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Carol H. Wysham, MD: Hello. I'm Dr Carol Wysham. Welcome to season three of the Medscape InDiscussion: Type 2 Diabetes podcast series. Today we'll discuss new insights into heart failure and type 2 diabetes.
First, let me introduce my guest, Dr Christopher Kramer. Dr Kramer is a cardiologist at the Heart and Vascular Center at University of Virginia (UVA) Health. His areas of expertise are hypertrophic cardiomyopathy and cardiovascular imaging, including echocardiography, cardiac magnetic resonance imaging, and cardiac computed tomography. He is the George A. Beller/Lantheus Medical Imaging Distinguished Professor of Cardiovascular Medicine and the chief of the Cardiovascular Division at UVA Health. Dr Kramer, welcome to the Medscape InDiscussion: Type 2 Diabetes podcast.
Christopher M. Kramer, MD: Thank you for having me, Dr Wysham.
Wysham: I'd like to start by having you discuss the increased risk for congestive heart failure in patients with type 2 diabetes.
Kramer: As it turns out, the incidence of heart failure is two and a half–fold increased over a group of patients without type 2 diabetes. The risk factors that increase the likely prevalence of heart failure in this group include diabetes onset at a younger age, underlying coronary disease, hypertension, elevated body mass index, obesity, and poor glycemic control. Other markers associated with obesity, including increased waist circumference and fat mass, are also associated with a higher incidence of heart failure in type 2 diabetes. As it turns out, type 2 diabetics make up 35%-45% of all heart failure patients, with a higher incidence in patients with heart failure with preserved ejection fraction (HFpEF) as opposed to those with reduced ejection fraction (HFrEF).
Wysham: I found it interesting when I learned that there's a marked increase in the percentage of patients with heart failure who actually have preserved ejection fraction. Do you want to comment on that?
Kramer: Yes. There is definitely a higher incidence of preserved ejection fraction. The combination of obesity, diabetes, and hypertension definitely leads to that higher incidence.
Wysham: Would you give us some insight into the pathobiology of why heart failure occurs in this population?
Kramer: It's complicated, in part due to the hyperinsulinemia associated with type 2 diabetes. Inflammation is a major part. Increased fat mass around the heart leads to an increase in adipocytes and the release of adipocytokines, which are hormones that lead to inflammation and hypertrophy, as well as oxidative stress. All of those issues lead to an increased incidence of heart failure. The other major issue that is brought on by obesity is reduced natriuresis, and that, along with diabetes, can lead to a volume overload state.
Wysham: That's really interesting. Is there a role of microvascular dysfunction and disease that we frequently see in patients with longstanding diabetes?
Kramer: Absolutely. Microvascular dysfunction is a major issue leading to heart failure. There can be a disorder of the microvasculature within the heart muscle. This leads to abnormal myocardial perfusion reserve, and that can lead to ischemia in the absence of epicardial coronary artery disease.
So, without atherosclerosis in the major epicardial arteries, there still can be ischemia in type 2 diabetics. Now, often, they have concomitant epicardial coronary artery disease as well, but you can have, due to microvascular disease, ischemia, an abnormal perfusion reserve without epicardial disease.
Wysham: Great. Thanks for that. You are probably aware that the American Diabetes Association has recommended routine screening for congestive heart failure in patients with diabetes. Obviously, there are patients who have symptoms, and that makes sense, but can you comment on whether it is appropriate to screen and who to screen?
Kramer: Yes. Symptoms are obviously going to be the most important tip-off as to who to screen. I think talking to your patient about exercise intolerance is the single most important question one can ask in terms of how far they can walk, whether they can go up hills, what happens when they walk their dog, and whether they can go upstairs. Any change in their ability to tolerate exercise should be a tip-off. If the patient is completely asymptomatic and able to do significant exertion without symptoms, I'm not sure that screening those patients makes sense. However, for anyone with any symptoms, and certainly older patients, I think screening may make more sense. There's a discussion about chest x-ray and B-type natriuretic peptide (BNP).
