George Netto, MD (Host): Greetings from the University of Pennsylvania in Philadelphia, and welcome to a new episode of Precision Pathology Podcast. There are few pharmacologic agents that have recently grabbed the public's attention and had a wide—potentially wide—public health impact as the agents we're going to discuss today with our guest.

And I'm referring to GLP-1 receptor agonist. These a—y You've all seen the commercials agents commercially named like Ozempic like Zepbound, which their impact, of course, started with their indications for treatment of type 2 diabetes and, uh, more recent approval in the last few years for treatment of obesity.

But the wide-ranging effect, potentially positive effect on lowering cardiovascular risk, potentially even in, in addiction, alcoholism, and what, what have you, is the reason they've garnered such, such attention. We don't know as much, or we haven't discussed as much about the interplay between this class of drugs and the risk of other types of cancers. And, uh, given our interest as pathologists in pathogenesis and cancer, I thought it would be a great idea to bring one of the global experts on the field, Professor Edoardo Mannucci from Florence, to discuss his recent review on the topic that came out in Nature Reviews Clinical Oncology just recently.

The review is co-authored with his colleague, Ilaria Dicembrini and allow me for a couple of minutes to, uh, introduce, uh, Edoardo. Edoardo is a full professor of endocrinology at the University of Florence. He's the director of the sections of diabetes and metabolism at the affiliated hospital, Careggi Teaching Hospital in Florence.

He's published over 450 publications on the topic, and his research clearly focused on obesity, on diabetes, but, uh, with a more recent interest in pharmacological agents in this field. So welcome, uh, Edoardo, and I'm really grateful that you found the time to join our podcast today.

Edoardo Mannucci, MD: Thank you, George, for your invitation and your very kind presentation.

Host: Thank you. So, uh, given that many of our audience, but not exclusively, are pathologists and physicians, it would be nice to step back and first start with some background about, uh, GLP-1 receptor agonists and about the relationship between obesity, uh, and cancer

Edoardo Mannucci, MD: Okay. Well, G GLP-1 is really a peptide produced by some endocrine cells in our intestine. It is glucagon-like for its structure, but not for its biological effects because it is a glucose-lowering hormone, which is produced mainly after meals. So the normal stimulus for the secretion of GLP-1 is nutrients in the lumen of our intestines small intestines when that happens, those endocrine cells and the intestinal mucosa produce and, diffuse in the bloodstream GLP-1 that targets beta and alpha cells in the pancreas, where it stimulates insulin release and inhibits glucagon release in a glucose-dependent manner. Meaning that these effects on the secretion of insulin and glucagon are clearly evident when glucose levels are high, but they tend to disappear when glucose levels approach norm- the normal values.

And for this reason, GLP-1 was originally developed as a possible treatment for type 2 diabetes. Well, not GLP-1 per se because the human hormone has a very short half-life. It is very rapidly inactivated by a number of different peptidases. So its half-life is just a few minutes after subcutaneous injection.

So the pharmaceutical industry has developed a number of receptor agonists, often with a structure which resembles that of natural GLP-1, but with a different kinetics, so with a much longer half-life, which is compatible with clinical use. And right now what we are using is a very long-acting GLP-1 receptor agonist that usually-- are usually administered once a week, uh, subcutaneously.

And those were originally developed as drugs for type 2 diabetes, and they proved to be extremely effective for reducing hyperglycemia. They're probably the most effective drugs we have apart from insulin. They don't induce hypoglycemia because their effect is glucose dependent, so it-- the effect on insulin secretion disappears when glucose levels are normal.

So they're not capable of inducing hypoglycemia, thus so they are very easy to manage. And in addition, they have some further beneficial effects for people with type 2 diabetes, like a clear reduction of cardiovascular risk, and this has been demonstrated in a number of randomized clinical trials. So reduction in the risk of both cardiovascular, meaning coronary artery disease, and cerebrovascular disease, so reduced incidence of myocardial infarction and stroke and cardiovascular mortality as well.

