Anti-Inflammatory and Anti-Oxidative Effects of GLP1-RAs and SGLT2i: The Guiding Star Towards Cardiovascular Protection in Type 2 Diabetes

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic and progressive dysmetabolic condition related to several complications, including cardiovascular disease, whose incidence is increasing worldwide. Sodium–glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) are two new molecules recently made available for T2DM treatment, with the aim of reducing hyperglycemia. Recent evidence has also highlighted that in addition to the glucose-lowering action, both SGLT2i and GLP1-RAs ensure significant beneficial effects in reducing cardiovascular damage in T2DM patients. Interestingly, these benefits cannot be exclusively attributed to the improved glycemic control. Indeed, experimental and clinical studies have shed light on the protective role of SGLT2i and GLP-1RAs against inflammation and oxidative stress, especially in the heart and vasculature. In our review we elucidate the potential cardiovascular benefits provided by SGLT2i and GLP1-RAs to T2DM subjects by exploring the molecular pathways involved in the process of cardiovascular protection.

1. Introduction

Among people with diabetes mellitus (DM), cardiovascular disease (CVD) is considered the major cause of morbidity and mortality [1]. DM increases the risk of myocardial infarction (MI) by coronary atherosclerosis and promotes diabetic cardiomyopathy, inducing diastolic or systolic heart failure [2,3]. In this clinical scenario, the advent of two new compounds marked a turning point in the prevention and treatment of CVD in type 2 diabetes mellitus (T2DM) [4]: sodium–glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1-RAs). The main goal of these molecules is to reduce blood sugar in patients with T2DM. SGLT2i exert their action in the kidneys, where they inhibit the sodium–glucose co-transporter 2 (SGLT2) responsible for glucose reabsorption, lowering blood glucose levels in doing so. On the other hand, GLP1-RAs mimic the action of the glucagon-like peptide 1 (GLP1) hormone, which promotes insulin production from the pancreatic β-cells, thus stabilizing glycemic levels. Mounting evidence is showing that both molecules exhibit a wide range of clinical applications far beyond DM treatment. SGLT2i control blood pressure by hemodynamic effects such as promoting osmotic diuresis and natriuresis, modulate systemic inflammation, and improve metabolic control with a modest body weight loss [5]. GLP1-RAs induce a significant body weight loss, promote islet β-cell proliferation, and create a protective shield against metabolic and oxidative insults. The common denominator of these two classes of drugs is the ability to significantly decrease major cardiovascular events in patients with T2DM. Studies have shown that these compounds provide cardioprotection in patients with established atherosclerotic CVD and lower cardiovascular and all-cause mortality [6].

In this review, we delve into the possibilities of ameliorating cardiovascular health offered by these molecules, exploring, in particular, their protective molecular effects.

2. The Cardiovascular Damage Mediated by Inflammation and Oxidative Stress in T2DM

Diabetic cardiomyopathy is a diabetes mellitus-induced pathophysiological condition which occurs in the absence of coronary artery disease (CAD), valvulopathies, or hypertension [2,3,7] and can frequently lead to heart failure in diabetic patients [2]. Diabetic cardiomyopathy establishment is caused by different pathogenic processes, including reactive oxygen species (ROS) and proinflammatory cytokine production, autophagy dysregulation, endothelial dysfunction, and epicardial adipose tissue (EAT) impairment [2,3,7].

2.1. ROS Production

The development of diabetic cardiomyopathy is rooted in the diabetic milieu of oxidative stress and chronic inflammation, which induces impaired metabolic processes, reduced insulin sensitivity, and progressive β-cell dysfunction [8]. Hyperglycemia and lipotoxicity are actually associated with increased ROS production [8]. ROS in turn generate advanced glycation end-products (AGEs) which bind their receptors, stimulate protein kinase C (PKC) isoforms, enhance the hexosamine pathway, and activate the nuclear factor-κB (NF-κB) signaling [8]. The burden of oxidative stress and systemic inflammation induces mitochondrial dysfunction and myocardial apoptosis and fibrosis, worsening myocardial stiffness with eventual diastolic and systolic dysfunction [9].

