Next Article in Journal
Evaluation of the Ecological Environment Affected by Cry1Ah1 in Poplar
Next Article in Special Issue
Diabetes Mellitus and Heart Failure: Epidemiology, Pathophysiologic Mechanisms, and the Role of SGLT2 Inhibitors
Previous Article in Journal
Why Iron Deficiency in Acute Heart Failure Should Be Treated: A Real-World Clinical Practice Study
Previous Article in Special Issue
Protein Hydrolysates from Brewing By-Products as Natural Alternatives to ACE-Inhibitory Drugs for Hypertension Management
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Life
Volume 12
Issue 11
10.3390/life12111829
life-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Anti-Inflammatory Effect of Novel Antidiabetic Agents

by
Panagiotis Theofilis
1,†,
Marios Sagris
2,†,
Evangelos Oikonomou
1,2,
Alexios S. Antonopoulos
1,
Gerasimos Siasos
1,2,
Kostas Tsioufis
1 and
Dimitris Tousoulis
1,*
1
1st Cardiology Department, “Hippokration” General Hospital, University of Athens Medical School, 11527 Athens, Greece
2
3rd Cardiology Department, Thoracic Diseases Hospital “Sotiria”, University of Athens Medical School, 11527 Athens, Greece
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to the work.
Life 2022, 12(11), 1829; https://doi.org/10.3390/life12111829
Submission received: 7 September 2022 / Revised: 28 September 2022 / Accepted: 5 November 2022 / Published: 9 November 2022
(This article belongs to the Special Issue Cardiometabolic Disorders: From Pathophysiological Mechanism to Therapeutic Target)
Versions Notes

Abstract

:
The incidence of type 2 diabetes (T2DM) has been increasing worldwide and remains one of the leading causes of atherosclerotic disease. Several antidiabetic agents have been introduced in trying to regulate glucose control levels with different mechanisms of action. These agents, and sodium-glucose cotransporter-2 inhibitors in particular, have been endorsed by contemporary guidelines in patients with or without T2DM. Their widespread usage during the last three decades has raised awareness in the scientific community concerning their pleiotropic mechanisms of action, including their putative anti-inflammatory effect. In this review, we delve into the anti-inflammatory role and mechanism of the existing antidiabetic agents in the cardiovascular system and their potential use in other chronic sterile inflammatory conditions.

1. Introduction

Diabetes mellitus type 2 (T2DM) is a major pandemic in Western societies, with serious consequences such as chronic kidney disease (CKD), atherosclerosis, and heart failure. Traditional therapeutic approaches have tried to improve hyperglycemia, with evidence indicating no links to the prevalence of complications. As a result, recent breakthroughs in T2DM pharmacological therapy point to the reversal of the complicated pathophysiology rather than merely dysglycemia. In this context, novel antidiabetic medications have shown substantial efficacy in improving cardiorenal outcomes, according to the landmark randomized clinical trial results.
Low-grade sterile inflammation has been identified as a significant risk factor for cardiorenal diseases [1,2,3,4,5,6]. It is also necessary to emphasize the effect of established cardiovascular risk factors in increasing inflammation [7,8,9]. Moreover, inflammation plays an important role in the pathogenesis of T2DM [10]. Therefore, in this review article, we highlight the deleterious effect of inflammation in T2DM pathophysiology and complications, while we also elaborate on the evidence concerning the anti-inflammatory potential of novel antidiabetic medication, namely, dipeptidyl peptidase-4 inhibitors (DPP4is), glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors.

