Dr. Manish Shah (Host): Welcome to Weill Cornell Medicine CancerCast: Conversations about new Developments in Medicine, Cancer Care, and Research. I'm your host, Dr. Manish Shah. And today, we'll be talking about GLP-1 weight loss medications and cancer.

There has been a lot of buzz lately about GLP-1 weight loss medications, and this class of drugs may be one of the most noteworthy medical breakthroughs of the decade, or even the century.

Maintaining a healthy weight is an important part of overall wellness. There is a lot of ongoing research related to the link between weight and cancer, and many people have questions about what this means in the context of cancer care and prevention, as well as treatment and outcomes.

Our guest on CancerCast today is Dr. Louis Aronne. Dr. Aronne is Director of the Comprehensive Weight Control Center and the Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine. He is a leading authority on obesity and metabolism, and has been heavily involved in weight loss and obesity research, including the FDA approvals of many of the weight loss medications that have recently become available.

Dr. Aronne has been an investigator on numerous studies for various obesity treatment modalities, including a wide range of injectable and oral medications, devices and diets. Dr. Aronne's research has been instrumental in developing successful strategies for long-term weight management.

I can't wait to get started. Dr. Aronne, thank you for joining us today.

Dr. Louis Aronne: Thank you very much, Dr. Shah. I appreciate you having me on.

Dr. Manish Shah: So, let's start with the basics. What is a GLP-1 agonist and how does it work?

Dr. Louis Aronne: GLP-1, glucagon-like peptide, is a hormone that was discovered in the early 1980s. And it took a while, but after a few years, it became clear that it was part of the fullness mechanism. In other words, if you give GLP-1 to an animal or a human, it reduces their food intake.

So, it's clear that it's part of the satiety mechanism. There are, however, multiple other hormones that are also involved. Ones like GIP, which is a glucose-dependent insulinotropic peptide, and many, many others.

The thing that's so interesting about GLP-1 is that it has produced such terrific weight loss. It's something that initially didn't look like it was going to be that helpful. But now, it has really come through to produce the kind of weight losses that we've been looking for, for many years.

Dr. Manish Shah: So, for our audience, essentially, these drugs make it easier for insulin to be used by the body. Is that right?

Dr. Louis Aronne: So, they do several things. They stimulate the release of insulin by the pancreas. But by reducing appetite and reducing food intake and causing weight loss, they improve sensitivity to the hormone insulin, and that's for the pure GLP-1 receptor agonists or “stimulators”. So, an agonist means that it stimulates a particular receptor.

So, semaglutide, is Ozempic or Wegovy. And now, there's an oral form, oral Wegovy. Another medicine that is currently available is tirzepatide, which is Mounjaro or Zepbound. That's only available as an injectable. And that's a combination of two effects. One is GLP-1, the other is GIP. That has a slightly different mechanism of action. Where semaglutide is a very potent GLP-1, tirzepatide is a weak GLP-1, but a very potent GIP agonist. Now, that's a little bit different. It does more to improve insulin sensitivity, maybe a little bit less in stimulating insulin release.

Dr. Manish Shah: And these drugs, they're developed from a natural occurring protein called glucagon. And glucagon is part of the whole process with regard to how the body regulates blood sugar and insulin. And GLP-1 is a peptide, a small portion of this entire protein glucagon. So, this is an important thing for our listeners to understand, these drugs, they're mimicking drugs that exist in our body. Is that correct?

Dr. Louis Aronne: These medicines mimic naturally occurring hormones that are produced in the intestine and tell your brain how much you've eaten and do various things to help store calories. And one of the key things is figuring out how much of which effect you need.

So, glucagon, for example, which is the base peptide from which these are derived. So, most of these hormones are pieces of the glucagon molecule. And one end, you have GIP. The other end,  GLP-1. And these reduce appetite and reduce blood sugar. Glucagon, on the other hand, while it reduces appetite, can increase blood sugar. So, it's a very complex balance of effect, all derived from one molecule, and part of the magic of making these things has been figuring out how to make them longer acting.