2.2. Autophagy

Both an altered cellular metabolism and organelle damage are pivotal in the pathogenesis of diabetic cardiomyopathy [2]. Autophagy is a catabolic process that, through lysosomal degradative action, allows the cell to get rid of unnecessary or damaged intracellular waste [10]. It is regulated through 5′ adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy, and its effector silent information regulator (Sirt) [2,11]. The autophagic pathway AMPK-Sirt1 acts as a protective mechanism against cell apoptosis and preserves normal cellular function in pathologic conditions such as T2DM [2,11]. In diabetic cardiomyopathy, defective autophagy distorts autophagosome and lysosome fusion at the cardiomyocyte level [12]. In the case of cellular stress and increased adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio, AMPK enhances the expression and translocation of glucose transporter type 4 (GLUT4) to the cell membrane, insulin-induced glucose uptake, and mitochondrial biogenesis, leading to free fatty acid (FFA) oxidation and glycolysis [13]. At the same time, in cardiomyocytes, activated AMPK negatively regulates the mechanistic target of rapamycin (mTOR) pathway, gluconeogenesis, and lipid and protein synthesis [14]. Therefore, AMPK activation prevents the progression of diabetic cardiomyopathy and may be a promising therapeutic target in this field. AMPK activation is decreased in DM, thus growing FFA oxidation and triacylglycerol depots while reducing glucose uptake [11,15]. Indeed, defective autophagy related to AMPK suppression has been regarded as a possible cause of dyslipidemia, which in turn intensifies the mTOR pathway, suppressing autophagy in cardiomyocytes [16].

2.3. Endothelial Dysfunction

Physiologically, multiple vasoactive substances, including nitric oxide (NO) and prostacyclin play a beneficial vasodilatory role [17]. Although NO-induced vasodilation may be decreased, vascular status in early DM is mostly conserved, or even enhanced by induced endothelium vasoactive factors, such as endothelium-derived hyperpolarizing factors (EDHFs) [17]. Eventually, vasodilation induced both by NO and EDHFs is affected, leading to significant microvascular complications in the later stages of DM [17]. Moreover, recent evidence in diabetic patients has shown that persistently high plasma endothelin-1 levels, along with decreased endothelium nitric oxide synthase (eNOS) activity and NO production, is related to cardiac fibrosis and diastolic dysfunction [18]. Endothelial dysfunction is also due to altered insulin metabolism. Insulin resistance leads to reduced endothelium-dependent vasodilatory responses and, subsequently, to hypertension [19]. On the other hand, hyperinsulinemia contributes to high blood pressure enhancing sodium reabsorption in the renal distal tubules, which in turn increases its blood concentration. Finally, hyperinsulinemia aggravates vascular stiffness and leads to vascular remodeling by promoting smooth muscle cells proliferation [20].

2.4. EAT

In addition to the aforementioned mechanisms, EAT has recently been identified as a possible player in the multifactorial scenario causing CAD [21]. Proximity of EAT to the coronary arteries and the amount and activity of EAT are elements that may play a role in CAD pathogenesis. Inflammation, exacerbated responses of innate immune cells, oxidative stress, vascular damage, and glucolipotoxicity are all factors contributing to atherosclerosis and are induced by EAT [22]. In patients with CAD, EAT is characterized by dense inflammatory infiltrates of macrophages, mast cells, and CD8+ T cells [23]. In this context, proinflammatory M1 macrophages are more present than anti-inflammatory M2 macrophages. Genes encoding proinflammatory cytokines, such as IL-6, monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor alpha (TNF-α), and chemokines and proinflammatory adipokines [24,25,26] are upregulated in the EAT of patients with CAD. Due to the proximity of EAT to the coronary arteries, the rich proinflammatory milieu surrounding the coronary adventitia reaches the coronary level via paracrine or vasocrine pathways. The inflammatory process and coronary atherosclerosis become more severe proportionally to the thickness of EAT and to its proximity to the coronary arteries [23]. The imbalance between anti-inflammatory (e.g., adiponectin) and proinflammatory EAT adipokine secretion has a pivotal role in the development and progression of coronaropathy [27,28]. While EAT proinflammatory adipokine production is higher in patients with CAD, local gene and protein expression of adiponectin is lower [29]. The responses of adaptive and innate immunity also contribute to EAT inflammation in people with CAD. First of all, EAT of diabetic individuals is frequently characterized by high concentrations of adaptive immune cells [30,31,32]. Moreover, in the EAT of people with CAD, the activation of innate immune mediators, such as NF-κB, can lead to the upregulation of proinflammatory cytokines [27]. EAT may also secrete factors that regulate the endothelial state, such as resistin, which is related to improved endothelial cell permeability [33]. Studies suggest that the pathogenetic mechanisms of diabetic coronaropathy include upregulation of signaling between AGEs and their receptors in EAT [34]. The epicardial adipocytes of people with CAD upregulate stress cellular factors such as mitogen-activated protein kinase kinase 3 (MAP2K3) and mitogen-activated protein kinase kinase 5 (MAP3K5), related to inflammation at the coronary level, and multiple proteases involved in apoptosis pathways [35]. EAT is also a heart depot of ectopic lipids: epicardial adipocytes infiltrating the adventitia could release FFAs, thus contributing to lipid accumulation at the coronary level. Indeed, EAT has a greater insulin-stimulated lipogenesis than other visceral fat depots, but a particularly low glucose uptake, leading to a reduced expression of GLUT4 [36]. A self-powering circuit is thus created: EAT provides a substrate capable of fueling systemic inflammation, while increased levels of ROS and decreased expression of antioxidant enzymes sustain cardiac atherosclerosis.

