E164: Highly Successful Weight Loss Drug Semaglutide Explained

Tuesday, May 3, 2022
Related to: Addiction & Food | Obesity | Weight Stigma |

Much attention has been paid recently in both scientific circles and in the media to a drug for weight loss newly approved by the FDA. A flurry of articles in the media hailed this drug as a breakthrough. This was prompted by the publication of a landmark article in the New England Journal of Medicine addressing the impact of this medication in a large clinical trial. Today’s guest is one of the authors of that paper. Another flurry of media attention occurred as the drug became available, with news that supply couldn’t keep up with demand. Dr. Thomas Wadden is the Albert J. Stunkard Professor and former Director of the Center for Weight and Eating Disorders at the University of Pennsylvania School of Medicine. He is one of the most highly regarded experts on treatments for obesity, having done some of the most important research on very low-calorie diets, a variety of medications, bariatric surgery, intervention in primary care settings, and more.


Interview Summary

You and I grew up together in this profession, having spent some early years together working on treatments for obesity. You’re one of the people in the field I admire most, both for the quality of your work and the breadth of your knowledge across various treatments for obesity. So let me begin by asking something regarding our former mentor, Albert Stunkard. So one of the most famous quotes of all time in our field came from Mickey Stunkard in 1959, no less, way before the field was really paying attention to obesity. He wrote that “most obese persons will not stay in treatment. Most will not lose weight. And of those who do lose weight most will regain it.” There was a stark honesty to this, and it motivated Stunkard to help overweight people. So if we fast forward to today, do you think this is essentially still true?

Well, first, let me say that Dr. Stunkard’s statement sounds somewhat critical. Today, we might say stigmatizing people with obesity. You know, they won’t stay in treatment, they won’t lose weight, they’ll regain it. And Stunkard, as you know perhaps better than anybody, was an extremely compassionate, empathic person. To clarify that, he knew that the limitations to success were with the treatments available and not with the people who had obesity. So to answer your question, the first two parts of Stunkard’s statement that people won’t stay in treatment and people won’t lose weight were probably no longer true by the early to mid-1980s. And pioneers like yourself showed that if you gave people a structured program of diet and physical activity, and most importantly, if you gave them behavioral strategies to improve their treatment adherence, then 80% of people would stay in treatment for 16 to 26 weeks. They’d lose an average of 6% to 10% of their weight. So what remained, however, and remains today, was that people have trouble maintaining the weight loss. And that’s something that still challenges us.

Well, it’s nice to start on that optimistic note with the hope that people will go into treatment. Let’s talk about the drug. So what is the new drug, and how does it work?

Well, the new drug is called semaglutide. It comes in a dose of 2.4 milligrams and is injected subcutaneously once per week. The drug at the retail level is known as Wegovy. Some people will know about semaglutide for the management of type 2 diabetes. It is used at a dose of 1.0 milligrams and it’s called Ozempic. So Ozempic was approved first many years ago. Now, semaglutide is a glucagon-like peptide 1 receptor agonist, and that’s a mouthful. But glucagon-like peptide 1, GLP-1 for short, is a naturally occurring hormone that is released by the body when food, particularly carbohydrates, hits the stomach. GPL-1 is released by cells in the small intestine, and it does several important things. First, it signals the pancreas to release insulin to pick up the glucose that’s coming in. And then it also slows gastric emptying, which as you know, leads to greater feelings of fullness. And then finally, these GLP-1 receptor agonists are hitting a part of the hypothalamus that stimulates fullness or what’s known as satiation receptors, so people feel full earlier when they’re eating and don’t eat as much food. I think you may remember, Kelly, that naturally occurring GLP-1 has a very short life when it’s released. It’s active for about two to three minutes, so you have a temporary feeling of fullness. But these new drugs, semaglutide 2.4 milligrams, have a seven-day half-life. So people are feeling greater fullness and less hunger sort of around the clock, and as a result, they are just eating less. And to use your terms, they are less responsive to all the cues in the toxic food environment that are saying come on, it’s time to eat more. It’s time to have a large serving of ice cream or sugar-sweetened beverages, whatever it is. People don’t seem to be as vulnerable to the toxic food environment.

I really appreciate that you’ve taken a pretty complex subject, namely the physiology of this drug, and made it come alive in terms that most of us can understand. So thanks for that. So before you talk about the weight losses that the drug produces, you mentioned that some treatments are producing weight loss of 5-6% of body weight. Can you place that in context for us? I mean, is that enough to produce medical benefits? Are the people losing weight happy with that degree of weight loss?