Because in your body, you make them, but they last a very short period of time, just a few minutes. So again, it does mimic a naturally occurring hormone. All these mimic them, and they're mimicking them in combination. Now, they're far more potent, far longer acting. That's part of what makes them so effective.

Dr. Manish Shah: Thank you for highlighting the complexity of this. So, we've known for decades that insulin regulation and the ability for a cancer cell to coopt some of these pathways to grow has been very important in cancer. And now, we have these drugs, semaglutide, tirzepatide, and some of the newer ones that actually have very potent effects on this pathway. So, I guess it's kind of natural to think that they may have cancer properties.

Dr. Louis Aronne: It's been pretty clear for probably 30 years that cancer and obesity overlap. Back in the old days, when I started in the 1980s, it was believed that fat cells were just a passive vessel for storing triglyceride, for fat. That was it. They didn't do anything. It wasn't until the mid-1990s that it became clear that fat cells produce all kinds of hormones, dozens of hormones, and these are critical for the normal functioning of your body. To maintain your blood pressure, for example, to maintain your blood sugar, being stable.

But when these hormones are present in excess, that's when the diseases that we associate with obesity occur. So, chronic inflammation is associated with an increase in body weight. We see inflammatory markers are higher. It's because fat cells produce multiple pro-inflammatory hormones.

The thing that is so powerful about obesity as a cancer-causing entity is that multiple hormones that can affect the growth of tumors are released by fat cells.

So, let's look at breast cancer as an example. You get higher estrogen levels when you expand fat mass. You get higher insulin levels. And you get higher levels of pro-inflammatory hormones, PAI-1 and others, TNF-alpha. You have inflammation, high hormone levels, and high levels of growth factors like insulin, and maybe it doesn't cause the cancer, but it promotes the growth of the cancer.

And that's why we believed for a long time that getting people to lose weight would be associated with a reduced risk. And there are studies that have nothing to do with these drugs showing that lower body weights seem to reduce the risk of cancer, metastases, other factors relating to the outcomes of cancer treatment.

Dr. Manish Shah: On the podcast, we've mentioned in the past that inflammation is a common cause of many different cancers. An inflammatory state, for example, if you have chronic hepatitis, you're going to be at higher risk of getting liver cancer. If you have inflammatory bowel disease like Crohn's or ulcerative colitis, this is a chronic inflammation of the colon, you're at a little bit higher risk of getting colon cancer.

But the concept is that just having obesity is associated with a more inflammatory state, and that leads to a slightly increased risk of multiple different cancers. That's really remarkable. Is there a difference in where the obesity is and what the risk of inflammation and cancer is?

Dr. Louis Aronne: It turns out that fat inside the abdomen is probably the worst fat to have. Visceral fat or intraabdominal fat is in the circulation of the liver. It's metabolically more active, as opposed to fat that's under the skin.

And so, fat that's inside the abdomen seems to be fat that's associated with greater levels of inflammation, resistance to insulin, and all of the bad things that occur.

Interestingly, fat on the hips and thighs in some studies looks like it's a negative prognostic factor, meaning that better outcomes are associated with having fat on the hips and thighs. Maybe because it's a very deep store for fat that metabolically doesn't do much, but it gives you an energy source if you need it.

Dr. Manish Shah: So really, the location of where the fat is makes a difference. This concept of metabolic dysfunction, there is a formal definition of this. It involves things like elevated waist circumference, and I guess that's what you're getting at, where if the fat is stored in the waist, your waist circumference would be a little bit larger, and that would be one of the parameters, in addition to an elevated blood sugar, triglycerides, blood pressure, and things like that.

But ultimately, these are all surrogates of an idea that says that you have fat that's in a bad location, associated with worse inflammation, and associated potentially with a higher risk of cancer.

And getting back to GLP-1, one of the factors you mentioned, it does more than regulate insulin. It also delays gastric emptying. It also alters the way that fat metabolism occurs. Can you speak to that a little bit?