And besides all these, they have also been shown to reduce body weight, which was at first quite unexpected because we thought of GLP-1 as a hormone acting on, on pancreatic islets and nowhere else basically. But later on, after, after some time after some years, we discovered that there are receptors for GLP-1 in many other cell types, including some populations of neurons in the hypothalamus that can be reached by the GLP-1 secreted by our, our intestines after meals in the postprandial phase.

And the stimulation of those central GLP-1 receptors inhibits food intake, so reduces appetite and, and inhibits, stops the meals basically. So after, after you have eaten and the nutrients have reached your intestine, there is this signal coming from your intestine going to the hypothalamus saying to your brain, "You have eaten enough.

Don't eat anything more. that's enough."

Host: The key is, is to listen to those signals and, and stop eating. Most of us have a problem, especially if you're in Italy and, uh, with all the great food that, that we have there

Edoardo Mannucci, MD: Well, in fact, GLP-1 also reduces the palatability of some food. So things that are extremely palatable that you like very much, well, they-- the amount of pleasure that you receive from eating is somewhat blunted by GLP-1, and that's one of the mechanisms for its action on food intake, which is extremely important because it was the basis for a further application of the, of those drugs in the treatment of obesity.

not all the drugs that originally developed for diabetes have also been developed for obesity because depending on their chemical structure, some of those drugs don't pass through the blood-brain barrier, and so they, they can't effectively reach the central receptors of GLP-1. But some of the drugs of the class, most notably liraglutide first and then semaglutide, are capable of going through the blood-brain barrier, and they, and they do determine a, I, I would say, quite wide weight, weight loss. there was a complete development for-- with phase III randomized trials for those drugs for the treatment of obesity. And in phase III trials, for example, semaglutide is capable of producing a weight loss of up to 15 16 17 percent of initial body weight, which is really very much.

In patients with a, a baseline body mass index around 36 or 37 they produce that kind of weight loss, which is quite substantial. And so they were approved for treatment of obesity as well. And more recently, we have also a new drug, which is a, a double agonist for the GLP-1 and GIP receptor.

GIP is another, intestinal hormone, with peripheral actions on the pancreas, which are very similar to those of GLP-1. And when administered together, I mean, when the two receptors are stimulated at the same time by the, by one double agonist, the stimulation of the GIP receptor, I would say, enhances the effects of the stimulation of the GLP-1 receptor.

So we have a greater efficacy on blood glucose on one side and type 2 diabetes, but at the same time, we have also a greater efficacy on obesity. And with this dual agonist, GLP-1/GIP agonist, the weight loss can reach up to 20 21 22 of initial body weight versus placebo, which is not very far from the effects of, uh, bariatric surgery, basically The effect-- the, the efficacy is quite close to that of a gastric bypass.

Host: Wonderful And without having to do surgery

Edoardo Mannucci, MD: Exactly

Host: So just to summarize--and I love that you

mentioned

It's glucagon-like in structure but not in effect because, uh, a lot of people get confused how is a glucagon-like hormone is, or agent is, is leading to decrease, uh, lowering glucose. So these agents act on beta cells, increased insulin, and on alpha cells, decreased glucagon. So it's exactly what you want.

And what you mentioned about the crossing the brain barrier is also pertinent because it's also pertinent potentially for why addiction, their, their, uh, potential impact on treating addiction can happen because those receptors present in the hippocampus or in the limbic system can be reached. And you mentioned the, the significant impact on lowering body weight, and many of us even before these were studies have shown the relationship of, being overweight and obesity either increasing your risk or, uh, impacting the aggressiveness of your cancer.

I know in my field in prostate cancer, for example, that's something a couple of decades ago was a topic of significant research. So can, can you, uh, give us a, an overview on—it's hard to discuss all cancers—an overview on why obi- how obesity what is the mechanism for us pathologists where obesity is really increasing the risk, of cancer?

Edoardo Mannucci, MD: I would say several cancers, not all cancers really. We think of cancer as a general category, but in fact, it is a number of different diseases. And there are at least 10 or 11 different types of malignancy that are, uh, increased in patient, in patients with obesity. Ranging from breast cancer, colonic cancer, hepatocellular carcinoma, thyroid cancer, papillary thyroid cancer, esophageal cancer, endometrial cancer, ovarian cancer, prostate cancer.

