsus.

So Doctor Buse, thanks for joining us today and updating us on these important topics and developments. Really appreciate your time. It's a pleasure. Thanks. So can you briefly explain what ribelsus is and and what was the purpose of this clinical trial, the sole clinical trial? Yeah. So ribelsus is an oral formulation of somaglitide, the same drug that's in Wiegovy and Ozempic. Wiegovy is the weight loss injected form and Ozempic is the diabetes injected form. Somaglitide is a protein, a peptide, and so if you just ate stomaglitide it would be digested like steak and would never enter the body.

And what the Rubellsis tablet does is it packages the stomaglitide with a buffer and something that helps to helps to get the peptide across the stomach lining. But it only works if people take the Rubellsis on an empty stomach first thing in the morning with a small swallow of water. Just 4 oz and nothing else. No coffee, no brushing your teeth, no other tablets, no food, nothing. Just that small swallow of water for at least 1/2 an hour and that allows the, because the the stomach is really like a, a virtual space.

It's kind of flat when it's empty. So when you take the Rubellsis with just a small swallow of water, it kind of nestles into the nooks and crannies of the stomach and is able to be absorbed. If you fill up the stomach, then it's like a big bag and the Rubellsis is just going to flop around and it basically turns into meat and is not absorbed. So it's pretty slick tablet to put things into context, the big dose of Ozempic is 2 milligrams. The big dose of Wygovia is 2.4kg, but that's a once a week and the top dose available today of of Rebelsis is 14 milligrams, but that's every day.

So it's only, you know, despite the fact that all these things have been done to make it better absorbed, it's not very well absorbed. So it's about 1-2 percent absorbed. And the only other thing I'd say about it is once it's into the body, it's just like Ozempic and Wygovy. Now, the reason we needed to do the SOUL trial, there was a small study, it's called a safety study done with oral Stomaglita rebelsis a number of years ago. But it was small, it was impressive. There was, you know, more than 20% reduction in the risk of heart attack, stroke or cardiovascular death.

But it was surprisingly impressive, but not really designed to take advantage of that impressive result. And so they needed to do a bigger study and to, to to get the indication from the Food and Drug Administration. And so SOUL was the big study to see if if oral synagogotite or Rebelsius really reduce the risk of heart attack, stroke and cardiovascular death. So it reduces the risk of getting a heart attack and and a stroke, which are the two leading killers in the USA, right? Right. So to be technical about this, the way these studies are done, it was the the time to the first occurrence of a heart attack or stroke or cardiovascular death.

So we kind of lumped 3 outcomes together there. It wasn't powered even though it had 10,000 patients and it went for four years. It's not power to look individually at heart attack, strokes and cardiovascular death, but the trend was in the right direction for all of them. Overall, it was a 14% reduction in the risk of heart attack, stroke and cardiovascular death. And just to put that in perspective, they've been and others of these cardiovascular outcome trials with Ozempic and Wygovy and now with Majaro and before with Trulicity and before with Victoza and before with Bydurian.

You know, so they've been many of these cardiovascular outcome trials. You take all of them together and get what the average result is. It's 14%. So the sole trial did exactly what all the other trials did. Now the reason, you know the reason, well the reason I was a little bit nervous as one of the Co leaders of this trial is because a, it was 10,000 people for four years. This was a very expensive trial to do. And you know what I hoped is that patients would take the medicine the right way because this medicine, if you don't take it the right way, you might as well just throw it in the toilet.

So if patients weren't good about taking the medicine, we would not have seen a benefit. So the first thing that's important to realize is not only does Rebelsis work Rebelsus with its current instructions, if people are properly educated about it and reminded at their visits, it it should produce blood sugar lowering in the setting of diabetes weight loss and provide for cardiovascular benefit. Wow, now this study, the sole trial that was in patients who have diabetes already. Yeah. So the sole trial was people with diabetes and cardiovascular disease or chronic kidney disease.

