Response to “Liraglutide effect on epicardial fat: Missing the forest for the trees”

TO THE EDITOR: I thank you for the opportunity to respond to Munoz and colleagues' comments and expand the discussion on our recently published paper (1). We pioneered the research on epicardial adipose tissue (2). In addition to its peculiar and unique anatomical, genetic, and biological properties and functions, epicardial fat has recently emerged as a modifiable and measurable cardiometabolic risk factor and well-responsive therapeutic target. Our most recent trial showed a rapid and large reduction (around 36%) of the ultrasound-measured epicardial fat thickness in type 2 diabetic subjects treated with additional liraglutide, a glucagon-like peptide 1 (GLP-1) analog, as compared to subjects on metformin monotherapy. Our study had the power to detect statistically significant differences in epicardial fat between the two arms. We acknowledged that our clinical trial had some limitations, as it was not a double-blinded placebo control study, the two groups were relatively imbalanced, and no other visceral fat markers were measured. We suggested a potential direct effect of liraglutide on epicardial fat, although we cannot rule out that weight loss could be contributory. Our position is based on actual data and some speculative mechanisms. First, both groups lost a similar percent of weight (around 10%), whereas epicardial fat thickness decreased only in those treated with additional liraglutide. Second, the 6-month Δ BMI did not correlate with Δ epicardial fat in the liraglutide group (R = 0.22, P = 0.09). Our findings are well in agreement with a recent meta-analysis that found no or insufficient evidence of any correlation between the amount of epicardial fat reduction and the amount of weight loss post intervention, including post bariatric surgery as one could expect (3). We and others have previously shown that BMI is not a major determinant of epicardial fat. So the lack of correlation and the significant disproportion between BMI and epicardial fat changes can be intuitively appreciated in our study. The assumption that “weight loss interventions are expected to preferentially mobilize visceral fat” is questionable or at least controversial. A recent meta-analysis showed that subcutaneous fat loss is actually always greater than visceral fat loss, regardless of the weight loss interventions (4). This meta-analysis did not include studies with liraglutide. Interestingly, the Liraglutide Effect and Action in Diabetes-2 study showed that abdominal visceral fat reduction was greater than that in the abdominal subcutaneous fat (5). Epicardial fat could be mobilized faster than larger visceral fat depots, due to its intrinsic fast metabolism and relatively small amount. Hence, the epicardial fat reduction was not that unexpected, yes, but more likely explained by a direct GLP-1 agonistic effect, rather than simply driven by the weight loss, which undoubtedly occurred in our study. We are currently analyzing the presence of the GLP-1 receptor gene and mRNA expression in human epicardial fat to sustain the hypothesis of direct targeting. The GLP-1 agonistic effect may increase epicardial fat lipolysis and insulin sensitivity, decrease lipogenesis, and, therefore, cause a fat mass reduction. Future and larger studies would certainly be warranted for our observations to be confirmed.