Jasmine Sukumar, M.D. Hi, I'm Dr. Jasmine Sukumar, and I'm an assistant professor and breast medical oncologist at MD Anderson Cancer Center with a research focus in metabolic health. Today, I'm joined by Dr. Sonali Sahni, who is an associate professor in the department of Endocrine Neoplasia and Hormonal Disorders at MD Anderson, with a clinical focus in managing glycemic complications in cancer patients. We are both very excited to participate in this Cancerwise Podcast. Welcome, Dr. Thosani. Thank you for being here. Today we're here to talk about GLP-1 drugs, the flourishing class of pharmaceuticals for diabetes, and now weight management and their effect on cancer patients. This has been a very hot topic. First, could you explain to us how these drugs work? 

Sonali Thosani, M.D. Absolutely. Jasmine. Thank you so much. It's so great to talk about these drugs that have been now at the forefront for patients with cancer who have Type 2 diabetes and obesity. I'm going to tell you a little bit about the history and then talk about the mechanisms. So, these drugs back in the 1970s, there were some glucose clamp studies done. And they found out that patients who took oral glucose had more insulin release than patients who took IV glucose. And scientists discovered that there were some hormones that the body was producing, called incretins, that were contributing to that increased insulin response with oral glucose. So, in the 1980s, these molecules were discovered. They were GLP-1. The problem was that we make enzymes in vivo that break down the GLP-1 right away. And so, you know, fast forward to the 1990s, there were some scientists doing research with Gila monsters, which are these venomous lizards. And they found that in the saliva of those Gila monsters, there was a molecule that was like GLP-1 that did not get broken down by DPP4 or that enzyme that's naturally produced. And with that, that kind of paved the way for the current GLP-1 agonist that we're seeing. So, these include drugs like exenatide, which was approved in 2005, liraglutide, which was approved in 2010. And then in the last decade, we've had some newer generation of GLP-1 agonists. So, these are drugs that can actually be dosed once weekly, which is really convenient for patients. So, you have liraglutide in 2010, semaglutide in 2017 and then tirzepatide in 2022. Now, the way GLP-1s work, they basically slow down gastric emptying. And it's all in a glucose-dependent manner that they increase insulin secretion. And that's really important because if there's no glucose around, it doesn't increase insulin secretion, which is good for patients because it doesn't cause hypoglycemia. So, the patient isn't eating, they're not going to get low blood sugars. Because it slows down gastric emptying, patients feel full. So, there's increased satiety. And they also act at the level of the hypothalamus and really decrease appetite. So, they have both kind of central effects and also peripheral effects. Now, when you look at some of the dual agonist like you have cause appetite which is both GLP-1 and GIP agonist, now you're going to see added benefit of the GIP. So, what GIP does in the presence of GLP-1 is it increases adipose tissue metabolism. And we're also seeing less GI side effects, which is a great thing for patients in terms of tolerability. For FDA approval, again, we have these drugs approved for Type 2 diabetes, and you have the same molecules at higher doses approved for obesity treatment. 

Jasmine Sukumar, M.D. Very interesting. And can you also walk us through some of the data about how effective these agents are for weight loss? 

Sonali Thosani, M.D. Absolutely. Because that's one of the things that patients care a lot about. And when we get patients sent to us by our surgical colleagues here, they really are wanting us to motivate these patients, get on these drugs, lose a certain amount of weight so that they can get their surgery, their cancer-related surgery. Now, as I mentioned to you, there are, these drugs are approved both for Type 2 diabetes at lower doses and then you have the same drug approved at higher doses for obesity treatment. So, the amount of weight loss is also a kind of a dose-dependent effect. So, if you take a look at some of those first-generation drugs that I told you about like exenatide, liraglutide and dulaglutide, they cause about 2-to-5-kilogram weight loss compared to placebo. So, not a lot. But then you take a look at the newer generation drugs that are now at maximal doses for obesity, like same drugs, liraglutide, semaglutide and tirzepatide, and we're seeing much more weight loss. So, for example, 8% with liraglutide, 15% with semaglutide and tirzepatide causes 22% weight loss, which is huge. And so, you know, again depending on your patient and how much weight loss they need, what the insurance is going to cover, those are some of the things you're going to think about as you decide which one to use for your patient. 

Jasmine Sukumar, M.D. Yeah, and that weight loss magnitude seems quite significant when we're comparing to, you know, these older pharmaceuticals used for weight management. Now we've also learned about some of the additional benefits of these drugs. And can you touch on some of these health benefits that go beyond their blood sugar and weight management control? 

