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. This podcast is Narrator - ? 00:12 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 142 I'm your co host, Dr. Kane, I'm Dr. Khyati Patel 00:35 Dr. Patel, and today with us back is Dr. Srivastava. Thank you for being back with us. Dr. Srivasa, Speaker 1 00:42 thanks for having me join you. I'm very excited to talk about this very important topic. Dr. Khyati Patel 00:47 And that said, the title of our episode today is New gains in weight loss pharmacotherapy. And so just to remind our audience, we did record very long time ago, Episode 13 about pharmacotherapy of weight loss, medications we since then, Belviq, lorcaserin, which was the five HT two receptor agonist, has been pulled out of the market. They're reciting some malignancy concerns. Qsymia, which is a combination of phentermine and topiramate, the over-the-counter Alli, or the prescription Xenical, as well as the short term therapy with phentermine, the Adipex, is still available in the market. Since then, we have few new agents, and so we figured it will be nice to talk about those agents. They definitely have made some stir lately in the news market as well. So figured we can talk about that along with some guideline updates which were long due. And so for that, we have Dr. Shaba with us. So Dr. Shaba, can you kind of just lay out the background and tell us what obesity is, really, definitely. Speaker 1 01:59 So obesity is something you know that we have known about for a very long time, but it's taken also a long time to truly see it as it is currently defined, you know, as a chronic and progressive disease, just like any other chronic condition that's there, it requires long term management, and We need to think about it as other medical conditions. We're getting there, but not completely there yet. And it's defined, of course, on BMI, the body mass index, which is based on height and weight. It's not a perfect measurement, because we can have some people that have lots of muscle mass, and they may have a higher BMI versus somebody else who does not. And so that's not the only way we can define obesity, but it is the current standard that we have. Dr. Khyati Patel 02:52 And when you combine the BMI along with the waist circumference, those like Central adiposity, that's where you start adding the long term risk for cardiovascular disease, developing diabetes and some of the related comorbidities, so you're absolutely right. Dr. Srivastava, when you say, you know, we look at the BMI, and it's probably not good to just look at that, but adding weight circumference and overall assessment of other underlying conditions that patients may have that contribute to obesity is also good to factor in. Dr. Sean Kane 03:26 And you know, just to put kind of a hard and fast number to it, if you look at the CDC or NIH, they define obesity as a BMI above 30, and then above 30, they have different classifications, like class one is 30 to 35 class two is 35 to 40. Class three, also called severe or extreme obesity. This is a BMI of 40 or more. And as we'll talk about, you know, from an FDA indication standpoint, for the most part, they stuck with that in terms of BMI is above 30, are typical indications for some of these weight loss therapies, but they did go down a little bit into the overweight category. So that's a BMI between 25 and 30. And as we'll talk about, some therapies do have an indication. If your BMI is 27 or higher and you have obesity related comorbidities, like hypertension, diabetes, dyslipidemia, although these are obesity therapies for obese patients the overweight category. It does spill into that category to some degree, Speaker 1 04:24 absolutely, and it just brings us back to how we have to look at each person individually, and not just at the numbers, but also just holistically, to see what other conditions that they have and how they may benefit from weight Dr. Khyati Patel 04:38 loss and talking about individualization, you know, just alone, the BMI numbers, these numbers are probably all the patient population, except South Asian. So the cut out for South Asian patients on what's considered overweight and obese, it's slightly different. Dr. Sean Kane 04:53 So in terms of commonness, I think it is not a surprise to anyone that obesity in the United States is fairly common. So we're looking at more than 100 million people with obesity in the US. It is the third largest direct economic impact on the world's economy. Costs about $2 trillion a year. It's attributed to about 5% of all deaths worldwide, and roughly about half of the total cost of chronic conditions are associated with obesity and being overweight, and for patients with a BMI of 40 or higher, again, that's our severe extreme or class three obesity. A weight loss of only 5% could actually reduce medical costs by about $2,000 per year. So that's quite a bit of obesity in the US and really worldwide, and also a huge economic and clinical impact of obesity as well. Dr. Khyati Patel 05:48 And so Dr. Kane, the numbers you put in and the vastness of how obesity is spread in our surrounding, you mentioned it brings back to discuss. Why are we talking about it, right? So what it's there? Well, it does have impact, like you said, on other chronic conditions and comorbidities. About 60 plus comorbidities are associated with obesity and even the little modest weight loss. And you will hear these numbers, you know, five to 