Chest x-ray, in my mind, is insensitive for heart failure, especially in this population. So that's a very late finding in heart failure, pulmonary congestion, and Kerley B lines or enlarged heart. That's a very late finding. Elevated BNP is probably the best single screening test for heart failure.
The problem with BNP alone is that it can be falsely low in obese patients with diabetes. Obesity actually lowers the BNP. BNP is probably most helpful in the nonobese diabetic, and we can get fooled in the obese diabetic, which was one problem with that biomarker.
Wysham: But if you have an obese patient with an elevated BNP, it's something that probably needs some follow-up.
Kramer: Absolutely.
Wysham: Do you think it's appropriate for the primary care endocrinologist to go ahead and order the echocardiogram while they await the cardiology consult?
Kramer: I certainly think it's reasonable if the BNP is elevated. I think getting an echocardiogram would be the first test we would order, and it's always helpful if that's done by the time the patient comes to see us.
Wysham: Let's move to the treatment of congestive heart failure. I know that there's a lot of interest in the incretin therapies, the glucagon-like peptide-1 (GLP-1), or the dual agonists for people with type 2 diabetes and comorbid congestive heart failure. Can you tell us about the known effects at this point?
Kramer: Yes, that's something I've actually been involved in with the SUMMIT trial, studies in obesity, and some of the patients with heart failure, so I'm happy to comment on the use of incretin therapy. As you're aware, the mechanism of incretins is that they regulate insulin and glucagon secretion by the pancreas. They can actually promote the proliferation of the beta cells. They're associated with reduced inflammation and oxidative stress, and from a cardiac perspective, they can actually improve left ventricular contractility, reduce systemic vascular resistance, and reduce end-diastolic pressure.
They have a lot of potential benefits in the heart, and more recently, clinical trials have shown us that they're especially beneficial in patients with HFpEF, which, as we've spoken about, diabetes is a major risk factor for that condition. HFpEF makes up about half of all patients with congestive heart failure. And we know it's the number-one morbidity and cause of hospitalization in the US. So, it is a major hit to the cost of healthcare.
In HFpEF, about 50%-60% of patients are obese, and 40%-50% have type 2 diabetes. So, in terms of how incretins work, they reduce weight. Most recently, the two major trials in obesity and heart failure, with preserved ejection fraction, are the STEP-HFpEF and the SUMMIT trial.
In the STEP-HFpEF, there was a diabetic subgroup of 616 patients who were randomized to either semaglutide or placebo. The active therapy group was associated with it. It was not an event-driven trial. It was driven by symptoms and quality of life. It turns out that the active therapy with incretins and the semaglutide was associated with an increase in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score, which is a quality-of-life marker. Body weight fell by 10%. The overall win ratio was positive, and the marker of inflammation, C-reactive protein (CRP), which is probably the best biomarker of inflammation, fell. So, certainly, evidence in diabetics with HFpEF is that incretin therapy is associated with those patients feeling better. That was the first step. The patients feel better and are able to do more exercise.
Then along came the SUMMIT trial, which was presented at last year's American Heart Association (AHA) meeting. There were four presentations, one of which was mine. Dr Milton Packer was the first author of the paper, which was the main principle findings of the SUMMIT trial. The SUMMIT trial involved over 700 patients with obesity and HFpEF, not all diabetics, but there was a good proportion of patients who were diabetic within that population, who were randomized to tirzepatide therapy vs placebo over the course of up to 2 years, but the trial itself was a 1-year event-driven trial.
The main outcomes were combined endpoint of cardiovascular death and heart failure events, primarily heart failure hospitalization. The active therapy with tirzepatide was associated with a hazard ratio of approximately 0.5 compared with placebo for that combined endpoint. Most of the difference there was in cardiovascular hospitalizations and cardiovascular events' requirement for intravenous diuresis. There's actually a numerically slightly higher incidence of death in the treatment group, but it was not powered for death, so there was no statistical difference. Most of the difference was in heart failure, hospitalization, and heart failure events.
Wysham: That's really important. What is your perspective on whether or not these studies are robust enough to get an indication for these medications for the treatment of heart failure?
