Latest / DOC Updates / Beyond Diabetes and Obesity: Expanding Applications of Incretin Biology

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Beyond Diabetes and Obesity: Expanding Applications of Incretin Biology · DOC Updates

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  Welcome to this special edition of the American Diabetes Association's Diabetes
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  Obesity and Cardiometabolic Update podcast,
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  where we will be discussing beyond glucose and weight,
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  the pleiotrophic effects of GLP1-based therapies.
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  I'm your host, Dr. Neil Skolnick,
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  professor of family and community medicine at the Sidney Kimmel Medical College
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  of Thomas Jefferson University.
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  This special edition.
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  Is sponsored by Lily. And joining us today to discuss this critically important
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  topic is one of the icons of obesity research,
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  Dr. Donna Ryan. Dr. Ryan is a professor emeritus at
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  the Pennington Biomedical Research Center in Baton Rouge,
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  Louisiana. She is a past president of both the Obesity Society and
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  the World Obesity Federation. Dr.
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  Ryan's research includes
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  Being an investigator, and many of the trials we're all familiar with
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  and use every day, ranging from the diabetes prevention program trial,
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  way back in 2002, the DASH dietary studies,
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  the look-ahead study, to more recently the SELECT trial.
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  And then this past year, the Maritide Study of once monthly GLP1 RA GIP antagonists,
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  recently the attained two trial of orphryprin,
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  and
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  I decided to take a look last night to make sure I didn't miss anything that
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  ~ Donna, you were author on ~ more recently than March.
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  And it seems like you've published ~ five studies since then.
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  I don't know I don't know how you'd do it.
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  But but what I do know is we are all filled with thanks that you're joining
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  us again to ADA's podcast. Welcome back.
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  Neil, I'm delighted to be here.
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  So when we talked with you about six months ago,
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  you and I discussed obesity as a chronic disease,
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  and we went over the biology of obesity.
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  And it is no secret that all of us know that obesity is difficult to treat,
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  but but you summed it up with a phrase that I've actually repeated many times since
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  then. And that phrase was you've got to fight biology with biology.
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  The GLP1s and the dual GIP GLP1 agonist really have allowed
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  us to treat obesity and diabetes in ways we wouldn't even have imagined possible
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  just a few years ago. We've talked about the effects of GLP1s
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  and obesity and diabetes on other podcasts that we've had.
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  And so today we're going to focus on ~ the effects of GLP1s and the dual agonist
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  on things other than diabetes and obesity.
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  And let's start with cardiometabolic benefits and particularly ~
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  the effect on atherosclerotic disease,
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  MI and stroke. Donna, can you can you go over that?
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  Yeah, I love talking about this,
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  Neil, and thank you so much for bringing up this topic.
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  You know, I think everybody has these ideas that,
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  yeah, these these new medications,
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  these GLP1s, yeah, they're great for weight loss.
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  They're great diabetes drugs, but you know,
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  they we tend to trivialize them.
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  We think, yeah, it's all about weight.
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  No, these drugs are powerful medications,
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  and we're learning a lot about them and their effects beyond.
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  weight loss and glycemic control.
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  So I think the the door into this was through the understanding their effects
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  on the cardiovascular system. You know,
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  so, you know, the FDA required these cardiovascular outcome trials of
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  the GLP1s for diabetes. And indeed,
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  we have four GOB1s that have positive cardiovascular outcome trials.
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  You know, terzepatide ~ yeah it's it's true it's cardiovascular outcome trial
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  in diabet patients with diabetes compared it to doula glutide.
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  And guess what? It was non-inferior non-inferior.
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  But we know doula reduces cardiovascular events.
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  So we think terzepatide does too.
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  So we're hoping for a dedicated placebo control out outcome
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  in surmount MMO that's gonna really bring terzepatite to the front.
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  But it was it it was first the appreciation
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  That the incretin drugs, that's what we used to call them because
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  of their incritin effect, that they were reducing cardiovascular events.
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  And ~ you know, our basic scientists led the way in helping us understand
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  how they might do this. Because when we would do mediation analysis,
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  yeah, there was a little effect of glycemia,
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  but it was not the entire ~ you did not need to have a strong glycemic effect
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  to have.
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  these cardiovascular effects. And so I think our basic scientists,
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  our physiologists really showed us that native GLP1 does a lot more than just have
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  this incredible effect that just promotes the secretion of insulin when your blood
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  glucose is high. And a lot more than just an effect on appetite that produces
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  the weight loss, delayed gastric emptying,
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  yes, we knew about that. That could have an effect on postprandial lipids.
