Understanding the Diabetic Heart

Steven R. Smith, MD; Daniel P. Kelly, MD

Disclosures

February 21, 2012

Editorial Collaboration

Medscape &

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Steven R. Smith, MD: Hello, I'm Dr. Steven Smith, Professor at Sanford Burnham Medical Research Institute. Welcome to this segment of Developments to Watch from Sanford Burnham and Medscape. Joining me today is my colleague, Dr. Daniel Kelly, Director of the Diabetes and Obesity Research Center, and a cardiologist.

Today’s program will focus on key research addressing the effects of diabetes on the cardiovascular system, particularly heart failure, and how this research will affect clinical practice. Thank you for joining us, Dan.

Daniel P. Kelly, MD: My pleasure.

Dr. Smith: Tell us a little bit about how diabetes and cardiovascular disease intersect, particularly with regard to heart failure.

Dr. Kelly: As you know, we are witnessing a worldwide pandemic in obesity that is leading to, and has created, a secondary epidemic in type 2 diabetes. As cardiologists, and really for any physician who cares for either the diabetic population or patients with heart disease, it’s clear that the 2 have converged.

It’s actually very interesting -- but also very alarming -- that the usual types of therapies used for heart disease that have been developed over the years and have been shown by many different studies to be effective -- for example, after a heart attack or for preventing a heart attack -- are not working nearly as well in this diabetic population.[1,2]

So we have, on the 1 hand, an increase in the diabetes part of the equation, and we also have a more aggressive form of heart and vascular disease that seems to be perhaps unique and different from what we would call run-of-the-mill heart disease in the nondiabetic population. In many respects, we have a health crisis. It will be very important for us to try to understand the differences between what causes heart disease and vascular disease in the diabetic vs the nondiabetic.

Dr. Smith: Historically, heart failure has been treated fairly effectively, but mortality rates are still very high. Those treatments have changed through the years, particularly with the advent of diabetes-related heart failure. Tell us a little bit more about the pathophysiology so maybe we can begin to understand how that therapy is going to change in the future.

Dr. Kelly: That's a great question. As you know, the main drivers of heart failure, for instance, in our population over the past 50 years, have been high blood pressure, as well as ischemic heart disease, or heart attacks. And then, of course, there is a category of idiopathic forms of heart failure that probably represent a whole spectrum of diseases, from genetic to infectious and what have you.

The vast majority of therapeutic intervention trials have been aimed at these causes of heart failure, rather than diabetes. As you know, these therapies are largely aimed at what we call “afterload reduction,” which is reducing the impedance, or pressure against which the failing heart beats, as well as some therapies that are modestly effective, such as digoxin and other types of therapies, that are directed right at the heart itself.

These, as you’ve pointed out, along with diuretics and some of the other newer therapies, have had an impact on the mortality in heart failure. Although, quite frankly, it’s been disappointing because we still experience and we still see quite a problem in terms of mortality due to heart failure.

As it relates to the diabetic heart -- whereas these therapies are somewhat effective, as I had mentioned before, it would lead us to believe that there are metabolic components that contribute to heart failure that are distinct from what happens with, for example, high blood pressure or a heart attack.

Diabetes, as you know, is a metabolic disease, and it not only affects the ability of insulin to allow the tissues to take up glucose and use it as a fuel, but it also has profound effects on lipid and fat metabolism.[3]

Some of the work that we and others are doing in this broad field is to try to understand whether these metabolic derangements actually contribute, in addition to hypertension and heart attacks, to heart failure in diabetics (of course, these derangements run rampant in this population). If we could identify the component or contribution of each of these, it would, in essence, begin to guide us in a more personalized way to be able to treat the individual patient.

One patient may have more of a contribution of their diabetes. One patient may have more of a contribution of high blood pressure, or some combination thereof. Of course, we’re not even at a point where we know how to treat diabetic heart failure yet. So many studies are ongoing, both in the laboratory as well as in humans, and are aimed at looking at whether the metabolic derangements that are driven by diabetes begin to lead to the failing heart, and in many cases, for vascular disease that leads to heart attacks.

Dr. Smith: I believe that many people think about glycemic control in diabetes, but this issue of lipid metabolism is really interesting. Tell us a little bit more about that and how the research is informing the pathophysiology.

Dr. Kelly: Yes, this is another fantastic question. For years and years, because of the nature of what happens in diabetes, the investigators and the physicians have been, if you will, glucose-centric. That makes sense because, of course, the mainstay of therapy for a diabetic is to lower glucose, either with insulin or with hypoglycemic agents. But, interestingly, many studies have indicated that tight glucose control, whether it starts in the pediatric age group or in the adult age group, has not had a major impact on long-term cardiovascular events.[4] So as you point out, there seems to be another part of this equation.

What we’re beginning now to find, both in human studies and in preclinical studies, is that the diabetic heart begins to accumulate fat. This also occurs, by the way, in skeletal muscle and in the liver -- essentially in all organs.[5] These organs can't use sugar because the insulin is not working well, and therefore they’ve shifted over to use fat as the main fuel.

So you might think it sounds like a reasonable switch. The problem is that these organs -- and we believe the heart is included -- are taking up too much fat and developing what we refer to as "lipotoxicity."

There is significant evidence now that lipotoxicity actually contributes to heart failure through mechanisms that are not completely clear. But, if the accumulation of excess fat in the heart cell is reduced in animal models, the heart failure becomes much better.[6] And based on magnetic resonance spectroscopy [MRS] studies and other types of very sophisticated imaging in humans, the correlation of lipid accumulation within the heart is tied with the development of both diastolic and systolic dysfunction.[7]

This has been a very exciting finding but also raises the question of whether our current therapies for heart failure, which are not directed at all at the lipid problem, will be ineffective in the diabetic population.

