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Obesity, a driver of inflammation, is prevalent in patients with HFpEF. Ileana Pina asks Ambarish Pandey about GLP-1 inhibitors and SGLT2 inhibitors in HFpEF. Are these drugs anti-inflammatory? https://www.medscape.com/viewarticle/993980?src=soc_yt -TRANSCRIPT- 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. 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? https://www.medscape.com/viewarticle/993980?src=soc_yt