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  But look,
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  Native GLP1 reduces platelet aggregation.
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  Yeah. In animals, it has cardioprotective effects.
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  If you give the ~ the animal a ~ block one of their coronary arteries,
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  you have less less myocardial damage with with GLP1 on board.
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  ~ you know, so they're and the powerful anti-inflammatory effects
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  of native GLP1 all give this sort of background hypothesis that we may be getting.
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  Effects that are not mediated through glycemia,
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  they're not mediated through weight loss.
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  And guess what? In the SELECT trial,
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  and I really consider this the high point of my career,
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  we demonstrated that in people without diabetes,
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  about ~ they did have were allowed to have pre-diabetes without diabetes
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  but established cardiovascular disease,
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  there was a 20% reduction in cardiovascular events.
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  This was
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  I don't know. I felt like the the the the earth moved when when I saw
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  the results of this trial. I was really it was wonderful.
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  Yeah, it was a big deal. ~ so I think that you know what what ~ you know what that
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  means is that we have a medication that we're using for obesity.
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  And guess what? It prevents heart attack,
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  it prevents stroke, it prevents sudden death.
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  Our treatment for obesity is not just moving the numbers around.
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  It's not just lowering your glucose.
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  It's not just making you feel better.
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  It is also having an impact on disease.
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  And that was, I think, a really for for me a career defining moment.
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  Thank goodness we had that.
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  Yeah, I I thought it was amazing when it came out.
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  And I'm so glad you went over the CVOTs for diabetes,
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  beginning with the leader trial way back ~ in I think 2000
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  and in somewhere mid 2010s,
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  and ~ surpass of terzepatide,
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  which we actually had talked to Darren McGuire on this podcast about six months ago,
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  going over the details of that and the imputed placebo,
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  all that.
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  ~ and the SELECT trial is just amazing.
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  And I noticed when I glanced at what you've published recently,
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  you actually were an author on an article in circulation looking
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  at HSCRP in the SELECT trial.
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  And you know, as as as you just mentioned,
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  the decrease in inflammation as one of the ~ drivers
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  of this remarkable 20% decrease in
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  mace in that trial that that just is not fully explained by weight loss alone.
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  Yes. Do see a very early reduction in HSCRP.
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  And you know, Neil, we think the the physiologists have done studies
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  and they think this inflammation effect is coming not just from reducing those
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  abnormal fat cells that are pro-inflammatory,
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  not just the reduction of adipose tissue.
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  It's coming from the brain. Neil,
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  I want to talk to you about about what we learned from Select.
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  about ~ about how we think that smaglicyde
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  is producing these effects on the cardiovascular system.
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  You know, one of the things that we observed in this study is that there
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  was a very early observation of reduction in mace.
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  You know, the the two curves separated right away.
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  ~ And indeed, when we went back and analyzed it at 30 days
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  There was a statistically significant reduction in MACE events.
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  So very early. And then there's an when we looked at whether patients lost weight
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  or not, there was no effect of weight loss on the MACE events.
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  So what we did, and this is published last year in Lancet,
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  John Deanfield was the lead author.
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  What we did is we looked at ~ patients who lost 5% or more in the first 20 weeks.
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  zero to five percent and less than five percent.
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  You know, some patients don't respond well to these medications in terms
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  of weight loss. Well guess what?
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  The MACE effect was there for all three groups.
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  Yeah. So they may not be responding with weight loss,
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  but that is not linked to their cardiovascular improvement.
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  So we, you know, we and we also think this is true for glycemia.
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  So there was another study in the Sophia
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  You know, was just this large European ~ registry.
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  And they looked at patients on GOP1s and whether the weight loss
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  was required for the A1C improvement.
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  And no, it's not. So that's another thing that's not linked.
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  So what appears to be happening is that smagletide and the other GOP1s
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  are having effects that are on glycemia,
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  on weight, on appetite and producing weight loss.
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  And these other disease modifying effects,
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  and then you don't have to have one to have the other.
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  They're not linked. They're mediated by things we don't fully understand.
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  We've just submitted our mediation analysis,
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  and ~ it is it's and we've presented this before in
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  ~ at at meetings in abstract form,
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  but we don't fully understand what is mediating the cardiovascular event reduction
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  in select. No, no, no.
