Anti-inflammatory Pathways of Novel Anti-diabetic Therapies. A Literature Review

Abstract

SGLT2 inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP-1RAs) are two novel anti-diabetic therapeutic classes with an important impact on cardiovascular outcomes. Ongoing clinical trials are further investigating their potential beneficial effects on multiple cardiovascular conditions. Even though the underlying mechanisms are not yet fully understood, it is speculated that their cardiovascular protection goes beyond simply lowering plasma glucose levels. By reducing chronic inflammation through multiple pathways, these therapeutic agents seem to have pleiotropic effects on the cardiovascular system. This descriptive review summarizes the most important anti-inflammatory pathways of SGLT2is and GLP1-RAs, as described in present literature. We focus on inflammatory cytokines, oxidative stress, immune cell and mitochondrial function modulation, inflammatory pathway regulation and endothelial dysfunction improvement, with particular emphasis on their role in cardiovascular protection. A better understanding of the molecular mechanisms leading to the beneficial effects of these drugs could be crucial in developing a more specific therapeutic approach to various cardiovascular diseases.

Introduction

One of the last few years’ most important advances in cardiology is represented by the development and introduction of novel antidiabetic therapies, SGLT2 inhibitors (SGLT2is) and GLP1 receptor agonists (GLP-1RAs), due to their proven role in improving major cardiovascular outcomes, in addition to their hypoglycemic effect. Furthermore, they have led to a major revision of the standard medical treatment for several important cardiovascular conditions such as heart failure or atherosclerotic disease (1,2).

Initially introduced primarily as glucose lowering medications, these antidiabetic agents have demonstrated multiple cardiovascular beneficial effects, which go beyond controlling glycemic levels, showing a substantial reduction in mortality owing to cardiovascular disorders, as well as all-cause mortality. These outcomes have been highlighted in patients with heart failure with both reduced (HFrEF) and preserved ejection fraction (HFpEF) treated with SGLT2is, irrespective of the presence of type 2 diabetes mellitus (T2DM), in trials like DAPA-HF, Emperor- Reduced, CANVAS, Emperor-Preserved or Preserved-HF (2-7).

Regarding GLP-1RAs, trials such as LEADER, PIONEER-6, SUSTAIN-6 or SELECT have highlighted beneficial effects in lowering major adverse cardiovascular events (MACE) or death by lowering levels of glycated hemoglobin, weight loss or renal function improvement, seen both in diabetic and non-diabetic subjects (2,8,9).

Furthermore, STEP-HFpEF and STEP-HFpEF DM trials showed a significant improvement in HF related outcomes under semaglutide treatment in patients with obesity-related HFpEF with or without diabetes (10,11).

The exact mechanisms by which SGLT2is and GLP-1RAs exert their cardiovascular effects are not yet fully understood. It is speculated that their cardiovascular protection goes beyond simply lowering plasma glucose levels. By reducing chronic inflammation and oxidative stress, by improving endothelial, cardiomyocyte and mitochondrial function, these therapeutic agents seem to have an overall pleiotropic effect on the cardiovascular system (12).

Chronic systemic inflammation is known to be closely associated with multiple cardiovascular conditions (atherosclerosis, heart failure, atrial arrhythmias, etc.). Understanding the anti-inflammatory role of SGLT2is and GLP1-RAs might be the key to better address these diseases. This descriptive review aims to summarize the main anti-inflammatory pathways of these drugs as highlighted by both human and experimental animal-model studies, which can lead to their protective cardiovascular effects.

We conducted a PubMed database research using the following keyword combinations for our search: “SGLT2” and “cardiovascular inflammation”, “SGLT2” and “cardio protection” and “inflammation”, “GLP-1” and “cardiovascular inflammation”, “GLP-1” and “cardio protection” and “inflammation”. We mostly selected original studies, but also literature reviews and metanalyses centered on demonstrating the main protective cardiovascular effects of SGLT2is and GLP-1RAs, along with providing their underlying pathophysiological mechanisms. Both human and animal studies were included. The most recent and relevant articles for this purpose were selected, and a descriptive review of current literature data was written.

Our search resulted in 49 original studies from January 2017 to May 2025, after excluding duplicates and editorials. The studies relevant to this review are summarized in Table I, Table II, Table III, and Table IV. They were grouped into each table according to drug class but also to the type of subjects involved (human vs. non-human studies). The main anti-inflammatory pathways of these novel classes of drugs will hence be described in detail below.

Table I. Characteristics of the main SGLT2 inhibitors human studies included in the review.

BHB: β-Hydroxybutyrate; CKD: chronic kidney disease; CMECs: cardiac microvascular endothelial cells; CM: cardiomyocyte; GMP: cyclic guanosine monophosphate; GSHr: glutathione; HUVECs: human umbilical vein endothelial cells; mTOR: mammalian target of rapamycin; PAI-1: plasminogen activator inhibitor- 1; PKGIα: protein kinase G α; sGC: soluble guanylate cyclase; SOD: superoxide dismutase; TAC: total antioxidant capacity.

Table II. Characteristics of the main SGLT2 inhibitors derived from non-human studies included in the review.

AMPK: Adenosine monophosphate-activated protein kinase; βHB: beta- hydroxybutyrate; DM: diabetes mellitus; EF: ejection fraction; ISO: isoprenaline; eNOS: endothelial nitric-oxide synthase; FS: fractional shortening; LV: left ventricular; MI: myocardial infarction; NHE1: sodium hydrogen exchanger 1; SERCA2a: sarco/endoplastic reticulum Ca²⁺ - ATPase; ROS: reactive oxygen species, TAC: transverse aortic constriction, TXNDC5: thioredoxin domain containing 5; VSMC: vascular smooth muscle cells.