Dr. Louis Aronne: So, that's not quite as clear. But the important point is that there are multiple effects. So, while the stimulation of the pancreas to produce insulin is certainly important, the overall treatment with these medicines reduces insulin levels.

A lot of people think, "Oh, you're stimulating insulin. Insulin has been associated with cancer, then how could these reduce cancer?"

It's because the overall net effect is that the weight loss is great enough to improve insulin sensitivity so that even though you are stimulating insulin release, the overall effect is a significant reduction in serum insulin levels.

Dr. Manish Shah: So, the insulin that is being released is more effective essentially.

Dr. Louis Aronne: That's correct. And so, you need less insulin overall. The improvement in insulin sensitivity is greater than the amount of insulin that's produced. So, the net is whenever you use these, insulin levels go down.

Dr. Manish Shah: So, that's why they're called insulotropics. They work like insulin. But they make insulin more effective.

Dr. Louis Aronne: Yes. So, saying that it's insulinotropic means that it makes insulin. But again, the net effect is to reduce the level of insulin. So, you would expect that something that's an insulin sensitizer or something that works this way should not only treat diabetes, but also prevent it.

And what we've seen in trials over a three to four-year time period in people with pre-diabetes is that semaglutide reduces the risk of developing type 2 diabetes by about 75%, and tirzepatide reduced it about 92%.

Dr. Manish Shah: Oh, that's incredible. We used to think that if you were pre-diabetic, unless you made drastic changes, you were certainly going to get diabetes. But here, you have a medicine that could reverse that.

Dr. Louis Aronne: That's right. Just imagine, I speak all the time at the Diabetes Association, and this is something that the Diabetes Association has thought about for a long time, a world without diabetes. Well, here we are. We could reduce the risk of developing diabetes by 90%. That's unbelievable. If we got people early enough in the development of diabetes, maybe it would be 100%.

So, type 1 diabetes is different. We're not talking about that. But type 2 diabetes, which has increased dramatically over the years as a result of the epidemic of obesity, is almost completely preventable.

Dr. Manish Shah: Wow, what an exciting time. So, you mentioned some of the trials that show the benefits of this class of drugs. They all started with improving blood sugar control and reducing the hemoglobin A1c. But then, over the last few years, they've shown other benefits like cardiovascular benefits and benefits on kidney function and things like that. Do you want to walk us through that?

Dr. Louis Aronne: So initially, the first GLP-1, which was called exenatide, was twice daily, and it was approved in 2005. And it helped to control blood sugar and did not produce weight gain. It was the first treatment that didn't really produce weight gain.

And weight gain, since the discovery of insulin, has been associated with treatment of type 2 diabetes. The more insulin you give, the more weight people gain, the more insulin you have to give, and it becomes a vicious cycle.

But exenatide was really novel. One of the problems, however, was it was twice daily. It caused significant amount of nausea. We tried to treat people for obesity with it at that time, and you would get nausea before you could get people to lose much weight. So, the efficacy was kind of limited.

Over the next few years, once-a-day version came out, once-a-week versions came out, but they were all somewhat limited in their impact on body weight.

It was the discovery of semaglutide, Ozempic or Wegovy, which really was the breakthrough that people had hoped for. And that had unprecedented weight loss impact. So the drug that semaglutide was derived from, which was called Victoza, produced 5%, 6%, 7% weight loss. Semaglutide produced 16% weight loss. Really striking. In people with diabetes, it produced less weight loss, 11%. But this was something we had never seen before.

So, when it was approved for the treatment of diabetes, people started using it to treat weight problems right away. So, that's why Ozempic, which was the first version, became very popular. Following that, Wegovy became available. That was the weight loss version. Somewhat higher doses were available. It was very clearly a completely different ballgame when we were using Ozempic and then Wegovy.

Following that, tirzepatide became available, and interestingly, it first became available a few years after semaglutide, but the weight loss was on the order of 20%. Really unprecedented. Something that we've dreamed of because it's in the ballpark of bariatric surgery. And so, we were able to see things that we never saw before.