3. The Role of SGLT2i and GLP-1 RAs in Cardiovascular Protection

Cardiac inflammation and fibrosis are the basis of the pathogenic process leading to ischemic heart disease and heart failure [37]. Numerous in vitro and in vivo studies have demonstrated that SGLT2i and GLP1-RAs are therapeutic options that counteract both inflammatory and fibrotic processes in the cardiovascular system [38,39]. The distinct and yet complementary molecular effects of these compounds are shown in Figure 1.

3.1. The Anti-Inflammatory and Anti-Oxidative Effects of SGLT2i

SGLT2i are a class of drugs used in the treatment of DM2 that inhibit the glucose transporter SGLT2 in the proximal renal tubule, lowering glucose reabsorption in the kidney and promoting urinary glucose excretion in an insulin-independent manner, thus inducing a negative caloric balance [40]. Carbohydrate deprivation triggers ketogenesis which promotes FFA mobilization from adipose tissue stores and fatty acid β-oxidation in the liver [41]. While FFA oxidation can reduce lipotoxicity and inflammation, excessive reliance on fatty acid metabolism can sometimes increase oxidative stress in certain contexts, such as heart failure [41,42]. The metabolic shift from glucose to FFA utilization is more favorable for energy production, as it provides three times more ATP than glucose oxidation and twenty times more than anaerobic glycolysis. Together with mitochondrial renewal, the net effect is the improvement in cardiac fuel supply and, consequently, in cardiomyocyte performance, thus attenuating adverse cardiac remodeling [5,43]. The positive metabolic changes related to SGLT2i have been confirmed in several studies [44], even if excessive reliance on FFA oxidation may be detrimental in certain cardiac conditions. Evidence from diet-induced obese mice showed that the SGLT2i-induced ketogenesis is associated with M1 to M2 macrophage polarization in adipose tissue, along with a fat-browning process [44]. M2-polarized macrophages contribute to the restoration of metabolic homeostasis through production of anti-inflammatory cytokines and reduction in insulin resistance [44,45,46]. In a small randomized clinical trial, treatment with dapagliflozin was associated with a decrease in TNF-α plasma concentrations and a reduction in EAT volume compared with other antidiabetic therapies [47]. In another study, EAT collected during cardiac surgery and incubated with dapagliflozin showed an increased uptake of glucose via GLUT4 and a reduced secretion of proinflammatory chemokines [48]. Recent experimental evidence [49] showed that inhibition of SGLT2 significantly increased the blood concentration of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), a well-known activator of AMPK. In this study, a short-term administration of AICAR had a senolytic effect similar to canagliflozin, suggesting that the AMPK pathway contributes to senolytic action of SGLT2 inhibitors. Therefore, the starvation condition induced by SGLT2i upregulates the AMPK pathway and its protective effects on cardiomyocytes [40], specifically stimulating cellular autophagy and mitochondrial biogenesis [5,43]. The replacement of dysfunctional mitochondria leads to reduced oxidative stress and greater ATP synthesis. Moreover, the autophagic processes prevent endoplasmic reticulum stress and cardiomyocyte apoptosis [43]. Specifically, AMPK downregulates the expression of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1), an immune checkpoint molecule that suppresses the senescent cell removal system [50]. An aforementioned study [49] showed that SGLT2i may reduce PD-L1 expression by AMPK activation, ameliorating various pathological aging traits [51]. However, the AMPK pathway has also been reported to regulate T cell activation, and it is possible that SGLT2 inhibitors control T cell activity and their production of inflammatory mediators [52]. Apart from AMPK activation, recent evidence showed that SGLT2i were also able to regulate T cell signaling by a decreased phosphorylation of downstream T cell receptor (TCR) targets [53]. Therefore, SGLT2i reduce proinflammatory molecules associated with atherosclerosis [54]. Specifically, they inhibit cytokines, such as IL-1β, IL-6, and TNF-α, and attenuate NOD-like receptor protein 3 (NLRP3) inflammasome activation [55,56]. The expression of pro-inflammatory molecules, like MCP-1 and vascular cell adhesion molecule-1 (VCAM-1), is also reduced [57]. Furthermore, SGLT2i promote plaque stabilization by reduced metalloproteinase-2 (MMP-2) activity and improved vascular stiffness [58]. Indeed, in diabetic mice SGLT2i reduce vascular dysfunction and control smooth muscle cell abnormal proliferation, contributing to the preservation of the normal microvascular condition [59]. Among SGLT2 inhibitor-induced mechanisms providing vascular protective effects there is also NO bioavailability restoration [54,60]. In vitro experiments showed that SGLT2i reduced cell death and oxidative stress improving NOS activity in cardiac muscle cells [61], while SGLT2i was shown to restore NO bioavailability in endothelial cells by inhibiting ROS production in TNFα-stimulated cells [62,63]. Other studies have indicated that SGLT2i can reduce the generation of nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase subunits such as NADPH oxidase 2 (NOX2), thus moderating oxidative stress. A pilot study on patients with T2DM regarding the plasma levels of soluble NOX2-derived peptide (s-NOX2-dp) proved that SGLT2i significantly decreased the level of both factors [64]. Moreover, experimental evidence showed that SGLT2i induce a quiescent-like phenotype on human fibroblasts, reducing the extracellular matrix remodeling and decreasing the expression of profibrotic factors [65]. In murine models with heart failure, cardiac anti-inflammatory effects were also observed following SGLT2 inhibitor administration without any changes in ketone body or ATP production, suggesting the involvement of other pathogenic processes. Specifically, the study showed a reduced cardiac and systemic activation of NLRP3 inflammasomes and a lower ROS production [66]. While SGLT2i have demonstrated cardioprotective effects, their impact on fibrosis remains debated, and more human data are needed to confirm their long-term effects. Such evidence suggests that the cardiovascular benefits provided by SGLT2i extend well beyond the anti-fibrotic effects [67,68]. The protective mechanisms of SGLT2i on cardiovascular system by metabolic changes and anti-oxidative and anti-inflammatory effects are reported in