Table III. Characteristics of the main GLP-1RAs derived from human studies included in the review.

AGE: Advanced glycation end products; Akt: protein kinase B; HUVECs: human endothelial cells; mTOR: mammalian target of rapamycin; ROS: reactive oxygen species; T2DM: type 2 diabetes mellitus.

Table IV. Characteristics of the main GLP-1 RAs derived from non-human studies included in the review.

eNOS: Endothelial NO synthase; Epac: exchange protein directly activated by cAMP; LPS: lipopolysaccharide; MLC: myosin light chain; NAFLD: non-alcoholic fatty liver disease; NO: nitric oxide; NOS: nitric oxide synthase; PKA: protein kinase A; T2DM: type 2 diabetes mellitus.

SGLT2 Inhibitors

Located in the initial part of the nephron’s proximal tubule, the SGLT2 protein ensures reabsorption of 90% of glucose from the glomerular filtrate, while the remaining 10% is reabsorbed by SGLT1 proteins (13,14). SGLT2 is also a co-transporter for sodium in exchange with reabsorbed glucose (15).

Inhibition of the SGLT2 protein results in renal excretion of glucose, leading to lower glycemic levels and a decrease in blood pressure, thus explaining the main therapeutic effect of SGLT2is in treating T2DM. Another consequence of the SGLT2 blockade is represented by increased natriuresis. These effects partly explain the importance of SGLT2is in lowering blood pressure or improving cardiac function in heart failure subjects (13).

As already highlighted by multiple trials, SGLT2is have pleiotropic effects leading to improved cardiovascular outcomes: renal protection, cardiac and endothelial function enhancement (16). These effects cannot be explained solely by natriuresis and glycosuria, suggesting a more complex mechanisms of action (13).

Although the underlying mechanisms remain incompletely understood, several clinical and preclinical studies have shown the extensive anti-inflammatory effects of SGLT2is, suggesting potential pathophysiological explanations for their protective cardiovascular effects (12,17-19).

Some of the SGLT2is’ most important anti-inflammatory pathways are represented by the direct suppression of pro-inflammatory cytokines, reduction in oxidative stress, inhibition of NF-kB pathway, shifts in immune cell function and inhibition of the NLRP3 inflammasome (Figure 1).

Figure 1.

The main anti-inflammatory pathways of SGLT2 inhibitors and their cardiovascular beneficial effects (adapted after Zhang et al.) (19).

Suppression of Pro-inflammatory Cytokines. Both clinical and preclinical studies have researched the effects of SGLT2is on the most common inflammatory biomarkers. The importance of biomarkers such as interleukin 6 (IL-6), interleukin 1β (IL-1β), high-sensitivity C-reactive protein (Hs-CRP) or tumor necrosis factor-α (TNF-α) have been widely described in the literature, highlighting their implication in the formation and progression of the atherosclerotic plaque, as well as in the occurrence of cardiovascular thrombotic complications (20-23).

In the EMPA-CARD randomized controlled trial, Gohari et al. investigated the anti-inflammatory effects of empagliflozin treatment in patients with T2DM and coronary artery disease. The results showed decreased levels of IL-6, IL-1β and Hs-CRP in patients treated with empagliflozin compared to placebo (24).

Kolijn et al. researched the effects of empagliflozin on human and murine HFpEF myocardium, demonstrating reduced inflammation, consistent with lower levels of TNF-α, IL-6, ICAM-1 and VCAM-1 with empagliflozin treatment (25).

Furthermore, a study performed on non-diabetic mice treated with doxorubicin showed a significant decrease in IL-8, IL-6 and IL-1β for the group treated with empagliflozin as compared to placebo controls (26).

An experimental study designed to assess the importance of dapagliflozin and/or liraglutide in the treatment of diabetic cardiomyopathy concluded that the levels of proinflammatory cytokines IL-1β and IL-6 were significantly lower in cardiac tissue of rats treated with either dapagliflozin or liraglutide. Moreover, an additional anti-inflammatory effect was observed in the group treated with both drugs (27).

SGLT2is increases serum levels of adiponectin, while decreasing leptin and IL-6 levels. These changes may lead to improved insulin sensitivity and reduced atherosclerotic risk, as foam cell formation is inhibited by adiponectin. Furthermore, lower serum leptin levels contribute to improved endothelial function, vasodilation and lower intra-vascular inflammation (28).

Empagliflozin treatment showed beneficial effects in patients with HFrEF and T2DM by improving quality of life and functional capacity, as well as reducing IL-6 levels, leading to the hypothesis that the anti-inflammatory properties of SGLT2is could be one of the underlying protective mechanisms in heart failure (29).

Oxidative Stress Reduction, Mitochondrial Function Improvement. Oxidative stress refers to increased production and/or accumulation of oxygen-reactive species (ROS) that are not neutralized by natural antioxidant systems. Overproduction of ROS plays a crucial role in the pathogenesis and progression of atherosclerosis or other cardiovascular conditions (30-33). Oxidative stress is also associated with the onset and progression of T2DM, contributing to further complications like chronic kidney disease, obesity or cardiac disease (34).

Higher levels of ROS have other deleterious effects, leading to decreased nitric oxide (NO) bioavailability, vascular smooth muscle cell phenotype switch, endothelial cell dysfunction and monocyte dysfunction (32).