They're all increased in patients with obesity, and they show generally in epidemiologic study kind of a linear or exponential relationship with BMI, depending on the, with body mass index, depending on the, on the type of cancer. The mechanisms, well, there are probably several concurrent mechanisms in this.

There are some mechanisms that go through, for example, the management of estrogens. several of the cancers that are increased in patients with obesity are estrogen-dependent or estrogen-sensitive cancers. And when you have a, a ha-- a greater amount of, uh, adipose tissue, your aromatase activity is increased, and so you have a greater conversion of androgens into estrogens in the periphery.

And this means that you have a, a higher level, higher tonic level of estrogen, continuously. So you're exposed to, uh, relatively increased levels of estro estrogens in a continuous fashion, which is not very physiologic because i in our physiology, the stimulation with estrogens in women occurs only in certain periods of the menstrual cycles and not all throughout.

And this probably facilitates the onset of several forms of cancer. here I'm thinking of, breast cancer, of course, or endometrial cancer. But the same is true probably for colonic cancer, which is also quite estrogen-sensitive in many cases. And then we have other mechanisms that are related to the complex endocrine activity of the adipose tissue per se, that produces a number of hormones that can in turn determine, cell growth in several cell types.

And then we have the effects of insulin resistance. One of the consequences of obesity, and, I would say of increased adiposity, is that a reduction of insulin sensitivity, of total body insulin sensitivity, meaning that you need higher amount of ins-- a higher level of insulin to maintain normal glucose levels.

And the pancreas, the islets of Langerhans react to insulin resistance by producing a greater amount of insulin. So insulin-resistant patients are exposed chronically to higher levels of insulin. And insulin per se is another growth factor for, well, I would say almost all cell types in our body. all those that have insulin receptors are stimulated in their growth by an overstimulation of the insulin receptor.

And then a further mechanism is inflammation. Obesity is associated with low-grade inflammation. The-- Even the, the adipose tissue, you can say, infiltrates of mononuclear cells, inflammatory cells that produce cytokines, cytokines. And those cytokines are also secreted in the bloodstream, so you have a higher level of circulating inflammatory cytokines that can also stimulate cell growth in several different cell types.

So we have a number of different mechanisms that are probably different from one cancer to another.

And the good news in all this story is that if you treat obesity effectively and you reduce body weight, you also reduce the risk of cancer. And we have data from bariatric surgery that long-term weight loss in morbidly obese patients substantially reduces the incidence of many different malignancies.

Host: Excellent. So that's, that's also preceded these new class of, of drugs. So, uh, in general, lowering your body, the BMI, lowering your-- getting rid of obesity has a positive effect in terms of lowering your risk of cancers, as you mentioned. So, so in summary, it sounds like the obesity, uh, relation to cancer, in addition to the aromatase enzyme's effect on transforming androgen to estrogen, so that explains especially breast and, and gynecologic malignancy. It's that inflammatory effect of obesity, and we all know that chronic inflammation is a factor in general. So that milieu of, of, uh, cytokines leading to, to cell injury. And in the same time is the insulin growth factor receptor that get, because of the insulin resistance and higher insulin level, drive that IGF. And that signals, uh, which I was reading your, your amazing review, signals through MAP kinase and mTOR pathways, which we know they're important role in carcinogenesis. So with that preamble then It's obvious if these drugs lower cancer that there is some beneficial effect, potential beneficial effect.

But I know from reading your paper that we still need more and more trials. But before we talk about the beneficial, I wanted you to spend a few minutes talking about some, uh, some issues that were brought in the safety profile. Mainly we know about medullary, but if you can, uh, briefly discuss for us the relationship or lack of with papillary thyroid cancer and then pancreatitis and pancreatic cancer, which I think the answer is no, but I would like you to—because uh, we don't want to scare anyone.

We want, uh, to inform of, uh, the level of data that there is there.