And the reason why we lump cardiovascular disease and chronic kidney disease together, they're the two, well, they're, they're 2 related complications in people with diabetes and people with chronic kidney disease are at extreme risk of cardiovascular disease. So they're they're considered sort of a cardiovascular risk equivalent. So these people were at very high risk of having a heart attack, stroke or dying of cardiovascular disease. Right. So a 14% reduction is is huge in that population which is at high risk of getting those problems right.

Right. And you know, particularly impressive 'cause these people almost all were on statins, you know, which lower cardiovascular risk. They almost all were on aspirin, which lowers cardiovascular risk in people who've had prior cardiovascular disease. They were almost all on blood pressure medications, including the ones that specifically reduced the risk of cardiovascular disease. So they were very well treated for their cardiovascular risk and nevertheless, they still had additional lowering of cardiovascular risk.

They were. Yeah, that's very important because these patients are already optimally treated with every medication. So the adding of Rebelsis reduced it 14% more, right? And then the other thing is there's another class of diabetes medications that's associated with cardiovascular benefit. These are so-called SGLT 2 inhibitors. We'd love to have letters and numbers in our drug class names and diabetes. So that's drugs like Jardiance, Farxiga, Invokana, they've been shown to reduce cardiovascular risk and heart failure and kidney disease.

So we had a fair number of people in the trial that were on these SGLT 2 inhibitors because people had cardiovascular disease and kidney disease. And the people that got the the rubellsis as opposed to those people who got placebo tablets and nobody knew what they got. Those people who got the rubellsis, probably because their blood sugar went down, they stopped their SGLT 2 inhibitor more because they felt like they didn't need it. And the people they got placebo, they started SGLT 2 inhibitors more.

So the deck was kind of stacked against the rebelsis because they got less of this more effective drug. But nevertheless, we showed that with the Rebelsis, whether or not people were on SGLT 2 inhibitors, they seem to derive the same benefit from from taking Rebelsis. So it works seems to work even on top of the other diabetes drugs that are good for heart disease. That's great. And this was published in the New England Journal of Medicine, probably top medical journal in the world, right? Yeah, certainly the top medical journal in the United States.

In the USA right that that's that's pretty amazing. Now, just from your experience in, in treating patients like this, what's the compliance rate? Would a patient doing the right thing with the rubellsis, meaning they they just take it with some water and wait half an hour before they eat? Do you find that people can comply with that or it's easier to just give them the injectable forms of Ozempic and Wegovi? Yeah, this is kind of a funny story. So I would say people that come to me having been treated with rubellsis before in the community, I would say maybe one in five are taking the drug correctly on a regular basis.

So it really takes some some talking to. And so instead of just saying with take it with four oz, you know, telling the story, if they don't do it that way, they should just throw it in the toilet, you know, cut your losses. You know what I tell patients is if they can't take it the right way that day because let's say they forgot and they already had their coffee, just don't take it. Wait until the next day. The drug has a half life of seven days. So the drug once it's in the body lasts a long time.

But we need to take it every day to build up the levels. If you miss 1 tablet or if you take 1 tablet improperly, it's the same thing. It's not going to add to the amount of drug in your body. So you might as well keep the tablet because it's pretty expensive and not take it wrong. So I mean, I, I tend to talk in detail to patients and then every visit for the patients on rubellsis. And there are other medicines like this Synthroid or levothyroxine, a thyroid hormone needs to be taken first thing in the morning by itself on an empty stomach.

And if you don't take it right, you know, I won't be able to figure out how to manage your Synthroid or your Rubellsis. So I talked to every patient at every visit, but tell me exactly how you're taking it. And they tell me they take it with a swallow of water. And, and then I said, and then what do you do? And, you know, sometimes people say, well, you know, then I go downstairs and I have my coffee and I go, no, no, no, no, no, can't have your coffee. So you, it's, it's really important to ask questions about this.

But I would say that in my practice, people are pretty good at taking it. I do think many people choose to take the injected Somaglitide instead because they just sort of feel like maybe net, net, net, it's easier than doing this stuff of taking the tablet and waiting at least 1/2 an hour. Another thing I'd like to mention though, if you wait an hour or two hours, it's absorbed even better and so you may be able to get away with fewer tablets. And that's a trick we play sometimes when people have a hard time getting their diabetes medications covered fully by insurance plans.