A study conducted by Kolijn et al. aimed at investigating the effects of empagliflozin on the human myocardium of patients with HFpEF and Zucker diabetic fatty obese rats. It showed that treatment with empagliflozin significantly reduced oxidative stress parameters (H2O2, 3-nitrotyrosine, GSH and lipid peroxide) in the cytosol and mitochondria. Additionally, an improvement in endothelial vasorelaxation was highlighted. Empagliflozin reduced protein kinase Gα polymerization and oxidation, both associated with echocardiographic signs of diastolic dysfunction and increased cardiomyocyte stiffness (25).

An in vitro experiment performed in high glucose exposed human endothelial cells concluded that empagliflozin treatment significantly reduced mitochondrial Ca²⁺ overload, ROS production and cellular permeability. An improvement in cell viability was also noted due to an overall reduction in oxidative stress (35).

A potential protective effect of SGLT2is against vascular calcifications has recently been highlighted. By reducing oxidative stress, dapagliflozin determined the modulation of thioredoxin domain containing 5 (TXNDC5), thus leading to decreased intimal vascular calcifications. The results were consistent regarding the effect of empagliflozin on intimal and medial calcification models, reinstating the hypothesis that protection against vascular calcifications may be a class effect of SGLT2is and that inflammation could be an important mechanism (36).

It must be stated that the mitochondria play an essential part in Ca2+ homeostasis, representing a major source of energy (ATP) through oxidative phosphorylation, as well as key signaling hubs for the immune and endocrine systems. In pathological, high inflammatory conditions such as T2DM or heart failure, the damaging mechanisms of oxidative stress and mitochondrial dysfunction are intertwined, as mitochondrial damage results in further production of ROS with secondary cardiac and vascular negative effects (contractile dysfunction, fibrosis, increased arrhythmia risk and endothelial damage). Moreover, less energy is being generated for the myocardium itself, leading to systolic dysfunction (37,38).

Based on various studies on cell cultures and tissue/organs of both diabetic and non-diabetic animal models or humans, it can be stated that SGLT2is provide protective effects on mitochondrial function. This class of drugs has also been shown to restore the physiological balance of mitochondrial fission/fusion and therefore prevent DNA damage. SGLT2is also improve cell permeability and mitochondrial structure, increase energy production, decrease ROS production, rebalance mitochondrial Ca²⁺ levels and reduce apoptosis (12,35-43).

Owing to their complex effects on mitochondrial function regardless of glycemic status, SGLT2is could represent key assets in the treatment of various cardiovascular conditions, as well as in the prevention of diabetes-related cardiovascular complications (37).

Improved Endothelial Function. This review has already mentioned some of the underlying factors leading to endothelial dysfunction such as inflammation, oxidative stress, and mitochondrial dysfunction. Furthermore, the focus will be on NO synthesis impairment and adhesion molecule activation, other factors that contribute to endothelial dysfunction and MACE.

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, along with altered NO synthase and mitochondrial dysfunction, play a major role in vascular wall ROS production (44). SGLT2is have been shown to regulate NO production, one of the most potent mediators of endothelial homeostasis. By up-regulating adenosine monophosphate-activated protein kinase (AMPK) activity and increasing endothelial NO synthase (eNOS) phosphorylation, SGLT2is play a crucial role in maintaining physiological vascular function (38,45,46).

Soares et al. investigated the vascular effects of empagliflozin in aged mice with confirmed vascular dysfunction. Following the assessment of mesenteric artery endothelial function along with mesenteric and aortic arterial stiffness, the authors found that the SGLT2i-treated group had increased NO synthase activity with a reduction in overall ROS production, thus resulting in improved endothelial function and reduced arterial stiffness compared to controls (47).

In addition to altered eNOS, NADPH oxidase activation results in increased levels of ROS and endothelial dysfunction. Angiotensin II stimulates SGLT2 and amplifies oxidative stress through NADPH oxidase activation, whereas empagliflozin acts as a NADPH oxidase inhibitor, exerting protective effects on endothelial function (38,48-51).

In a rat model, canagliflozin demonstrated a similar antioxidant effect by stimulating AMPK activity and eNOS, but also by suppressing NADPH oxidase (NOX4) (52). In experimental diabetic and apolipoprotein E-deficient mice, canagliflozin inhibited NADPH oxidase and had a lowering effect on inflammatory adhesion molecules ICAM-1 and VCAM-1 (53).

Empagliflozin and dapagliflozin had an enhancing effect on glutathione, glutathione peroxidase and superoxide dismutase, which all act as antioxidants, counterbalancing intracellular ROS production and increasing NO bioavailability. This confers an endothelial protective effect (38,54-56). One of the potential explanations is that in endothelial dysfunction, increased oxidative stress enhances the expression of cellular adhesion molecules such as ICAM-1 or VCAM-1, resulting in the attraction and adherence of leucocytes to the endothelium, leading to atherosclerosis progression (57,58).

In an in vitro study performed on human vascular endothelial cells exposed to TNF-α and hyperglycemia, Gaspari et al. demonstrated that dapagliflozin administration decreases ICAM-1 and VCAM-1 levels, implying a potential anti-atherogenic effect for dapagliflozin through its direct anti-inflammatory effects (59). Other in vivo and in vitro research also reported reduced levels of ICAM-1 and VCAM-1 with SGLT2i (empagliflozin) treatment (25,60).

However, some in vitro studies reported less significant effects of empagliflozin and dapagliflozin on adhesion molecule expression, although the conflicting results could be due to different SGLT2i concentration used, as well as variable TNF-α treatment regiments between studies (58,61).

