GLP-1 Agonists in HFpEF With Obesity: Are We There Yet?

Recorded July 21, 2023. This transcript has been edited for clarity.

Ileana L. Piña, MD, MPH: Hello, everyone. I'm Ileana Piña, professor of medicine at Jefferson University Hospital in Philadelphia. I'm the chief of quality. This is my blog. We have been hearing a lot of conversation about obesity. It's coming out of our endocrine division and our weight management division. And the patients are asking for things like bariatric surgery and maybe a holistic program of weight loss.

A lot of the primary care doctors are starting to recommend glucagon-like peptide-1 (GLP-1) receptor agonists for those patients. But we deal with patients with heart failure with preserved ejection fraction (HFpEF), and a lot of our phenotypes are patients with obesity who happen to have hypertension and/or diabetes, and they are difficult to manage.

Inflammation, Obesity, and HFpEF

Piña: For today's conversation, there is nobody better than Dr Ambarish Pandey, who has a HFpEF program at the University of Texas Southwestern. Ambarish, welcome. Give me your thoughts overall about the link between obesity, inflammation, and HFpEF.

Ambarish Pandey, MD: Thank you, Dr Piña. I'm excited to be on your blog and I'm glad that we are discussing such an important topic. The burden of heart failure, particularly HFpEF, has been increasing and is not just affecting older individuals. We see more younger folks with obesity in our HFpEF clinic coming in with symptoms of shortness of breath and fluid buildup. Our understanding of HFpEF has evolved quite a bit over the past two or three decades. Initially, it was thought to be a disease of largely impaired myocardial relaxation. And then Walter Paulus was one of the pioneers who proposed the concept of inflammation leading to HFpEF, and obesity being one of the important drivers of the inflammation that leads to the development of HFpEF.

Now our understanding of HFpEF has evolved to it being a multisystem disorder that leads to dysfunction in different organ systems. One of the cardinal features that drives this dysfunction is upregulation of inflammatory pathways, increased inflammatory burden — and a lot of that is driven by obesity. Obesity is one of the most important modifiable risk factors for HFpEF.

Piña: It is so common. In my clinic the other day, probably 3 out of 4 patients were obese.

Pandey: Up to 75% of patients that we see in our program are over the 30 BMI cut-off, and a lot of the literature that has come from US HFpEF cohorts shows a very high average BMI in these patients.

Piña: When we talk about inflammation, what are the chemical pathways of inflammation? For example, a long time ago, we tried to block TNF-alpha and it didn't quite work out. So, what pathways are we talking about?

Pandey: I think a lot more work needs to be done to really understand the key drivers of inflammation and what pathways are being upregulated. As we know, inflammation is most commonly identified by elevation in levels of C-reactive protein (CRP), which serves as a marker of increased inflammation, but the upstream upregulation in IL-1– and IL-6–mediated pathways has been implicated in inflammation that drives development of diseases like HFpEF.

There is an ongoing trial of ziltivekimab, which is an IL-1 inhibitor in patients with HFpEF (Editor's Note: ziltivekimab is an IL-6 inhibitor). That's the HERMES trial led by Paul Ridker, one of the pioneers of inflammatory therapies in heart disease. We are starting to understand more about the key molecular pathways that are driving it. And now we're starting to target them, with the hope that we can actually halt the progression of HFpEF and improve the symptom burden as well as the risk for adverse outcomes in these patients.

Are GLP-1 Inhibitors Anti-inflammatory?

Piña: Do you think that the GLP-1s, or even now the SGLT2 inhibitors, are anti-inflammatory since we really don't know all the pathways?

Pandey: I do think that GLP-1s, by virtue of causing weight loss and reduction in visceral adiposity and the bad fat depots that exist in our body, have a significant anti-inflammatory effect. And if you look at the data from the STEP trials that were done, looking at weight loss effects of semaglutide, a commonly used GLP-1 inhibitor, there was a good 30%-40% reduction in CRP levels, and that suggests that there is a significant anti-inflammatory effect. Now, whether it's a direct effect on anti-inflammatory pathways or is related to weight loss is a matter of debate.

Piña: Are you using GLP-1 inhibitors in your HFpEF clinic? And what trials can we look forward to seeing concerning the use of these agents?