Sure, most individuals who go through a behavioral treatment program will lose about 7% to 8% of their weight on average. And those weight losses are associated with significant improvements in health. The landmark study in this area is the Diabetes Prevention Program published in 2002. People with pre-diabetes lost seven kilograms, about 7% of their weight, and they exercised 150 minutes per week. And those individuals with pre-diabetes reduced their risk of developing diabetes over 2.8 years by 58% compared to the control group. So that’s a really important finding that modest weight loss, and modest physical activity prevents the development of type 2 diabetes. And weight loss is also going to improve blood pressure, and it can improve sleep apnea, so modest weight losses have benefits. But two things. First, larger weight losses have greater improvements in health. That’s important to know. It’s in a linear relationship there. The more you lose usually, the better the health improvements. And two, most people seeking to lose weight want to lose about 20% of their body weight. So if you’re a 200-pound female, a 250-pound male, you want to lose 40 to 50 pounds, respectively. And so, larger weight losses are highly desired.

So how do you deal with that psychologically when somebody’s goal is far beyond what treatment typically produces? Can people come around to the fact that the smaller weight losses are really good for me, and I’ve accomplished a lot even though I may not get to my goal?

Well, I always tell people, I know you want to lose 40 pounds. So let’s start with the first 15 to 20. Let’s focus on that because you have to go through 15 to 20 to get to 40, and let’s see how you feel after you’ve lost the initial weight. And I can’t promise you you’re going to get to 40 pounds for potential genetic or biological reasons, but let’s try to achieve what we can achieve and focus on larger weight loss. And many people are more satisfied than they’d imagined with a more modest or moderate weight loss, even though the dream is to lose more than that.

Okay, so back to the drug then. This big clinical trial you were involved with, published in the New England Journal of Medicine, can you quickly explain the trial and tell us what you found?

There were four big clinical trials of this medication that were presented to FDA for approval, but the seminal paper published in New England Journal treated about 1,961 participants. And everybody got lifestyle modification every month with a dietician for 15 to 20-minute visits. And then on top of that, half the participants got assigned semaglutide 2.4 milligrams, and the other half got a placebo. And they were followed for 16 months. And the reason it’s a 16-month trial is that you have to introduce the drug slowly over four months to control gastrointestinal side effects. So as you start to take this drug, you’re likely to experience a little bit of nausea. About 45% to 50% of people do so. So some patients, about 20%, will experience vomiting. Constipation and diarrhea also occur in response to the drug. So if you slowly introduce the drug, you can prevent some of those symptoms. And so it’s not till four months that you’re on the full dose of the drug, and that’s why they run the trial for 16 months, so people have been on the drug for one year. And so what happens at the end of these 16 months is that the participants who get lifestyle light with placebo lose 2 1/2 percent of their weight. That’s about what we’d expect. Those who get semaglutide, lose 15% of their body weight. So a remarkably robust weight loss. And when you break it down a little bit further, what happens is that 69% of the people on semaglutide are losing 10% or more of their weight. And then 50% are losing 15% or more of their weight. So that’s a substantial loss. And this is something that I’d never seen in this kind of a trial. One-third have lost 20% of their body weight. And those weight losses are cumulative. So the 69% who lost 10% of their weight include the people who lost the 15% and 20% of their weight. But as you well know, those are substantial losses where the average loss is 15%, and that’s achieved by 50% of the people. That is double what we get with our best behavioral treatment, and it’s about double what you get with most weight loss drugs.

Yeah, that’s pretty darn impressive to double the impact. I mean, most people will be excited with a a little bit of improvement. That’s a lot of improvement. So certainly, we have to take note based on that. When you talked about the side effects, you were talking about the fairly immediate side effects of beginning to take the drug. And then it takes four months for people to get up to the full dose. Are there side effects that exist beyond those four months?

Well, most people will be through those gastrointestinal side effects within the four months. But, if you go out to 16 months, there will be a small percentage of people who have nausea, diarrhea, et cetera, throughout the trial. And you try to help those people with their side effects by doing things like chewing their food more thoroughly, eating smaller meals but more of them, and drinking more water. All of that can help them control their nausea if it’s persistent. I think that the most serious side effect, Kelly, is that about 4% of people will develop gallstones or need to have a gallbladder removed. That is just a consequence of the large weight loss. Anytime you have large weight loss, whether it’s from a very low calorie diet, from bariatric surgery, or these medications, you will find that a small percentage of people have gallstones and will need attention.