10% could result in pretty significant clinical benefits in terms of impacting these comorbidities. And so we have to talk about them, because it does put a dent into some of these chronic conditions that patients may carry. And as you mentioned, you know, it kind of adds to the overall cost of treating the patient because of not just obesity, but the chronic conditions. And so those chronic conditions, you know, examples would be depression, cancer, you know, sleep apnea, arthritis, you know, having to go through replacements and things like that. So we have to talk about the elephant in the room, definitely. So Dr. Srivastava, that being said, you know, new medications have come out, and I feel like the science of obesity is always changing. We're always learning new things. Can you share with our audience as to what we know about obesity and what are some of the new things the scientists are looking into? Speaker 1 07:25 Definitely, so for the longest time and even now, many of our patients here, while weight loss is just about eating less and moving more. And I don't know about both of you, but I, myself included, know so many people that you know you follow something, and you eat a little bit better, and you lose some weight, and then you gain some weight. And there has to be more to it than just what it is that we're eating and how often it is that we're moving. And the science has shown that there absolutely is, and of course, all of that's important. Nutrition is important. Nutrition is important. Physical activity is important, but obesity and this weight loss is about a little bit more than that. And so one understanding that we have a little bit better is this whole thought of metabolic adaptation. And so part of the reason that people may lose weight and then, you know, still be doing kind of the same changes that they already have been but not able to lose weight as much anymore. Is this concept where the resting metabolic rate decreases as does the total energy expenditure. So one way that it's been explained to me, and I really like this analogy as tug of war. Right on one side, you have weight loss that's from decreasing calories and increasing this physical activity, but on the other side, and sometimes this other side is even just stronger, and pulling even harder is an increase in hunger hormones and a decrease in metabolism and fullness hormones, and so there's this struggle between the two sides, which can make weight loss a lot more difficult. And our brain has a critical role in all this. Many of these hormones from our body trigger our brains, and that's where many of these decisions are made. Dr. Khyati Patel 09:18 And just to make it a little bit more tangible. Dr. asked you when you say hunger hormone, one of the example is ghrelin, which makes you feel like you're hungry and you got to eat. And then the satiety hormones, or the fullness hormones, you're referring to, are hormones such as Amylin, insulin, the GLP, one, leptin, etc. Dr. Sean Kane 09:39 What I like about that is there's kind of a saying out there for weight loss called calories in equals calories out, meaning, you know, if you want to lose weight, you have to expend more calories than what you take in. And while that may be true, Dr. S, as you mentioned, your body changes how many calories you need based on if you're dieting and things like that. So there is this adaptation that happens. Ins, and also, willpower is not part of the calories in calories out equation. So you know, when you have a lot of ghrelin or not enough, GLP one, and you start having this tug of war, it makes it harder to maintain the amount of calories in that you need to be able to lose weight, because your body is literally making you feel these emotions and this feeling inside you that you're you're not getting enough, and that makes it really difficult. And that's really the role of some of our pharmacotherapy, right? Is to fix some of those metabolic adaptations that are making it harder to have that net negative calorie balance. Speaker 1 10:36 And thank you, Dr. Kane, I'm so glad that you use the word willpower. And so if I'm allowed to say this, I do listen to other podcasts in addition to this, especially related to obesity and willpower, some a concept that's often discussed, because oftentimes it's been, you know, people are left thinking, Well, I just don't have enough willpower. Or, you know, there's just, it's just about me and if I could just do better. But it's not always that. That sense, it's not just willpower. There's so much more going on that's contributing. Well, why Dr. Sean Kane 11:07 don't we talk about some of the pharmacotherapies? And you know, we've set the stage to say that there are certain hormones in the body or certain cognitive processes that happen that maybe would be reasonable drug targets to help patients be able to maintain a net negative caloric balance and lose some of that weight. Dr. Khyati Patel 11:25 We have discussed some of the agents in Episode 13. They were kind of older agents, and since then, have in 2014, Contrave was approved. It's a combination of naltrexone and Bupropion. So with that nature. You know, Naltrexone is an opioid antagonist, and Bupropion is a weak norepinephrine–dopamine reuptake inhibitor. We we get to see kind of like effect of weight loss by two different mechanism combined. Overall, we don't know how it works. However, in the non clinical studies, it shows that