Dr. Ildiko Lingvay stresses the importance of glucose control and the cardio(renal) benefits of GLP-1RA and SGLT2 inhibitors.
is dr you'll giggling V. A. L. B. As we know her. Um uh from those of us that have been at many conferences with her. She's a wonderful adult endocrinologist coming to us from Ut Southwestern where Darren McGuire was just from as well. She specializes and does a lot of clinical research in the fields of obesity, diabetes and metabolic complications. She has contributed to numerous uh journal articles, book chapters, case reports related to these conditions uh has been recognized with a number of honors and awards in her work as a as a researcher and a mentor. And I can say that I have truly enjoyed working with building a on so many of these projects. So I'm so happy you're here today, LD um you're gonna talk to us about a very interesting topic and we've already had a question around this. Does a one c matter how low should we be going? How do we take this all into consideration with heart disease? Um So we're looking forward to hearing you today. Take it away. Thank you Tina and thank you for inviting me and for your introduction and for assigning me this very non controversial topic whatsoever. But I will do my best to sort of present the state of the situation in the topic and hopefully leave you with some sort of guidance on at least what's my thinking on the topic? Like I said, it's quite controversial. So let's uh let's see what we're gonna talk about today Prevalence of complications. Micro and macro vascular complications in type two diabetes are quite common. This graph is from N hey, so U. S. Data and it shows the prevalence of complications early on. So even at the time of diagnosis or within two years of diagnosis of diabetes, many of our patients already have both micro and macro vascular complications And then going forward within 10 years of diagnosis, these complications continue to accumulate and we have here ten-year risk of macro vascular complications at approximately 27% and microvascular complications and approximately 9%. Right, so high blood sugar, lots of complications. Then people would say of course lowering blood sugar will minimize these complications. And this is a question that's been around for decades on end. And if you've grown up in the same thinking and school of medicine, like I have, you've been told that lowering blood sugar is very good for you and that because it reduces complications. And most of this information comes from the U. K. PBS study, which was a wonderful study and way ahead of its time back in 19 seventies. And what it did, it took patients with newly diagnosed diabetes and randomized them to what was considered unconventional treatment basically lifestyle, which we should all be recommending our patients versus medications. And in that case they were using Soften Hillary as our insulin. And the goal was to see where the lowering blood sugar too more normal levels would minimize such complications. And we've probably all seen these graphs that show that this is one of the UK PDS publications and it shows that uh the X axis here got cut off unfortunately. But it shows the different A. One C values, average values throughout the study and the lower the A. One C. The fewer complications. And it was estimated from data from the study that, for example, for nonfatal myocardial infarction for every 1% lowering in hemoglobin, A one C, there was a 14% decrease. And for stroke, a 12% decrease for everyone. Now, this was compared to micro vascular complications which were overwhelmingly positive at 37% decrease for each 1% reduction in a one c. So it looks wonderful and so compelling data. Right? But we need to stop for a second and think because this study um didn't actually show a significant reduction in am I during the 10 years of follow up of these patients? So one group had an A one C. Of 79 on average, the other group had an A one C. Of seven on average, So a 70.9 difference. And when we look at the non fatal m I over the 10 year follow up, It wasn't statistically significant. It took another 10 years of follow up to cross that significant margin and not not withstanding multiple testing and so forth. But it basically took a long time and uh two to show positive results for me and it never actually showed positive results for stroke when comparing the two groups. So this question was needs to be interpreted in the context of all those other studies around. And I'm showing you here the UK PDS was the biggest study among all the studies at that time but and it had a fair amount of endpoints. Am I alone with 595 events over the 10 years. But it did not reach statistical significance. And if you look at the C. V. A for example it was it did not reach statistical significance but it was slightly in the opposite direction. So if we were to apply that respectively the mace endpoint that we're now so familiar with major adverse cardiovascular events. CV death am I and stroke. This actually is not a positive study. Not even 10 years of follow up and it's still not a positive study. So of course lots of people looked at this and said well we need another study to see whether whether lowering blood sugar truly reduces macro vascular complications. And three studies were actually done the v. D. T. advanced on the court. And uh to answer this question, all these studies enrolled patients that were high risk for cardiovascular disease. So not the younger newly diagnosed folks. But those about 10 years into their disease process. He had a nice long follow up duration and achieved an intensive a one C group a one C control of 6.4 to 7 with a conventional group of 7.3 to 8.4. And if we look at the results for? Am I in particular? You know they're in the right direction. Most of these studies with one of them near court actually showing a significant reduction. This didn't hold true for