From Blood Sugar to Blood Cancer: Surprising Benefits of GLP-1s

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a Medical Oncologist, Director of International Programs for the Cancer Institute and Co-Director of the Sarcoma Program at Cleveland Clinic. Today I'm happy to be joined again by Dr. Abhay Singh, Staff Physician and Director of the CHIP Clinic at Cleveland Clinic. He was previously a guest on this podcast to discuss risk factors for secondary malignancies in breast cancer survivors. He's here today to discuss hematologic cancers in patients with diabetes treated with GLP-1 receptor agonists. So, welcome back.

Abhay Singh, MD, MPH: Thank you, Dr. Shepard. Great to be back. Thank you for having me.

Dale Shepard, MD, PhD: Absolutely. So remind us again, I gave your title, but give us a little idea of what you do here at Cleveland Clinic.

Abhay Singh, MD, MPH: Yes, so I'm a physician scientist, physician researcher at the Cleveland Clinic. I see patients with acute and chronic leukemias, and my research interests are in the clonal hematopoiesis of indeterminate potential, CHIP, a precursor condition to myeloid malignancies. And it has implications in both onset of hematological malignancies as well as cardiovascular disease. My focus has shifted towards survivorship care, and then looking at these cancer survivors risk of cardiovascular disease and secondary malignancies. I do some work at the intersection of metabolic health, cancer, and cardiovascular disease.

Dale Shepard, MD, PhD: Okay, very good. And we're going to talk a little bit about that specifically as it relates to diabetes and impact on cancer. So give us a little bit of an idea. We're going to talk about diabetes, we're talking about cancer, cancer risk. Being a solid tumor oncologist, we oftentimes have this realization that diabetes, obesity have a really strong relationship for solid tumors. What do we know about diabetes? And hem malignancies?

Abhay Singh, MD, MPH: So not a whole lot. So a lot of work has come from solid cancer and obesity data. And then the thought process there being obesity, being a chronic low state inflammation state, leads to immune dysregulation and probably onset of several solid cancers. There was data out of Cleveland Clinic where they looked at patients with obesity, and then those who underwent bariatric surgery and those who did not. And they found that just having that cardio metabolic reversal through bariatric surgery, their risk of cancers decreased, solid cancers primarily.

And then there was recently data that showed decreased risk by using GLP-1 agonist in 13 obesity related solid cancers. So certainly, a lot of information's out there in terms of obesity, diabetes, cardio metabolic health, and solid cancers. But there wasn't a whole lot in hematological malignancies. There has been some data that has shown that precursor conditions, such as CHIP, clonal hematopoiesis associated with diabetes, overall state of overweight-ness or obesity. So there was some connection there, but in terms of direct correlation there, things have been lacking. We've been behind the solid tumor field.

Dale Shepard, MD, PhD: I'm going to shamelessly take a pause. And the bariatric surgery relationship to cancer risk, we actually have a Cleveland Clinic Cancer Advances podcast that discusses that. So I'll be shameless and mention people can go back and listen to that.

Abhay Singh, MD, MPH: I think I've been a listener of that. Was it with Dr. Ali Aminian?

Dale Shepard, MD, PhD: Yeah, so just a little shameless plug. So what do we think? You mentioned about metabolic dysfunctions and things, do we have any idea what a mechanism might be? You mentioned inflammation and solid tumors. Do we think inflammation has the same role for hematologic malignancies? Or are these things we're still learning?

Abhay Singh, MD, MPH: I think, yeah, most of these things we're still learning. But I think similar mechanisms, I think low grade inflammation, immune dysregulation, and then the bone marrow microenvironment is so important to have healthy cells. And if the bone marrow microenvironment, through altered cytokine profiles, and leading to immune dysregulation is altered, that can lead to hematological malignancies. And I think I'm personally biased. I think it's going to be by the way of clonal hematopoiesis. But these are all provocative thoughts, mechanisms that are in hypothesis state, but none proven so far.

Dale Shepard, MD, PhD: All right. We're going to switch over here and talk about your work that you looked at, these relationships. GLP-1 receptor agonists, certainly really popular these days for their originally intended diabetic control. And of course, weight loss is a big use now. What sparked your interest in looking at the effects of these in relation to hematologic malignancies?