it affects brain, as Dr. S mentioned, brain plays a huge role in regulating appetite and, you know, satiety, and so it impacts the appetite regulation center in hypothalamus and the dopamine circuit in the mesolimbic area, which is our reward system, and kind of balances those satiety and hunger triggers and helps lose weight. But we don't know exactly how that happens. Dr. Sean Kane 12:29 And just to piggyback on that kind of interesting, you know, Naltrexone is also used for alcohol abstinence, so again, focusing on kind of that reward system, we do see this effect and other disease states where we think that the reward system is a component of the disease state itself. Speaker 1 12:49 And then with the dosing of this medication, and all the medications that we talk about, actually there is a titration. So for this medication, it's a gradual titration. You know, we eventually reach to two tablets, twice a day by week four, and the maximum dose is 32 milligrams, slash 360 milligrams. Renal adjustment is necessary. And when we're counseling our patients, we want to tell them to take this medication with food, but definitely not a food that is high in fat. And the reason for this is that fat increases the concentration of both medications. And so if they get too much of that Bupropion, it can increase the risk of seizures. If they get too much of that naltrexone, it can be hepatotoxic. And so to make sure that we're talking about the dose titration, having them take it with food, but avoiding foods that are high in five Dr. Sean Kane 13:41 and just to kind of add on to that, you know, as we mentioned, Naltrexone is an agent that's already in the market. Bupropion is an agent that's already in the market. And actually, some of the other therapies we'll talk about are therapies that are approved for other indications already, that we've adopted as therapies for obesity. I do think it's reasonable to talk about, for example, the dose of Bupropion here is actually a pretty good dose. So Max dose of 360 milligrams a day. That's a fairly normal Bupropion dose. So this is not like under dosing any of these therapies. So everything that you know, the clinicians listening that you know about Bupropion, like Dr. S, you mentioned the risk of seizure, for example, or certain patients that shouldn't take Bupropion, you know, those with anorexia, bulimia, history, seizure disorders, alcoholics, things like that. All of those still apply to this, contrary of combo medication, because you still have a normal amount of Bupropion in it that you would have, in comparison to if you're to use Bupropion for smoking cessation or depression, things like that, right? Dr. Khyati Patel 14:46 And diving more into what's the bottom line with this medicine? How much weight loss does it provide, right? So when we talk about all three agents and their efficacy, we're kind of looking for it's their comparison against place. Well, that's how the individual studies, obviously, were done. But then we're also looking at that clinically meaningful weight loss. We're looking at how many patients got to that 5% weight loss in the clinical trials, many patients got to that 10% weight loss. And so when we talk about Contrave the one year mean weight loss was a 4.9 kilograms. And I know we go by pounds, so about 11 pounds more than placebo. In studies, 48% of the patients with contrary therapy were able to get to that 5% weight loss, and 25% of the patients were able to get to that 10% weight loss, in comparison to 16 and 7% with the placebo. So while talking about efficacy is important, bottom line also for a lot of patients, is tolerability of these medications, right? And if you consider looking at older guidelines and stuff even, like, for example, the 2013 ha ACC guidelines, they didn't even talk about pharmacotherapy, but back in 2016 AAC had their publications, and they were saying like, try to make sure that patients are only on FDA approved medication. Because while these weight loss medications are helping with what we try to achieve, they come with added risk and side effects and stuff, right? So these are not medications for everyone, but you gotta always do that checks and balance the benefit versus risk, so the risk, but Contrave, really, when you're looking at side effects, commonly, or constipation, nausea, vomiting, headache, some of the rare issues kind of go in line with what doctor Kane mentioned earlier, not ideal for people who have suicidal behavior due to the Bupropion combination. Have underlying liver disease because of the naltrexone component. It does increase heart rate and blood pressure. So those who have, you know, CVD probably not a good medication. And also then it causes the closure of the glaucoma, so causes the narrow angle glaucoma. So, you know, kind of these are kind of like the rare issues and warnings associated with them, but also kind of guides us as to who we shouldn't use this medication in particularly Speaker 1 17:23 so, then who we should consider this medication for is understanding the FDA indication, which is adjunct to diet and exercise, and all of these agents do have that caveat in there. You know it is in addition to diet and exercise for people with a BMI of greater than 30 or as Dr. Kane was saying earlier greater than 27 with certain comorbidities, that includes things such as hypertension, type two diabetes, dyslipidemia, and then we want to avoid use In those with acute opioid