It's just tell them you know, or eat even when I tell them is, you know, have dinner relatively early, like 6:00 PM. It's OK to drink after dinner, but don't eat any food after dinner. So then your stomach is going to be empty by 2:00 in the morning when you wake up in the middle of the night to pee, which almost every older patient with diabetes and heart disease does. Take the rubellsis then with the swallow of water and just go back to bed. That's a good idea. Right. And so and then, you know, if you don't wake up to pee, just don't take it, right?

You don't have to take it every day. It's about, you know, getting the exposure over a week. So anyway, I think my patients do pretty well. But you know, obviously I spend a fair amount of time educating them about how to do it properly. Right, you can. You need to keep reminding them. Yeah, I notice you pronounce it semaglutide and I've been saying semaglutide. Which is the correct one or both pronunciations correct? I think both pronunciations are are correct. I'm a old school guy. So we started our first drug was called exenotide and our second drug was called araglutide.

And so that's how I got kind of into that semaglutide thing. But I do think most people do pronounce it semaglutide. All right, it's the same drug though, so that's important. Now with with every drug and especially new drugs, safety is a big concern for for many people considering medications. What did the SOUL trial reveal about the safety of Rebelsis, especially in terms of side effects or risks of the drug? Yeah, basically the same as we've known from other somaglitide studies. So GI or stomach issues are the biggest problem, nausea and vomiting.

It's usually mild to moderate usually in the beginning when you first start the drug it the, the tablets are three milligrams, 7 milligrams, 14 milligrams. There's a A20 plus milligram tablet that's under review at at the FDA that may be available soon. But anyways, you go from dose to dose. Sometimes there's a little bit of recurrence, but the people who really bothered about it by it usually have most of their trouble in the beginning and then it tends to get better over time. And for most people, it just goes away.

About 40% of people have at least one episode of nausea. About 15% of people have at least one episode of vomiting, you know, over six months or a year. So it's not like everybody gets it. Some people get some sort of queasy belly. Constipation is the problem that I find is the showstopper for people you know, who get past the first week more than anything else. Some people get diarrhea. What it does is it it works in the brain to enhance satiety is the word, which is kind of related to appetite.

It's sort of the opposite, you know, appetite is what you have before a meal and satiety is that feeling full after a meal. This really does more for satiety, but sometimes it makes you feel satiated or have satiety even before the meal. So it kind of cuts your appetite that way. And one thing that definitely is a problem if if you're, if people are sort of, they eat very quickly, they gulp their food, food down. Sometimes that satiety signal doesn't kick in fast enough And so they feel completely stuffed, like when you completely overdone it at at Thanksgiving.

And that sometimes brings on nausea. So I always talk to patients, whether they're taking tirzepatide or somaglitide or any of these drugs to, to, you know, to definitely start with smaller meals, just serve yourself less food to eat slowly and chew it thoroughly. And then to, you know, after each bite to think to yourself, you know, am I, am I feeling full? Am I feeling full? And definitely once you feel full, you're not hungry anymore. Stop eating. Some people have to eat more meals a day. But, and you know, frankly, what they have is they have more appetite because they're losing weight and, and they're eating less calories, but they have to, you know, they don't, they don't eat very much with a meal, but then they might get hungry 3 hours later.

But that's OK. If you ate very little at lunch, you know, you can have a snack at 4:00 PM and then, you know, some people end up being not very hungry at supper and maybe they get hungry at bedtime. So people have to sort of adapt to that, but avoiding eating when you're already feeling food full. And then the concern that's probably out there the most now is that people will lose muscle mass. The best studies suggest that the muscle that you lose with with these GLP 1 based drugs is the same amount of muscle that you would lose if you went on a diet, you know, just ate less.