2. Inflammation as a Pathophysiologic Mechanism in DM and Its Complications

The inflammatory hypothesis of T2DM has been evaluated in several human studies, which have assessed the relationship between DM and inflammatory biomarkers. In a case–control study of 2333 subjects, the presence of T2DM was associated with elevated high-sensitivity C-reactive protein (hsCRP) in both male and female participants [11]. The significance of this relationship remained unaffected even after adjustment for multiple confounders. Body mass index, waist circumference, HbA1c, fasting insulin, and C peptide were the factors influencing hsCRP levels in diabetic subjects [11]. A correlation between HbA1c and hsCRP was observed in T2DM subjects irrespective of coronary artery disease presence, as shown by Bahceci et al. [12]. Moreover, TNF-α was positively correlated with HbA1c and insulin resistance, measured by the Homeostatic Model Assessment for Insulin Resistance index, in subjects with DM [13].
Multiple inflammatory pathways are involved in the pathophysiology of DM. First and foremost, β cell dysfunction may be regulated by the nuclear factor-κB (NF-κB) signaling pathways. Proinflammatory molecules, including cytokines and pathogen- or damage-associated molecular patterns are able to activate NF-κB through activation of the inhibitory κB protein (IκB) kinase (IKK) complex [14,15]. In the noncanonical NF-κB induction, the TNF receptor-associated factor 2 (TRAF2) recruits cellular inhibitors of apoptosis 1 and 2 (cIAP1/2), leading to TRAF3 proteolysis and NF-κB-inducing kinase (NIK) accumulation. Consequently, NIK phosphorylates IKKα, causing the inhibitory protein p100 to be processed into the active component p52, which binds to RelB and translocates to the nucleus to promote gene expression [16]. However, the deleterious effect of the noncanonical pathway and its ability to promote DM has been characterized by controversial evidence [17,18,19].
The emerging role of nucleotide-binding oligomerization domain and leucine-rich repeat pyrin 3 domain (NLRP3) inflammasome in DM ought to be stressed. Its activation is a two-step process consisting of initial “priming” with the aid of NF-κB-mediated cytokine transcription [20] and subsequent activation mediated by lysosomal instability, mitochondrial damage, and potassium efflux [20]. Mitochondrial injury is of great importance since it can promote NLRP3 inflammasome activation in multiple ways, such as the release of mitochondrial reactive oxygen species, DNA, and cardiolipin, which is an activator of NLRP3 [20]. Impaired autophagy, the vital process of lysosomal clearance of cellular debris, may constitute another factor aiding NLRP3 activation [21]. The inflammasome assembly occurs after NLRP3 activation, and the pro-IL-1 and pro-IL-18 are cleaved into IL-1 and IL-18.
Alterations in the gut microbiome is a novel mechanism that may lead to DM via several pathways, including the augmentation of inflammation. It is known that several intestinal bacteria modulate inflammation. Among the bacteria known to possess anti-inflammatory actions are Roseburia intestinalis [22], Bacteroides fragilis [23], Akkermansia muciniphila [24], Lactobacillus plantarum [25], and Lactobacillus casei [26], by promoting IL-10 production, thus preventing ageing-related insulin resistance [27]. Moreover, Lactobacilli could provide anti-inflammatory effects by regulating the expression of proinflammatory cytokines [28]. Moreover, butyrate-producing bacteria such as Roseburia spp. and Faecalibactrium spp. may inhibit NF-κB activity [29]. According to this evidence, we can assume that the lack of such bacterial strains in the gut environment may play an important role in the constitution of a proinflammatory state and, ultimately, the development of DM. Additionally, the abundance of other strains such as Fusobacterium nucleatum and Ruminococcus gnavus leads to proinflammatory cytokine overexpression [30,31].
Inflammation plays a detrimental role in the development of diabetic complications, most notably atherosclerosis and kidney injury. Beginning with atherosclerosis, inflammation has emerged as a critical mechanistic component [1,32]. DM, through inflammatory stimuli, is an important regulator of endothelial dysfunction, which is among the initial steps of atherogenesis [33]. As a result of hyperglycemia, the overexpression of advanced glycation end products (AGEs) and their receptors (RAGE) disrupts nitric oxide bioavailability and promotes reactive oxygen species production from the vascular endothelial cells [33]. Moreover, hyperglycemia-induced overexpression of AGEs and reactive oxygen species promotes monocyte recruitment, low-density lipoprotein oxidation, and, ultimately, foam cell formation [34].
Renal inflammation is among the main pathophysiologic mechanisms involved in the development of diabetic kidney disease. This inflammatory state is propagated by high glucose levels and AGEs [35], with ensuing release of damage-associated molecular patterns and activation of pattern recognition receptors. It has been previously proven through kidney biopsies that macrophages invade glomeruli and renal interstitial space [36], as a result of bone marrow-derived monocyte recruitment and differentiation in the setting of renal injury [37]. The degree of macrophage accumulation has also been associated with the progression to end-stage kidney disease (ESKD) [38]. Other than macrophages, the renal concentration of activated T cells is significantly higher in patients with T2DM and is attributable to proteinuria [39]. Apart from the increased expression of well-established inflammatory mediators such as IL-6 [40], the upregulation of complement C3, CXC-chemokine ligand 6 (CXCL6), and CC-chemokine ligand 2 (CCL2) has been observed in kidney biopsy samples [41]. Concerning human studies, increased high-sensitivity C-reactive protein was associated with incident diabetic nephropathy in African Americans in the Jackson Heart Study [42]. Biomarker-based approaches have further highlighted the role of inflammation in the progression of kidney disease in subjects with DM by showing an association of an inflammatory risk signature with incident ESKD during 8-13 years of follow-up [43]. The detrimental combination of chronic tubulointerstitial inflammation and mitochondrial dysfunction ultimately leads to a profibrotic milieu that is responsible for irreversible kidney injury.