withdrawal seizure disorders, chronic opioid use, uncontrolled hypertension, thinking about both of those agents separately, and thinking what those contraindications are as well. Another thing that's unique to this one versus the other two options is that it is an oral option, and so some of our patients are averse to injections. Although what I found surprising over the years, even in the world of diabetes, people are willing to take an injection, and where our assumption might be, oh, a patient may not want to, once they truly know the benefits and the risks, and so this whole shared decision making, many people are okay with that thought of an injection. But it's good to know that there is an oral option as well Dr. Sean Kane 18:44 Dr. S, because a lot of these come as pre filled pens, as opposed to a patient having to take a needle and a vial and pull it out of a vial into a syringe. I think that the needle phobia is a little bit different, because the length of the needle is not as long, the preparation of the product is way different. Many of these, you just dial up your dose and inject it and you're done. I think that that distinction is really important, and patients may not realize it until they actually use the medication to see kind of how simple it is to take that injection. Absolutely. Speaker 1 19:15 Just the other week, I had somebody in my clinic, and they were so scared of the thought of injecting, and so I had them do it in front of me, which, you know, if you're able to sometimes teach them how to use it, if they're able to use it in front of you, I think that helps with some of that anxiety. And right after she was done, she actually thought she wasn't done yet, like, that's, that's how little she felt that needle. And of course, it's different for everybody, and so we don't want to generalize that. But to your point, once they see how small the needle is and how it is in a pen, it does sometimes take away that anxiety of the injection. Dr. Khyati Patel 19:50 Both of you laid out the discussion about injectable and, you know, teaching patients how to use it. So that lands us to the platform of Saxenda, liraglutide 3 milligram, which was approved in 2014 Speaker 1 20:03 so we have two GLP, one receptor agonists on the market. One was approved in 2014 as Doctor Patel said, Saxenda, which is liraglutide. And then we have Wegovy, which is semaglutide, 2.4 milligrams, which is our latest agent, which was just approved this past year in 2021 and so we know both of these medications, the generic versions of them, at different doses, are already approved for patients with type two diabetes, and we know that one of the side effects of the GLP one Ras was weight loss, and so it wasn't that much of a surprise when these medications came out, marketed for and indicated for obesity. Both of these agents work in the same way. They increase satiety by stimulating GLP one receptors in the hypothalamus. This, in turn, suppresses the appetite signaling. It also decreases gastric emptying, and so one feels full for longer. And when we think about how this works, we also have to then relate it to the side effects when we're talking about it with our patients. Dr. Sean Kane 21:19 So from a dosing perspective, both of these agents, you start at a low dose, and actually the starting dose is the same dose that you'd have for a diabetic patient. The difference, though, is that the max dose, or the target dose in obesity, is always higher than that of type two diabetes. So for example, with liraglutide, you start at 0.6 milligrams subcutaneous injection using a multi dose pen once a day, and then you go up to three milligrams. And the reason that you're going from point six all the way up to three fairly slowly is that you're trying to help the patient tolerate these gi side effects, especially things like nausea or just feeling full and things like that in comparison. So again, liraglutide, we're looking at three milligram target dose in obesity for type two diabetic patient, the max dose is 1.2 maybe 1.8 milligrams. So we are using higher doses for obesity. And if we look at semaglutide, it's the same thing. So semaglutide is dosed once a week, which is kind of nice. Instead of once a day, it is a pre filled pen injection, and the starting dose is point two five. Same with diabetes, the target dose, though, goes up to 2.4 milligrams. As opposed to an obesity, the target or max dose is point five to one. So again, always higher doses in the obesity indication compared to the diabetes indication, but the initial doses are the same. Dr. Khyati Patel 22:45 I think it's important to mention that while there is this optimal dosing for both of them, the three milligram and the 2.4 milligram is it that's that's the ultimate dose to be at. But let's say a patient has GI issues, and they cannot tolerate that higher dose. Maybe they're comfortable with a lower dose. It's okay to keep them there, as long as they're getting the benefit of weight loss. You don't always have to push it to the limit where you know they're miserable with all those gi side effects. So the optimal dosing is kind of like a guideline. You could maintain patient at a slightly lower dose, with the expectation laid down that that slightly lower dose may not get them the outline weight loss, as the clinical trials have mentioned, because obviously most of those patients were on those optimal doses. Speaker 1 23:41 And just to add to that, you