And what about the fact that people need to get this by injection? Are people able to do that okay, or is that a deterrent for people using it on a broad scale?

It’s an excellent question. I can tell you that I have injected myself on several occasions just to see what it’s like. You find a fat fold in the stomach and inject yourself. The needle is so small that you can’t feel it. So once people try it, there’s really very little hesitancy. I think certainly some people would think, “I don’t want to be injecting myself with this thing,” They may not even come in, but once you try it, there’s no problem. And right now, there is an oral version of Ozempic. It’s called Rybelsus. So it’s the same medication for type 2 diabetes but in oral form rather than sub-q injection. And a trial is currently underway to see if we can make an oral version of semaglutide injectable drug, and I think that’s going to prove acceptable. So that barrier should be eliminated over time.

So what happens if people stop taking the drug?

I think you know the answer. People who stop taking the medication are vulnerable to regaining their weight. And some people would say, well, that illustrates the drugs a failure because you take it and you lose weight, and you regain it, and you’re no better off. But I am on a medication for high blood pressure and on a medication for high cholesterol. I can assure you that if I stop taking those medications, my cholesterol and blood pressure would go up. So this speaks to a very important issue which we have to look at obesity is probably a majority of persons as being a chronic health condition for which they’re going to need long-term ongoing care and you would need to take these medications indefinitely just like I take my hypertensive or cholesterol medication indefinitely.

You know, the description of the cholesterol and blood pressure drugs is a great example. And I think this really speaks to the issue of obesity stigma, doesn’t it? Because if you have these blood pressure, cholesterol drugs, and lots of others, if people are taking them and they’re effective and then they stop taking them and then the medical condition comes back, it’s even more evidence that a drug works. But in the case of some of these obesity drugs, people say, well, if you stop taking it and you regain the weight, it’s proof the drug doesn’t work. So how do you think that might be bound up with kind of general social attitudes about people with obesity?

It’s such an important point. So persons with obesity are still stigmatized, as you, Rebecca Puhl, and many people have shown. And there’s just so much unrelenting stigmatization of people saying, you know you should be able to control your weight by exercising more, cutting down on what you eat, push back from the table. You see, it’s your problem, your shortcomings in self-control. So people with obesity are stigmatized. Similarly, obesity medications are stigmatized. Anytime I give a talk to physicians, I’ll ask how many would consider prescribing an obesity medication? And only about 10% of hands go up at most. Then I’ll ask, would you prescribe a drug for hypertension or cholesterol? Everybody’s hand goes up, and I say, what’s the difference here? And people invariably say, well, people should be able to control their eating and exercise with their willpower. And I say, well, it’s an illness, it’s a disease partly caused by this toxic food environment, so why are you treating that differently? You allow diabetes medications. That’s caused by eating behavior to some extent. So I think you’re correct. There’s this profound stigmatization of people with obesity and of the medications. And I think that view is beginning to change. One of the most important things about this new medication semaglutide, and there’ll be a new drug from Eli Lilly called tirzepatide, is that doctors, endocrinologists, and primary care physicians, are comfortable with these glucagon-like receptors because these are diabetes drugs that they prescribe. They’re willing to prescribe that long-term. Now they may be willing to recognize obesity disease, which requires long-term treatment. They feel comfortable with the drug and that it’s not going to have adverse side effects. So I hope this is a turning point in stigmatizing persons with obesity and obesity drugs.

Tom, how much does the drug cost, and is it covered by insurance? And what about people on Medicare and Medicaid?

This medication, if you go to your pharmacy and ask for it, I think is currently priced at about $1,300 per month. And so that is a very high barrier to the vast majority of people who would want to take this drug. It’s possible, and I hope that the price will come down, but I haven’t seen any indication of that. Some insurers and some employers cover the medication so that some people will benefit from it. But I think, as you know, Medicare and Medicaid do not cover any obesity medications at this time. There’s a very important piece of legislation in the Senate and in the House called the Treat and Reduce Obesity Act, and part of that bill is to get Medicare to cover obesity medication. So even though they’ve got a terrific new medication, most people who would benefit from it, and particularly people of color who have higher rates of obesity, minority members, will have a very difficult time getting this drug to use it appropriately.

You mentioned that Eli Lilly may be coming out soon with a competitor drug. Do you think the competition will reduce the cost?