stroke and certainly did not hold true for all cause mortality or cardiovascular mortality. And in fact the a court study, the one that showed some benefit for M I Actually had a 43% increased risk of death, cardiovascular death and all cause mortality. And if we look at what side effects we had with these intensive approaches, the price to pay was severe hypoglycemia which was across the board increase at least two fold in all of these studies. And wait game which was prevalent in all of these studies. So in short, no randomized trial to date demonstrated a Nike vocally that glucose control provides macro vascular benefits. The U. K. P. D. S. Uh You know the benefit was only shown for AM I after a long 2010 10 year extension After the 10 year of intervention. It was the lowest population to begin with out somehow outdated interventions there. The court showed a benefit for a my but it really was stopped for death. So I'd rather keep my patients alive if I can the A. T. T. In advance did not actually show a benefit. So you know we don't have that that unequivocal support for glucose control. And I'm sure a lot of people are asking about what if we intervened at the wrong time? What if we got the wrong population? What if we use the wrong drugs? What if we stop too short? And what if still glucose is good for lowering blood sugar? And I would say we're probably never gonna have another study comparing different glucose controls. And and this is why, you know, we now have at least two classes of glucose lower engagements that have been proven anarchy vocally with standard of care with with like the highest standard of evidence now available in randomized controlled trust against placebo on top of standard of care showing that these agents lower the risk of events of my stroke and heart attack in a significant fashion. Not only that, but one of these classes, the Stld two inhibitors in patients at high risk for atherosclerotic cardiovascular events, Even lower heart rate, hospitalization, heart failure, hospitalization by more than 30%. So also these patients, these uh these classes the STLD do inhibitors showed in patients with heart failure with reduced ejection fraction, a very significant result on prevention of hospitalization for heart failure, both in patients with heart failure with reduced ejection fraction. And now, the latest study on heart failure with preserved ejection fraction also also showed a significant benefit. So, if that's the case. All of these agents are glucose lower engagements? Right? So you're probably gonna ask me, well, are these cardiovascular benefits that we're seeing with these GLP one receptor agonist actual T two inhibitors due to low glucose lowering there because lower engagements after all. So, here's what I want to show you about that. Well, first of all, this slide is not showing well, but I'll tell you what this side, it's all about. Uh in the in every study, every cardiovascular outcomes study that was done looked at the effect of the primary endpoint, the maze by baseline hemoglobin. A one C not in a single one of these cardiovascular outcomes study. Did baseline a one C make a difference when it came to the effect of the drug on mase. I wanted to highlight here that the one study and unfortunately this is cut off. But in the early one study was interesting because the inclusion criteria did not have a lower entry criteria. So even patients with an A one C of five could have been enrolled in the study. And actually the starting a one c in this study was 7.3 overall. So quite normal, I would say. And still it showed a significant benefit of doula glue tied on major cardiovascular events. We have also various evaluations like in the canonical gospels in this is one of the examples also we look by baseline hemoglobin, a one C. And there is really no significant difference uh of baseline A one C onto the overall endpoint. So I would say the effect on Mace does not depend on baseline a one c. Not only that, but some of the heart failure studies these big heart failure studies enrolled patients with as well as without diabetes. And uh these are the results broken down by diabetes status and this panel is for patients with heart failure with reduced ejection fraction and this one is for heart failure with preserved ejection fraction. The result on heart failure. Hospitalizations was irrespective of diabetes status exactly the same results exactly the same. Prevention of heart failure, hospitalizations, whether your patient had diabetes or not. So what I would say is that the fact of these agents do not even require the presence of diabetes. All right. So then you're gonna say, well, there's some studies suggesting that the lower the A. One C reduction, the greater the A one C reduction during the study. The greater the results on May's reduction. All right. That's a tough one to de tangle because there's a lot of confounding here that we have to deal with. But here's some data that might help. All right. So, this is the emperor which is the mpeg levels in versus placebo cardiovascular outcomes study and the mediation analysis that will start. So, if we look here, a lot of different variables were analyzed to look into whether each of these contributed to the prevention of maize and cardiovascular that that was seen in the study. A one C. And fasting plasma glucose are the first to hear on the list that were evaluated and well these were significant contributors. Their contribution to the effect faded in comparison with some other factors. Some of these quite surprising like hematocrit or albumin or uric acid. So the contribution of glucose lowering is fairly small. Another mediation analysis was done in the leader trial and different methods were used of course. You know that statistics are statistics and these are all sort of backward analysis and post hoc analysis. But this is sort of the most um uh This is the