One of the things we've now recognized is that many of the complications that we associate with obesity can be managed if you get 15% or more weight loss. With 5% or less, you can lower blood sugar, you can lower blood pressure. You get up to 10%, a number of other things improve. You get up to 15%, more things get better.

Once you get past 15% and 20%, you're seeing everything improve. And that's really the power of treating obesity, is that all of these things improve. You're not just improving someone's blood pressure. You're not just improving their blood sugar. You're getting everything at the same time.

And that's why obesity treatment is turning out to be such a powerful tool in improving overall health. So, we've seen now things that you were alluding to, like chronic kidney disease. You can actually reduce the risk of someone developing kidney failure. So, you take someone whose kidney function is deteriorating because they have type 2 diabetes, or now we're seeing even other kidney diseases, and you treat them with semaglutide. And what happens, for the first time, we've been able to stop the inexorable decline in kidney function to kidney failure. That is having an impact on metabolic disease management, unlike many things that we've seen. So, fewer people developing complete kidney failure, fewer people needing dialysis, and fewer people needing kidney transplants.

The same thing is true with the liver. The leading cause of the need for liver transplants and liver failure is obesity. So, we think you're going to need less treatment for that as well. We are only beginning to explore all of these different areas.

Dr Manish Shah (Host): So, the kidney disease and the cardiovascular disease, it's associated with poor blood sugar levels and diabetes. But it sounds like these medicines can help even if you're not diabetic in some instances. Like for example, the liver fibrosis and NASH, even non-diabetic people might benefit from that.

Dr. Louis Aronne: Yes. It's very clear to get benefit from these drugs, you don't need to have diabetes. And that’s where we’re seeing the biggest use, is in people without diabetes.

Dr. Manish Shah: So, it comes back to the obesity-related changes that happen in the body. If you can reverse that, you can have multiple effects and multiple benefits.

Dr. Louis Aronne: That's right. But let me say that there's something that goes beyond it, and you had alluded to this earlier. The GLP-1 mechanism seems to have a direct effect on cardiovascular disease and also cancer. So, it looks like even without tremendous weight loss, there is benefit in giving people a GLP-1, and that is a really interesting new finding.

We initially thought that all of the benefit was from weight loss, but it's clear that before much weight is lost, there is a reduction in the risk of heart attack and stroke. That's one finding.

In another finding, even people who don't lose a lot of weight seem to have a reduced risk of developing cancer. And receptors for GLP-1 have been found in a number of different places that could suppress cancer growth or tumor growth. So, we're only beginning to discover how these things work.

It's still too early to tell you that I have a randomized trial where a GLP-1 was added to chemotherapy and shown to reduce the risk of recurrence. But there have been a number of large-scale trials looking at this, showing that there's benefit.

There's a reduced risk of recurrence, metastatic disease, of progression from stage I or II to stage III or IV, in people with diabetes. Most of this has been done in people with diabetes because they've been taking these for the longest period of time.

But looking at people who are taking other medications compared to taking a GLP-1, there's pretty clearly an association with a reduced risk of metastatic disease and disease progression if you're taking a GLP-1.

Dr. Manish Shah: So, at ASCO this year, there were a couple large studies that were really observational studies that I might highlight just to piggyback on what you had said.

So, there was a study from the Penn Medicine group by McDonald, and they looked at over 100,000 women in their electronic medical record. And they were able to identify a group of women who were on a GLP-1 inhibitor. And then, they were able to follow them over years through the electronic medical record. And it turned out that women who were on a GLP-1 inhibitor had about a 30% reduction in the incidence of breast cancer compared to women that were not on a GLP-1 inhibitor.

And then, there was another study by Jones looking at leukemia diseases, a 33% reduction in AML and a significant reduction in CLL as well.

So, there are large observational cohorts that are now being reported, hundreds of thousands of people, where if you compare groups that were on a GLP-1, they seem to have a reduction in the rate of developing certain cancers. And this is exactly what you're saying.

Dr. Louis Aronne: Yes. We're still in the phase where we have observational data, but I think it's only a matter of time before the kind of trials we need to prove the relationship are going to be done.

