The Effect of SGLT-2 Inhibitors on Epicardial Adipose Tissue and Cardiac Function in T2DM Patients With CAD (EpiCAD)

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder affecting at least 90% of the population with diabetes globally (Bhupathiraju & Hu, 2016). T2DM is a disorder characterized insulin resistance, insufficient insulin production, and eventual pancreatic beta-cell failure (Cantley & Ashcroft, 2015).The global prevalence of T2DM has been increasing steadily, with an estimate of 463 million individuals suffering from T2DM in 2019 and the number is projected to increase by 15.7% in 2030 (Saeedi et al., 2019). T2DM is also increasing at an alarming rate in Malaysia and as of 2019 (Akhtar et al., 2022), approximately 3.5 million (17.5%) Malaysians were diagnosed with T2DM, which doubled in number since 1996 (8.3%) (Zhu et al., 2019).

Evidently, T2DM patients are predisposed to various forms of both short and long-term complication, with cardiovascular disease (CVD) being the main cause of death among T2DM patients (Raghavan et al., 2019), T2DM has been shown to decrease life expectancy by 10 years with CVD responsible for half of the mortality (Einarson et al., 2018). Although a close link between T2DM and CVD is established, the etiology is complex and remains a significant research topic. Obesity, traditionally defined as excess body weight and adiposity, is closely linked to the pathogenesis of T2DM. Obesity associated with T2DM is linked with a cluster of metabolic and biochemical abnormalities with insulin resistance central in promoting these disturbances. It could manifest itself in various pathophysiological states which includes hyperglycemia, atherogenic dyslipidemia, inflammation, and endothelial dysfunction (Galicia-Garcia et al., 2020). These pathological states have been shown to exacerbate the progression of CVD; and according to a global systematic review, patients with T2DM had a 10% greater risk of coronary artery disease (CAD), approximately 50% higher risk of developing myocardial infarction (MI) and stroke, and a staggering 112% increased risk for heart failure (Einarson et al., 2018).

The discovery of new pharmacotherapy to reduce complications associated with T2DM has brought global attention to sodium-glucose co-transporter 2 (SGLT-2) inhibitors, a relatively new anti-diabetic medication. SGLT-2 inhibitor exerts its hypoglycemic action by primarily blocking glucose reabsorption in the proximal convoluted tubule of the kidney which subsequently leads to glycosuria. This, in turn, promotes the utilization of lipids for energy production in response to high glucose lost resembling prolonged fasting state(Ferrannini et al., 2016; Yokono et al., 2014; Zaccardi et al., 2016). Due to these metabolic changes, SGLT-2 inhibitors reportedly induce weight loss due to its ability to reduce visceral and subcutaneous adipose tissues accumulation (Bramante et al., 2020; Pereira & Eriksson, 2019). Evidently, a clinical trial conducted by Zinman et al. (2016) reported remarkable reduction of cardiovascular-related mortality, and decreased risk of hospitalization and re-hospitalization for heart failure in T2DM patients receiving SGLT-2 inhibitors. In addition, one meta-analysis conducted by Zheng et al. (2018) also demonstrated that SGLT-2 inhibitors are able to reduce all-cause mortality in T2DM patients with CAD. Thus, emerging evidence suggested that SGLT-2 inhibitors are capable of decreasing the occurrence of cardiovascular events in T2DM patients, and closely linked to their ability to reduce fat content (Scheen, 2014).

As the indirect target of SGLT-2 inhibitors is towards reduction of adiposity, adipose tissue measurements were also shown to be an important indicator of SGLT-2 inhibitors effectiveness. According to Singh et al. (2007), visceral adipose tissue (VAT) which surrounds the internal organs of body cavities, could predict an undesirable metabolic and cardiovascular risk stratification. For this reason, epicardial adipose tissue (EAT), a type of visceral fat surrounding the heart supplied by major branches of coronary vessels, is increasingly studied to be the measuring point for the efficacy of SGLT-2 inhibitors (Sato et al., 2018; Yagi et al., 2017).

EAT originates from splanchnopleuric mesoderm, in which embryonically similar to intraabdominal adipose tissue and actively produces numerous cytokines that are essential for metabolic homeostasis (Muñoz et al., 2014). Physiologically, normal EAT distribution is required to provide a protective physiological role to the heart (Iacobellis et al., 2008). Normal EAT thickness is reported to be between 4.5mm- 7.0mm (Iacobellis et al., 2008). Physiologically, normal EAT thickness provides protective metabolic and thermogenic function towards both myocardium and coronary arteries (Wu et al., 2017; Iacobellis & Willens, 2009). EAT also produces adipokines, a signaling protein that regulates lipid and glucose-insulin metabolism in the heart (Talman et al., 2014; Wu et al., 2017). However, excessive EAT depot has been hypothesized to be involved in the pathogenesis and the progression of coronary artery disease, with the release of inflammatory mediators which prompt the atherosclerotic process through several paracrine mechanisms (Alexopoulos et al., 2010). Apart from metabolic disorders, there are various determinants that can contribute to EAT thickness, including age, gender, race and ethnicities (Lima-Martínez et al., 2014; Verma et al., 2017). Given that the estimation of cardiovascular risk is significantly relevant with EAT as compared to other visceral fat, the SGLT-2 anti-obesity effect on EAT accumulation may serve as a significant cardiovascular predictor in T2DM patients (Sato et al., 2018; Yagi et al., 2017).Evidently, due its significant metabolic effect, SGLT-2 inhibitors have also been shown to reduce the amount of visceral adipose tissue by caloric elimination and thereby reducing EAT in multiple pilot studies (Fukuda et al. 2017; Braha et al. 2019; Yagi et al. 2017).