Table 1. The protective mechanisms of SGLT2i on cardiovascular system by metabolic changes and anti-oxidative and anti-inflammatory effects. SGLT2i, sodium–glucose co-transporter 2 inhibitors; FFAs, free fatty acids; NO, nitric oxide; NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; NLRP3, NOD-like receptor protein 3.

	SGLT2i
Metabolic Changes	- Promote a metabolic shift towards FFA utilization and ketogenesis, increasing cardiac efficiency (depending on the metabolic state of the patient) - Provide a negative caloric balance, promoting autophagy and weight loss - Promote fat-browning effect, providing polarization of M1 to M2 macrophages in adipose tissue
Oxidative Stress	- Decrease apoptosis - Increase NO production - Provide cytoprotective effects in endothelial cells - Reduce hydrogen peroxide and NADPH formation
Inflammation and Fibrosis	- Decrease the expression of profibrotic factors, decreasing extracellular matrix remodeling - Lower activation of NLRP3 inflammasomes - Reduce left ventricular mass and provide beneficial effects on diastolic function - Reduce cytokines, chemokines, and adhesion molecules - Promote plaque stabilization by antiproliferative effects and prevent endothelial dysfunction, reducing vascular stiffness

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3.2. The Anti-Inflammatory and Anti-Oxidative Effects of GLP-1 RAs