Sonali Thosani, M.D. Absolutely. And I think that part is probably the most exciting thing for endocrinologists, cardiologists and nephrologists because these drugs have both cardiovascular and renal benefits. So, there have been lots of publications, probably in the last five years in the New England Journal of Medicine, really large-scale studies highlighting the cardiovascular benefits. So, we had the LEADER and SUSTAIN-6 trial. That trial looked at patients who had Type 2 diabetes who are high risk for cardiovascular complications, and they found that the patients that got put on GLP-1 agonist, they actually had a decrease in all-cause mortality, decrease in cardiovascular events. And then there was another trial done, the SELECT trial, that one actually looked at patients who didn't have underlying diabetes but were obese and had already had a major cardiovascular event. And what they found is that addition of a GLP-1 agonist actually reduced cardiovascular, like secondary prevention. So, because of these studies, now FDA has approved for both, like several GLP-1 agonists for patients who have Type 2 diabetes and known cardiovascular disease, but also for patients without diabetes who have obesity and have had cardiovascular events for prevention. Now, in terms of renal, there was a study done called the FLOW study. They looked at about 3,000 patients and divided them into two groups. All of these patients had Type 2 diabetes and CKD, and what they found was that the patients who were given the semaglutide, that arm, there was actually decreased progression of kidney disease. They saw decreased cardiovascular death compared to the placebo arm. So, based on this, these findings from all of these large scale studies, a lot of our national organizations, like the American Association of Clinical Endocrinology, the American Diabetes Association, they really are recommending using GLP-1 agonists as first line therapy for patients that have Type 2 diabetes and known comorbidities, like they have heart failure or they have CKD, or they have had a major cardiovascular event. Now, there are also a lot of exciting studies in the, you know, they're not FDA approved yet, but a lot of exciting research going on looking at how GLP-1 agonists could benefit, like fatty liver disease or neurodegenerative disorders like Alzheimer's. Looking at addiction disorders, PCOS just recently, in December of 2024, tirzepatide was actually given FDA approval for treatment of sleep apnea. So, patients who have sleep apnea and obesity. Now there's an FDA approval to use this these drugs and in that patient population. And that's really great because the more indications we get for these drugs, the better access we have for patients. 

Jasmine Sukumar, M.D. Yeah.  These drugs have many promising health benefits across different comorbid conditions. And I think we'll continue to follow the exciting research on that. And Sonali, what are some of the potential side effects of GLP-1s and how does this all intersect with cancer care? 

Sonali Thosani, M.D. Yeah, I mean that's a great question. And definitely things that we are thinking very much about as we prescribe these drugs. So, these are again, we have to keep in mind that all of these clinical trials that were done with these drugs excluded cancer patients. So, we're kind of in a, you know, new arena where we're trying, we want to use these drugs because of their multiple benefits. But taking care of cancer patients really requires that unique, tailored approach. In terms of side effects, the most common side effects are GI side effects. So, we see, again, nausea, vomiting. We have patients complaining of abdominal pain. We see constipation. Some patients have diarrhea. And then there are those kind of rare side effects. But when we look at the most common side effects, when and, you know, consider the care of the cancer patient, we want to be careful. Like if we're looking at patients who are on active chemotherapy, they already have nausea and vomiting. We give them these drugs. You can worsen the nausea vomiting. Now they get dehydrated. Now there's increased toxicity from their chemotherapy. In terms of constipation, that can also be a problem which could be compounded in a cancer patient who's on opioids. They already have problems with bowel motility. You give them this drug and now their constipation could worsen. The other kind of rare side effects, for example acute pancreatitis. It's rare with GLP-1 agonists. But if you had a patient with known pancreatic cancer, that having that tumor itself is increasing the risk of pancreatitis, you'll be probably cautious using GLP-1 agonist in that patient population. In general, when we talk about GLP-1 agonist use in cancer patients different than how we would use these drugs in the general patient population, we want to make sure that we're titrating slowly. Typically, we would titrate these drugs every four weeks. But in cancer patients we may be a little bit more cautious about that. The other major side effect from these drugs, which is one of the reasons we use them, is weight loss. But the challenges that, you know, in cancer patients that especially are at risk for cancer induced cachexia, we want to be very cautious how much weight they're losing. Right? Because we know that when you lose weight, you lose adipose tissue, but you also lose muscle mass. And muscle mass loss can be pretty significant in our cancer patients. It can affect their functional status and may affect their ability to get chemotherapy. And so, when we start these drugs, we generally tell patients that it's really important to be intentional in taking protein and also adding some, you know, routine for weight resistance exercises. So, when they looked at studies for patients getting GLP-1 agonists, who did weight resistance versus patients who did not, what they found was that the patients doing weight resistance exercises long term had less muscle mass loss, and also had less weight regain when they stopped the GLP-1 therapy. So, that's why we're really intentional in telling cancer patients that, okay, we want to see how much weight you're losing, but make sure you hold on to that muscle mass. So, again, I've talked a lot. So, I want to hear from you, Jasmine from an oncologist perspective, you know, what do you think? What are, what is the impact of these drugs on cancer patients? 