The reason why you need less muscle is you're not moving around as much bulk. Literally with the same amount of activity, you're going to burn less calories. You need less strength. So the body adapts by by reducing muscle. Good point. Right, right. And, and, but some people I do think lose too much muscle and those are people who don't eat enough protein and don't get any exercise. And so, and I think the people who don't eat enough protein and don't get enough exercise are often people who lose weight too fast.

So we try and dose the drug instead of just going up as fast as we can, which we used to do with the older drugs going up very slowly. And as long as people are losing a pound a week of weight, just staying with that dose. And you know, if, if they get down to just losing a pound a month, you know, maybe then it's time and they still need to lose more weight, then it's time to go up on the dose. Because when you lose weight really quickly, it's hard for people to eat enough protein to avoid muscle loss.

And that amount of protein, the number we use is 1g per kilogram per day. So, you know, a 220 LB person is 100 kilograms. They need to eat 100 grams of protein a day to to really not have the diet be part of of the loss of muscle mass and try to exercise. And again, if you lose weight too fast, you just feel so weak and tired it's hard to exercise. But you do do want to get both cardio and weight training if you can when you're using these drugs. So what percentage of patients would you say have to stop the drug because of the side effects being extremely annoying or unbearable for them?

I think with the right counseling about limiting the portion sizes and all that kind of stuff, probably 95% of people can take it, can, you know, can get to an effective drug dose. I think there are maybe another 5% who have a little bit of kind of ongoing issues with nausea who, you know, after two years or after a year, after four years, they just say, look, I, I'm tired of having these spells of nausea, I'm going to quit. But I'd say, you know, in the community with less counselling. And then I, me personally, I think particularly people who have tried these compounding pharmacy preparations and gotten basically no counselling, you know, I think they're, you know, quit rates of 20% or more are common.

You might read in the newspaper that after a year, only 50% of people are taking the drug after starting it. I think a lot of that is problems with health insurance and switching, you know, switching insurance schemes and that kind of stuff. And so we also spend a lot of time counseling people about, you know, how are they going to afford this medicine, You know, how we can get get access to these medicines, which is getting better. Right. So it's very effective. Sounds like it's very safe. Have you seen any really serious adverse side effects that might land somebody in the hospital or or something like that?

Well, there, yeah, there there are some things that are that are in the package insert. So when we do these clinical trials, we ask patients at every visit anything untoward happened since the last. Whatever they say, we write down and that ends up in the package insert of the drug saying these are the side effects. Now, when you look at placebo, you also get side effects. So something that's in the package insert that is a terrible thing when it happens and it happens to people with diabetes is something called pancreatitis, inflammation of the pancreas, very painful, you know, in its worst form, just horrible pain that goes on for days and weeks.

Thankfully, most of the cases that are reported with the GLP one drugs are tend to be mild and relatively short. Still not pleasant, but importantly, in these trials like Soul, you know in the big trials where they're placebo-controlled, there doesn't seem to be really any increased risk of pancreatitis. So that's one which is kind of on the fence whether that's really a problem for these drugs or not. The second one that's quite worrisome is sometimes the the slowing down of the GI tract with vomiting and Constipation gets to be really bad.

And there are people who've needed procedures basically to get rid of the Constipation. You know, they have bowel obstructions. Again, very uncommon. Unclear whether that's directly related to the drug, probably is, but you know, the provider needs to help patients. Patients need to tell doctors, look man, I am just not pooping when I take this drug and we have to do some poop engineering to make sure people don't get completely plugged up. Like stool softeners and and things like that. Actually, the thing I find more effective is things like milk of magnesia and some people just have to do it once a week to poop.

And then the the the other thing that has become a more recent concern is eye problems. It is well known that if you take people with poorly controlled diabetes who are at risk of having eye disease anyway and you improve their blood sugar control very rapidly, that sometimes their eye disease just kind of blows up. And this is the the GLP one drugs are the most effective drugs on the planet for controlling diabetes. And so we try and make sure that people that their eye disease is well controlled before we put them on the drug.

And that seems to have largely mitigated the main or the eye problem that we've known about for for some time. There's a new eye problem called NAION. It's a long acronym.