Shifts in Immune Cell Function. The immune system consists of two types of macrophages. While M1 macrophages are involved in inflammatory response through the production of IL-6, IL-1β, TNF-α and ROS, M2 macrophages play an important part in inflammation resolution and have protective vascular effects by releasing IL-1 receptor agonists, IL-10 and collagen (19).

Macrophage polarization is also associated with a particular response of the adaptive immune system (T cells). Predominant M1 polarization determines an increase in Th1 and Th17, along with production of pro-inflammatory cytokines that physiologically protect cells from various pathogens but have adverse cardiovascular effects when their serum concentration is exacerbated such as in chronic conditions like obesity or diabetes. M2 polarization, however, is associated with Th2 up-regulation. This subpopulation of regulatory T cells (T_Reg) is essential for maintaining a normal immunological balance (62).

Various studies showed that SGLT2is have anti-inflammatory effects via M2 polarization. In a study conducted by Chen et al. on an ischemia-reperfusion injury mouse model, SGLT2i treatment determined a shift in macrophage polarization from M1 to M2. The reduction in intramyocardial hemorrhage and adverse ventricular remodeling seen with dapagliflozin treatment could be explained by macrophage polarization regulation (63).

Xu et al. found that in obese mice empagliflozin resulted in a reduction in M1 polarized macrophages and to an increase in M2-type macrophages in the white adipose tissue and liver, thus suggesting an underlying mechanism for reducing chronic inflammation associated with obesity (64).

A study on mouse cardiac fibroblasts and M1 macrophages showed that both dapagliflozin and empagliflozin inhibited pro-inflammatory cytokines and reduced M1 macrophage activation, also suggesting a potential anti-fibrotic effect of SGLT2is (65).

In a hyperlipidemia induced diastolic dysfunction model, inflammatory cytokines secreted by activated macrophages affected cardiomyocytes by inducing hypertrophy, fibrosis and disrupting autophagy. Treatment with dapagliflozin led to an improvement in cardiac function and lower inflammation possibly through its ability to reinstate macrophage homeostasis (66).

NF-kB Pathway and NLRP3 Inflammasome Inhibition. High oxidative stress conditions trigger the activation of nuclear factor kappa light chain enhancer of activated B cells (NF-kB) pathway, which in turn leads to ROS generation, as well as increased inflammatory cytokines (TNF-α, IL-1 and IL-6), adhesion protein molecules and monocyte chemotactic proteins production (25,67). The NLRP3 inflammasome activation also relies on the NF-kB pathway (68).

NLRP3 activation is believed to be involved in atherogenesis and heart failure by sustaining an inflammation cascade, which eventually leads to IL-1β and IL-18 production (67,68).

Studies have shown an inhibitory effect of SGLT2is on the NLRP3 inflammasome, potentially through the down-regulation of the NF-kB pathway. Other touted mechanisms are oxidative stress reduction and β-hydroxybutyrate production (which is an NLRP3 inflammasome inhibitor, thus providing anti-inflammatory properties) (68-72).

Xu et al., however, showed that dapagliflozin inhibited the activation of NF-kB pathway in the renal proximal tubular cells of humans with diabetes, therefore conferring nephroprotective effects (73).

Another studied mechanism is the AMPK pathway activation, which is associated with reduced vascular inflammation and improved endothelial function, and may regulate cardiac remodeling and systolic function (74,75). Its protective cardiac and vascular effects have been shown to be partly obtained through the inhibition of NF-kB activity (76,77). SGLT2is also enhance AMPK activation, leading to multiple anti-inflammatory responses such as decreased blood levels of inflammatory cytokines and improved autophagy (78-80).

Metabolic Shifts, Ketogenesis. Ketone bodies (such as β-hydroxybutyrate - BHB) are an additional source of energy, independent of glucose, and are abundant in the brain, heart and skeletal muscles. Additionally, ketones seem to have anti-inflammatory properties, as Youm et al. demonstrated that BHB has inhibitory effects on NLRP3 inflammasome and the production of IL-1β (68,81).

Hypoglycemia secondary to SGLT2is-induced glycosuria leads to a decrease in insulin/glucagon ratio, which promotes a metabolic shift from glucose oxidation to lipolysis and facilitates ketogenesis (19,82). In patients with T2DM, SGLT2is increase serum ketone concentration. Moreover, they seem to lower serum levels of insulin, glucose and uric acid (67). All these mechanisms lead to an important anti-inflammatory effect, besides metabolic improvement.

Byrne et al. highlighted the role of BHB in suppressing the activation of NLRP3 inflammasome. Also, chronically increased serum ketone concentrations are associated with a protective effect against heart failure-induced by myocardial fibrosis, hypertrophy and inflammation (83).

In HFrEF, higher ketone concentrations, as seen with SGLT2i treatment, provide additional “fuel” to the heart by increasing ATP production and energy supply (84). Further studies showed the importance of ketone bodies in inflammation attenuation by inhibiting activation of the NLRP3 inflammasome and therefore lowering athero-sclerotic progression. It also provides cardio-renal benefits, independent of glycemic status (19,68,82,85).

GLP-1 Receptor Agonists

GLP-1 is an incretin hormone secreted in the brain after nutrient intake. It binds to the GLP-1 receptor determining insulin secretion of pancreatic β cells, while reducing glucagon secretion by pancreatic α cells, as well as delaying gastric emptying (86). GLP-1 is rapidly degraded by the dipeptidyl peptidase- 4 (DPP-4) enzyme (87).