Jasmine Sukumar, M.D. Yeah. And I know these drugs clearly have a lot of health benefits, as you've discussed. In the specific context of cancer care, I think we really want to weigh these potential benefits with the potential risks, as you've pointed out. I think these decisions really need to be individualized for every patient. Things to consider is where the patient is in their cancer journey, and there should be shared discussions between the patient and their health care provider. Factors to consider are, you know, what are the benefits the patients receiving from their GLP-1 therapy, the potential side effects, and then again, where they are in their cancer trajectory, whether it's during active therapy or post treatment. So, you know, I can highlight some examples. You know, in my clinic I treat breast cancer patients. And many times, patients are on chemotherapy. And so, those patients could be struggling with nutrition and nausea issues because of their chemotherapy. And so, for that patient you know it may make sense to hold their GLP-1 or at least not consider, you know, rapidly increasing that dose at least to get them through that active treatment phase. But, you know, I can think of another patient, for example, with endometrial cancer getting chemotherapy. That patient may be doing just fine on their systemic therapy regimen with no gastrointestinal side effects. That patient could have had obesity as a major risk factor for developing their own endometrial cancer. And they've had a big benefit from getting that GLP-1 drug to help successful weight loss. And so, in that patient, you may consider continuing their GLP-1concurrent with their chemotherapy. But again, these are all individualized decisions. And then lastly, you know, patients who have finished their active therapy, for example, a prostate cancer survivor. You know, there is a link between obesity and prostate cancer, and maybe that person is struggling with weight loss despite optimal diet and exercise. And so, for optimal cancer survivorship care, they could really benefit from initiating such a drug if approved for them. 

Sonali Thosani, M.D. That makes sense. So, I think what you're saying basically is like really tailoring the care depending on what's going on with the patient. You mentioned for your endometrial cancer patient, how having obesity was one of the risk factors. What is the published literature out there about obesity and cancer risk? 

Jasmine Sukumar, M.D. Yeah, and I think, you know, this is still an emerging important area of research. I think the current evidence does not consistently show a harmful impact of these GLP-1 drugs in cancer patients that is necessarily different from the general adult population. And we don't know of consistently any specific link to increased cancer risk. But we do need focused research, especially specialized in different cancer types.

Sonali Thosani, M.D. So, Jasmine, can you tell me about the available research on GLP-1 drugs in cancer risk? 

Jasmine Sukumar, M.D. Yes, absolutely. So, this is now a key research question. And I think we should separate that this out into the emerging lab data and then what we're seeing in large patient populations. So, in the lab, the effects of these drugs are being studied in cancer cell lines across different cancer types like colon cancer, endometrial cancer, breast cancer amongst others. Some experiments are showing that GLP drugs can improve metabolic dysregulation and potentially decrease tumor growth. Now, this effect could be irrespective of body weight, though this is still an ongoing area of research. I think what we really need to tease out is whether these potential anti-cancer benefits are indirect, meaning related to their metabolic health effects and their weight loss, or are there also potentially direct anti-cancer, anti-proliferative pathways? Now, some cancer cells do express GLP-1, but not all of them, and the clinical implications of this are still not yet well understood. And then the other important question is what is the link between insulin pathways, GLP-1 and cancer pathways? And so, this is all being further studied. On an observational data standpoint, I think there's some really interesting human population studies now emerging. I think one very seminal national study was looked at more than 1.6 million patients with Type 2 diabetes without a prior diagnosis of cancer. Now, in those patients, the ones who took GLP-1 compared to insulin actually had a significant reduction in the risk of developing ten of 13 obesity-related cancers. This included esophageal cancer, colorectal, endometrial, gallbladder, kidney, liver, pancreatic cancer, as well as meningioma and multiple myeloma. Now, there was overall a 20 to 60% risk reduction depending on the type of cancer. And there was another, more recent large population study in the United States that showed very similar findings. 

Sonali Thosani, M.D. That's so fascinating. I mean, I think we'll be hearing a lot of exciting things coming up in the next five years as these studies kind of finalize their results. So, you mentioned, you know, in this last large-scale study where we, where patients getting treated for obesity with GLP-1 agonists, we're actually now preventing cancer. So, is there any research for patients who have a cancer diagnosis? They survived their cancer, and now we want to put them on a GLP-1 therapy. Do we have any data on cancer survivors? 