I'm an ophthalmologist so I'm not aware of it. It's non arteritic ischemic optic neuropathy, basically reduction of blood flow to the optic nerve. But it hasn't been proven that these drugs 'cause that it's just an association and and many of the patients are in an age group and a disease group where they're prone to that. So it's not clear yet. And it's so rare that from the clinical trials, we really don't have much insight into it. But so people are concerned about potential eye complications.

So I think the main thing is if patients have issues with their GI tract, with their stomach, with their bowels, they need to let their doctors know. If they have problems with with their vision, they need to let their doctor know. The one thing that is for sure, they're more more gallbladder events, people that need their gallbladder taken out. That's true for essentially all weight loss therapies, including diet and exercise. There's something about losing weight that tends to cause more gallbladder sludge.

Stones that just plug up the gallbladder and you need to have it surgically removed. Right. So you have to weigh those side effects compared to the huge benefits of of the drugs. Right. And that, you know, that's an important consideration, right. So I do think for the, you know, 25 year old who, you know, wants to look extra good for the wedding that they're they're going to in a month or two, you know, just need to be aware of this is a drug and some people have serious side effects. And and so the benefit, you know, the benefit is pretty fleeting.

If you're going to take it for a month to get thin for a wedding. Personally, I do not support people doing that. I think if you have diabetes or you have medical problems or you know, trouble, you know, trouble with self-confidence, etcetera, I mean real issues with, with overweight or obesity, there is enough benefit where, you know, you could consider taking these drugs. But if it's sort of a silly idea, you definitely shouldn't do it right? Now how does this new approval position for Rebelsis as a drug that reduces major cardiovascular events, how does that put in a category for treating diabetes?

Should it be the first line drug for for treating diabetes in view of the cardiovascular benefits? So what the American Diabetes Association says is that these drugs should be used in people with diabetes who have cardiovascular disease, independent of how well controlled their diabetes is or what their background therapy is. So they're saying if you're diagnosed with diabetes when you have a heart attack, for instance, you have heart disease, you have diabetes, you should be on a GLP one. It doesn't matter what else you're on.

Most people would start a patient with new diabetes, new type 2 diabetes on metformin because it's dirt cheap and has been around forever. SGLT 2 inhibitors, that other class of drugs that we talked about earlier are, are quite attractive as well. And so some people would use that kind of pill that doesn't require any kind of special taking. Me personally, if I had diabetes I would want to take a GL P1 receptor agonist because most people with diabetes are also substantially overweight and these are the most effective weight loss drugs in addition to being the most effective blood sugar regulating drugs.

But it's not a for sure for everyone. Oral Rebelsis, though, is the only oral GLP one receptor agonist available today. There is another one that's being developed by Eli Lilly that could be available early next year, but it'll be a while before we know about its cardiovascular effects. Right now, do the cardiovascular benefits from Rebelsis, which we just discussed, do they also happen with Ozempic and Wegovi? Because these are all basically the same drug as you mentioned, they're all made by Novo Nordisk.

So do patients who don't want to take Rebelsis for various reasons, can they take Ozempic and Wegovi and get the same cardiovascular benefits? Has that been shown in clinical trials also? Yes, so Ozempic was shown in a previous clinical trial to reduce cardiovascular risk in a, in in one of those small safety studies and Wygovy which is the obesity formulation is was study in the select trial, which I think in the introduction you've mentioned is something else that you want to talk about. Yeah, that's the select is the obesity cardiovascular disease study for Wygovy.

Right now the the Lilly drugs that you mentioned, do they also have this cardiovascular advantage that's been proven with Rebelsis? Yeah. That's the most recent, we call it disclosure in the business. The most recent clinical trial that was reported in September. It's still under review with a journal. It should come out in print soon. But it's been presented a couple of times. That was the so-called SURPASS cardiovascular outcome trial with with tirzepatide in patients with diabetes and cardiovascular and kidney disease.

