Dr. Darren McGuire discusses modified therapies to optimize cardiovascular disease risk mitigation in patients with diabetes.
So our next speaker is Dr Darren McGuire. And uh I've worked with Darren before on cardiovascular outcomes trials. He is an amazing cardiologist and has really specific expertise in the conduct of cardiovascular outcome trials in people with diabetes. So very specialized niche. And you've done a ton of work in this area. Uh Darren your uh he is a professor in the department of Internal Medicine at U. T. West Southwestern um in addition to working on large scale international clinical trials and he's also done registries at the Duke Clinical Research Institute and really has a specific research interest in long term prevention of cardiovascular disease. You're gonna put yourself out of business Darren. Right, But that's okay, it's the right thing. Um and in particular his work has revolved around people with diabetes. So we're very lucky to have you here with us today, Darren, uh Darren is going to give us two lectures first, really related to underlying effects of diabetes on the heart. Will take a few minutes break if you have questions on those and then he's gonna move on to the CBO cheese that have been conducted directly in people with diabetes. So Darren. Okay. Hi thena thank you for that introduction and and for having me at this symposium. Um it's great as a cardiologist to be convening with endocrinologist and primary care providers to to get to the to the heart of diabetes which has been my focus of research and clinical practice for now, about 25 years Unfortunately um in the last 5-10 of those years we've been developing all of these outcomes evidence are all of this outcomes evidence to help us treat these patients and improve outcomes. These are my disclosures, all of which have to do with the design and conduct of large scale randomized clinical outcomes trials and the cardio metabolic space. And just to show you where we are. So it is clear that diabetes is associated with increased cardiovascular risk. But we've really made a lot of progress. You know, we hear all the time that cardiovascular disease is the number one cause of death for patients with diabetes, but at least in the United States. And we also have data like this from Sweden. That really hasn't been true since about 1999. And as you can see here, these are the cause attributable causes of death. Um age and sex adjusted in the United States by epics of time from 1988 to 2015. And as you can see in the blue bars, that's cardiovascular death. The green is cancer. And um the pink is non vascular and non cancer. So everything else including infections and trauma and everything else. And so as you can see since 1999, the blue bar is no longer the number one cause it's it's non vascular non cancer. And we've been whittling away at that ever since 1999 there's been about a 40% reduction in cardiovascular death risk agents X adjusted and an overall mortality associated with diabetes. And so we've made great progress across the board. But again, as recently as 2015, our cardiovascular disease is still attributing a third of the death deaths in patients with diabetes. So we still have a lot of work to do. But we are making progress. These are data from the Swedish national diabetes registry. I had the privilege of collaborating with these authors on this paper and I'll show you a few slides from this uh this uh set of publications that we have from the Swedish National diabetes Register. What you can see here is patients in blue are patients with Type two diabetes in the registry and patients in red represent five age and sex and county of residence matched controls. So blue with diabetes read without diabetes. This is about 500,000 patients with diabetes and about 2.5 million patients without diabetes. So, a huge data set from 1998 to 2013. And on the left, you can see with cardiovascular death. Similarly to what I just showed you on the previous slide as we are making headway in both patients with and without diabetes for age and sex adjusted cardiovascular death risk. And as you can see if you squint your eyes, these curves on the left are are converging slightly. So not only are we making progress in both groups, the progress is slightly faster with type two diabetes. And that means we're slowly whittling away the incremental risk associated with diabetes, but still there's almost a two fold higher risk with diabetes at the end of the study. Similarly, with myocardial infarction, the convergence is much more evident. We're doing much better at whittling away risk associated with developing acute coronary syndrome complications. And here we've reduced the risk from almost uh from over two fold to about 1.5-fold increased risk still somewhere to do but making progress patients with diabetes as you know, have a burden of cardiovascular risk factors in this Swedish national diabetes registry, patients with an average age of 65 slightly leaner in Sweden and they would be in the United States A. B. M. I just under the obesity threshold, 60% had diagnosed and treated hypertension. Over a third had diagnosed hypercholesterolemia and still 13% were smoking. And so not only is diabetes or risk but associated