GLP-1RAs decrease glucagon secretion and favor glucose-dependent insulin biosynthesis and secretion. As a result, there is less stress on β-cells and hepatocytes, with better tissue insulin sensitivity. In adipose cells, GLP-1RAs stimulate glucose uptake and promote lipolysis and free fatty acid synthesis. Also, at the muscular level, there is an increase in glucose oxidation and glycogen synthesis. One of its most famous effects is at the gastrointestinal level where GLP-1 modulates gastric motility and acid secretion, thus stimulating gastric emptying and promoting cardioprotective effects by favoring renal natriuresis (87-89). These effects have been studied in multiple clinical trials that have shown a significant reduction in body weight and HbA1c levels with GLP-1 RA treatment, both in percutaneous and oral formulations. This is most likely because of the drug's ability to act on the GLP-1 receptor in the neuroendocrine system, promoting a sensation of fullness and reducing food intake, independent of hypothalamic reflexes (90). GLP-1RAs have cardiovascular, neurologic and gastrointestinal benefits that go beyond strict glycemic control, as is the case for SLGT2is. Potential benefits on atherosclerosis and ischemic heart disease protection have been extensively studied, although their exact pathophysiological mechanism remains a topic of discussion. Some of their anti-atherosclerotic properties are thought to be due to their anti-inflammatory effects, which are in most cases like those demonstrated for SGLT2is. The anti-inflammatory benefits of GLP-1RAs are both direct and indirect, by improving metabolic factors, better glycemic control, lower insulin resistance, lipid profile improvement and weigh loss (91,92). The main anti-inflammatory pathways exerted by GLP-1RAs will be discussed in the following section and are illustrated in Figure 2.

Figure 2.

Potential inflammatory mechanisms targeted by GLP-1 receptor agonists.

Reduction of Pro-inflammatory Cytokines. Various studies have demonstrated the role of GLP-1RAs in immune system modulation. A decrease in pro-inflammatory cytokines like TNF-α, IL-1β and IL-6 has been shown. This is in conjunction with increased levels of anti-inflammatory cytokines like IL-10 (93-97).

Withaar et al. recreated a murine HFpEF model that that was characterized by alterations such as cardiac hypertrophy and fibrosis, atrial enlargement and increased blood pressure. Liraglutide administration resulted in a decrease in pro-inflammatory and pro-fibrotic markers such as galectin-3 or IL-6, alongside a regression in cardiac hypertrophy and fibrosis, atrial weight and lung congestion (98).

The reduction in inflammatory response might be partly attributed to the inhibition of the NF-kB pathway, whose role in inflammation has already been described in detail above (99-101).

Immune Cell Modulation. Macrophages play an important part both in the inflammation cascade, but also in atherosclerotic plaque formation and progression. GLP-1RA treatment reduces foam cell formation, thus suppressing atherosclerotic plaque development. Similar to SGLT2is, GLP-1RAs stimulate the polarization to anti-inflammatory M2 type macrophages, while decreasing M1 type levels, thus leading to lower concentrations of IL-6 and TNF-α cytokines in the vascular lumen. Furthermore, macrophages enhance adiponectin secretion from adipocytes when under the direct effect of GLP. The inhibitory role of adiponectin in the development of atherosclerotic plaques is well- known (102-104).

Another anti-inflammatory pathway is represented by T cell modulation. GLP-1RAs decrease pro-inflammatory Th1 and Th17 leukocytes and increase regulatory T cells (105,106).

Finally, neutrophil recruitment has been shown to be decreased after GLP-1RA treatment contributing to their overall anti-atherosclerotic effects, through the prevention of plaque formation but also through stabilization of existing atherosclerotic disease (95,101,106,107).

NF-kB Pathway Inhibition. It is well known that NF-kB is an important transcription factor involved in inflammatory response and NLRP3 inflammasome activation, both of which play key roles in atherogenesis and heart failure. Studies have concluded that GLP-1RAs suppress the NLRP3 inflammasome and exert their inflammatory effects through the inhibition of the NF-kB signaling pathway (108,109).

By suppressing hyperglycemia-induced NF-kB and superoxide dismutase 2 expression in endothelial cells, GLP-1RAs could delay diabetes-associated microvascular complications, promoting vasodilation and improving endothelial functions (110).

A recent study showed that by reinstating Raf kinase inhibitor protein expression and suppressing the TANK- binding kinase 1- NF-kB pathway, semaglutide had the capacity to attenuate cardiac inflammation and thus, reduce fibrosis, ameliorate cardiac dysfunction, reduce oxidative stress and apoptosis of myocardial cells. Furthermore, the same study highlighted the importance of Sirtuin 3 in reducing cardiac inflammation (111).

Activation of cAMP-Protein Kinase A (PKA) Pathway. GLP-1RAs activate the cAMP-PKA pathway, thus having an antioxidant effect by decreasing ROS production and therefore improving cell protection. An example of such an effect could be the decrease of hypertension-related oxidative stress in vascular smooth muscle cells, thus improving their function through the anti-inflammatory effects of cAMP enhancement (99,109,110).

