Visceral adipose tissue (VAT), anatomically located around certain organs, is now accepted as an endocrine organ which secretes various adipokines that influence both nearby and distant tissues. Imbalance between pro- and anti-inflammatory adipokines secreted from VAT contributes to the pathogenesis of certain cardiovascular and metabolic disorders, including insulin resistance.1 Epicardial adipose tissue (EAT), an organ-specific VAT, is mainly found in the atrioventricular and interventricular grooves and along the major branches of the coronary arteries, and to a lesser extent around the atria, over the free wall of the right ventricle and over the apex of the left ventricle.2 Evidence is accumulating that bioactive molecules secreted by EAT can directly affect intima-media thickness and regulate vasomotor function.3 Furthermore, there is emerging evidence that EAT has a direct association with coronary atherosclerosis.4 In view of the putative proatherogenic effect of EAT, several clinical trials have shown a positive correlation between EAT thickness and coronary atherosclerosis.5–7

Although its exact mechanism of action is unknown, metformin is regarded as the gold standard treatment for type 2 diabetes.8 Beside its glucose-lowering effect, metformin also has a favorable effect on body weight, primarily due to reduction of VAT.9 In this study, we investigated the effects of metformin on EAT thickness and body mass index (BMI) in type 2 diabetes patients.

Seven patients were excluded due to metformin intolerance during the follow-up period, and so a total of 40 patients were analyzed. Of the study population, 23 (57.5%) were male and mean age was 48.6±1.99 years. Fourteen patients (35%) had hypertension, 12 (30%) had hyperlipidemia and 13 (32.5%) were smokers. Mean fasting blood glucose was 280.38±14.88 mg/dl before beginning metformin monotherapy, falling to 129.01±17.00 mg/dl after three months of therapy.

EAT thickness was significantly decreased after three months of metformin monotherapy (EAT0= 5.07±1.33 mm vs. EAT3=4.76±1.32 mm; p<0.001) (Figure 2).

Figure 2.

Effect of metformin monotherapy on EAT thickness. EAT0: EAT thickness before initiation of metformin monotherapy; EAT3: EAT thickness after three months of metformin monotherapy; EAT: epicardial adipose tissue.

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Furthermore, BMI was also significantly decreased after three months of metformin monotherapy (BMI0=28.27±2.71 vs. BMI3=27.29±2.10; p<0.0001) (Figure 3).

Figure 3.

Effect of metformin monotherapy on BMI. BMI0: BMI before initiation of metformin monotherapy; BMI3: BMI after three months of metformin monotherapy; BMI: body mass index.

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We also analyzed the correlation between the decrease in EAT (formulated as EAT0 - EAT3) and mean fasting blood glucose level before beginning metformin monotherapy and BMI0. A statistically non-significant positive correlation was found between decrease in EAT and mean fasting blood glucose before beginning therapy (r=0.19; p=0.056) and BMI0 (r=0.17; p=0.053).

In this study we demonstrated that metformin monotherapy significantly decreases EAT thickness and BMI as early as the third month of therapy.

Because of its vital endocrine function and close anatomical relation to the coronary arteries, many studies have set out to determine the effects of EAT on cardiovascular disease. Mahabadi et al. showed the existence of a relation between cardiovascular risk factors, myocardial infarction and EAT thickness,10 while Cavalcante et al. found a significant association between subclinical coronary atherosclerosis, metabolic syndrome, diastolic dysfunction and EAT thickness.11 In a recently published study, Abazid et al. also concluded that higher EAT volume is associated with greater coronary artery calcification,12 and Wu et al. showed that EAT thickness is positively correlated with obstructive coronary artery disease (CAD).13

Although the exact mechanism is unknown, several hypotheses have been put forward to explain this relation. EAT is a metabolically active fat depot which is rich in proinflammatory and proatherogenic cytokines including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α.14 In a recent study, Vrselja et al. demonstrated that TNF-α levels were increased in CAD patients.15 Furthermore, Eiras et al. postulated that the extent of CAD was associated with the expression of IL-6 mRNA in EAT.16

EAT shares the same embryologic origin as mesenteric and omental fat.17,18 They all encase viscera in close contact, with no fascial barrier.19 Hence it has been suggested that EAT may have endocrine and paracrine effects on the adjacent coronary arterial wall that could result in atherosclerotic plaque development.20–22 These findings highlight the potential role of increased EAT thickness in atherosclerosis. It could therefore be postulated that decreased EAT would produce less proinflammatory and proatherogenic cytokines and be less likely to cause atherosclerosis.

Metformin is now accepted as the first-line drug for use as monotherapy in type 2 diabetes patients. It is thought to affect certain aspects of the body's metabolism. It inhibits hepatic gluconeogenesis, augments peripheral glucose uptake, and reduces insulin demand.8 Various studies have also investigated the effect of metformin on body weight and visceral adipose tissue. In a recent study, Alfaras et al. showed in mice that metformin significantly reduces body weight within the first weeks of treatment, without affecting food consumption or energy expenditure.23 Yanovski et al. showed that metformin significantly reduced body weight in children with insulin resistance,24 while Tokubuchi et al. demonstrated that metformin treatment caused significant reductions in visceral fat mass, probably through a potential shift of fuel resource into fat oxidation and upregulation of thermogenesis.25

Although there have been many studies on the effects of metformin on body weight and VAT, there is hardly any data about its effect on EAT. In our study, we showed that metformin significantly reduces BMI and EAT thickness. Magnetic resonance imaging (MRI) and computed tomography (CT) are the gold-standard techniques for quantifying EAT volume. Due to the difficulty in standardizing localization of the measurement site, reference values for EAT assessed by CT are uncertain.26 Iacobellis et al. were the first to propose that transthoracic echocardiography could be an easy and reliable imaging method for EAT prediction.27 MRI and transthoracic echocardiography provide comparable results for detection of EAT volume.28 Hence measurement of EAT by transthoracic echocardiography is practical, cost-effective, safe, rapid, and well correlated to gold-standard techniques.29

As this is the first study to investigate the effect of metformin on EAT thickness, it is subject to some limitations, the main ones being its relatively small sample size and the lack of data on inflammatory markers. Due to financial constraints we were unable to analyze the possible effects of inflammation on the results. Larger-scale and more detailed studies should be designed to clarify the exact mechanisms underlying the favorable effects of metformin on EAT thickness and BMI.

To the best of our knowledge, our study demonstrates for the first time in the literature that metformin significantly reduces EAT thickness in newly diagnosed type 2 diabetes. Because EAT volume is closely related to atherosclerosis, it could be concluded that EAT is a modifiable risk factor for atherosclerosis and that metformin could significantly reduce the frequency of coronary atherosclerosis. Metformin could even become the aspirin of the 21st century. Further studies on a larger scale are needed to support these findings.

The authors have no conflicts of interest to declare.