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  It doesn't appear to be improvements in A1C.
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  It doesn't appear to be weight loss.
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  Everything we looked at, we came we came up with,
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  well, there's a small effect. But most of the effects we don't fully understand
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  is that what is it?
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  We don't know it's it's remarkable.
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  And you know, as clinicians, we look at the clinical outcome data.
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  That is rock solid when it comes from randomized controlled studies
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  and ~ also supported by real life data.
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  And then we look for explanations,
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  but so often we don't find them.
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  I mean, we don't fully know the way SGLT twos impart their effect.
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  We don't fully understand the GLP ones,
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  what we know is
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  We have these robust effects that have been shown repeatedly,
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  and then we try to sort out is it just in this case weight loss?
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  It doesn't appear to be, and it it's really remarkable.
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  We've talked about ~ heart and stroke mace risk.
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  Let's move on now to a another critically important heart issue,
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  which is hefpef, which I think has been like we see the tip of the iceberg.
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  There's a lot of it out there.
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  ~
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  Can you go over the effects on heart failure with preserved ejection fraction?
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  What's the evidence?
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  So they're dedicated trials of both semagaltide and terzepatide.
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  Semagaltide has two studies, HEFPEF and HefpefDM.
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  So HEFPEF in patients without diabetes and HEFPEF in patients with diabetes.
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  And terzeptide has a study of ~ of HEFPEF.
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  And all these trials show that there is improvement in both how patients feel
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  and how they function. So the way they do these studies is they
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  do this questionnaire.
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  called the Kansas City questionnaire and it really measures,
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  you know, symptoms and patients do improve significantly compared
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  to those on placebo. They also measure function and they use a six-minute walk test.
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  And patients can walk further.
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  And this has been demonstrated with in both isomangaltide and with
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  the trzeptide study. But interestingly the s the in the terzepatide study there
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  was also a reduction in in for FPEF.
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  And as you know, one of the problems
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  with heart failure are these recurrent hospitalizations and
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  is extremely ~ disruptive to patients and families and it's very costly.
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  So we've talked about the effect on coronary disease,
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  on other vascular disease, stroke,
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  peripheral vascular disease, mace.
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  We've talked about the effect on heart failure.
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  Let's now go to consistent with cardio kidney metabolic disease.
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  Let's go to kidneys effect there.
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  Wow, here's the kidney, here's the here's the scoop on on the GLB1s and kidney.
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  You know, we did have a ~ secondary outcome that was positive on
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  our on our composite kidney ~ outcome.
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  But I think that really the best evidence for GLP1 efficacy in ~
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  in kidney disease comes from flow.
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  And this is a dedicated trial in people with diabetes,
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  over 3,000 patients with
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  Chronic kidney disease and and albuminurea ~ and diabetes.
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  And indeed there was a reduction in that ~ in that composite kidney event
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  in in patients with chronic kidney disease.
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  And guess what? It didn't matter whether they were on SGLT2 inhibitors or not.
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  Both the SGLT2 inhibitor can help you,
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  as can semangaltide. So the GLP1.
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  So remember
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  Yeah. Yeah, I remember
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  good news there.
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  that it sure is. And I remember when that was presented at ADA,
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  and there also was, if I recall correctly,
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  either a cardiovascular or mortality benefit,
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  ~ so that it is, you know, up there with SGLT2s in terms
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  of its broad effect in patients who in that case you know with chronic kidney
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  disease. ~ next up, liver,
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  ~ an important part of our body.
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  Thinks that magalotide ~ gets the gold star because they have
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  an indication for MASH. Isn't that good news?
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  ~ so this is based upon their ~ their study ~
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  in patients who have established metabolic associated steatotic hepatitis with
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  fibrosis proven by biopsy. So in this study,
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  there was a reduction in both fibrosis,
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  in both inflammation.
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  And in steatosis, and both. ~ so this this has been given provisional,
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  ~ a provisional indication based on the one-year results being so positive.
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  And we're ex, you know, there'll be two years after that,
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  there'll be another ~ liver biopsy and we'll we'll know more,
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  but we but we think that is a very welcome indication and treatment
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  for our patients with MASH.
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  Yeah, it's it sure is. It it's we've talked about MASH on some
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  of our other podcasts. It has become somewhat of an epidemic.
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  I think sixty percent of people with diabetes have ~ mass L D
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  and a significant proportion go on to develop fibrosis.