know, some people just need to titrate a little bit slower. And so some of these people may still get to that optimal dose, but not in that dosing schedule that's been laid out in the package insert. And so even the package insert does say that if somebody needs to stay at that middle dose for a little bit longer, then you can go ahead and continue to have them at that dose and then reassess. Dr. Khyati Patel 24:05 And in order to kind of help them tolerate some of these gi side effect while they're taking this drug, a lot of dietary modifications and behavior changes around the diet will come in place. So eating smaller meals kind of making a diary of what their body agrees to at that point and doesn't cause nausea. Less oily, you know, less fatty. All of that is also going to help them tolerate the medication better, and obviously lead to better weight loss too. Dr. Sean Kane 24:38 So speaking of the weight loss, doctor s, what kind of weight loss did we see with liraglutide? Speaker 1 24:43 So with liraglutide, the one year mean weight loss was about 5.8 kilograms, which is 13 pounds more than the placebo. And then all these studies always look at how many patients are reaching that 5% weight loss or that 10% weight loss, because those are. Are the percentages we're typically looking at to see some of these clinical outcomes. And so for those patients, reaching the 5% weight loss, it was 63% versus 27% and the 10% was 33% versus 10% with that placebo. Dr. Sean Kane 25:15 And then in terms of what we saw with semaglutide, again, similar endpoints, and we're looking at about 12 kilograms, or 26 pounds more weight loss than placebo, so numerically, the most. But again, different studies are going to have different patients, so it's a little bit dangerous to compare apples to oranges in terms of study a versus study B. Ideally you want to head to head trial to show it, but in this case, it was 26 pounds of weight loss. Those reaching 5% weight loss, it was about 83% which is a really high number compared to other obesity trials. 10% weight loss was about 66 to 73 again, a really high number. And then they also have 15% weight loss, which is quite a lot of weight loss actually, and somewhere between 25 and 53% of patients met that endpoint. So again, really fantastic numbers. We'll talk about true comparative data in a little bit. But numerically, the semaglutide phase three trials were very promising in terms of its efficacy. Dr. Khyati Patel 26:14 And Dr. Kane, the pandemic has just, you know, made covid news everywhere. But when we go we trial had that 15% weight loss marker, and that data came out. It was all over the place. Even New York Times had an article over it, and the news channels were discussing how great of a weight loss that it is providing. So yeah, it's a little bit stronger. But when we say stronger, we want to make sure we understand these trials. We're looking for these drugs in comparison to placebo, and we will talk in a little bit about the newest child that compared the two agents. But these numbers are really in comparison to the placebo, and so both of these drug being from the same pharmacologic category, the side effects are very similar, and we've been kind of talking about this gi side effect. So commonly, patients had issues tolerating these agents due to nausea, diarrhea or constipation. However, some elevation in heart rate were also noted, but there were no additional risks to development of arrhythmia in those who had increased heart rate. And then these agents are agents for diabetes at a lower dose. And so they're always putting that asterisk that if you're using these agents to aid weight loss in patients with diabetes, and they might be on other medications to control their blood sugar, that hypoglycemia can occur. But if, because these agents are glucose dependent, meaning in patients without diabetes, when there is no elevation of glucose, they're not going to go out there and, you know, start lowering blood glucose. So that's just a disclaimer in the label from a safety perspective, to be considered, what are some other rare issues we get to see with this Dr. S. Speaker 1 28:09 So some of the things that are rare but still important to think about is acute pancreatitis or gallbladder disease. And so if you have patients that have had pancreatitis in the past, you may really need to consider it's an absolute contraindication in starting patients on a GLP one, but it's definitely cause for concern and really weighing the risk and benefit. And if they've had pancreatitis because they've been on a GLP one Ra, then I would avoid it completely. Some other things that are just there, that were found as a rare ADR, include acute renal impairment, suicidal behavior and ideation, and then this medullary thyroid carcinoma, it was seen in animal models, but that does translate at this time to patients if they do have a history of that, or a family history, this medication should be avoided. Another thing I want to talk about, Dr. Patel, was when you brought up that increase heart rate, I found that very interesting, because I was trying to think of, you know, we're always linking adverse effects to mechanism of action, and why would that be happening? And I believe in the studies they were seeing like maybe three to five beats per minute, if I'm remembering correctly as an increase. And so as I was considering why it's happening, I think part of might be that we have