Pandey: At least in our HFpEF patient population, as we talked about earlier, the majority are obese and have an indication based on diabetes or obesity for use of weight loss agents like GLP-1s. So, more than half of my patients who are obese or have diabetes are on a GLP-1 currently for management of their comorbidities as well as potential direct benefit in HFpEF.

I think more evidence, directly for benefits of GLP-1s in HFpEF, will be coming out with the STEP HFpEF trial that is being presented at ESC in Amsterdam in August. We are looking forward to the data from those trials, which will further consolidate the evidence, hopefully, in favor of using GLP-1s for management of patients with HFpEF.

Piña: I, for one, will be looking forward to hearing those results because, again, the patient population that I treat is seldom thin.

Pandey: Same here.

SGLT2 Inhibitors and Inflammation

Piña: When you're giving an SGLT2 to your patients, which we're all doing, do you think you're giving them an anti-inflammatory?

Pandey: With SGLT2 inhibitors I think it's a little more complicated. We have much less understanding of how they work and how they reduce risk for adverse outcomes. We know it works and it is a class I indicated therapy for HFpEF, so we use it in all our patients, but I use it for its pleiotropic effects.

It is one of those cardiometabolic drugs that improves almost every bad thing: It has been shown to improve kidney function, it has been shown to improve filling pressures in the heart, it has been shown to also have favorable effects on glucose. Just as HFpEF is a multisystem disorder, SGLT2 inhibitors are a multisystem regulator with favorable effects across different domains of the physiology.

I personally don't think there's enough literature to suggest that SGLT2 inhibitors are anti-inflammatory, but they are very effective in patients with HFpEF, and we have been using them quite a bit ever since the DELIVER and EMPEROR-Preserved trials came out.

Piña: So have I. Do you see weight loss in those patients?

Pandey: We do see weight loss in patients with the SGLT2 individuals, but every time I see patients, the most important thing that we do, in addition to pharmacotherapy, is lifestyle counseling and encouraging them to exercise, so there is always that component. If you're seeing an HFpEF expert or in a clinic, you will have other therapies that are going to lead to weight loss; but in the trials, there was some weight loss shown with the SGLT2 inhibitors.

Piña: I've never used a drug that's so easy to give. As long as I don't give it to a dialysis patient until we get those trials, at how low an eGFR can we tell our audience to use a flozin?

SGLT2 Inhibitors and Kidney Functions

Pandey: Given the results from EMPA-Kidney and DAPA CKD, as long as the eGFR is over 20 mL/min/1.73 m², I think you're in fairly safe waters for using SGLT2 inhibitors. I use them in almost everyone except those who are on dialysis. But then patients who are on dialysis, whether they have HFpEF or you're suddenly diving in, is another question.

Piña: In EMPA-Kidney, I think the lowest eGFR was 20, but it was in a smaller group of patients. Hopefully, more studies will come out to see if we're able to use it safely in the dialysis patient, because those patients are also in trouble and they often get hospitalized.

Pandey: Dialysis patients are some of the highest-need patients when it comes to cardiovascular risk modification. That's one population that has often been excluded from the guideline-recommended-therapy trials for heart failure. I agree with you completely. We need more evidence for that subset of the population.

Piña: Ambarish, thank you for your time and thank you for spending time with us.

For the audience: I think you've heard again how complex HFpEF can be sometimes with multi-comorbidities, and maybe the heart is almost an innocent bystander to everything else that's going on. Don't forget things like obstructive sleep apnea, which often gets overlooked in symptomatology. And don't overlook the importance of the nonpharmacologic therapies, which Dr Pandey very nicely outlined, such as weight loss, exercise, healthy eating, and healthy living, to really complement everything else that we do. And for patients who qualify, please use the SGLT2 inhibitors.

I'll leave you with that. I hope you have a lovely rest of your day. This is Ileana Piña, signing off.

Ileana L. Piña, MD, MPH, is a heart failure and cardiac transplantation expert. She serves as an advisor/consultant to the FDA's Center for Devices and Radiological Health and has been a volunteer for the American Heart Association since 1982. Originally from Havana, Cuba, she is passionate about enrolling more women and minorities in clinical trials. She also enjoys cooking and taking spin classes.

Follow theheart.org | Medscape Cardiology on Twitter

Follow Medscape on Facebook, Twitter, Instagram, and YouTube

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.