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  So much needed therapy. And I if I recall,
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  I think Terzepatide had its phase two study ~ also that was positive
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  and we're we await the phase three ~ results.
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  That's practice changing is getting that in indication.
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  Yeah, it it is it is so important.
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  Cause I can tell you in primary care,
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  MASH has become a big issue that we are now looking for with our Fib four scores.
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  And now that we're looking, we're finding it.
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  Now, before we move on to other errors,
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  we said we're not gonna specifically talk about treatment of diabetes.
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  We know the GLP1s and dual agnes work well here,
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  but how about for prevention of
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  Diabetes. You were in the large lifestyle study,
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  DPPT, that showed that lifestyle works to decrease progression from prediabetes
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  to diabetes, if I recall, compared to usual care by about all around 60%.
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  ~ how do the GLP ones and dual agonists do in that group with
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  prediabetes in preventing progression?
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  Yeah, great question, Neil. And you know,
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  my mantra was look, modest weight loss is good for you.
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  We got 6.7% weight loss in ~
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  in in in DPP, and we got ~ a almost 70% reduction
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  in risk from progression from IgT to diagnosed type 2 diabetes.
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  So when we re when we looked at that study.
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  in other ways and we analyze by the amount of weight loss.
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  10% weight loss pretty much maximize the diabetes prevention potential.
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  So we know this relationship between weight loss and improvement in
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  in in in prediabetes is very powerful.
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  And indeed we have evidence for ~ in terms of the GOP1s,
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  we have evidence for loragaltide,
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  trzeptide, and ~ somagaltide in terms of
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  of prevention of progression of of type two diabetes.
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  Very powerful. What's going on here with these drugs is,
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  yeah, there's a benefit that's achieved through weight loss
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  and improved insulin sensitivity,
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  but then we also have that insulinotropic effect also.
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  I was amazed when the article came out.
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  I think it was a sub-analysis of the ~ surmount study in people with prediabetes
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  and had like a 93% decrease compared to placebo in
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  ~ group in prediabetes going on to to diabetes.
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  That was just ~ amazing. ~ let's let's move on from metabolic disease
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  now to
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  biomechanical effects of obesity.
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  And ~ let's start with osteoarthritis,
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  Donna.
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  Yeah. So osteoarthritis, yeah,
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  there's a ~ r there is a ~ a study with semagatide that shows
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  improvements in knee pain and and functionality.
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  You know, I think we ~ we're waiting for the ~ retitrutide study to come
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  out because there's a what's called a bucket.
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  So in their phase three trial they had a bucket.
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  of osteoarthritis patients and they're gonna analyze that separately.
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  So we're hoping for a f positive outcome from that too.
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  But yes, ~ you know, there's preclinical evidence that that with osteoarthritis that
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  there seems to be some protective effect on the cartilage.
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  And there also is this anti-inflammatory effect in the joints.
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  But ~ you know in we we don't we haven't resi reached disease
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  modification.
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  in terms of osteoarthritis. I think what we do with our GLB ones is
• 20:26
  we really unload patients and that improves knee pain significantly.
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  So we don't have an indication,
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  but we do have a lot of evidence of of improvement in knee pain.
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  Yeah, I mean, anecdotally, people in the office who I I I put on,
• 20:43
  you know, the GLP one or dual agonist,
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  that is one of the main things they talk about.
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  And I know low back pain hasn't been studied,
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  but that's what I hear about in the office.
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  ~ Knee and hip pain. And sure enough,
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  certainly the knee arthritis study of somagmatide supported that and
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  I believe also showed less pain medicine use and you know
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  We we certainly benefit whether it is NSAIDs that increase cardiovascular risk
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  or opioids, the less pain medicine,
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  the better. Let's move on to another mechanical area,
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  which is obstructive sleep apnea.
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  Any effect there? Well, we know the answer,
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  but can you share share with
• 21:27
  Yeah.
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  It has the indication for obstructive sleep apnea.
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  And what they did is they looked,
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  there are two big studies with terzepatide in in obstructive sleep apnea.
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  One in patients who were taking CPEP and one in patients who were not on CPEP,
• 21:43
  either couldn't tolerate it or refused it.
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  And in both cases, the the the average apnea hypopnee index was pretty severe.
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  It was about on average, about 50 events per hour at baseline.
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  And with in both cases, there was this fell by about 50%,
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  by about half. And furthermore,
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  about half of the patients achieved an apnea-hypopnea index of less than 15.