these GLP receptors in many places in our body, and we're not even sure exactly where. And so part of the cause of that side effect may be because of that. Dr. Khyati Patel 29:39 Yeah, there is some preliminary hypothesis that there are GLP one receptors located in the myocardium, and so there is that impact. But like you said, the increase was minimal. Three to five, none of those patients resulted into, you know, tachycardia or any, any source of arrhythmia. So baseline monitoring for those who have arrhythmias and cardiovascular. Their disease of their heart rate is recommended, but those who don't have underlying heart conditions, the increase in heart rate should be non significant. Dr. Sean Kane 30:10 And I think it's worth mentioning that semaglutide does have a very interesting warning, and that warning is actually an increased risk of diabetic retinopathy complications in those who have diabetes. And this is interesting, because, you know, when we think about treatment of diabetes, we think about why do we lower glucose? Because we're trying to prevent macrovascular complications like heart attacks and strokes, and then also microvascular complications like retinopathy, neuropathy, nephropathy. So this one actually caught me by surprise. Dr. Patel, can you maybe expand on this a little bit in terms of who's at risk? And was this also a surprise for you when you looked into this? Dr. Khyati Patel 30:50 Yeah, absolutely. And I really think that it is carried from semaglutide trials when it was trialed in patients with diabetes. So the lower dose semaglutide, it's not necessarily an agent dependent. They've also seen this with exenatide and dulaglutide studies, but these were in patients who had diabetes. So these were diabetes trials, and really the issue was people who had pre existing diabetic retinopathy. There's lot of talks in the clinical community about whether this retinopathy development is clinically significant, because once, once the patient has, you know, diabetic retinopathy, they are in this extended care, and they're going to have their eyes checked out and things like that. So it kind of traces back to comparing the benefits of these agents versus that slight increase in retinopathy that may come through. But one distinction that I would like to make is that this was seen in diabetes trials. This was not seen in obesity trials, meaning patients who do not have diabetes are not at higher risk of retinopathy due to the use of some agents. So that's like the bottom line. We need to make sure we reiterate, because patients will hear about this, you know, and they will ask questions. Dr. Sean Kane 32:16 So in terms of place in therapy, Dr. S, is this similar to what we saw with Contrave oral therapy, or are these different patients that would qualify for this injectable GLP? One approach. Speaker 1 32:27 So I guess there's two parts to that answer. So the first simple part is yes, it's similar. It's adjunct to diet and exercise. The same BMI requirements greater than 30 or greater than 27 with other comorbidities. But one thing that is different for the liraglutide is that it is approved in younger patients. So it's approved for use in ages 12 and above if body weight is above 60 kilograms and BMI is adult equivalent of 30 which is great to hear that we have this option, because we know obesity is not just increasing prevalence in our adult population, but it is also increasing prevalence in the pediatric population. And so that is one difference, specifically for liraglutide, and both with liraglutide and semaglutide, we can, you know, think of it as kind of double dipping for our patients that have diabetes. So once again, if we're looking at kind of the patient holistically, we may consider a GLP, one Ra, especially if they have diabetes versus the other agents for obesity, if both diabetes and obesity are present. Dr. Khyati Patel 33:34 So Dr. Kane, you know, this episode happened very timely, because you just brought forward to us before getting started, is that there was a new study that compares these two agents head to head that was published yesterday. Can you provide us with what is the overall outcomes from that study? Dr. Sean Kane 33:54 Sure, so that this is called the step eight randomized control trial. So it was published in JAMA, January, 11 of this year, and this is one of the very few true head to head weight loss trials that are available. So as we mentioned, the standard way to do a weight loss trial is you compare your cool drug versus placebo, and you show that, wow, you're better than placebo, which is really not a high bar to achieve, right? And the problem is that it's hard to compare the semaglutide trial versus the Contrave trial, because they potentially had different patients with different rates of placebo weight loss. So it's hard to compare apples to apples. The step eight trial is really neat, because it compared semaglutide versus liraglutide. So it was a true head to head comparison of the two therapies, and what they found was the percent weight loss was almost 16% weight loss with semaglutide versus only about 6% weight loss with liraglutide. That was a statistically significant difference between the two. In addition to that, they also showed that those who got semaglutide tolerated therapy better and were less likely to stop because of side effects. So about 3% of semaglutide patients stopped because of side effects, versus almost 13% of