About two years ago, we released a podcast with Dr. Thomas Wadden of the University of Pennsylvania describing work on a new generation of medications to treat diabetes and obesity. They were really taking the field by storm. Since then, much more is known since many additional studies have been published and so many people have been using the drugs. So many, in fact, the market value of the Danish company, Novo Nordisk, one of the two major companies selling the drugs, has gone up. It is now greater than the entire budget of the country of Denmark. This single company is responsible for about half of Denmark's economic expansion this year. So, a lot of people are now taking the drugs and this is a great time for an update on the drugs. And we're fortunate to have two of the world's leading experts join us: Dr. Wadden, Professor of Psychology and Psychiatry at the University of Pennsylvania School of Medicine and the inaugural Albert J. Stunkard Professor of Psychiatry at Penn. Joining us as well as Dr. Robert Kushner, a physician and professor of medicine at Northwestern University and a pioneer in testing treatments for obesity.

Interview Summary

Tom, you and I were colleagues at Penn decades ago. And I got frustrated the treatments for obesity didn't work very well. People tended to regain the weight. And I turned my attention to prevention and policy. But you hung in there and I admired you for that patience and persistence. And Bob, the same for you. You worked on this tenacious problem for many years. But for both of you, your patience has been rewarded with what seems to me to be a seismic shift in the way obesity and diabetes can be treated. Tom, I'll begin with you. Is this as big of a deal as it seems to me?

Well, I think it is as big of a deal as it seems to you. These medications have had a huge impact on improving the treatment of type 2 diabetes, but particularly the management of obesity. With older medications, patients lost about 7 percent of their starting weight. If you weighed 200 pounds, you'd lose about 15 pounds. That was also true of our best diet and exercise programs. You would lose about 7 percent on those programs with rigorous effort. But with the new medications, patients are now losing about 15 to 20 percent of their starting body weight at approximately one year. And that's a 30-to-40-pound loss for a person who started at 200 pounds. And with these larger weight losses, we get larger improvements in health in terms of complications of obesity. So, to quote a good friend of mine, Bob Kushner, these medications have been a real game changer.

Thanks for putting that in perspective. I mean, we're talking about not just little incremental changes in what treatments can produce, which is what we've seen for years. But just orders of magnitude of change, which is really nice to see. So, Bob what are these medications that we're talking about? What are the names of the drugs and how do they work?

Well, Kelly, this transformation of obesity really came about by finding the target that is really highly effective for obesity. It's called the gut brain axis. And when it comes to the gut it's starting off with a naturally occurring gut hormone called GLP 1. I think everyone in the country's heard of GLP 1. It's released after we eat, and it helps the pancreas produce insulin, slows the stomach release of food, and reduces appetite. And that's where the obesity story comes in. So pharmaceutical companies have taken this hormone and synthesized it, something similar to GLP 1. It mimics the action of GLP 1. So, you could actually take it and give it back and have it injected so it augments or highlights this hormonal effect. Now, that same process of mimicking a hormone is used for another gut hormone called GIP that also reduces appetite. These two hormones are the backbone of the currently available medication.

There's two on the market. One is called Semaglutide. That's a GLP 1 analog. Trade name is Wegovy. Now, it's also marketed for diabetes. Tom talked about how it is used for diabetes and increases insulin. That trade name is Ozempic. That's also familiar with everyone around the country. The other one that combined GLP 1 and GIP, these two gut hormones, so it's a dual agonist, the trade name for obesity is called Zep Bound, and the same compound for diabetes is called Mounjaro. These are terms that are becoming familiar, I think, to everyone in the country.

Tom mentioned some about the, how much weight people lose on these drugs, but what sort of medical changes occur?

Just to reiterate what Tom said, I'll say it in another way. For Semaglutide one third of individuals are losing 20 percent of their body weight in these trials. For Tirzepatide, it even outpaces that. And I got a third of individuals losing a quarter of their body weight. These are unheard of weight losses.

And with these weight losses and these independent effects from weight, what we're seeing in the trials and in the clinic is that blood pressure goes down, blood sugar goes down, blood fats like triglyceride go down, inflammation in the body goes down, because we marked that with CRP, as well as improvement in quality of life, which we'll probably get to.

But really interesting stuff is coming out over the past year or two or so, that it is improving the function of people living with congestive heart failure, a particular form called a preserved ejection fraction. We're seeing improvements in sleep apnea. Think of all the people who are on these CPAP machines every night. We're seeing significant improvements in the symptoms of sleep apnea and the apneic events. And lastly, a SELECT trial came out, that's what it was called, came out last year. Which for the very first time, Kelly, found improvements in cardiovascular disease, like having a heart attack, stroke, or dying of cardiovascular disease in people living with obesity and already have cardiovascular disease. That's called secondary prevention. That, Tom, is the game changer.

Bob, I'd like to go back to Tom in a minute but let me ask you one clarifying question about what you just said. That's a remarkable array of biological medical benefits from these drugs. Just incredible. And the question is, are they all attributable to the weight loss or is there something else going on? Like if somebody lost equal amounts of weight by some other means, would these same changes be occurring?

Those studies are still going on. It's very good. We're thinking it's a dual effect. It's the profound amount of weight loss, as Tom said. Fifteen to 21 to even 25 percent of average body weight. That is driving a lot of the benefits. But there also appear to be additional effects or weight independent effects that are working outside of that weight. We're seeing improvements in kidney function, improvement in heart disease, blood clotting, inflammation. And those are likely due to the gut hormone effect independent of the weight itself. That still needs to be sorted out. That's called a mitigation analysis where we try to separate out the effects of these drugs. And that work is still underway.

Tom, one of the most vexing problems, over the decades that people have been working on treatments for obesity, has been long term results. And I'm curious about how long have people been followed on these drugs now? What are the results? And what was the picture before then? How do what we see now compared to what you saw before?

The study that Bob just mentioned, the SELECT trial followed people for four years on Semaglutide. And patients achieve their maximal weight loss at about one year and they lost 10 percent of their weight. And when they were followed up at four years still on treatment, they still maintained a 10 percent weight loss. That 10 percent is smaller than in most of the trials, where it was a 15 percent loss. But Dr. Tim Garvey showed that his patients in a smaller trial lost about 15 percent at one year and while still on medication kept off the full 15 percent.

I think part of the reason the weight loss in SELECT were smaller is because the study enrolled a lot of men. Men are losing less weight on this medication than women. But to your question about how these results compare to the results of earlier treatment, well with behavioral treatment, diet, and exercise back in the 70s beyond, people lost this 7 or 8 percent of weight. And then most people on average regain their weight over one to three years. And the same was true of medication. People often stopped these earlier medications after 6 to 12 months, in part because they're frustrated the losses weren't larger. Some people were also worried about the side effects. But the long and short is once you stop taking the medication, people would tend to regain their weight.

And some of this weight regain may be attributable to people returning to their prior eating and activity habits. But one of the things we've learned over the past 20 years is that part of the weight regain seems to be attributable to changes in the body's metabolism. And you know that when you lose weight, you're resting metabolic rate, which is the number of calories your body burns at rest to maintain basic bodily functions. Your resting metabolic rate decreases by 10 to 15 percent. But also, your energy expenditure, the calories you burn during exercise decreases. And that may decrease by as much as 20 to 30 percent. So, people are left having to really watch their calories very carefully because of their lower calorie requirements in order to keep off their lost body weight....