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  And you know, that's when we recommend starting CPAP.
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  So really a positive outcome for terzepatide and it has gotten an FDA indication.
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  You know, I think the importance of these FDA indications is that they pretty much
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  drive reimbursement.
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  And change practices because of that.
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  Yeah. That's that's been another area so appreciated by my patients.
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  And what I was so impressed when it got the FDA indication,
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  it wasn't an indication to use terzepatide along with CPAP.
• 22:42
  It was to use terzeptide to treat ~ obstructive sleep apnea because like you said,
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  fifty percent of the people got to a point below which they no longer need
• 22:53
  ~ PAP therapy, which is is just amazing.
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  So let's move on now to a less well appreciated area,
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  but where there's a lot of potential.
• 23:04
  And can you tell us about work looking at prevention of neurodegenerative disease?
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  And let's start with Parkinson's.
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  Yeah. You know, there's a lot of epidemiologic evidence that individuals
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  on ~ GOP1 receptor agonists have lower incidence of Parkinson's disease.
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  And there's a there's also a lot of preclinical and we have a good hypothesis
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  of why GOP1s might be good. And it's because of this neuroprotective effect,
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  the effect on neuroinflammation and other other things that can go
• 23:39
  on that drive these neurodegenerative diseases.
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  So
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  ~ and we did have two early studies,
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  one a small study with a xinotide and another one with lixacenotide that were
• 23:52
  positive, but they were small.
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  ~ we don't have ~ any evidence though of efficacy
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  in large trials. And in fact there were two that looked at the axinotide molecule,
• 24:04
  one in pegylated axinotide and the other in long-acting axinotide,
• 24:08
  and both of those studies were negative.
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  I think we're asking a lot.
• 24:13
  for medications to go into the brain and repair neurons.
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  You know, I do think that the the there's still enthusiasm around Parkinson's
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  disease, but I think the the it's the focus has shifted to maybe trying
• 24:28
  to treat earlier and to try to to intervene more in the prevention
• 24:34
  and early diagnosis and prevention of progression area.
• 24:39
  That that makes sense, which leads us to the next and I think most feared neurologic
• 24:45
  illness, which is Alzheimer's disease.
• 24:48
  Yes. Wouldn't that be wonderful?
• 24:51
  ~ you know, and and again here there's ~ we there's
• 24:57
  a great hypothesis about why these sh these should work.
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  And we have two big studies, Evoke and Evoke Plus,
• 25:04
  ~ looking at oral semagnetide.
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  And ~ unfortunately those studies did not hit their primary endpoint.
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  So here again, I think in Alzheimer's disease,
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  the
• 25:18
  the all our early enthusiasm has been modulated somewhat.
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  And I think it the the focus is really shifted again,
• 25:25
  trying to identify high risk patients with metabolic disease especially
• 25:30
  and intervening there. But to ask the GOP ones to go in and do something about
• 25:36
  the amyloid deposits, that's asking a lot.
• 25:39
  So I think, you know, more on the prevention end,
• 25:42
  there's still enthusiasm around Alzheimer's disease rather than reversing it.
• 25:47
  Yeah, and and that's a big difference because we've reviewed on the podcast some
• 25:51
  of the trials that have looked at a decreased incidence of Alzheimer's
• 25:57
  and people with diabetes on GLP ones.
• 26:00
  And there repeatedly we've seen in real-world studies a decrease of thirty
• 26:05
  to forty percent in the d ~ the number of people who develop it who are on GLP ones,
• 26:11
  but very different. And I if I remember correctly in the evoke trial.
• 26:15
  There was a decrease in amyloid ~ positivity in the amount of biomarker,
• 26:21
  but but it's a different thing to prevent something than to reverse
• 26:25
  it once it's there. And ~ boy,
• 26:28
  I hope we see studies on prevention of Alzheimer's because that would be
• 26:34
  all of us know or have a close family member who has this very prevalent disease.
• 26:40
  And if these could help there it would be amazing.
• 26:43
  I'm gonna touch on we're almost toward the end of our time,
• 26:46
  Donna. there's a lot of excitement around substance abuse disorder treatment,
• 26:52
  ~ alcohol cannabis, opioid.
• 26:55
  ~ what is the current thinking there?
• 27:00
  Okay, very good epidemiologic evidence,
• 27:04
  you know, especially from this large study in over 600,000 individuals
• 27:08
  at the VA hospitals. Very strong evidence that for people on the GLP1s,
• 27:14
  there's a reduced ~ incidence of the diagnosis of substance use disorders.