cardiovascular risk factors drive that risk even higher. This is an analysis from that same data set is fairly complicated and I'll walk you through it. But we identified the five key predictors of cardiovascular risk among these patients with Type two diabetes listed on the left here, um elevated blood pressure, elevated LDL cholesterol higher than target Hemoglobin. A one C. The presence of albumin urea and active smoking. And as you can see from the top to the bottom. We've clustered patients who have no risk factors out of range at the top all the way to all five risk factors present at the bottom. And as you can see as you add risk factors going from the top to the bottom, the relative risk increment of patients with diabetes versus the cohort without diabetes continually gets higher. And so the more out of range cardiac risk factors you have, the more they accelerate or exaggerate the risk associated with diabetes. But the corollary is at the top. If you have all of your risk factors within therapeutic range, either whether it's medically treated or de novo in range, we could not detect any additional cardiovascular risk across all age groups associated with diabetes alone. So this tells us that we have hope that if we treat effectively the cardiovascular risk factors in patients with diabetes, we should be able to materially affect their cardiovascular risk. And that's also depicted in a different way on this slide. We've added a few risk factors to this multi variable statistically adjusted model. So we have hemoglobin a one C as we did before. We have now broken hypertension down into systolic and diastolic blood pressure, LDL abdomen area and tobacco use are the same as we used before. And now we've also added B. M. I. To the model and once we add all of these to the model and adjust for them, there's almost no detectable difference associated with diabetes versus their controls with regards to cardiovascular risk. As shown here again, underscoring the importance of risk factor monitoring and risk factor control for these patients. Now we've heard for years and largely from the East west study in Sweden of patients with diabetes that diabetes is a coronary disease equivalent. And that's really not true. We took all of the patients in this in the uh the infrared outcome trial. And we stratified them by baseline characteristics and modeled their cardiovascular risk as we detected in the trial. And as you can see for for all of the individual outcomes listed along the bottom cardiovascular death, all cause mortality, three point mace, which is cardiovascular death. Myocardial infarction and stroke. If we look at hospitalization for heart failure or the composite of hospitalization for heart failure or cardiovascular death. Within each of these outcomes, you see a clear gradient of risk when we do multi variable modeling and we took we took all of these risk factors on the left and we developed an integer score and then we divided the cohort in the trial into court. Als. And so by quartile of estimated risk at base using baseline characteristics, we actually observed an increment of risk as we would have predicted. and it ranges from 3 to 6-fold increased risk. And if you look all the way over at the at the far right, the cardiovascular death or hospitalization for heart failure. There's a six fold increased risk across the gradient. And so all patients with diabetes are not the same. And these are patients who have prevalent atherosclerosis as was an eligibility criterion for getting into the infrared outcome trial. And so even among patients with cardiovascular disease there's individual risk that we still need to pay attention to and titrate therapeutics according to their risk. Now we've known for a long time, at least the signal from this trial, the steno um to study from the steno diabetes center in Copenhagen. They took 100 and 60 patients who had cardiovascular risk identified by albumin urea in Type two diabetes and randomized them 80 versus 80 to usual care versus multifactorial intensive control. So the patients who got intensive control had Lifestyle counseling at every intervention. They had an aggressive hemoglobin a one C target of 6.5 A cholesterol target. Total cholesterol target less than 175 triglyceride. Target less than 150. An aggressive blood pressure target of 1:30 over 80. Uh the use of aces and arbs, the use of aspirin and exercise counseling and monitoring, pushing towards 150 minutes per week. Now these are very aggressive targets even in today's standards and this trial was eight years in follow up and was published in 2003. So, so this trial must have been designed around 1990 or 1991. So that was even before the first statin trial. So these were really forward thinking investigators and very aggressive targets that we would consider aggressive targets today but appropriate targets for most in most cases. As you can see on the right, the cumulative incidence curves. The curves begin separating within the first year and continue to diverge throughout the eight or the eight year follow up period. And you can see over a 50% relative risk reduction for a multiple component cardiovascular outcome. So it's a small study. It's only 160 patients. There's not that many total