So that trial also more complicated because instead of comparing to placebo, they did a very brave thing and compared it to Trulicity, another one of these drugs. It's been proven to have cardiovascular benefit before and they showed that it was not inferior to Trulicity. Statistically, it wasn't quite to the point where you could say it's superior, but it was 8% better than. So, you know, effectively I think tirzepatide has a great track record for cardiovascular disease and kidney disease like Ozempic.

They don't yet have an FDA decision on that. So the, the formal decision isn't out yet, but I, I expect it will come. It may take six months. Right. So Rebelsis has that official FDA approval. The other ones probably will get it in the future. Right. So Trulicity, the one that that Manjaro compared to does have it, Ozempic has it, Wegovi has it, Rebelsis has it, Victoza also has it all. Right now, you mentioned several different drugs, five of the most popular ones. How do you decide what to put the patient on?

Let's say they have diabetes, they're overweight, they're at risk for heart attacks, strokes. Do you start with Rebelsis or Wegovi? Or you tell the patient the pros and cons and so on and let them decide. Yeah, I'm a big believer in telling people the pros and cons. And part of that is I think when patients make the decision about the drugs that they're on, they're kind of more invested in it to begin with. They feel like they had some say in it. And at least my experience is that patients that I put on drugs tend to stay on drugs in the long run.

And I try to kind of put myself in the patient's shoes and think about what they may want. So some people already at baseline have a fair number of GI complaints. You know they're gassy or they're bloated or you know whatever symptoms they have. You know one nice thing about Ozempic is you can do this thing called micro dosing. There clicks in the pen. So you take these little tiny doses and when you go up really, really slowly on doses, that is the best tolerated way to go. So in people with lots of GI overlay, we may do that or the the Bydureon is one that's been around for a while that also has a very slow release pattern from its injection site.

And that one also has a, you know, a much better GI profile. Frankly, Tirzepatide when Jaro Zep bound is the obesity formulation that's the most powerful one out there. So if someone is really heavy, we might start with that one. It doesn't have quite the track record that Ozempic does, Ozempic and Wygovy. So if they if they're concerned about, you know, how safe the drug is, how long it's been around, that's much less of an issue now that we have that tirzepatide cardiovascular outcome trial. But any case, so some people would start on Ozempic and then if they really needed more, we would switch to tirzepatide.

So there there are things that you can say that are nice about all the drugs and, and frankly in the United States now often it's your insurance company that tells you which drug you use. Right. You mentioned it briefly before I noticed this TV and Internet ads for these GLP one drugs that are not the originals made by Novo Nordisk. Are those safe to use? Are they the same thing? And how do companies sell them to the public if they're not FDA approved? All the Nova Nordis drugs are FDA approved.

They've gone through clinical trials. The companies spend, you know, 10s of millions of dollars studying them. The FDA reuse it. And then these companies that I never heard of advertise these drugs on TV and people buy them. What? How does that happen? Yeah, it's actually gotten even more complicated. So it used to be that if you saw an ad and it wasn't from Lily or Novo, it was compounded, which meant is probably the chemical. And you know, for the most part it seems like it's the right chemical made sort of in a bootleg way, you know, probably in a factory in China.

Not to be disparaging about factories in China, just that that's where it comes from usually. And you know, I think in some places the compounding pharmacy is extremely responsible and does it's very best to ensure the safety of that product, but it's not the FDA's level of supervision and that kind of stuff. So there's a there's some uncertainty with that. Now some of those, those compounded or those companies that were selling compounded symagglotide or tirzepatide, now they have relationships with Lily and Novo.

So they may be giving you the real stuff. And you know, you just have to do your due diligence about that now. So some of there are companies from which you can get the, the, the Realtor's Zapatite, the real, some magnetite in the in a vial that will say, I mean in a pen that will say when I go V or, or Ozempic or a vial or a pen that says Zepbound or Banjaro. So that's, you know, very likely the, the real stuff, you know, and the price is coming down. I don't know the full details of the very recent agreement with the, with the White House that Novo and Lily have had about prices, you know, that hasn't quite been implemented.

