Since the 1990s, the incidence of heart failure with preserved ejection fraction (HFpEF) has risen, especially among patients with obesity. HFpEF is often accompanied by excess fat around the heart, called epicardial adipose tissue (EAT). EAT puts pressure on the heart and causes inflammation, leading to heart failure.
The SUMMIT trial sought to uncover important insights into the role of the GLP-1/GIP receptor agonist tirzepatide in managing obesity-related HFpEF. The SUMMIT CMR Substudy, led by Christopher Kramer, MD, a cardiologist and cardiovascular imaging expert, garnered further insight on the impact of tirzepatide on EAT and cardiac function.
Says Kramer, “Obesity-related heart failure (HFpEF) is a known entity and something that is an obvious target for a drug that reduces obesity. HFpEF causes increased left ventricular mass, called LV hypertrophy.”
With an increase in EAT, “the fat around the heart releases circulating adipocytokines, molecules that lead to issues like increased inflammation, fibrosis, and an increase in hypertrophy and stiffness,” notes Kramer.
“There has been a recent rush of classes of medications that have shown benefit in this space now. So, the question now becomes, which do you start first? What is the most powerful? What is the most effective?”
Does Tirzepatide Reduce LV Mass?
The SUMMIT CMR Substudy included 175 patients from the SUMMIT trial. Of those, 106 completed the study. Using cardiac magnetic resonance (CMR) imaging, Kramer and his team examined the left ventricular (LV) and atrial structure and both epicardial and pericardial adipose tissue changes at 52 weeks compared with the baseline measurement.
It showed that patients treated with tirzepatide had significant reductions in LV mass and paracardiac adipose tissue compared to the placebo group.
“In the 106 patients, we did cine imaging of the short axis of the entire heart, from the apex all the way to the back of the left atrium,” recounts Kramer. This measured:
- LV mass
- LV volume
- Diastolic and systolic volume
- Stroke volume
- Ejection fraction
- Left atrial size
- Paracardiac fat
LV mass decreased by 11 grams in the tirzepatide group. This is the first demonstration of any benefit of GLP-1 receptor agonists on LV mass.
This reduction in LV mass was also linked to changes in body weight and systolic blood pressure, showing that weight loss contributed directly to heart health improvement. “It was clear that patients felt better on the drug, and they lost weight,” says Kramer.
EAT & Paracardiac Fat
The researchers also found that paracardiac adipose tissue decreased by 45 mL.
Paracardiac adipose tissue is linked to worse heart outcomes, including increased inflammation and fibrosis. The reduction in this fat, especially the pericardial fat, could have important implications for improving heart function in obesity-related HFpEF.
“It turned out that paracardiac fat fell markedly in the treated group, whereas it didn't change in the placebo group,” says Kramer. “And as that reduces, there's a reduction in circulating cytokines, those molecules that are released from the paracardiac fat that do damage.
“So basically, everything surrounding obesity-related heart failure with preserved ejection fraction was improved with active therapy.”
No Effect on Other Heart Measurements
While the reduction in LV mass and fat was significant, tirzepatide didn’t affect:
- LV end-systolic volume
- LV function
- Left atrial (LA) volumes and function
In another recent study, the SELECT trial, the GLP-1 semaglutide did show an impact on LA volumes and other markers of heart function, but no effect on LV mass. This difference may be due to study design and the imaging methodology used (ultrasound in this study as compared to CMR) or the specific medication used.
What's Next for Obesity-Related HFpEF & Tirzepatide?
This study is the first to show a reduction in LV mass due to GLP-1 therapy in obesity-related HFpEF. The findings are particularly striking because this may explain a significant part of the clinical benefit of GLP-1 therapy, especially with tirzepatide.
The results of the SUMMIT CMR Substudy suggest that tirzepatide could be a key treatment for obesity-related HFpEF. LV mass and paracardiac adipose tissue reductions may help lower the incidence of the kinds of adverse heart failure events that were seen in the main SUMMIT trial.
“We’ll need a much larger study to show mortality benefit, because the mortality rates are low in a one-year study,” notes Kramer. “A larger study with longer follow-up might have been useful to know if there is a mortality benefit from the drug. I don't think that question was answered by this study.” However, tirzepatide clearly reduced heart failure events compared to placebo.