liraglutide patients. Most of those side effects were gi in nature. Potentially, that's also why liraglutide didn't have as good of a weight loss effect. Is that patients were more likely to stop therapy. But really, this is kind of the best of both worlds, right? So you have a drug that gives you more weight loss and you're less likely to stop it because of the side effects. So I could really see some of the guidelines in the future having a preference for semaglutide because of its better efficacy and better safety profile. So Dr. Patel, in terms of those guidelines, where do we sit from a guideline perspective, in terms of what they think we should be doing for these patients with obesity? Dr. Khyati Patel 35:43 I think that's a great question. And this kind of ties back to the progression and the acceptance of pharmacotherapy for weight loss in healthcare coverage, insurance coverage, as I mentioned, goes, is it directly tied to how the guidelines have progressed? You know, we have the very early 2013 AHA/ACC guidelines, which did not even mention a single drug. It just said use FDA approved pharmacotherapy. And at that time, the focus was really using some of even the shorter term therapies, like phentermine, which, as we know, it's not approved for the long term; six months is considered the average trial time, because that's how long the studies are done, and there are some side effects and things like that. And clinicians thought that it was okay to consider but then tying back to what Dr. S said, you know, this is a chronic issue, and we need to be able to use medications for those patients who qualify for a longer term and we got to come up with some safer alternatives. And as those alternatives started to come out, and the body of evidence started to grow, we can kind of see some of the other organizations created their guidance. So the AACE, for example, in 2016 their guidelines kind of looks into multi different factors, and when it comes to the pharmacotherapy, it's looking at the evidence, so not again head to head, but kind of putting those child with placebo side by side, but also looking into individualization of medications based on some of these concomitant conditions and comorbidities and contraindications and other patient factors. What it didn't have, really was the GLP one inhibitors, so the newest one, but all the other agents were kind of nicely summarized in that. And then we have the American Diabetes Association guidelines, and Dr. ask, please feel free to chime in. But what I've loved about ADA, and again, they talk about use of these agents for patients who are at risk of diabetes, so prevention of diabetes or treatment. Well, they have diabetes, but they also need weight loss, because we know weight loss has a huge impact on diabetes outcomes. And so they've always incorporated a chapter, I believe it's chapter eight, and they do a really nice job as the guidelines are updated once a year of updating that chapter two and and I see that semaglutide is included in the standards of care. 2022 there's a nice table, if you want to take a look, and nice comparison of when it should be used. What are the safety issues and things like that, including the cost too. Any other guidelines Dr. us, besides the three that I mentioned, that kind of now focuses on either treatment of obesity or kind of considering its association with certain other comorbidities. Speaker 1 38:50 Yeah, absolutely. So when we're thinking about our chronic conditions, in addition to diabetes, other one that pops into my mind is hypertension, right? And we have about the same number of people living with hypertension in the United States as we do obesity, and many of that population is the same. And so what does the AHA position statement say? They did publish an a position statement talking about weight loss as preventative and treatment strategies for hypertension, and they recognize that obesity is a major cause of hypertension, and they noted that there is a decrease in blood pressure after weight loss. We're not exactly sure what all the reasons are, but they've definitely hypothesized and know of certain contributing factors as to why we see a decrease in blood pressure after weight loss. And so they recommend pharmacotherapy, and they also talk about Metabolic Surgery, which we haven't covered in this but that is also another option for in the treatment obesity for certain patients, and they continue to call for more research to understand this long term impact. So we do see that weight loss we do so. Is that decrease in blood pressure, but they want to compare Metabolic Surgery versus continued pharmacotherapy, and also look to see what is the impact on N organ damage when it comes to lowering BP with different pharmacotherapy and Metabolic Surgery for obesity. Dr. Khyati Patel 40:17 And those are audience that are interested in looking into these guidelines, we have the links in the show notes, in the reference section, listed out. But I think one thing you mentioned Dr. S that you know the HA guidelines highlights, is the importance of Metabolic Surgery. And maybe while we talk about use of these pharmacologic agents for weight loss, you know, those who have very high BMI or morbid obesity, we know that maybe weight loss agents, along with lifestyle and behavior modifications, will help, but it may not get us to the goal where we need to be and Metabolic Surgery is if evaluated to be safe for