Abhay Singh, MD, MPH: So yeah, it all started, we have a growing CHIP clinic here. So there a lot of patients with clonal hematopoiesis of indeterminate potential. And then there were some associations that were coming out with anti-diabetic drugs, metformin, and then sulfonylureas in association with clonal hematopoiesis. So in my mind I was thinking that GLP-1 agonists, they're associated with decreased risk of cardiovascular disease. And then CHIP is associated with cardiovascular disease. Could there be an association between if we could use GLP-1 agonists in patients with clonal hematopoiesis, if they met the criteria to be on the drug?

And I was planning on designing this study, which I wanted to call CHLOE, clonal hematopoiesis loss of expression using GLP-1 agonists. But there was not a lot of attention to that thought because there was no preliminary evidence, no data to support that hypothesis.

So we have a wonderful fellow here. So we were discussing that could there be an association? She's also, Jasmin Hundal, she's interested in cardio metabolic health lifestyle interventions. And then she said, "Oh, Dr. Singh, there is a student in NEOMED and he's been looking at a large database." And then a similar question, "Would you be interested to learning more about what he's doing?" I said, "Certainly so." So I met with Omer Ashruf, who's the first author on this study. And he told me that there's this large database, and he's been looking at hematological cancers, and other cancers, and associated in GLP-1 agonists.

So we were able to define the study question, come up with a design, and then the rest is history. Then we were able to get this. That was the kind of motivation to get this study started.

Dale Shepard, MD, PhD: This is really no small undertaking, when you say a large database. We're talking really large, a lot of people. Tell us a little bit about how you gathered the data, and how many people might've been involved, in terms of, sometimes you look at these intervention studies and it's a handful of people, but not in this case.

Abhay Singh, MD, MPH: Not in this case. So this was certainly a really, really large database. It's called TriNetX Database, which is an electronic health record network across sixty-plus healthcare organizations. And it's updated in real time. And then all these electronic healthcare network databases, they talk to each other across these sixty-plus healthcare organizations.

So there's a lot of, lot of data. And then, it's pretty granular as well if you're looking at treatments, their outcomes, and all those kinds of things. So this database is not available here, but only some participating organizations have access to this database. And then the Metro Health System, NEOMED students from there, they're able to access their database.

So there were statistical support from Case Western Metro Health. There was a large team here at the Cleveland Clinic in the design of the study. And then students from NEOMED. So it was, in true sense, a multidisciplinary effort to get this study done.

Dale Shepard, MD, PhD: Just for perspective, large in this case was?

Abhay Singh, MD, MPH: 1.6 million.

Dale Shepard, MD, PhD: 1.6 million. So that's a lot of people.

Abhay Singh, MD, MPH: A lot of people, yeah.

Dale Shepard, MD, PhD: Then how did you take that 1.6 million people and distill it down into the question you were looking to answer?

Abhay Singh, MD, MPH: Yes. I think the important thing becomes that how do you define the time zero, where you want to start? What is the index event? So we decided that the index event is going to be prescription of the GLP-1 agonist. And then once we identified the population of GLP-1 agonist exposed patients, we wanted to find the comparator arm. The comparator arm was either insulin or metformin. And then we did propensity score matching.

Balanced them out on numerous, numerous different parameters and variables, had to balance any sort of confounding, which can be an inherent bias in a retrospective analysis. That was a retrospect study, so we were aware of that. So propensity score matching pretty similar groups, and then we were able to distill it down to a subgroup that had GLP-1 agonist, versus insulin, and a subgroup that GLP-1 agonist versus metformin.

Dale Shepard, MD, PhD: And those were patients who were receiving each of those drugs by themselves?

Abhay Singh, MD, MPH: Yes.

Dale Shepard, MD, PhD: So not combination therapy?

Abhay Singh, MD, MPH: Not combination therapy. Yeah.

Dale Shepard, MD, PhD: When you distilled it all down, you were looking at about 50,000 people in each group, if I remember?

Abhay Singh, MD, MPH: Similar, yes. Yes.

Dale Shepard, MD, PhD: Okay. So I guess, what did you find when you looked at relative risks with the GLP-1?

Abhay Singh, MD, MPH: Yeah, so what we found was that GLP-1 agonists, when compared to insulin, they decrease in about 50 to 55% risk reduction in all hematological cancers. And the effects were more pronounced. The point estimates were much larger for patients with myelodysplastic syndromes and myeloproliferative neoplasm. But all cancers, multiple myeloma, non-Hodgkin lymphoma, all cancers, the risk went down.

