Epicardial fat is relatively resistant to weight loss regimens [
26]; thus, the modest weight loss that is typically seen with caloric restriction has minimal effect on epicardial adipose tissue [
27] and exerts little benefit on AF [
28]. In contrast, marked weight loss (e.g., with bariatric surgery) can decrease both the mass and inflammation of epicardial fat [
29,
30]. In both observational studies and randomized controlled trials, striking degrees of weight loss can reduce the burden of AF or restore sinus rhythm in patients with established AF [
31,
32]. Interestingly, this degree of weight loss is also paralleled by an amelioration of the diastolic filling abnormalities typically seen in HFpEF [
33].
Additionally, in patients with type 2 diabetes, the effects of antihyperglycemic drugs on AF may parallel their actions on epicardial adipose tissue. Insulin promotes adipogenesis and cardiac fibrosis [
34,
35] (exacerbating the atrial myopathy) and exerts antinatriuretic effects (increasing atrial wall stress) [
36]. Also, by promoting episodic hypoglycemia, insulin may activate the sympathetic nervous system and enhance arrhythmogenesis. Accordingly, insulin use is accompanied by an increased risk of AF [
37,
38]. In contrast, metformin exerts anti-inflammatory effects on adipose tissue and decreases the release of proinflammatory adipokines from the epicardium [
39,
40], and its use has been accompanied by a decreased risk of AF [
41]. In addition, by promoting PPAR-γ signaling, pioglitazone can reverse the dysfunctional state of epicardial fat [
42,
43], thereby attenuating atrial inflammation and fibrosis. Pioglitazone ameliorates AF in experimental models [
44], and use of the drug has been associated with a lower risk of new-onset or recurrent AF in observational studies in the clinical setting [
45,
46]. However, thiazolidinediones did not reduce AF events in two randomized controlled trials of patients with insulin resistance or type 2 diabetes [
47], possibly because PPAR-γ agonism promotes sodium retention and increases cardiac volumes [
48]. The resulting atrial distension could negate any benefits on AF that might be expected from the action of these drugs to reduce epicardial adipose inflammation.