And I, I'm a little bit afraid they talked about a certain price for the starting dose, but I don't know whether that's going to be true for all the doses. But the price is coming down. If you travel internationally there, you know, it's 100 to $200 a a month in most countries around the world. So I encourage people that that do travel internationally to think about, you know, getting a three month supply or six month supply if they're overseas. In India, Ozempic is becoming generic. So it'll be regulated by the Indian equivalent of the FDA.

And my understanding is from colleagues over there that they have 30 companies teed up to make generic Ozempic for $10 a month. So. Yeah, but it won't be generic in the United States, I think until 2032. Right. I guess they have different patents in different countries and they last for different periods of time. I would think that getting drugs that are made in in China where you don't know who made it, what kind of lab, what kind of sterility they had is, is kind of risky. Hopefully these this new agreement between the company and the government will reduce the price so that more people can benefit from the drug.

Right. So that I mean, I think there are highly ethical compounding pharmacies that have done a good job through this period. It's just very hard to tell one from the other. Yeah, the average person out there, though, that doesn't. Know you're not going to know, right? They're not and some of them are not good. I mean, there have been some catastrophic problems with some of this compounded stuff. Yeah, they don't want to take that chance. Now I want to move on a little bit to. We discuss briefly the article in The Lancet medical journal, which is like the New England Journal of Medicine, which was published about two weeks ago on the SELECT trial.

That was a huge trial that showed the injection weekly of 2.4 milligram of the symaglitide, which is Novo Nordisk's medication equivalent to Wigovi, reduced major adverse cardiovascular events in patients who were just overweight and obese but didn't have diabetes. So how does that happen? Why? Why is just improving obesity or being overweight also reduce your cardiovascular risk? Right, that is the billion dollar question, you know that. So that study originally was reported about a year ago, the primary result with a you know over as I remember it over 20% overall reduction in heart attack, stroke and cardiovascular death.

So it's not because the diabetes is getting better, because these people did not have diabetes. There is a small reduction in glucose. So there's a small reduction in blood pressure, there's a big reduction in weight. So the smart money was that it's weight. Weight is what's making the the cardiovascular benefit. But what they showed in this study that you're referring to in The Lancet just very recently was that it wasn't either the baseline weight, you know, so it didn't matter whether you were just overweight, you know, ABMI of 27 or whether you were, you know, quite large, you know, BMI of 35 or 40.

That didn't affect whether you had the benefit from taking Wigovi. And it wasn't the amount of weight loss that seemed to drive it either. There has been speculation and some some data from animal models that the cardiovascular benefit of these drugs is really driven through independent mechanisms. Inflammation perhaps perhaps the stability of what we call plaques or the sort of the ticking time bombs that are in your heart that sort of tear open and cause your hearts, your arteries to block. All of a sudden, you know that that there there may be basic biology that's being affected by GLP one in the heart directly.

We don't really know. But what we now know is that the evidence that it's purely blood sugar lowering, you know, that case has gotten weakened a lot and that it's surely, wait, that case has gotten weakened a lot. It's likely intrinsic to how GLP one works in the heart and in the vascular system in general. It's interesting now these drugs also help patients with kidney disease. Do we know what the mechanism is for that? No, you know, it's amazing how much we know. And the same time all you have to do is ask one or two questions.

You get to, I don't know. So it's good for kidney disease, it's good for liver disease, the so-called mash or metabolic associated liver dysfunction. It's good for knee pain and osteoarthritis, it's good for sleep apnea. You know, this class of drugs, pretty much every two or three months we get another study where it's been studied in some other condition. The one the study that's cooking right now that we're the most interested in, we should hear about this month is for mild cognitive impairment, early Alzheimer's disease, and then one where we don't have proof, proof, proof.

But in Seoul it looked like it's also good for what we call peripheral vascular disease. So people have blockage in their legs enhancing their ability to walk distances and to not have recurrent events. So, you know, that's a relatively new one too. So very exciting. You know, there are over 200 medical conditions that are associated with overweight and obesity. And so it really is possible that this class of drugs and, you know, there's a tidal wave of development in this field with all kinds of other classes of drugs, but being able to attack obesity is a medical problem, is a way of cutting the legs under chronic disease.