that individual patient should be considered, because that in itself, provides the weight loss that that patient may deserve, rather than pharmacologic agent. Dr. Sean Kane 41:08 Well, you know, one of the big things that really stands out to me from today's episode is the concept that obesity is not just a lifestyle problem or a cosmetic problem, but it's a chronic condition, and for that reason we should treat it just like we treat any other chronic condition, and we should recognize that there's a combination of psychologic, social and environmental factors that are really contributing to the epidemic of obesity. And it's really good and exciting that we have drug therapies, even newer drug therapies that are proving to be even more effective and even more safe than what we've had historically. Dr. S, what are some of the key take home points that really stand out to you from Speaker 1 41:45 today's episode? So something we didn't touch upon today, but I definitely wanted to mention as well, is, you know, we just as we want to recognize obesity as a chronic disease, just like all these other chronic diseases, we don't want to define the person by their chronic disease, right? And so we don't want to call somebody with diabetes a diabetic. In the same way we want to move away from saying an obese male or an obese female. Rather talk about it versus individual. So a person who is obese. Dr. Khyati Patel 42:19 And I think one thing that I take away from working in my clinic with these patient is that it's never a single lane road here. The optimal approach is multi disciplinary as well as multi factorials. We are looking to combat obesity from various different angles, such as health behavior changes, medications, even potential consideration for Metabolic Surgery and obviously, management of any underlying causes whenever they're present, you know, such as depression or other mental health issues as an example. But we have to consider all different aspects Absolutely. Speaker 1 43:01 And just to add to that, you know, we are talking about the pharmacotherapy, but it's still in addition to that, lifestyle modifications that remain first line. It's just that we're understanding to truly treat obesity, it does have to be multifactorial. And you know, using our multidisciplinary team and our colleagues, we can all work together to help people with obesity. Dr. Sean Kane 43:25 One thing that I think is interesting is that really the science is still fairly new, even though we've known about obesity for a very long time. You know, I don't think that 20 years ago, we really thought that GLP one agonists were going to be this apparently potential blockbuster when it comes to obesity management, our knowledge about what makes people hungry, or knowledge about just caloric intake and what kinds of calories are better or worse for obesity, there's so many other things about the pathophysiology that we don't know that I promise you, we're going to know a lot more in the next five or 10 years, because this is such a health problem among Americans and really worldwide as well. Speaker 1 44:05 And as we're learning so much more, there is so much information and misinformation out there as well. On one hand, we have people that are starting to specialize. And so as we're thinking about our patients and who, who we want to refer them to, there are physicians that specialize in obesity medicine, and hopefully we're moving away from all these just fad diets and the shaming and the simple eat better, move more conversations, but those conversations and that information is still out there, and so as we're learning ourselves and also recommending things to our patients, it can be very helpful to kind of look through what might be a good recommendation versus and that's something that can speak in a scientific way versus misinformation that could be harmful. Dr. Khyati Patel 44:56 And I think one thing I took away from reading that chapter in a. A guideline is that our approach to help patients should be non judgmental and come with mutual respect. You know, as clinicians, we may see their weight as being issue with their other health conditions and their, you know, just overall well being, but that might not be on the priority list for the patient, you know. So it's always good to meet the patient where they are by employing shared decision making, that mutual respect and then kind of discussing those goals, SMART goals, and achieving them one step at a time to make sure again, this is a marathon and not a sprint, kind of an approach should be employed. Dr. Sean Kane 45:40 Well, Dr. S and Dr. Patel. Thank you so much for your involvement in today's episode. For the listeners, if you want to see some more resources, we have them on our website, HelixTalk.com episode 142 where you'll find some references and additional resources as well. We love the five star reviews on iTunes, so keep those coming. And we're also on Twitter at HelixTalk. If you want to receive a couple clinical pearls, every couple weeks, we release pearls from current and past episodes through Twitter as well. So with that, I'm Dr. Kane, Dr. Khyati Patel 46:14 I'm Dr. Patel, and thank you again, so much, Dr. Srivastava, for joining us. Thank you for having me. This was great. All right, and as always, study hard. Narrator - Dr. Abel 46:25 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 46:36 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.