Protein kinase A (PKA) is also responsible for suppressing NF-kB, a pro-inflammatory mediator (106). Liraglutide leads to NADPH oxidase suppression as well as cAMP-PKA increased activity, thus attenuating oxidative stress in laboratory mice (112). It has also been stated that in non-alcoholic fatty liver disease, liraglutide provides anti-inflammatory protection by promoting M2 macrophage polarization through the cAMP-PKA-STAT3 pathway (113). Furthermore, Tang et al. conducted a study on the barrier function of the aortic endothelium in diabetic rats on GLP-1RA (exenatide) treatment. In vitro studies on human umbilical vein endothelial cells were also performed. The results showed that treatment with exenatide lowered endothelial permeability, which is exacerbated under hyperglycemic conditions. Endothelial-cell contractility which is also enhanced through accumulation of advanced glycation end-products, was also reduced by GLP-1RA treatment. As a result, GLP-1RAs could have protective vascular effects and their underlying mechanisms manifesting mostly through cAMP-PKA activation (114).

GLP-1RAs lead to an increase in cellular cAMP, which, in turn, by activating PKA and exchange protein directly activated (Epac) is responsible for anti-apoptotic and anti-inflammatory effects. A recent study conducted on cardiac cells with lipopolysaccharide-induced acute inflammatory injury showed that by increasing cardiac cAMP levels, liraglutide reduced levels of TNF-α, IL-1β, IL-6, MMP-2 and MMP-9, iNOS, inhibition of NF-kB activity, therefore emphasizing the protective cardiovascular effects of GLP-1RAs (115).

Oxidative Stress Reduction. Superoxide dismutase (SOD) and glutathione are some of the antioxidant enzymes whose serum levels have been shown to be augmented by GLP-1RA treatment (12). Oxidative stress regulation through various pathways is one of the main mechanisms for exerting its well-known cardiovascular, renal or neurological benefits (97,106).

Lambadiari et al. highlighted that in newly diagnosed patients with T2DM who underwent a 6-month treatment regimen with liraglutide, a reduction in atrial stiffness, left ventricular deformation parameters and NT-pro BNP levels was observed, mainly due to oxidative stress reduction (as determined by measurements of malondialdehyde) (116).

Zhang et al. investigated the effects of liraglutide on cultured cardiomyocytes. A protective effect was found, through decreased IL-1β-induced ROS generation and NADPH (NOX)-4 expression. Furthermore, IL-1β-induced inflammation lowered the mitochondrial membrane potential, but also ATP production. These, along with abnormal triglyceride accumulation, were attenuated following liraglutide treatment, in an AMPK-activation-dependent manner, highlighting its anti-inflammatory role (117).

Advanced glycation end products (AGEs) bind to their receptors (RAGE) and mediate asymmetric dimethylarginine formation, a major contributor to ROS accumulation. This is an important endothelial dysfunction risk factor. Through suppression of this pathway, GLP-1RAs provide a decrease in overall oxidative stress. Moreover, it has been stated that GLP-1RAs are able to regulate autophagy abnormalities caused by oxidative stress, due to their effect on the GLP-1R-ERK1/2-HDAC6 signaling pathway (99).

An underlying cause of ROS augmentation is mitochondrial dysfunction. GLP-1RAs have mitochondrial protective effects in diabetic cardiomyopathy due to the restoration of their normal function and morphology by reducing mitochondrial fragmentation (118).

Luna-Marco et al. investigated the effects of GLP-1RAs on polymorphonuclear cells of patients with diabetes and concluded that mitochondrial membrane potential and O₂ consumption displayed improvements in the treatment arm compared to the control group. A decrease in ROS production was also noted in patients who underwent therapy with GLP-1RAs (96).

Modulation of Endothelial Inflammation. Alongside chronic inflammation, foam cell formation, immune cell recruitment and smooth muscle cell proliferation, endothelial dysfunction is one of the main underlying mechanisms responsible for atherosclerotic plaque formation and destabilization. The anti-atherosclerotic effect of GLP-1RAs have been demonstrated by multiple clinical trials, and some of its potential pathophysiological mechanisms are described below.

In patients with T2DM treated with GLP-1RA, a suppression in leukocyte-endothelial interaction has been noted. Furthermore, lower levels of adhesion molecules like ICAM-1 and VCAM-1 were also observed, as well as reduced inflammatory cytokine concentrations (IL-6, TNFα and IL-12), with an increase in anti-inflammatory IL-10 levels. A decrease in carotid intima-media thickness was documented among T2DM subjects who received GLP-1RA treatment versus the control group. All the effects could mediate endothelial protection and anti-atherosclerotic effects of this novel therapeutic class (96).

Wu et al. highlighted a restoration of the normal endothelial barrier after exenatide administration (119). Helmstädter et al. conducted a study aimed at investigating the effects of liraglutide on mice with polymicrobial sepsis induced by cecal ligature and puncture. The results showed improvement of endothelial function following GLP-1RA administration, with positive effects on oxidative stress and inflammation reduction (120).

A previous study, published by the same authors, which investigated the effects of liraglutide in mice with laboratory-induced hypertension, showed vascular protective outcomes. By inhibiting the uncoupling of eNOS, liraglutide led to an increase in NO bioavailability, thus promoting vasodilation and afterload decrease (121).

Liraglutide was also found to improve endothelial function in human umbilical vein endothelial cells. Some of the proposed mechanisms for this effect is enhanced eNOS phosphorylation and NO production (122). The same effects leading to an increase in NO production and eNOS phosphorylation were obtained by Aung et al. in human subjects, which led, at least partially, to an improvement in skin microvascular perfusion in subjects on GLP-1RA therapy (123).

Metabolic Factors. The indirect anti-inflammatory effects of GLP-1RAs through the improvement of metabolic factors, glycemic control, decrease in insulin resistance and promotion of weight loss have already been mentioned.