GLP-1 is an incretin hormone, secreted by the intestinal L-cells in a glucose-dependent manner, with the ability to lower blood glucose levels by different mechanisms such as insulin secretion enhancement, pancreatic β-cell mass increase, and the inhibition of glucagon secretion and gastric emptying. The need for synthetic analogues of GLP1 with a half-life suitable for clinical use arose from the fact that endogenous GLP-1 has a very short half-life due to degradation by dipeptidyl peptidase 4 (DPP-4); thus, a new class of antidiabetic agents has been created [40]. GLP1-RAs have a glucose-lowering effect thanks to the improvement in insulin sensitivity, reducing postprandial hyperglycemia [69]. In addition to the impact on insulin resistance, GLP1-RAs provide several other metabolic benefits, including weight loss obtained by stimulating GLP1 receptors on hypothalamic neurons and inducing a feeling of satiety [69]. Even if “browning effect” in human physiology should be used cautiously, these drugs showed this effect on EAT [70], further contributing to the restoration of EAT fitness, as brown fat tissue activation increases energy consumption and lipid depot depletion, resulting in the recovery of normal EAT volume. In murine models GLP1-RA administration was shown to promote adipocyte browning, independent of nutrient intake [70]. The anti-inflammatory potential of GLP1-RAs may be associated with a direct action on immune cells, an indirect effect caused by weight loss, or a combination of the two. Several studies have shown that GLP-1 RAs regulate innate immune cells, especially macrophages [71]. Experimental evidence suggests that lixisenatide can decrease atheroma plaque size and instability by reprogramming macrophages towards the M2 phenotype [72]. Some other studies revealed that GLP-1 RA administration also enhances the T regulatory cell (Treg) function [73], which in turn may promote M2 polarization [74]. A recent study showed that the velocity of leukocyte rolling and adhesion on endothelial cells were reduced in polymorphonuclear leukocytes (PMNs) of GLP-1 RA-treated patients. This direct effect on immune cells undermines the foundations of the atherosclerotic process [75]. Moreover, treatment with GLP-1 RAs reduces ROS production and proinflammatory cytokine levels, while recovering mitochondrial membrane potential, oxygen consumption, and myeloperoxidase (MPO) levels [75]. Several studies also support the positive impact exerted by GLP1-RAs on obesity-related heart disease, also in a weight-independent manner. An in vivo study on murine models of obesity showed that a short-term treatment with liraglutide improved cardiac function, counteracting the pathogenetic mechanisms of obesity-induced heart disease [76]. Among the several mechanisms involved in cardioprotection exerted by GLP1-RAs, the activation of the AMPK pathway plays a crucial role. It is likely that, through the AMPK pathway, GLP1-RAs may decrease myocardial triglyceride and diacylglycerol levels, NOX activity, and oxidative stress [77]. Moreover, Guo’s in vivo study showed that exenatide ameliorated the cardiac function of diabetic rats promoting cAMP accumulation and the increase in AMPK phosphorylation [78]. Another experimental study showed that exenatide significantly reduced cardiomyocyte apoptosis. Specifically, in exenatide-pretreated cultures, exenatide decreased cytochrome-c release and cleaved caspase-3 expression and Bax activation while increasing bcl-2 expression. These results suggest that exenatide has a protective role in mitochondrial function of cardiomyocytes, preventing TNF-α-induced apoptosis [79]. Another study showed that GLP1-RAs decreased IL-1β-induced ROS production and NOX-4 expression at the cardiomyocyte level [80]. Regarding the effect of GLP1-RAs on oxidative stress, studies on the novel oral GLP1-RA hypoglycemic peptide 2 (OHP2) and exendin-4 showed that these agents inhibited lipid accumulation and mitochondrial ROS generation in rat cardiomyocytes [81,82]. Other experimental evidence showed that the suppression of NOX-4, induced by GLP1-RAs, generated an increase in superoxide dismutase 1 (SOD-1) and glutathione peroxidase levels [83]. Therefore, GLP1-RAs inhibited oxidative stress and decreased mitochondrial dysfunction and collagen deposition in animal models [9]. In addition, in rats with MI-induced chronic heart failure, these molecules were able to arrest adverse cardiac remodeling [84], and the potential to prevent adverse cardiac remodeling has also been demonstrated in diabetic individuals. Indeed, intravenous pretreatment with GLP1 (7–36) amide showed a protective effect on ischemic left ventricular dysfunction [85]. Actually, GLP1-RA treatment had a positive effect on the clinical outcomes of diabetic patients hospitalized with acute MI [86]. The protective mechanisms of GLP1-RAs on the cardiovascular system by metabolic changes and anti-oxidative and anti-inflammatory effects are reported in

Table 2. The protective mechanisms of GLP1-RAs on the cardiovascular system by metabolic changes and anti-oxidative and anti-inflammatory effects. GLP1-RAs, glucagon-like peptide 1 receptor agonists; ROS, reactive oxygen species; NOX-4, NADPH oxidase 4; SOD-1, superoxide dismutase 1; AMPK, 5′ adenosine monophosphate-activated protein kinase.