I would hope it would reduce the cost, but I can’t say that I have any advanced knowledge of that or any assurance that that will happen. Eli Lilly has put a lot of money into producing their medication. Their medication tirzepatide looks like it will be as effective as semaglutide if not more effective by two or three percentage points. So I think probably the best bet for having a cost reduction is that another medication very similar in its mechanisms of action to semaglutide, it’s called liraglutide 3.0 for obesity. It is a GLP-1 receptor agonist, it’s just not as effective, it produces an 8% weight loss, it’s going off patent, I believe in 2023 or ’24 and when it goes off patent, I think that there will be generics to at least make that drug available at a very reasonable cost. I believe that that drug currently is at about $600 to $700 per month, but it should come down dramatically when it goes off-patent, and there are generics.

And for people who have health insurance, are insurers covering the drug?

A smattering of people are covering the drug. I don’t think there’s universal coverage. If you’re under Blue Cross Blue Shield or whatever your company may be, remarkably, the University of Pennsylvania is covering some of these medications, which I’m delighted to see. But you would have to check your insurance plan carefully. For people who do have coverage, there are coupons to get your costs down to as little as $25 a week. So it’s really worth looking into. And I know that Novo Nordisk, which manufactures semaglutide, is trying to work with insurers to get more to pick up the coverage of the drug. Let’s hope that they reach some insight that’d be important to reduce the cost of this drug to make it more available to people who really need it.

Let me ask a big picture question to end our conversation. So where does this drug fit in the broad scheme of various options for treatments for obesity and how would someone or their physician know if this medication would be a good option to pursue?

Sure, if we follow just the FDA guidance and the guidance of expert panels, this drug is appropriate for people who have a body mass index of 30. So you can go, and your doctor will measure your weight, calculate your height, and tell you what your BMI is. So at a BMI of 30, you’re eligible for this drug if you’ve tried diet and exercise, which just about everybody will have, and you haven’t been successful with that alone. I think that the drug is most appropriate for people with a body mass index of 30 or greater who have significant health complications, meaning they have type 2 diabetes or hypertension, or sleep apnea. If the drug’s going to be limited in availability because of it’s cost, I would try to get it to the people who have the most benefit in terms of improving their health. That’s the primary reason to seek weight reduction, I think. Technically, to address your question, the drug’s available to people with a body mass index of 27 who have a comorbid condition such as hypertension or type 2 diabetes. And if you’ve got a BMI of 30, you would like to get this drug to people who have the highest BMIs and have the greatest benefit to health. Those individuals with higher BMIs at 35 who have a comorbid condition are eligible for bariatric surgery, which is the most effective obesity treatment. If you look at the most popular surgical treatment right now, it’s called sleeve gastrectomy, where you remove 75% of the stomach so you can’t eat as much food, and it does have improvements in appetite-related hormones such as ghrelin, the hunger hormone. That is dramatically suppressed by the operation so people are less hungry, have less desire to eat. And so that operation produces about a 25% reduction in body weight in one year. And at three to five years, people still have 20% off. So a person who’s got a BMI of 35 or more with a comorbid condition such as type 2 diabetes wants to talk with his or her physician and see if they might benefit from bariatric surgery. If the doctor and patient don’t think that’s the option, you would like to consider an obesity medication to help you just control your feelings of appetite, hunger, and satiation, to make it easier to eat a lower calorie diet, to make it easier to want to get out there in physical activity. So that is the big picture of the options: Diet and physical activity for people who have overweight and obesity without health conditions. And then you add medications for people at a BMI of 27, 30, or greater who have health complications. And then you add bariatric surgery when medications don’t work.

Thomas A. Wadden, Ph.D. is Professor of Psychology in Psychiatry at the Perelman School of Medicine at the University of Pennsylvania. He served as director of the Center for Weight and Eating Disorders from 1993 to 2017 and was appointed in 2011 (through 2021) as the inaugural Albert J. Stunkard Professor in Psychiatry. He received his A.B. in 1975 from Brown University and his doctorate in clinical psychology in 1981 from the University of North Carolina at Chapel Hill. Wadden’s principal research is on the treatment of obesity by methods that have included lifestyle modification, very-low-calorie diets, physical activity, medication, and surgery. He has also investigated the metabolic and psychosocial consequences of obesity and of intentional weight loss, the latter as represented by findings from the 16-year long Look AHEAD study. He has published over 500 scientific papers and book chapters and has co-edited seven books, the most recent of which is the Handbook of Obesity Treatment (with George A. Bray). His research has been supported for more than 35 years by grants from the National Institutes of Health.


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