one point of data that showed the greatest association or the greatest mediation by hemoglobin A one C. And in this case it was as high as 82%. All right. But like I said, depending on which way they looked at it, the 82 was the most uh the most contribution that the agency might have had to the beneficial effect. So I would say that these data are important to to look at but take with a grain of salt because you don't know if this lowering in a one C. That these drugs achieve are really just a market of an unmeasured factors. So basically is it a confound er these drugs happen to also lower a one C. But is that just a confound er or is that truly why their glucose lowering effects that we're seeing their their cardiovascular prevention effects that we're seeing. So I would say that the changing glucose during the trial probably has a minimal contribution to the cardiovascular outcomes but that the majority of the effect is not explained by the changes in glucose nor blood pressure. No wait no lipids or on and on suggesting that for these particular classes the direct effect of the drug on SV your heart failure is the prevailing effect. All right. So you're probably gonna tell me that the purest experiment as far as glucose and and lowering a microvascular complication should come from a type of model because you don't have the confounding of insulin resistance of weight of a bazillion. Other risk factors for cardiovascular disease. And here glucose lowering its at its pure purest effect. And you can be tangle this question. Well there was a landmark study from a landmark publication from this study in 2000 and five in New England Journal of Medicine which reported on the 20 year follow up of patients enrolled in the D. C. C. T. And then continued in the edict study and they reported an astounding Over 50% reduction in macro vascular events. So these were nonfatal MI stroke or death from cardiovascular disease. So mais events Over 50% reduction. So absolutely mind blowing. Right. But let's look at this for a moment. We're talking about 11 events versus 25. And if you look at the two curves It takes way it took way longer than 10 years to see the two curves significantly separate from each other. So, yes, it probably makes a difference. But in in absolute terms it's quite a small difference that glucose control contributes to the lowering in micro vascular complications and this. I want to bring you to this and leave you with this because it's an important point that how much glucose contributes to in the big scheme of things to the risk of cardiovascular events needs to be put in context. When you compare that with how much lowering cholesterol contributes or how much blood pressure lowering contributes. It's a much smaller contribution. So lowering cholesterol by one million more or lowering blood pressure by 10. Mercury gets you about twice the effect on on cardiovascular events compared to lowering lizzie mia by or a one c by 1%. So in the big scheme of things, not that it's not important, but the contribution of glucose lowering it's much less than managing all these other risk factors which are more important. All right. So, here's what my conclusion is from all of this. In patients who have heart disease and diabetes, you want to prioritize your approach first. You want to start with guideline directed medical therapy. What that is is the fancy term for drugs with proven benefits to decrease events. And by that, I mean, the SGL T two's and the GLP one receptor agonist. Now, luckily there's also lower glucose. So you don't have to you know worry about that too much. But those have proven effects on cardiovascular events. And before anything else you want to get your patient on one of these also intensively control modifiable risk factors, lipid blood pressure, smoking. Wait, these have a great contribution to reduction in cardiovascular events and then if your glucose is still above the target, I'll come back to that in a little bit. But if your glucose is still a concern to you, yes, by all means lowering glucose will get your patient a little bit of extra added benefit in reducing complications. But please only do so while avoiding hypoglycemia in your low risk patients without cardiovascular disease. Focus on sustainable lifestyle changes and then treat all existing modifiable factors including glucose but favor agents that do not promote waking. All right. So all of these are pretty much reflected in the A. D. A. Standards of care. This whole left side here shows the cardiovascular patients. The patients with A. S. C. B. D. With heart failure. CKD I haven't talked about that today. But basically guideline directed medical therapy. GOP one's as Sheldon shoes are recommended Independent of based on a one C independent of your agency target independent of Metformin use you should use this on the right side are all the patients without cardiovascular disease in those I would say focus on promoting weight loss. That's minimizing hypoglycemia and that's what's gonna get you the biggest long term benefit. All right. So I've shown you that maybe glucose matters but not a whole lot when it comes to your heart. You don't want to neglect it now. So here's what you get for glucose control. There is strong evidence that managing glucose will avoid symptoms of hyperglycemia. Now we're really talking symptoms when your glucose is really high. It avoids hyperglycemia crisis, it minimizes microvascular complications. But keep in mind that this relationship with the micro vascular complications is hyperbolic. Your impact of A one C reduction is much greater when you're going from 12 2011 A one C than if you were to go from an eight to A. Seven. So keep that in mind. There's some evidence that maintaining good glucose control. It prevents macro vascular complications and decreases risk of infections. So how do you put all of this together? It's all about