I mean, everything from asthma and COPD to many forms of cancer, depression, anxiety. You know, we talked about heart disease, liver disease, kidney disease. It's very impressive the spectrum of diseases that might get better with weight loss. Seems like the common denominator is reducing fatty tissue or adipose tissue in the body. Maybe fat cells release some sort of toxin that's toxic to every organ in the body, and if you reduce the fat cell content or a number of cells then every organ benefits maybe.

Yeah. Well, so fat cells are the site of inflammation, and so that's one of the reasons why that inflammation hypothesis is out there. But in the SELECT trial, it didn't matter how much fat you lost as far as the driver of cardiovascular disease. But, you know, it could be more subtle. In any case, it's unknown. And to me personally, it'd be great to know how it works because that way we could developed, you know, new therapies that address that target. But I'd much rather know that it works. Didn't know how it works.

Right. Very important that you mentioned before that you spend a lot of time talking to your patients. Very important. How much time do you spend telling them about exercise and diet and lifestyle in combination with Rebelsis and Wigovi and Ozempic? Yeah, I mention it at least in every visit. And the reason is, you know, without the lifestyle effort, you can eat your way through any drug program. So, you know, we need to have some, you know, we had to fetter food intake and increase physical activity for good health in general.

I mean it. This is not specifically about diabetes or overweight obesity and what I would say the kind of miracle to the GLP one receptor agonist is they will help you with diet. So, you know, I, I, I was heavy my almost my whole life and you know, I would lose 10 or 20 lbs. And by the end of my spree of being good, you know, I'd find myself in front of the refrigerator or in front of the pantry just gazing in there going, man, I got to eat something, but I can't eat something because I've eaten my calories in the day.

You know, it's called food noise. And it would get to be deafening after I would lose 15 or 20 lbs. And I, I take these drugs, I lost nearly 70 lbs and I got no food noise. So it, it's a lot easier to follow the lifestyle plan once you know, on these drugs than it was before. And it makes it, you know, it makes it more fun than it used to be. You know, it used to sound just like nagging when you say, you know, what do you have for breakfast? What do you have for lunch? What do you have for supper?

What do you snack between meals? What do you drink with your meals? And then having to say, well, you know, instead of having two sandwiches, could you have one? Could you switch to, to low fat mayonnaise? Don't get the no fat mayonnaise. It's terrible. But low fat mayonnaise might help, you know, so we, we used to always try and come up with one or two, two things that people would agree to do that would make a difference. I mean, it's still a valuable technique to know. But the truth matter is these GOP one drugs are much more powerful than willpower.

That's, that's an excellent summary. Do you tell your patients that, that you took the drug? Because that would be super convincing if anybody who had doubts about it. And you say, look, you know, I take this drug and it's awesome. You kind of have to when you lose this kind of weight because otherwise people think you're dying. So my patients used to be really worried about me a couple of years ago when I or three years ago when I first started. Yeah. So I came clean. I you know, I overshare in general.

That's that's really, that's funny because I, I run a lot and sometimes before I run in competitions and races, I increase my mileage and I lose a lot of weight. And sometimes my patients ask my assistant, is he OK? Yeah. So I, I know how you feel, but, you know, 70 lbs is a lot, but you're a living example that these drugs are very beneficial. That's great. And. Then you know, my blood pressure got better, my liver got better, everything, my triglycerides got better, my HCL got better. I mean, on paper I'm like a healthy 20 year old even though I'm not so healthy 67 year old.

You, you look, I don't, you don't look like you're 20, but I would go with 30 or something. Oh, right. You look awesome. Well, this has been extremely educational for me. I learned a lot and I'm sure the public out there in the audience will love watching this and will learn a lot as well. So I really appreciate your taking the time from your busy day to share your knowledge and experience and expertise with us about these very important drugs. Well, thank you. It's really been a pleasure having this chat.

Thank you.

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