Adipokines, produced by adipose tissue, are hormones involved in metabolism, inflammation, and immunity. However, in various chronic conditions, a dysregulation of adipokines is linked to a pro-inflammatory status and to increased risk of metabolic and cardiovascular disease (specifically atherosclerosis). The main pro-inflammatory adipokines are represented by leptin and resistin. On the other hand, adiponectin seems to have mostly anti-inflammatory effects, an impaired secretion leading to increased inflammation (124,125).

A meta-analysis concluded that GLP-1 RAs significantly reduce serum levels of both leptin and resistin, thus providing cardiovascular protective and anti-inflammatory effects (126).

Moreover, an increase in anti-inflammatory adiponectin has been reported by various studies after GLP-1 RAs administration (127,128).

Tirzepatide

A notable addition, which should be added as a discussion to this review would be tirzepatide, a dual GLP-1 and gastric inhibitory polypeptide (GIP) receptor agonist that has shown promising results in patients with T2DM by significantly reducing HbA1c concentrations as well as through weight loss and improvement of cardiometabolic parameters (129). Its effectiveness compared to GLP-1RAs in modulating hyperglycemia has been demonstrated by trials such as SURPASS-2 (130).

Regarding cardiovascular events, the role of GLP-1RAs in reducing MACE has been outlined by various clinical trials, which have already been discussed throughout this review. However, research centered on the potential protective cardiovascular effects of the combined impact of GIP and GLP-1RA are still ongoing.

Trials such as SURPASS-CVOT will provide additional information regarding cardiovascular effects and safety of tirzepatide vs. dulaglutide (a GLP-1RA) in patients with T2DM (131). Moreover, the SURMOUNT-MMO trial will investigate the effects of tirzepatide compared to semaglutide in patients with obesity without diabetes, in terms of both morbidity and mortality (132).

Even though limited studies suggest that tirzepatide reduces the risk of MACE, its effects on specific conditions such as heart failure are still being investigated (133). It is presumed that tirzepatide exerts direct beneficial cardiovascular effects, which go beyond glucose lowering, weight loss and insulin sensitivity improvement. Most of these effects might be attributed to its anti-inflammatory properties.

In patients with T2DM at high cardiovascular risk, treatment with tirzepatide led to a significant decrease in hsCRP when compared to insulin glarigine (134). Another study conducted on patients with diabetes showed a decrease in inflammatory markers associated with cardiovascular disease, such as YKL-40, ICAM-1, hsCRP and leptin (135).

In a mouse model with lipopolysaccharide-induced cardiac dysfunction, pretreatment with tirzepatide led to a decrease in serum levels of TNF-α, IL-6 an IL-1β, as well as reduced cardiomyocyte apoptosis via TLR4-NF-kB/NLRP3 inflammatory pathway inhibition. Additionally, there was a lower risk of ventricular arrythmias under tirzepatide pretreatment (136). It has also been shown that GIP reduced AGE-induced ROS generation in HUVECs, having a potential protective endothelial and anti-atherosclerotic effect (137).

In an in-vitro study performed on human AC16 cardiac cells exposed to high glucose concentrations, treatment with tirzepatide showed a direct inhibitory effect on markers linked to cardiac hypertrophy and fibrosis, such as TNF-α, MMP-9 and collagen, while also inducing down-regulation of FBXO32 and up-regulation of MURF1 gene expression. All of these have important anti-inflammatory outcomes. Tirzepatide also reversed high glucose-induced apoptosis, with an inhibitory effect being noted on mRNA expression and protein level of BAX, one of the main apoptotic genes. Additionally, a higher level of GIP receptors vs. GLP-1 receptors was found in the human cardiac cell line. As a result, a potential protective effect of tirzepatide on high glucose induced-cell death, fibrosis and hypertrophy could be expected (138).

In conclusion, with multiple ongoing trials investigating its safety and efficacy in various cardiovascular conditions, as well as experimental studies aimed at determining the underlying mechanisms, available data suggests that tirzepatide targets anti-inflammatory pathways that are similar to those targeted by SGLT2-is and GLP-1RAs, making it a valuable option for cardiovascular protection in diabetic and non-diabetic overweight individuals.

Discussion and Future Directions

In this review we summarize the various anti-inflammatory effects of SGLT2is and GLP-1RAs. They stem mainly from directly reducing pro-inflammatory cytokine levels and oxidative stress, but also through modulating immune cells such as macrophages, improving mitochondrial function, regulating multiple inflammatory pathways (reduction of NFkB pathway and NLRP3 inflammasome; activation of cAMP-PKA pathway) and improving endothelial function (through an increase in NO bioavailability, lowering adhesion molecules and ROS). Moreover, the metabolic effects of these novel therapeutic classes have been shown to lead to additional anti-inflammatory properties, both being closely intertwined.

This article brings into focus both in vivo and in vitro studies involving human and animal models. Hyperglycemic and normoglycemic subjects, but also experimental models have been analyzed to examine the importance of SGLT2is and GLP-1RAs in modulating the inflammatory response.

Due to their various anti-inflammatory proprieties, SGLT2is and GLP-1RAs improve endothelial function, provide anti-atherosclerotic protection, but also exhibit anti-remodeling and anti-fibrotic myocardial effects. Most of the studies, which highlight these beneficial effects, were unfortunately based on animal models. Therefore, more research based on human subjects is needed to correlate the anticipated anti-inflammatory outcomes enlisted in this article with clinical and imaging parameters. This will also provide further understanding of their relevance and applicability in cardiovascular prevention or treatment.

Moreover, additional studies should be conducted on non-diabetic subjects or normoglycemic models in order to undoubtedly prove that these therapeutic agents maintain their beneficial role in reducing chronic inflammation and improving cardiovascular outcomes, independent of glycemic status.