Edoardo Mannucci, MD: With GLP-1 receptor agonists and with dual agonists as well, since we reduce body weight, we should expect to reduce the incidence of cancer overall for everything we have said about the benefits of weight loss. But at the same time, we have to consider that GLP-1, the hormone GLP-1, on many of its Top principal target cells is a growth factor itself.

It stimulates cell growth. If you take beta cells, for example, GLP-1 stimulates the growth of beta cells and beta cell precursors. This is irrelevant in our species, in humans, because we don't have a relevant potential for beta cell growth. Beta cells are stable cells in our species. But in other species, in rodents, for example, where there is a, a certain turnover of beta cells, uh, GLP-1 expands the population of beta cells.

They are its principal target. And the same probably occurs in other cells that are targeted by GLP-1 and GLP-1 receptor agonists. So the question is, is the effect of weight loss prevalent, and so the benefit of weight loss prevalent over the weight, uh, over the growth-stimulating effect, direct growth-stimulating effect of GLP-1 in different cell types?

Uh, so that was a question that really moved us to, to perform that kind of systematic review. you asked about pancreatic cancer and medullary cancer, medullary thyroid cancer. Well, for pancreatic cancer, there were some warnings a few years ago about a possible, possibly an increased risk of pancreatitis with, uh, GLP-1 receptor agonists, particularly at higher doses.

Those were pharmacovigilance reports that are, I mean, not truly completely reliable because with pharmacovigilance, you really see what doctors deem relevant, so the, the episodes that doctors consider relevant for report at the pharmacovigilance authority, uh, but not real, but not the real occurrence, the real...

You have no real information about the actual prevalence or incidence of the conditions you're studying.

Host: So allow me to clarify here. When you're saying pharmacological vigilance is regulatory agencies like FDA and AMA so when you're doing those trials, you're, you're over-vigilant in, in looking at the data or collecting that data. Is

that what you're

referring to

Edoardo Mannucci, MD: No

didn't come from trials. It came from post-marketing surveillance, uh, through pharmacovigilance. When you have a, a major adverse event, you should report it to pharmacovigilance As a routine. But, well, uh, I'm a clinician, so we are all clinicians, and we all know that, we report only a small fraction of the real adverse events that we observe during our routine clinical practice, okay?

You will never report diarrhea with metformin, for example, because that's obvious. And what do you report? You report something that is somewhat striking for you, but that you think could have some kind of relation with the drug you're administering. So there is a bias in reporting that is quite crucial, I would say, in pharmacovigilance records.

So we need other means of exploring this issue. Another interesting mean obviously is, uh, observational studies. That is systematic observations, retrospective observational studies on large databases that allow us to collect all the cases of pancreatitis, in this case, uh, associated with the use of GLP-1 receptor agonists.

And what we see really is that there is no actual increase in the incidence of new cases of pancreatitis, while there is probably the possibility of some kind of re-acutization of chronic pancreatitis in patients who already have a chronic pancreatitis. This is not strange because GLP-1 has a modest but, uh, perceivable effect of stimulation of exo- exocrine pancreatic secretion.

And the stimulation of secretion of pancreatic enzymes when you already have inflammation in your pancreas is certainly not very f- very beneficial for the subsequent evolution of your chronic pancreatitis. So those drugs should not be used in patients with a history of pancreatitis, either acute or chronic.

Otherwise, you have a risk of re-acutization of pancreatitis. Of course, pancreatitis is, in its turn, associated with an increased risk of pancreatic cancer. We know that. But there is no evidence present that GLP-1 receptors, uh, receptor agonists either, uh, increase the risk of either pancreatitis, new cases of pancreatitis, or pancreatic cancer.

So I think that we have to reassure the, the public about this issue. The other issue of medullary thyroid cancer is a little bit more complicated. In rodents, there are a lot of GLP-1 receptors on pancreatic c-- um, thyroid C cells, and their stimulation stimulates both calcitonin release and growth of those cells.

And so it increases the risk of medullary, uh, thyroid cancer in rodents. We are not rodents. Our cells express just very few receptors for GLP-1—very few, but some, meaning that at the highest doses of GLP-1 receptors or dual agonists, you can see a modest increase in calcitonin levels cir-- uh, uh, in the circulation, but nothing more than that.