events, only about 36 events total, I think in this first analysis eight years. But they did achieve statistical significance. And of course, um, the curves demonstrate what we might expect if we aggressively controlled every risk factor. This is the same study except now continued for uh, for five years of passive follow up after the eight year randomized treatment. And you can see on the right the curves continued to diverge even after the protocol. Ized intensive care stopped. And so this is a bit of a legacy effect of the multifactorial cardiovascular risk mitigation. And there's remaining statistical significance. Even out to 13 years. Follow up. So again, underscoring the importance. So how do we mitigate the cardiovascular risk? Well, the end all be all is not glucose control. Glucose control is safe. And we have a number of medical therapies that have been proven safe from a cardiovascular perspective, but there's very little cardiovascular risk mitigation associated with intensification of glucose control. As you can see in the top panel that's a meta analysis of the intense more versus less intense glycemic control trials. Myocardial infarction is statistically reduced by 15%. So a modest relative risk reduction for M. I. But at the bottom unfortunately all cause death. And then we see the same thing for cardiovascular mortality. There's no signal of benefit for all cause mortality or cardiovascular mortality associated with tight versus less, tight by statement control. It's not to say that glucose control is not important. It's important for many other things. And it may be that we have not studied these populations long enough to detect a benefit that may be present. And so I'm not gonna throw glucose control out with the bathwater. It's still a very important part of the care of these patients. But we have to expand our focus um to tend to all of the risk factors for cardiovascular disease. Mm What do we know about blood pressure control? More versus less intense. If you I'll just call your attention to the middle of this slide. If we look at various cardiovascular outcomes, there's no clear signal that treating to less than 130 target makes incremental improvement except for stroke. And it does look like there's slightly more risk reduction. If your target is less than 1 30 vs. A targets anywhere north of 1 30. And usually that would be less than 1 40 target. So we still believe in cardiology that you should try to intensively control patients with diabetes with regards to blood pressure control and for those patients who can tolerate it without adverse or side effects. I think a target of less than when 30 remains fairly sound and evidence based. Of course we know status work for patients with diabetes. These are this is an individual patient level meta analysis of all of the statin trials, stratify patients by diabetes and the top point estimate and no diabetes in the bottom. And you can see there's exactly the same relative risk reduction with statins and among patients with diabetes and no diabetes. And because patients with diabetes have a higher absolute risk, the number needed to treat with a statin to prevent a cardiovascular outcome is lower in patients with diabetes than those without diabetes. So it's a more cost efficient intervention in patients with diabetes. If you want to try to stratify parcel out the relative contribution to cardiovascular risk reduction associated with the targeted therapeutic interventions, you can see on the left for four millimeters of mercury lowering you get a relative risk reduction of 12.5% Her one million low per liter, which comes out to 38 mg per deciliter. Um you get an additional 8% relative risk reduction And glucose control on the right. Again, it's not zero, but it's it's it's a smaller relative to blood pressure and LDL cholesterol, but you still get an additional 3% relative risk reduction for a composite of cardiovascular outcomes and again this is all modeled data from the randomized clinical trials. We focused a lot of our attention over the past few decades on a three. Socratic cardiovascular disease in patients with diabetes. But what has really come to the forefront in the past five or so years as heart failure, we've had an increasing awareness of the risk of heart failure is as at least as strong as the risk with atherosclerotic cardiovascular disease. And as we were whittling away the risk of A. S. C. V. D. We were failing to address the risk of heart failure. Heart failure is the second most common primary cardiovascular diagnosis among patients with Type two diabetes, peripheral arterial disease leading the way. Which was quite a surprise to me honestly. Um Nonfatal mes scheming stroke and cardiovascular death are all less frequent than heart failure in patients with Type two diabetes. And so again underscoring the importance of paying attention to this important risk factor. These are data from the U. S. National inpatient sample. Heart failure remains the number one reason for admission in the United States to acute care hospitals. And it's the number one cardiac cardiac reason for admission as you can see in the red plot at the top that represents heart failure in both women on the left and men on the right heart