Dr. Manish Shah: In my preparation for this, I found a study regarding bariatric surgery, and you had mentioned this as well, that the bariatric surgery population also has many of the similar benefits, including cancer reduction benefits. And I think people don't realize that. So, this is not a one-off thing. This is multiple ways if you can reduce obesity and improve your overall health, you're going to have benefits in cancer.

Dr. Louis Aronne: Yes. And many people don't realize, but for a long time, people like myself have said that getting people to lose weight will make them be healthier and live longer. But there are many people who did not agree with that. They used to talk about the obesity paradox, that people with obesity would do better in certain situations. So, maybe there is some benefit.

Why do we store fat? It's so we have nutrition readily available in case there's a nutrition catastrophe. Illnesses used to be chronic and wasting. So, tuberculosis, people used to waste away from getting a chronic infection like tuberculosis. That's what killed them, not the infection itself. Those no longer happen because we can give people nutrition. But that's what the system is built for. It's built for providing energy for inflammatory cells, to maintain your blood pressure and blood sugar, and in case of emergency, when the food runs out, you have a very compact energy store.

But now, given how readily calories are available, it's gone to the other side. We have too much inflammation. We have too much of everything, and that's causing disease.

Dr. Manish Shah: A key theme is the importance of balance. If you have too strong of an immune response, you can have autoimmunity. But the right balance, you can fight the cancer. Here, you're saying the same thing, too much of it is a bad thing. And this class of drugs is really allowing us to get back into balance.

Dr. Louis Aronne: Well, you need some fat so that you can fight off infection and kill tumor cells, but if you have too much, the inflammation can promote cancer and do all the other things that we associate with obesity.

Dr. Manish Shah: Let's talk a little bit about the side effects. So, we make sure that people understand that these drugs, they're generally well-tolerated, but they do have some side effects.

Dr. Louis Aronne: Yes. The most common are gastrointestinal side effects, as you might imagine. So, it's like you ate too much food. Nausea, vomiting, diarrhea, constipation. Those are far and away the most common.

There are rare adverse events, including loss of muscle mass. Loss of muscle mass is something that goes along with losing weight. So, we've seen this since we've gotten people to lose weight. It's just that we can get more weight loss with these medicines, and it's more widely available.

Bariatric surgery causes muscle loss. But now, we can get that kind of result in many people. The most recent data with a new medicine that hasn't been approved yet, retatrutide, showed a weight loss in people who would qualify for bariatric surgery of 30% -- 30% of their body weight -- which was about 85 pounds. That's unbelievable. So, we have succeeded in mimicking bariatric surgery weight loss without people having to have surgery.

If you're not eating very much for a long period of time, your body finds calories wherever it can. If you're not eating enough protein, then your body is using muscle as an energy source. It's actually for certain purposes may be easier for it to use muscle than it is to use fat. And so, if you don't have enough protein while you're losing weight, from any way that you're losing weight, you can wind up with muscle wasting.

When you look at body composition, we just did a study like this, where we had people lose weight, and we used a compound that stimulates muscle growth. And we saw that we could almost completely prevent the loss of muscle mass. But then, we followed people for a year after the trial was over to see what happened. And everything kind of came back to where it started, including people who were taking semaglutide in this study, whose muscle mass went down, their muscle mass came back up again, close to where it was before. But their body weight went up close to where it was before.

So, when you take these medicines away, this is another thing people should realize, the effect goes away. And they will regain weight over a period of time. So, some people think they can take this for a period of time, and then they'll learn how to eat.

It's the same as if you went to the doctor to treat your cholesterol, and he gave you a statin drug to reduce your cholesterol, your body doesn't learn how to metabolize cholesterol. Your body doesn't learn how to control your blood sugar or your blood pressure any better if you don't take the medicine. So, chronic use of these medicines for the time being is going to be necessary.

Dr. Manish Shah: Are there long-term side effects, things that we need to be worried about? How long can people take the drugs?