Kramer: I feel strongly that these medications are very powerful, probably one of the best therapies we have, especially for HFpEF, which, until the past 2 or 3 years, we really had no therapy for. Now we have three classes of therapies that are beneficial in HFpEF. Those include sodium-glucose cotransporter-2 (SGLT2) inhibitors and the renin-angiotensin receptor antagonists, specifically finerenone, most recently shown at last year's ESC and published in The New England Journal of Medicine. Now, a GLP-1 agonist or incretin therapy is used. We can speak some more about the mechanisms of how tirzepatide benefited patients with HFpEF and obesity.
Wysham: Yes, please. I'd be interested in hearing that. I'm sure the audience would as well.
Kramer: There were three separate publications after the AHA meeting. Dr Barry Borlaug published a paper on the hemodynamic and biomarker findings associated with tirzepatide therapy in HFpEF and noted that active therapy was associated with a fall in blood pressure, so it had an antihypertensive effect, a fall in blood volume, it was anti-inflammatory, CRP fell, it improved renal function, GFR improved, and urine albumin–to-creatine ratio fell. There was a fall in biomarkers, both NT-proBNP and troponin T. So, clearly, a benefit in terms of the hemodynamics, inflammation, and myocardial injury with BNP and troponin, as well as improved renal function. So, across the board, there were very positive effects in these patients who were treated with active therapy with incretins. That was published in Nature Medicine.
The second paper, in Circulation, by Dr Michael Zile, showed that in addition to the improvement in reduction in cardiovascular heart failure events, there was improvement similar to the STEP-HFpEF trial with semaglutide. With tirzepatide, there was an improvement in the KCCQ score. Patients felt better. There was an improvement in the 6-minute walk distance. Patients not only felt better, but they were able to walk further. There was an improvement, a decline in the New York Heart Association class, and a reduction in the need for associated heart failure medications. So, not only is Dr Borlaug's paper showing improved hemodynamics, but it also shows improved quantitative measures of patient functionality. Across the board, tirzepatide was beneficial in this patient group.
The last paper was my paper, published in JACC. As you mentioned at the top of the podcast, my expertise is in cardiac magnetic resonance imaging, and I led the CMR substudy of the SUMMIT trial, which was a substudy of 106 out of the over 700 patients who entered SUMMIT; they had a cardiac MRI at baseline before entering the study, and then at one year the end of the study. Again, half were treated, half received placebo. Importantly, it really helped delineate the mechanism of how incretins work in HFpEF. There were two important differences in the treated group: One was a reduction in left ventricular mass by about 10%. So, as an anti-hypertrophic effect, it's multifactorial due to the reduction in blood pressure and natriuresis, which is basically the load reduction that occurs with incretin therapy.
The other major difference was a marked reduction by about a third in pericardiac adipose tissue. There are two types of pericardial adipose tissue, or two components. One is epicardial adipose tissue and the other is pericardial adipose tissue. That is adipose tissue separated by the pericardial layer. Epicardial adipose is between the epicardium and the pericardium, and pericardial adipose is external to the pericardium, between the pericardium and the chest wall. Most of the adipose tissue in these obese patients was visceral fat, namely pericardial adipose tissue. About 75%-80% of the fat was outside the pericardium, and that's where we saw that most of the decrement in adipose tissue with active therapy was in the pericardial fat, the largest component of pericardiac fat. So this helps us understand again the mechanism of how incretin therapies are working.
As the patient is losing weight on these therapies, pericardiac fat is melting away. That reduces the adipocytes, the adipocytokines, and the proinflammatory, pro-hypertrophic, and paracrine cytokines that are released by the pericardiac fat. This leads to overall hemodynamic improvement.
Wysham: That is really interesting information. How would you recommend the placement of the GLP-1 receptor agonist or the dual agonist in the management of patients with congestive heart failure? You mentioned the three different medications. Do you think they should be started concurrently? Or do you have any order of which you think might be more important?