failure among patients with Type two diabetes is the single most common cause of heart of hospitalization and as you can see as recently as 2014 on the far right. Um, there's um, there's still a predominance of heart failure, hospitalization. And so we have to work on this risk factor. Getting back to our data set from the Swedish National Diabetes Registry. This is heart failure plotted again in the blue on the top are patients with diabetes in the red or ambulatory control agent, sex and county matched 5-1. And these are heart failure, diagnosis of heart failure, not just hospitalization but any diagnosis. And you can see there's more than a 2.5 fold higher risk of heart failure with patients with diabetes at the end of the study. So again, a lot of work to do. So like we did in the infrared outcome trial. We've taken data from several studies now and developed a heart failure risk score. So, using the characteristics at the top, we've modeled and developed an integer based risk score of patients without Heart failure. But with type two diabetes, the risk of developing heart failure during the follow up period. So over a five year follow up period, these are data from the accord randomized trial um, were able to demonstrate that are integer based risk or nicely stratified patients into cardio are into a risk for heart failure. And so again many of these are the very same risk factors for coronary artery disease. But we also add now things like QRS duration we've now added, creating as a kidney marker of risk where kidney disease is much more associated with heart failure than atherosclerosis. And again, of course, hypertension and age. And again when we look at tight versus less tight glucose control with regards to heart failure risk mitigation, we get a big fat zero. It's a point estimate precisely of 1.0 which means there's absolutely no signal of benefit, there's no signal of harm, um increasing risk for heart failure. But we're not moving the needle favorably when we tightly like glucose control patients um with regards to the specific outcome of heart failure. This is a plot just like I showed you before with risk at this time, the risk for heart failure. If you have no risk factors out of control, but you have diabetes at the top, it's a very different pattern. You remember, remember, for the A. S. C. V. D. We had all of these point estimates were lining up along the line of unity where which means if you control all the risk factors, you may not have any incremental risk with diabetes. In this case, if you control all of the risk factors, you still have a gradient of risk associated with age across patients with diabetes with increasing risk for heart failure and as you get more and more going from the top to the bottom of this plot more and more risk factors out of control. The point estimates go further and further to the right meaning a larger magnitude of incremental risk. And if you see at the bottom a 55 year old person with Type two diabetes and all of the risk factors out of control has 11 fold higher risk for developing heart failure. So very high risk. Even when all of the risk factors that we think about for A S. C. V. D. Are controlled and adding to that multi variable of point estimate plot I showed you before where if we adjust for all of the risk factors, most of the risk for A. S. C. V. D. Vanishes Not not the case for heart failure hospitalization. At the bottom you see almost a 50% higher risk for heart failure, hospitalization associated with diabetes even after adjusting for all of the risk factors associated with it. So I'll stop there. We know that patients with Type two diabetes are at very high risk for A. S. C. B. D. And heart failure. It's driven significantly by concomitant cardiovascular disease risk factors. The risk factors should be assessed in therapy is modified to each encounter to optimize cardiovascular risk mitigation and again that goes way above and beyond glucose control considerations. We have to maintain our focus on modifying the classic risk factors for cardiovascular disease as I've shown you. Glucose control has modest effects. But we have novel anti hypoglycemic agents that now have been proven and I'll show you in the next talk some of the granular data about A. S. C. V. D. And or heart failure risk that are independent of glucose control. So uh we'll take a positive questions absolutely. If anyone has any questions please send them in and I might touch on one that was asked earlier. But I just have to say after listening to all this um Darren the sort of the big message that I hear is we have to control risk factors and we probably have to do it very early on because even when you talked about heart failure what drives the development of heart failure? It's you know if someone's had cardio uh atherosclerotic diseases that they've had hypertension. If they've had things that we haven't controlled over time that then lead to that heart failure. And the most recent data shows The most rapid rise in diabetes is occurring in some of our younger populations. 