Dr. Louis Aronne: So, these have been around for 20 years. Right now, over 10 million people are taking a GLP-1 on a monthly basis. So, we're getting a tremendous amount of safety data from that. And I would say that long-term use is going to turn out to be quite safe. I think up to this point, we've seen it's safe, and I think it's going to continue to demonstrate that it's safe.

We already have cardiovascular outcome trials where you give people the medicine, do you have a heart attack, stroke, and die, or do you survive? And what has been seen is 20% or better reduction in the risk of not just cardiovascular death, but overall death. And this is just over a four or five-year period of time in a high-risk group of people. So, all of the evidence right now is pointing towards chronic use of these being not just acceptable and safe, but beneficial.

Dr. Manish Shah: That's incredible. And it sounds like over the next several years, the indications for this class of drugs will probably increase. So they're approved for people with diabetes, for obesity. Do you see a time where they'll be indicated in patients who have cancer or as a cancer prevention?

Dr. Louis Aronne: If you look at the other indications we now have, for arthritis of the knees and hips, these drugs can be indicated. For fatty liver disease, for obstructive sleep apnea, for chronic kidney disease, all of these are now indications because randomized trials have been performed that showed that there was clear benefit from taking them. I think the same things are going to have to be done with cancer.

When I first came into the field back in the 1980s, the idea that you were giving something that would produce weight loss to somebody with cancer, you would probably lose your medical license. The first National Institutes of Health guideline on obesity treatment that I participated in from the late 90s and early 2000s, that was the one absolute contraindication, besides pregnancy, to losing weight, was cancer.

Dr. Manish Shah: Well, I think we've really come a long, long ways. Is there an area of research that you're interested in with regard to this class of drugs that we want to highlight?

Dr. Louis Aronne: Our research has been on finding effective treatments. So, our Comprehensive Weight Control Center, which is part of the division of endocrinology here at Weill Cornell, participates in many clinical trials of the most novel agents and most effective agents that are out there because we feel we're pushing back the frontier, trying to find new things that work better and have fewer side effects.

And then, we're also doing studies where we're looking at these compounds in novel indications. So, we're looking at an oral medicine for the treatment of sleep apnea. Right now, there's an injectable for sleep apnea. We have one that looks like it's as effective as tirzepatide, the very effective injectable.

So, that's really where we are pushing back the frontiers and trying to manage people with chronic medical conditions. So, I'm very excited about the future. Right now, we're doing about seven trials. We have six research coordinators, which is an all-time high for us. And there are more and more drugs. There are probably a dozen in the near horizon that will work in different ways. Some will work in addition to what we have right now.

We're doing a study of tirzepatide, Zepbound, along with another medicine that by itself produces about 20% weight loss. So, that's 20-22% weight loss with tirzepatide and another 20%. I don't think we're going to get 40% weight loss, but we're probably going to get 32, 35, 37%. I don't know.

Dr. Manish Shah: So, it makes me think success begets success. So, congratulations on all the work that you've done.

I think a key take-home message is that obesity, particularly central obesity, is a inflammatory state that is associated with a higher risk of cancer. We have a new class of drugs, GLP-1 inhibitors, GIP inhibitors, that are phenomenal drugs associated with improvements in blood sugar control, and many other things, including cardiovascular risk. And we're now showing in large observational studies cancer reduction risk, as well. And there may be other benefits that we still need to evaluate. And I think this is just the beginning, not the end of the story. Any final thoughts before we end the podcast? This is really terrific.

Dr. Louis Aronne: I'm very optimistic about the future of research. It's not just GLP-1s. We have new mechanisms that will be as effective, but have fewer side effects, and that is very exciting, as well.

Dr. Manish Shah: Well, thank you very much. You can download, subscribe, rate, and review CancerCast on Apple Podcasts, Spotify, YouTube, or online at weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments, and topics you'd like to hear us cover in the future. That's it for CancerCast: Conversations About New Developments in Medicine, Cancer Care, and Research. I'm Dr. Manish Shah. Thanks for listening.

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