Now, there is a warning, at least in the FDA SPC, there is a warning that you should not possibly use GLP-1 receptor agonists in patients with a history-- with a personal or family history of medullary cancer. And patients with a personal or family history of medullary cancer are excluded from all randomized clinical trials.

Now, apart from the familial cases, the sporadic cases of medullary thyroid cancer are really very rare. And so you practically see nothing in clinical trials or in routine clinical practice. So I would say that the mess-- the general message here is do not use the drug in patients with a history of, uh, personal or family history of, uh, thyroid medullary carcinoma, and don't worry about calcitonin at all when you're using GLP-1 receptor agonists.

The other thyroid cancers are a completely different issue, uh, meaning papillary thyroid cancer, the most common form of thyroid cancer. In randomized trials, if you put all the data from all the trials together and you make a meta-analysis of all randomized trials, there is an increase in the risk, uh, versus comparators.

And the risk is more increased in trials with a longer duration or in trials with a higher dose of GLP-1 receptor agonists, meaning that something is really happening there. It is a moderate risk. Overall, the increase in the risk is around 40 to 50 increased versus baseline. This kind of cancer, I mean, it has a good prognosis in general.

So the mortality for papillary thyroid cancer is really very low today, so very easy to cure. But of course, it has to be considered when you are calculating your risk-benefit ratio. Uh, these drugs, when they were used in patients with type 2 diabetes, for example, with that great effect on blood glucose, or in patients with obesity and cardiovascular risk factor and high cardiovascular risk with a very wide reduction in the risk of major cardiovascular events, well, the advantages, the benefits are so wide that a moderate risk of usually non-fatal event as a thyroid papillary carcinoma is not really a problem.

So it is just a minor risk. Of course, if you're using those drugs for cosmetic purposes, I would say, in people with only a very mild overweight and no other risk factors, well, you should be much more careful. A cosmetic should be safer.

Host: Excellent. And that's, I think, a, a very-- I'm glad you mentioned this message because, uh, you know, all of us get asked, "Oh, should I be taking this drug?" Especially as pathologists, uh, from public, and, and the message should, should be is what you s- just consider the risk-benefit profile. Clearly, if you're somebody with diabetes, somebody with, uh, obesity, BMI above 30 and especially severe obesity with cardiovascular risk, in addition to that, the benefit is tremendous and outweigh the small risk that you just mentioned, as opposed to the cosmetic setting, uh, where you want to just lose a few pounds.

There are a million better ways of losing a few pounds, uh, or few kilograms than, uh, without putting yourself at risk. I think that's, that's a very important message. So, uh, let's, let's finish, uh, with—I know the, uh, evidence is not to the liking of, uh, what you would like in terms of prospective, uh, randomized trials, but touch upon a few of the cancers that potentially has a lowering effect on the risk of before we finish the episode.

Edoardo Mannucci, MD: Well, of course, the problem with randomized trials is that they are not specifically developed for cancer. The largest trials we have were designed for cardiovascular outcomes, and they have a follow-up of three, four years on average, five at most. We have nothing really longer than five years of duration, uh, as a follow-up, which could be insufficient for some forms of, of cancer.

And another issue is that in, in cardiovascular trials or in trials with metabolic outcomes, we are not selecting people at a particularly high risk of cancer because we are selecting patients for other characteristics. In cardiovascular trials, typically high cardiovascular risk patients, not high oncologic risk patients and so on.

So the number of events of malig-- uh, for each different malignancy that we observe in clinical trials is relatively small. And we can try and see if combining all the trials together, we can begin to see something. And we are beginning to see something for some cancers. Of course, we expect a particular, a particularly interesting beneficial effect on those cancers that are most affected by the reduction of body weight.

So the obesity-dependent or obesity-sensitive cancers that were mentioned before. And one of those that is, uh, uh, endometrial cancer is reduced by GLP-1 receptor agonists in obesity in clinical trials already. And there is some similar reduction also for esophageal cancer, which was not so easy to predict for esophageal cancer, uh, because one of the side effects of GLP-1 receptor agonists is gastroesophageal reflux, which is a risk factor for esophageal cancer.