• 27:19
  And for people who have established substance use disorders,
• 27:22
  there was a decreased ~ use of the emergency room for these substance use visits.
• 27:27
  ~ and again.
• 27:29
  a very strong sort of hypothesis,
• 27:32
  mechanistic hypothesis about why the GLP ones might work well here
• 27:36
  and primarily because of their effects on the area of the brain that that
• 27:41
  is involved in addiction and hedonic ~ aspects of of behavior.
• 27:46
  So unfortunately the enthusiasm for those two things is
• 27:51
  not really translated yet into ~ randomized clinical trials our
• 27:57
  our gold standard evidence.
• 27:58
  I think our best evidence is really around alcohol use disorder and
• 28:03
  ~ and I'm hopeful that something will come out there.
• 28:07
  Okay. And any other areas before we bring things to a close that you'd like
• 28:12
  to mention that I haven't specifically asked about?
• 28:17
  I have one that I want to talk about and that's COVID.
• 28:20
  Amazing. Yes. You know, in that select trial that we did,
• 28:23
  there were seventeen thousand six hundred patients and the COVID pandemic occurred
• 28:29
  smack in the middle of the trial.
• 28:31
  So there were some other ongoing trials with semagaltide.
• 28:34
  There were the flow trial and others.
• 28:37
  And we what we did is we pooled all that data together and I presented this
• 28:41
  at ADA this year.
• 28:43
  And there was a reduction in COVID hospitalization and COVID deaths
• 28:48
  in patients on semagalite. Now think about it.
• 28:51
  Why do patients die with COVID?
• 28:54
  Well, one reason is they can have this over sort of infection virus thing that
• 28:59
  occurs early on, or they have this sort of ~ immune,
• 29:03
  overactive immune response that occurs later that causes organ failure
• 29:08
  and kills you. So we believe that smagaltide has central effects.
• 29:12
  on inflammation, it has central effects that are driving the my the immune system.
• 29:18
  So that is very, very exciting to me.
• 29:21
  There's a study underway with long COVID that's being sponsored by the
• 29:25
  NI and that is going to be done in patients with a normal BMI.
• 29:31
  Yeah, BMI is down to 22. That's gonna be interesting.
• 29:34
  And then th there there are I think this whole idea of trying to use G OP ones in in
• 29:41
  lower BMI areas is something very interesting.
• 29:44
  There's a study in major depression that allows patients down to BMI of 22.
• 29:49
  So those two things. Is d is this going to be a good medication
• 29:55
  for prevention of COVID and other infectious deaths?
• 29:58
  And what how are we going to how are we going to use get try to
• 30:03
  get these benefits that are occurring outside of the weight loss arena
• 30:08
  in lower weight patients?
• 30:10
  Too exciting there is.
• 30:11
  Yeah. It it really is. Donna, we've covered an enormous amount of information.
• 30:16
  Any final thoughts you'd like to share with our listeners before we bring things
• 30:21
  to a close?
• 30:22
  Yes, I do, Neil. And thank you so much for having me here.
• 30:26
  As you can tell, I love talking about this.
• 30:28
  But I want everyone to really think about these medications seriously.
• 30:33
  These are serious medications.
• 30:35
  We need to take them seriously.
• 30:37
  These are not something on TikTok.
• 30:39
  These medications can transform our practices and we need
• 30:45
  to become skilled in their use.
• 30:49
  Dr. Donna Ryan, thank you so much for joining us.
• 30:52
  And to our listeners, thank you for joining us on this special edition
• 30:58
  of ADA's Diabetes, Obesity, and Cardiometabolic Updates podcast.
• 31:03
  We have covered an enormous amount of information in areas that are
• 31:09
  so important to all of us. We use GLP1s and the Dual Agonist.
• 31:14
  All the time for diabetes, for obesity,
• 31:17
  we are learning how to use them for a range of other illnesses,
• 31:21
  as we discussed from coronary disease treatment and prevention
• 31:26
  to heart failure to osteoarthritis,
• 31:30
  sleep apnea, on and on. This was such a helpful update.
• 31:35
  This special edition is sponsored by Lily.
• 31:38
  For the American Diabetes Association,
• 31:41
  I'm Dr. Neil Skolnick.
• 31:43
  Until next time, stay safe and keep learning.