the balance. I draw the line at 9%. Above 99%. It's no excuse range. I don't care. You should not have any patient with an A one C overnight. There's no excuses for that. Below nine. It's the area. I call it a marginal return and I'm not saying marginal return in a derogatory way because I want to highlight it is a return range but your return is much less in this range. So therefore it's all about balancing it all balancing the burden that cost the side effects with what you're getting out of this improvement In this range below 9%. So I'll give you an example if I have your 80 year old grandmother on three oral agents and you're asking me if you should with an A. One C. Of eight and you're asking me whether you should start insulin, I'd say please don't. Now if you have a 26 year old with diabetes and A. B. M. I. Of 40 and an A one C. Of eight uh sorry. And then a once you have 6.7 and you're asking me am I good here on Metformin alone? I'd say no, you should go for lower. You should add probably a GLP one receptor agonist and get the patient to lose weight. A. b. m. I. of 40 in somebody with diabetes, 25 years old. It's not okay. You can get to a much lower anyone seeing that in that patient population, especially if you're doing it safe, especially if you're not adding the 15th medication to their medication list And you're not going to have any significant side effects then yes, go for it. And if you can get to five A one C go to five A one C. As long as you're not burdening that patient, you're not creating side effects and you're not bankrupting it bankrupting yup. All right, So what have I told you today? I've told you that glucose matter. But how much it matters varies by the population and the priority of glucose control. Most importantly. Various by the population and the target. Various by the context. But what it's not controversial is that the cardio renal benefits of GLP one receptor agonist and Nashville between inhibitors are largely independent of their glucose lowering. And you should definitely use those in your patients with cardiovascular disease. Thank you ill be. Thank you so much for presenting that information data and really beginning to look at a more unique view of how we should manage um glucose within our patients. Um, you know, a couple of different things. Um I'm thinking about these large diabetes registries that we have here in our health system and they existed many health systems across the nation and they have these cut offs that are rather arbitrary. You know, a one c below 8%. This is where you want to get all your patients and those above um you need to target to get them down there. So allowing this individualization that you're talking about uh make sense. But in registries it doesn't always account for that. So I'm just wondering we need to be able to have that ability to say, you know, for one person it's okay to have a little bit higher for another person. We really do need to um to shoot for those lower targets. That's just sort of a comment. But but the other piece of that is part of these registries also have blood pressure in them and we seem to not be able to control blood pressure sometimes as well as glucose, but that's a huge factor. That's incredibly important. Absolutely. So, like I said, blood pressure probably makes even a bigger benefit at the biggest impact on cardiovascular event lowering. So we should definitely focus on that before worrying about the name on survey. Yeah. As long as your patients already on the right medications for uh, for diabetes. So let me go back to a question that was asked earlier in the day related to you have someone that has diabetes. It's on a couple of medications, Metformin and GLP one receptor agonists. We know that our GLP ones nowadays can be incredibly potent and drop someone's a one C 25% or six, you know, low sixes. Um, if they're doing well on this combination, would you stop it or reduce a medication? All right. So there are different scenarios here. But the one clear answer is no. And that's if you have a patient that doesn't have cardiovascular disease. Really, what you're looking at is what are the additional benefits that you're getting from these agents and what you're getting from this job you want receptor agonists are the weight loss and protection from long term weight gain and you're definitely wanting that you have the additional benefit on inflammatory markers on blood pressure, on lipid. So, you want all these sort of holistic benefits of these agents and again providing you're not you're not bankrupting your patient, providing your they're not really sick of their stomach all day long and they can function. But if the patient is doing well and they can afford it, you should keep the patient on these because again, You still have benefited lowering agency from 7-6-5. The benefit is the benefit is decreasing, but you still have a benefit. So if you can do it without causing a lot of problems, you should not back off in a patient with cardiovascular disease. I'd say hell, don't back off. You need these agents. They are proven to lower cardiovascular events. So if you want to back off back off of Metformin because that one is not proven to lower cardiovascular events. But you should never back off on medications that I labeled this guideline directed medical therapy. No matter what your A one says, you should keep those on. Thank you. So in 10 seconds a question I asked Darren. First line therapy, Should we be thinking about these other newer agents rather than metformin for a patient with heart disease. Yes, and 88 finally updated that guidance. Now in 2021 and even 88, that was sort of the last stronghold for format forming us. The first line therapy has made the notation that you should studies agents irrespective of baseline metformin therapy. Excellent. Thank you so much Hildy, this was fabulous. Really appreciate your being here