	GLP1-RAs
Metabolic Changes	- Promote fat-browning effect and brown adipose tissue thermogenesis - Reduce body weight, providing satiety signaling and increasing insulin sensitivity
Oxidative Stress	- Reduce intracellular and mitochondrial ROS production - Suppress NOX-4, increasing SOD-1 and glutathione peroxidase levels - Reduce myocardial triglyceride and diacylglycerol levels by the activation of AMPK pathway
Inflammation and Fibrosis	- Reduce collagen deposition, decreasing cardiac hypertrophy and myocardial fibrosis - Arrest adverse cardiac ischemic remodeling and improve the recovery of ventricular function after myocardial infarction - Provide antiatherogenic effects, reducing pro-inflammatory cytokines and delivering antiproliferative actions in vascular smooth muscle cells

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4. Conclusions

T2DM is a well-known condition related to CVD, and CVD is the leading cause of death in T2DM people. Recently, the clinical management of DM has been focused not only on improving dysglycemia, but also on reversing the pathophysiologic mechanisms of CVD. Even though the HbA1c target is an important cornerstone of cardiovascular prevention in diabetic patients with CAD, in some evidence, the only glycemic control is not associated with reduced cardiovascular mortality or reduced burden of cardiovascular disease [87]. Specifically, results of intensive glucose trials suggest that the value of glycemic control in determining the risk of major cardiovascular events in T2DM is uncertain (DOI: 10.1161/JAHA.119.012356). Indeed, historic antidiabetic agents effectively lowered glycemia, but evidence for cardiovascular benefit is lacking. Newer glucose-lowering medications such as SGLT2i and GLP1-RAs target numerous pathways in order to reduce cardiovascular damage in patients with T2DM by distinct, and yet complementary, actions [87]. The evidence seems to suggest that SGLT2i and GLP1-RAs induce distinct metabolic changes, but eventually, both of them improve cardiac energy and efficiency. However, the degree of cardiac energy efficiency improvement is still under investigation, particularly in different patient populations [88].

SGLT2i provide adipose tissue depletion and a slight weight loss through several mechanisms including increased production of ketone bodies, promotion of FFA utilization, and fat browning. On the other hand, targeted clinical trials have demonstrated that GLP1-RAs are also able to induce body weight loss [89]. Moreover, GLP1-RAs increase insulin sensitivity and reduce blood glucose levels [69]. Apart from the activation of different metabolic pathways, GLP1-RAs and SGLT2i share several anti-inflammatory and anti-oxidative effects. Both SGLT2i and GLP1-RAs target epicardial fat, contributing to the recovery of EAT fitness with a potential restoration of physiological epicardial volume [47,70]. However, the exact impact of these drugs on human epicardial adipose tissue remains an area of ongoing research. Furthermore, GLP1-RAs can reduce both proinflammatory cytokines through a direct effect on immune cells [71], and NOX activity and oxidative stress through activation of the AMPK pathway [77], with an anti-apoptotic effect on cardiomyocytes. In the same way, SGLT2i upregulate AMPK [40] thereby promoting autophagy and mitochondrial biogenesis stimulation in the diabetic heart [5,43]. Additionally, SGLT2i attenuate inflammation by reducing proinflammatory cytokines [54] and restoring NO levels, thus decreasing oxidative stress in cardiomyocytes and the vascular environment [54,60]. Both these drugs also contributed to a reduction in ROS production [62,83] and promoted M2 polarization [44,74]. All these findings prove the concept that both SGLT2i and GLP1-RAs provide cardiovascular benefits through anti-inflammatory and anti-oxidative effects beyond their metabolic actions. The effects of these two compounds against the inflammatory and oxidative diabetic milieu are the guiding stars on the route to cardiovascular protection. Future studies should explore the long-term effects and possible synergistic actions of SGLT2i and GLP1-RAs, paving the way for future therapeutic strategies in the field of cardiovascular care. There is also some evidence that the regulation of gut microbiota may be another cardiovascular benefit mechanism shared by GLP-1RA and SGLT2i [90]. Recent studies indicate that SGLT2i and GLP1-RA combination therapy may have additive kidney protection and thus indirect cardiovascular protection. This finding is supported by real-world data showing that this combination treatment was associated with a reduction in major cardiac and cerebrovascular events and heart failure compared with other glucose-lowering combination drug therapies for kidney disease in people with diabetes mellitus [91]. A pivotal point is deciding which drug should be used for which patient. In the future, readily available clinical characteristics of individuals can be used to tailor an optimal strategy (e.g., obesity may suggest GLP1-RA use; hypertension may indicate the SGLT2i choice). However, despite extensive efforts, there are no validated clinical features or biomarkers that predict a right response to this question.