30 to 40 years old now. So we need to start and be aware of this very early if we're going to do some interventions right. That's exactly right. Primary prevention for the classic cardiovascular risk factors is key as you can see on those plots going from the oldest age to the youngest age group. Almost paradoxically the relative risk increases as the age decreases People get often confused by that. But what that means is the younger people because they don't have all of the other competing risk driving the overall risk and accounting for for the outcomes. Then it's just diabetes alone. You've got a 55 year old with diabetes. They may have a five fold higher risk for all of the cardiovascular outcomes. And that risk is modifiable. And and so if we get to it early and so um and what we've learned in the glucose control field that you know fire away intensively early and you may want to liberalize as people get older and sicker. But the younger people who can handle the intensive glycemic control, it's probably gonna benefit them over a long legacy period. Same for hypertension. Not only are you preventing heart disease but kidney disease progression um aggressive control of LDL cholesterol is key for primordial prevention of atherosclerosis. And so these are these are important in everybody but very important in patients with diabetes. So that maybe brings me to another question. You mentioned blood pressure control less than 1 30 Which I agree on the A. D. A. Standards currently have pharmacological therapy for less than one if you're above 1 40. But I think I don't know how do you approach that, Do you? Is it individualized? Is it younger versus older? I think I do think it's individualized. I start at less than 1 40 and and and and and and really strive to get everybody at least less than 1 40. And then for individual patients who may tolerate it. I may push them a little bit to see if I can get by without bumping their creatinine or making them Ortho static. Um and and we find obviously, as you suggest, we find the younger, healthier people can tolerate a lower blood pressure. It's the so elderly and frail folks who may not tolerate it quite as well. Yeah, but you know, I don't I wouldn't target less than 1 30 but I might target 1 30 understanding there's a distribution around that. I think if we start targeting less than 1 30 we're going to have a lot of people in the one tens and twenties, which, you know, for some people they can tolerate that, but that for population is probably too aggressive. Yeah. Um I love the steno study and that you brought it up. It is a constant reminder when you do comprehensive management of all risk factors, what remarkable outcomes you can get. Do you think if they had access to the newer agents we have now that we would have seen even greater splitting of those lines? Yeah, absolutely. Um and the reason to say that is, you know, the patients enrolled in the recent outcomes trials that I'll get to in this next presentation. Um they're pretty well controlled. There's there's still no, like patients, you know, at study entry, it's really impressive to see, you know, 90% on aces and arbs 85% on a statin blood pressure on average is 1 35. You know, these are really well treated patients and work now stacking these novel anti hypoglycemic therapies and demonstrating incremental benefit on that background. So I do think the steno investigators would have shown that even even greater benefit if they had these agents. Yeah. Um, I know you touched on the glucose factors and there have not been outcome trials that say glucose control alone is enough to um, to make a difference in cardiovascular disease. Those many of the agents used in those trials were still agents that had a tendency towards hypoglycemia towards obesity. All the things that are not so good in terms of cardiovascular outcome trials. Um, doing you know, do we need anything else at this point? You know, it's a great point and we've had conversations as we design each new trial in this space, I've always pushed the sponsors to consider a couple of bells and whistles. One is let's say we have brand new STL T two inhibitor X and we want to study either against an active comparator or or a placebo. Let's add something to the trial. Let's add a factor of randomization and the two factors of randomization. I would love to see done one would be randomizing to Metformin or not to get to. The question is Metformin really necessary. Um, I would be, I would love to see that it adds to the benefit. And what we've been doing all along is correct, but I can't tell you today that I know that answer. So I think we need to get to that answer. And that was the spirit of the last question. The last session. The second thing I would love to see, a factor of randomization for is more versus less intensive control. I think it may be time to ask that question again. To your point. The accord. The advanced the V A. DT trials. They used combinations of therapies that we wouldn't use today. Um if we were trying to mitigate cardiovascular risk. So if we get to lower glucose, let's say, you know, targeting less than 6.5 versus 7.5. If we do that, get to 6.5 with a s guilty two inhibitor or GLP one receptor agonists or even a DPP four inhibitor, which does an increment benefit, but it certainly doesn't harm. So I think it would be reasonable to consider doing that trial again. I would love to see something like that. I agree
