Slimming cardiac adipose tissue with liraglutide: pericardial is not epicardial fat (the LIRAFLAME substudy)

To the Editor, We read with great interest about the LIRAFLAME substudy showing a significant reduction in pericardial adipose tissue (PAT) volume quantified with computed tomography (CT) in patients with type 2 diabetes treated with liraglutide 1.8 mg/day compared with placebo. We acknowledge that the rationale of the study is well founded and that the results provide interesting data on vascular and circulating markers of inflammation. However, we would like to raise some issues regarding cardiac ectopic fat assessment. In this study, PAT volume was assessed with CT, but the automated method did not separate its two components, paracardial and epicardial adipose tissue (EAT). The authors argue that manual measurement would have resulted in greater interobserver variability. EAT is the visceral fat deposit surrounding the heart, located between the myocardium and the visceral pericardium. It should be distinguished from paracardial fat (adipose tissue located external to the parietal pericardium), whose embryonic origin and blood supply differ from those of EAT. Recent research has shown that PAT was associated with impaired global longitudinal strain, while EAT was more associated with reduced diastolic function in subjects with type 2 diabetes. Furthermore, only EAT volume has been shown to increase the cardiac outcome predictive value of non-contrasted cardiac CT without additional radiation exposure or contrast administration. Accordingly, post hoc analysis of the prospective EISNER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) study, which included participants who underwent baseline coronary artery calcium (CAC) scoring by CT, revealed that the addition of artificial intelligence-based EAT volume to current risk assessment tools resulted in a significant net reclassification improvement for major adverse cardiovascular events over 14 years. Moreover, in recent years, several papers have reported the utility of using CT-derived perivascular fat attenuation (fat attenuation index) by non-invasive deep learning algorithms as a surrogate measure of early coronary inflammation. This could offer further insights. In the LIRAFLAME study, there was no association between changes in body weight and changes in vascular inflammation or CAC score, and no correlation between cardiac adipose tissue and CAC score. This is surprising, as we recently reported an independent association between EAT volume measured with CT and CAC score in 409 patients with diabetes. This may be atributable to insufficient statistical power, as this subanalysis was not prespecified in the original study and no sample size calculation could be performed beforehand. Finally, the authors suggest that it could be beneficial to compare glucagon-like peptide 1 receptor agonist (GLP1-RA) treatment to an active comparator that would also lead to weight loss and improved glycaemic control, although the change in PAT was not independent of weight loss in their study. The point is that currently no other antidiabetic drug class provides as much weight loss as GLP1-RAs. We previously showed that bariatric surgery and exenatide induced significant decrease in EAT, but metabolic surgery studies specifically dedicated to patients with diabetes are still lacking. To conclude, future comparative studies evaluating the effect of high doses of GLP1-RAs or dual gastric inhibitory polypeptide and GLP1-RAs and metabolic surgery on cardiac ectopic fat stores are awaited and will surely help to settle this debate.