Kramer: I think that that still needs to be worked out in HFpEF. We've really focused on the benefit of this class of medication in HFpEF. The benefits in HFrEF are less clear. I think in type 2 diabetes and obesity in HFpEF, we have clear benefits.
There are emerging data that the combination of SGLT2 inhibition and GLP-1 agonism may be complementary, additive, and even better. I think we need more studies with one, the other, and the combination. I don't think you can placebo-control them at this point, but looking at a combination better than either one will be important in this space to understand.
I think both SGLT2 inhibitors and GLP-1 agonists can be added to the renin-angiotensin-aldosterone blockade with finerenone or spironolactone. Although that TOPCAT study from years ago was negative, it's probably a class effect, though finerenone certainly has the stronger data associated with it.
All three classes of drugs are beneficial now in HFpEF. The order of how to stack them upon each other, I think, is less clear, and I think we'll find out in the coming 2-3 years whether there's a cadence of which to start first and how to add them on. But certainly, in the diabetic, where you're looking to control glucose, in my mind, SGLT2 inhibitors and GLP-1 agonists are preferable over the renal-angiotensin system blockade medications because you're treating the underlying disease in addition to treating the HFpEF. You're allowing weight loss as well as the benefits in terms of the effects on hyperinsulinemia, etc.
Wysham: Is there anything out there in terms of research or directions coming up in the next few years that you're excited about?
Kramer: Yes — more information about looking at subgroups and understanding, in all these trials, how diabetics fare vs nondiabetics. I can tell you that there are unpublished data from SUMMIT that suggest that the benefits of tirzepatide were similar in diabetics and nondiabetics. I think that's reassuring. We know that the weight loss in diabetics is somewhat attenuated relative to nondiabetics with GL1 agonists. But the benefits of, at least tirzepatide, appear to be equivalent, and also with semaglutide. In the STEP-HFpEF diabetes study, both agents were shown to be beneficial.
Also, understanding the mechanism and then understanding the cadence of which drug to start first, second, and third, and how to put them together. We now know in HFrEF that there are four pillars of therapy. We want to get all four medications started in these patients, and we start them at the same time. Research over the past decade has helped us there.
Now, with HFpEF, we have to do the same studies. I think that is the most important step in the next 5-10 years: Do we start them all at once? Do we start GLP-1s first? Do we hold on the MRAs? I think we have a lot to learn, and it should be exciting over the next few years to learn it.
Wysham: Coming from the endocrinology standpoint, because of the high association of kidney disease in patients with heart failure, it is likely that the patients are already going to be on a GLP-1 and an SGLT2 inhibitor before they even hit the door of the cardiologist's office. I want to thank you for a very interesting conversation about heart failure and type 2 diabetes, and the role of incretin therapies in management, particularly of HFpEF. I want to thank the audience for tuning in. I ask them to please take a moment to download the Medscape app to listen and subscribe to this podcast series on type 2 diabetes. This is Carol Wysham for the Medscape InDiscussion: Type 2 Diabetes podcast.
Listen to additional seasons of this podcast.
Resources
The Incidence of Congestive Heart Failure in Type 2 Diabetes: An Update
Hypertension in Diabetes: An Update of Basic Mechanisms and Clinical Disease
Insulin Resistance and Hyperinsulinaemia in Diabetic Cardiomyopathy
Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2024
The Paradox of Low BNP Levels in Obesity
Tirzepatide for Heart Failure With Preserved Ejection Fraction and Obesity
Beyond Weight Loss: the Emerging Role of Incretin-Based Treatments in Cardiometabolic HFpEF
Heart Failure With Preserved Ejection Fraction: Mechanisms and Treatment Strategies
Epidemiology of Heart Failure in Diabetes: A Disease in Disguise
Semaglutide in Patients With Heart Failure With Preserved Ejection Fraction and Obesity
Finerenone in Heart Failure With Mildly Reduced or Preserved Ejection Fraction
Spironolactone for Heart Failure With Preserved Ejection Fraction
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Cite this: Heart Failure, Incretin Therapies, and Type 2 Diabetes - Medscape - Apr 24, 2025.