But clearly, the effect of weight loss is largely prevalent there, and so we have a reduction in the, in the incidence of cancer of the esophagus as well. For other cancers, we still have no evidence from, from clinical trials, but we have good, a good body of evidence of indirect or preliminary evidence from observational studies.

That is retrospective observational studies. Of course, you can't trust completely observational studies when you're talking of therapeutic effects, uh, but at least they give you an indication. And the indication is that we should expect a major reduction, for example, in the incidence of hepatocellular carcinoma.

There are good reasons for that. These drugs, apart from, from weight loss, uh, probably even beyond weight loss, reduce liver fat content and have a therapeutic effect on...

Host: Steatohepatitis

basically

MASLD,

Edoardo Mannucci, MD: Exactly One of the drugs in the class, semaglutide, has recently been approved for treatment of steatohepatitis as well. So it, it also has the indication. And of course, if you reduce steatosis, fibrosis, and hepatitis inflammation in the liver, you also reduce the risk of hepatocellular carcinoma. We still don't have really, uh, very relevant results for colonic cancer or for breast cancer.

Probably if you ask most physicians which cancer is most clearly connected to obesity, most of them would, would answer post-menopausal breast cancer, which is not really true because the increase of risk in terms of odds ratio is not so high as for other cancers. Endometrial cancer, the odds ratio for endometrial cancer in obese patients is much higher than the odds ratio for breast cancer, for example.

So the increase of risk determined by obesity is greater for other forms of cancer. And probably we can suppose that breast cancer is, uh, more het-- biologically heterogeneous than other forms of cancers. And so there are probably some subtypes of breast cancer that are most sensitive to the reduction of body weight.

But what we are looking at in, in, uh, general clinical trials is only cases of breast cancer overall, and so we can't really discriminate.

Host: It's fair to say then, you know, through the relationship with MASLD or steatohepatitis and, uh, lowering that, and so hepatocellular, hepatocellular carcinoma, uh, is lower-- is expected to have a lower risk, uh, uh, in patients when, uh, in subjects who are taking these medications, uh, and, uh, also endometrial cancer for the explanation you mentioned, and the others remain to be seen.

So, uh, that's, that's wonderful. Thank you for, uh, taking the time and so eloquently, you know, uh, explaining such a complex topic. So we went through pharmacokinetics and, and, uh, and pathogenesis. Uh, you should be a pathologist, not an endocrinologist. You did it so well.

Edoardo Mannucci, MD: do you really think so? Well, uh, I don't know. If I was a pathologist, I wouldn't-- I would not have encountered GLP-1 many years ago in my research activities. True. yes, uh, I was a postgraduate student at the time when

I, uh, first, uh, uh, met, uh, GLP-1. And nobody was really interested in GLP-1s there was no, no drugs,

Host: Yeah

Edoardo Mannucci, MD: uh, related to GLP-1 by then.

But it's the biology of these peptides was so interesting. So I'm glad to be an endocrinologist, so I had the opportunity to meet this field early in my career.

Host: Maybe we can give you just a, a, an honorary pathology, degree, for all the great work you've done and all the patients, you've helped. I'm always amazed that, the receptors are so widely—you know, you don't think of that because you're always thinking glucagon, pancreas, and GI tract, but how, how widely these receptors, especially in the central nervous system, which, uh, will continue the story to unfold.

Thank you very much again.

Edoardo Mannucci, MD: Oh, you're welcome. It was really a pleasure to be your guest.

Host: All right.

And thank you for our audience. It's always a pleasure to, conduct these podcasts, but, uh, I want to emphasize that we look forward to your feedback and input, suggestions of topics or, uh, any comment you may wish to share either, uh, on, uh, my email or LinkedIn and Twitter account. And my email again is george.netto@pennmedicine.upenn.edu And easy enough, uh, we post all these episodes on LinkedIn and Twitter, so feel free to comment, and I will definitely address, those suggestions. Thank you again, Edoardo