When we compared it to metformin, those associated decreases in risk were not present in all hematological cancers, but they were only limited to myelodysplastic syndromes and myeloproliferative neoplasms. I think in part that might have been because metformin has been used for decades now. And then we know that there are some anti-cancer properties that are associated with metformin as well. So that could be the reason.

I think myelodysplastic syndrome and myeloproliferative neoplasms are disease states that are more inflammation-prone, so they're more cytokine-profile rich. And so I think, by the reversal of inflammation, both these drugs are able to provide the benefit. But GLP-1 agonists probably do that way more than what Metformin does.

Dale Shepard, MD, PhD: Maybe this is this comparison of the GLP-1 to the Metformin insulin independently, and showing that there's actually perhaps a protective effect with metformin might... This seems like this has been a question for, quite honestly, decades. And it kind of is cyclic. And we see these trials, it's like something alone, or something with metformin, and they never really quite show definitively, but there's pieces that suggest that it's true.

Abhay Singh, MD, MPH: That is.

Dale Shepard, MD, PhD: Another piece of the puzzle, right?

Abhay Singh, MD, MPH: Yes.

Dale Shepard, MD, PhD: So I guess, were you surprised? So when you think about, I noticed in the study that most of the people on GLP-1s had only been on for a relatively short period of time. And so was that surprising that there would be an effect after a fairly short exposure?

Abhay Singh, MD, MPH: Yes. So the median time they were on the drug was even less than, closer to a hundred days or less, something like that.

Dale Shepard, MD, PhD: Yeah, it was about 140, I think, somewhere around there.

Abhay Singh, MD, MPH: So independent of that exposure time, we were surprised by the profoundness of the effects, because there was always this hypothesis that was going on in the mind. But we were certainly surprised that it would be that profound an effect, 54% associate decrease in risk of hematological cancers when compared to insulin. That was certainly a surprise to us. Yeah.

Dale Shepard, MD, PhD: So we shifted with these drugs, from diabetes weight loss. Are we going to be doing cancer prevention now?

Abhay Singh, MD, MPH: Yeah, certainly, that's something that I'm trying to be a huge proponent of. I think the interest from the companies that make these drugs is not on cancer at this time, because they have other diseases, like cardiovascular disease, sleep apnea, and other things where their focus is currently.

But I think there's a huge room for cancer prevention. I would also say that cancer prevention certainly is something that should be explored with the setting of GLP-1 agonist. But in general, I think the mechanism that promotes this decreased risk of any sort of blood cancer is improved cardio metabolic health. And there are other ways to get to cardio metabolic health as well. Healthy living exercise, diet, and other things, which are much more harder to do than-

Dale Shepard, MD, PhD: They are harder to do.

Abhay Singh, MD, MPH: Yes, but I think-

Dale Shepard, MD, PhD: Cheaper, but harder.

Abhay Singh, MD, MPH: Cheaper, but harder. But there are other ways to get there as well. So I think, there's a strong message that comes out of this study, that it's probably, GLP-1 agonist, certainly, I think improved cardio metabolic health leads to decreased risk of cancers, and that there's other ways to get to improve cardio metabolic health as well. Cheaper.

Dale Shepard, MD, PhD: Yeah, makes sense. At the beginning, you said something about you were thinking of trying to design a trial, wasn't a lot of data. How does this data help support maybe moving forward? Where are we going from here?

Abhay Singh, MD, MPH: Yes. So I think we are much better positioned now to hold those conversations with our pharma colleagues, to say that we have the preliminary data to suggest that there may be reversal of possibly clonal hematopoiesis that leads to decreased risk of hematological cancers. So those discussions are ongoing. And hopefully, CHLOE can be designed. But we're still in very early on in this phase, but we have the preliminary data to move this forward.

Dale Shepard, MD, PhD: So compelling data, but I think you hit upon a good take-home message, is good healthy living always wins.

Abhay Singh, MD, MPH: Yes, certainly so. I think good health, healthy eating, exercise, those are all sure-shot ways of improving overall health in general, cancer, cardiovascular disease, and also improve public health overall, and decrease chronic disease burden in the community at large.

Dale Shepard, MD, PhD: Great. Well, great work, great insight, and thanks for being with us.

Abhay Singh, MD, MPH: Thank you, Dr. Shepard. Thank you for having me. Always a pleasure.

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