Jasmine Sukumar, M.D. Certainly. So, this is just emerging. I can share about one study our group conducted which was in breast cancer survivors specifically. And we actually evaluated over a thousand breast cancer survivors who received GLP-1 to better look at the real-world health effects in our patient population at MD Anderson. And actually, we did find that patients receiving these drugs did have successful weight loss. But interestingly, the effect was quite modest when compared to the magnitude of weight loss seen in the clinical trial patients. And so, this really begs the question of whether there are certain cancer-related factors that could impact weight loss success. Now, one signal we did see is that those patients receiving endocrine therapy or anti-estrogen therapy, which can classically be associated with weight gain, those patients had a harder time losing weight on their GLP-1 compared to those who did not receive concurrent endocrine therapy. Now, we didn't particularly see that these drugs impacted their breast cancer recurrence risk, but we did observe that in those patients who took the drug, they actually had improved survival, overall survival or lifespan, compared to non-GLP-1 users. This could be due to its additional comorbid benefits like cardiovascular disease, as you pointed out, but needs more study. There was recently another paper published on ovarian cancer survivors. This was in over 1,000 ovarian cancer survivors, and they also had improved overall mortality with using these drugs compared to non-GLP-1 users. And so, I think a limitation of some of these studies is that, you know, they do have this what we call retrospective design, and there may be some bias introduced. And so, future prospective studies or clinical trials are really going to be important to confirm these associations and better elucidate the impact on these drugs in cancer survivors specifically. 

Sonali Thosani, M.D. Yes, I agree, and I'm so glad to hear that you and your colleagues are working on this, because we really need more representation of cancer patients with using these drugs. So, kind of wrapping it up, putting it all into context, can you tell me, again, the relationship between obesity and cancer risk? 

Jasmine Sukumar, M.D. Yeah. So, this is super important because obesity, or an excess accumulation of body fat, is unfortunately increasing in the United States and has many health consequences, including those related to cancer. I think we now know that obesity is consistently linked to at least 13 cancer types, and there's many possible mechanisms, including chronic inflammation that related to altered hormone levels and changes in insulin. Now, obesity is predicted to surpass tobacco as a leading modifiable cancer risk factor. And we know that at least 18% of cancers in the United States are linked to modifiable risk factors like excess body weight, physical inactivity, alcohol consumption, or poor nutrition. Importantly, many reputable cancer societies like the American Cancer Society and ASCO have now put out guidelines emphasizing the importance of healthy lifestyle and optimal body weight as key tenants of optimal cancer survivorship care. So, this includes exercise, including both aerobic exercise as well as resistance training, which you pointed out, and a plant-forward diet rich in whole foods, and then to achieve, maintain a healthy body weight. And I would actually take that one step further and say it's really important to maintain a healthy body composition where there's less body fat percentage and increased lean muscle mass. Pharmacologic therapies can certainly help complement these lifestyle changes for successful weight loss. 

Sonali Thosani, M.D. Jasmine, I think you did a great job covering all of the stuff that has already been done, and you pointed out, again, that we know that there are tumor cells that express GLP-1s. And so, we just we don't really know what the direct effect is on tumor cells when you have a GLP-1 agonist given to a patient. So, I think that's definitely an unmet need. And then you also mentioned about the indirect effects, like for, because patients are losing weight, now you have a reduction in systemic inflammation. And is that changing that tumor microenvironment? I think there's a lot of research needed specifically for that. There are a lot of exciting drugs in the pipeline. So, we talked about the dual agonist, the GLP-1/GIP. But there's also in Phase II clinical trials, a triple agonist that is GLP-1/GIP and glucagon. And this can cause up to 25% weight loss, which is, you know, phenomenal. It's almost comparable to surgical weight loss. So, we need to understand, again, we need to see these drugs come through. And I think one thing that we will need to better understand is you have patients losing weight. They're losing muscle mass. How do we slow down the muscle mass loss but still maintain the weight loss? And there are some clinical trials done looking at drugs that can help do that. And so, we should hear more in a few years. 

Jasmine Sukumar, M.D. Yeah, I completely agree. And now that we have this growing body of data, I also think there's a need to pivot our research to these personalized clinical trials. I think some of these are now coming in the United States, but it will really help us better understand the impact of these drugs on cancer-specific endpoints, and studying these across different cancer types will be crucial. I think this type of high-quality data can really help impact clinical practice and hopefully also ultimately change policy for patients with cancer. Well, thank you, Dr. Thosani for that insightful conversation, and thank you all for tuning in today. If you enjoyed this episode, be sure to follow or subscribe on Apple Podcasts, Spotify, YouTube, or wherever you get your podcasts. And don't forget to comment or review. For more information or to request an appointment at MD Anderson, call 1-877-632-6789 or visit MDAnderson.org. Thanks for listening to the Cancerwise Podcast from MD Anderson Cancer Center.