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?
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.
Very interesting. And can you also walk us through some of
the data about how effective these agents are for
weight loss?
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.
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?
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.
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?
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?
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.
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?
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.
So, Jasmine, can you tell me about the available research
on GLP-1 drugs in cancer risk?
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.
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?
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.
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?
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.
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.
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.
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