More effective cardioprotective strategies for patients with cancer receiving treatment with cardio-toxic potential are still needed. The role of SGLT2is and GLP-1RAs in cardio-oncology has not yet been extensively studied. However, there is emerging research highlighting the anti-inflammatory and cardioprotective effects of both drug classes in patients undergoing chemotherapy with different agents (26,139-142). These results support further research regarding the use of these agents in the primary prevention of cardiovascular complications secondary to oncologic treatment.

The combination of SGLT2is and GLP-1RAs ensures additional cardio-protection as compared to a single treatment regimen. This is achieved through down-regulation of inflammation, apoptosis and oxidative stress (27). Additional studies focused on enhancement of cardiovascular preventive and therapeutic effects provided by combination therapy would be welcomed.

Regarding protective effects in acute myocardial infarction (AMI), literature data available to date is rather conflicting. While DAPA-MI and EMPACT-MI trials reported no significant reduction in the risk of hospitalization or death from any cause in patients with AMI who received treatment with SGLT2is compared to placebo, other smaller studies showed a significantly lower risk of cardiovascular events including all-cause mortality and hospitalizations for heart failure, conferred by early administration of SGLT2i in patients with AMI and T2DM (143-145). Furthermore, both the EMMY and DAPA-MI trials showed an improvement in cardiometabolic and functional parameters (145,146).

GLP-1RAs lead to a decrease in atherosclerotic-related events, but their role following an acute cardiovascular event is not yet fully established. Emerging studies suggest an improvement in cardiac function for patients with severe systolic dysfunction following an acute coronary syndrome with successful percutaneous coronary revascularization, in whom on top of standard of care treatment, GLP-1 infusion was administered (147). As SGLT2is and GLP-1RA have different mechanisms of action resulting in complementary effects on atherosclerosis and heart failure progression, their combination might prove beneficial in decreasing the risk of cardiovascular events and heart failure development following an AMI. This has been suggested by a few studies, but trials investigating the incremental efficacy of this combination treatment are needed both in patients with and without diabetes (148). Considering the available experimental evidence, one might expect that the beneficial anti-inflammatory properties should also be translated to post-myocardial infarction patients. However, there is limited data to suggest this and more studies in this area are needed before drawing a definite recommendation.

Due to their anti-inflammatory and anti-fibrotic effects, SGLT2 is and GLP-1RAs reduce atrial remodeling (98,115,149). Together with the direct decrease in inflammation and their positive metabolic effects, this may contribute to an intrinsic anti-arrhythmic effect, especially on the incidence of atrial fibrillation. Results on this matter differ greatly between studies, therefore highlighting the importance of larger randomized trials, as atrial arrhythmias are known to substantially increase morbidity in patients with HF (150-152).

The pathophysiology of atherosclerosis is closely connected to inflammation. The importance of macrophages in atherosclerotic plaque formation is well known. Under the excessive uptake of oxidized LDL-cholesterol, they convert into foam cells which in turn release inflammatory cytokines leading to further destabilization of the plaque (153).

M1 macrophages have been found to be predominant in atherosclerotic plaques as compared to M2 macrophages, which have a lower capacity to transform into foam cells and release anti-inflammatory cytokines (154).

The exact mechanisms leading to the transition of non-inflammatory macrophages into the M1 type are not yet fully understood, although studies outline the importance of enhanced oxidized LDL-C uptake in addition to signaling pathway alterations caused by hypoxemia and hyperglycemia (155).

All these factors are also involved in the activation of NLRP3 inflammasome, as well as in the NF-kB signaling pathway activation in macrophages, therefore accelerating foam cell formation, plaque inflammation and atherosclerosis progression (156,157). By blocking or delaying these pathophysiologic processes, one might expect to obtain better cardiovascular outcomes. Both SGLT2is and GLP-1RAs are extensively tested for this exact role.

Throughout this review, the importance of SGLT2is and GLP-1RAs in lowering pro-inflammatory cytokines, enhancing macrophage polarization to anti-inflammatory M2 type macrophages and the inhibition of NF-kB and NLRP3 inflammasome signaling pathways was outlined through the description of various studies. Understanding the formation and progression of atherosclerosis on a molecular level, as well as showing the potential mechanisms through which SGLT2is and GLP-1RAs target this process could be crucial in developing a more specific therapeutic approach to atherosclerotic disease. Although clinical trials have shown the relevance of GLP-1RAs in reducing cardiovascular events, their role in primary prevention or as part of the standard optimized medical treatment in chronic coronary disease is yet to be determined.

Conclusion

This review summarizes the vast anti-inflammatory effects exhibited by both SGLT2is and GLP-1RAs. Knowing that the pathophysiology of most cardiovascular conditions is directly influenced by different inflammation pathways, this suggests the potential preventive and therapeutic importance of these novel therapeutic classes. It also provides a promising background for clinical correlations and further research regarding their future indications.

Conflicts of Interest

The Authors have no conflicts of interest to declare in relation to this study.

Authors’ Contributions

Adina David Comșa: literature search and data curation, writing original draft. Horațiu Comșa: conceptualization, writing - review and editing. Gabriel Cismaru: editing, visualization/figures and tables. Radu Roșu: literature search and data curation. Dana Pop: supervision, approval of final manuscript.

Artificial Intelligence (AI) Disclosure

During the preparation of this manuscript, a large language model (Chat GPT, OpenAI) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning-based image enhancement tools.