Dr. Smith: That raises a clinical question: Is there any way now for us to sort this out in terms of being able to separate a more glucose or insulin-resistance mechanism from this lipotoxicity, or accumulation of lipid in the heart? Where are we in the clinic in terms of the ability to diagnose these different forms of heart failure in patients with diabetes?

Dr. Kelly: This is the Holy Grail, and it’s not only the Holy Grail for heart failure, but for many different diseases, and really underscores the importance of what we refer to as "personalized medicine." What we need, in the opinion of the investigators in this field, are biomarkers, which are diagnostic markers that will distinguish, as you point out, the different etiologies of the heart failure.

Wouldn’t it be great, for instance, to do a biochemical test or an imaging test or a genetic test, and be able to determine in a patient in your office whether his early heart failure was largely due to the lipotoxicity of diabetes, to hypertension, or to both?

We've made, as have others, significant progress in this area, at least in preclinical models. And there is hope now that with the combination of imaging lipid in the heart, metabolic imaging that looks at fuel utilization, and the broad area of what we call "metabolomics," which means measuring, detecting, and quantifying metabolites in the bloodstream and in the tissues, we believe that there is hope in the long term for developing personalized biomarker panels that, for the given patient who has heart failure with multiple risk factors, to be able to identify the main, or several main, drivers and to treat them accordingly.

Dr. Smith: So what can we look for in the next couple of years as these technologies get into the clinic? What is that going to look like for clinicians who treat patients with obesity and diabetes, and cardiologists treating heart failure? What's the next wave here?

Dr. Kelly: First of all, it’s important to note that many of these studies are being done at the preclinical level, so I think the clinicians can begin to look for studies in some of the more clinical journals that are human-related. As you know, some of the discoveries that occur in animal models or in cells don’t pan out. So the clinician should look for new studies that begin to put different categories of heart failure into different bins based on imaging or other biomarkers.

For instance, they will likely see studies come out that will use very sophisticated approaches for looking at lipid in the heart, MRS, positron emission tomography scanning -- those types of things. And the kinds of studies that will be published, I would predict, will really begin to look at whether the accumulation of lipid does track with the onset of heart failure, and whether lipid-lowering approaches make it better.

These proof-of-concept studies will pave the way for an explosion of different metabolic modulator therapies that might be useful, not only for the failing heart, but ultimately to prevent or treat the atherosclerosis, which is also quite aggressive in the diabetic population.

So it’s a very exciting time in this regard, and although the terms "personalized medicine" and "biomarkers" perhaps are sometimes overused, I think when you put them in this context, it begins to make a little more sense.

Dr. Smith: It sounds like we might be seeing a fundamental shift in the way we treat heart failure, moving away from afterload reduction, blood pressure control, and diuretics, for example, and into a more metabolic era of heart failure therapy. Tell us a little bit more about how that could work, and what we are going to see in the future in terms of these therapeutic areas. The diagnostics is absolutely fascinating, when you can bin individuals. But what will the therapies look like for lipotoxicity, for example?

Dr. Kelly: First of all, it’s not at all clear that the traditional therapies vs the metabolic modulators will be distinct. My guess is that the mainstay of therapies, afterload reduction or some diuretics, will be around for quite some time. It’s not clear that they’ll be replaced so much as that they wind up being a cornerstone, and then adding on something that is much more effective for a given etiology.

But getting back to your question about what would this look like -- it’s a great question, and there are several ways to think about this.

In the diabetic situation or in the insulin-resistant or even the obese patient -- even before overt diabetes -- as you know, there is constant bombardment of the heart of increased free fatty acids and triglycerides. This is from a combination of lipolysis and fat tissue and the liver working overtime to try to deal with all of the excess calories coming in. The excess calories have to go somewhere, and, after a point, the fat tissue expands until it cannot do so any further. It becomes “angry” and starts sending out other factors toward the other tissues.[8]

So, one of the culprits, interestingly enough, is the fat tissue itself. It needs to quiet down and perhaps regain its ability to hold onto the fat instead of sending it over to the heart. You could envision therapies that actually are aimed outside of the heart, such as at the fat tissue or the muscle tissue or the liver, that would actually burn up the fat. There are a number of different programs looking at this, not only for heart failure, but for obesity and insulin resistance and diabetes.

It could pan out that the therapies that are being looked at for obesity and insulin resistance will have profound benefit for the heart itself. With that said, there is also quite a bit of interest in developing metabolic modulators that are aimed at the heart per se. One possibility would be to burn the fat right within the heart. Another might be to close the door on the fat, so to speak. The fatty acids enter the cardiac muscle cells through cell-surface transporters, such as CD36 and other fatty acid transporters,[9] and it would be interesting if therapies could shut down the import of this excess fat. That, of course, does not get at the total body problem, but it would be helpful for the heart itself, maybe in conjunction with obesity therapies.

The other types of therapies are those that might allow the heart to begin to use appropriate fuel again. Of course, insulin would be the best thing to use, but these patients are generally insulin-resistant, so they don’t respond to that. And most of the hypoglycemic agents, interestingly enough, work in the liver or the muscle and not the heart. There is real interest in developing agents that would increase the ability of the heart to use glucose again, which, almost like a teeter-totter, would then reduce the amount of fat going in and would provide a healthy balance of fuel for the heart.

Dr. Smith: That was a very interesting topic. Thanks, Dan, for participating in this program.

Dr. Kelly: It’s been my pleasure.

Dr. Smith: And we both would like to thank you for joining us today. I hope you will join us for additional programs in the Developments to Watch series on Medscape.

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