3. Anti-Inflammatory Effects of Novel Antidiabetic Agents

3.1. DPP4 Inhibitors

DPP4 or CD26 is a cell surface type II transmembrane protein which exerts noncatalytic functions by binding to contiguous proteins on the cell membrane or in the extracellular matrix [44,45]. It is expressed in a variety of cells, including immune, epithelial, and endothelial cells [44,45]. Its main role is the inactivation of incretins and the post-translational maturation of chemokines secreted by the activation of T cells [46,47]. DPP4is are well-known drugs for their antidiabetic effect. DPP4i was first identified as a therapeutic medication for T2DM because of its ability to upregulate the half-life of incretins, GLP-1, and glucose-dependent insulinotropic peptide (GIP). Generally, these incretins control blood glucose levels after a meal by promoting insulin release, prolonging gastric emptying, inducing satiety, suppressing glucagon release, and conserving beta-cell mass [46,47]. In cases of T2DM, administration of DPP4i increases glucose metabolism by increasing GLP-1 receptor signaling in the pancreas, which stimulates insulin production while suppressing glucagon secretion [48]. Sitagliptin constitutes the first drug from the category approved for the treatment of T2DM in 2006; since then, a variety of selective DPP4is have been introduced [47].
DPP4is, in addition to their antidiabetic effect, present benefits based on their anti-inflammatory action [45]. More particularly, DPP4 may play important roles in other processes other than glycemic control, as shown by its wide expression on several types of immune cells [49]. It is well known that DM constitutes a progressive low-grade inflammatory condition burdening patients with metabolic syndrome or an overall atherosclerotic profile. The wide use of DPP4i during the last two decades has raised awareness in the scientific community concerning the research of their anti-inflammatory effect [50,51]. DPP4is, due to their biochemical structure and enzymatic function, can activate or inactivate several fragments of the targeted chemokines [46]. The mechanisms underlying DPP4i’s protective effects include increased bioavailability of its substrates; effects on mediators and signaling pathways that improve cardiovascular and renal function by suppressing oxidative stress, inflammation, fibrosis, and apoptosis; improved endothelial function; and tissue reparation [52]. Based on this effect, alogliptin, a DPP4i, was shown to suppress toll-like receptor 4-mediated extracellular signal-regulated kinase, IL-6, and IL-1β secretion [53,54]. In addition, in vitro experiments of sitagliptin’s analogue to human macrophages showed inhibition of NF-κB p65 nuclear translocation through the cAMP/protein kinase A pathway, resulting in attenuation of proinflammatory status [55]. In this respect, a recent meta-analysis of 16 studies assessing the anti-inflammatory effect of DPP4i in patients with T2DM showed a significant reduction in C-reactive protein levels [56].
In animal experimental models, the use of sitagliptin led to a significant reduction in the levels of circulating proinflammatory cytokines such as IL-1β, IL-6, TNF-a, and monocyte chemoattractant protein (MCP)-1 [55]. Using sitagliptin analogue in various doses, a reduction was observed in the infiltration of CD8+ T cells and proinflammatory (M1) macrophages in the adipose tissue of diabetic mice, as well as improvement in their metabolic status [57]. Regarding the inflammatory burdening of atherosclerotic plaques, sitagliptin and alogliptin administration improved plaque stabilization and expression of IL-6/IL-1 in atherosclerotic lesions [54,58]. DPP4is suppress macrophage accumulation and foam cell formation reducing the total aortic atherosclerotic lesions in atherosclerotic mice [54,58]. In human umbilical vein endothelial cells and monocytes, linagliptin was reported to decrease IL-6 production [59]. Only one study showed no correlation between linagliptin administration and ferritin levels in 25 diabetes patients on hemodialysis, confirming the scarcity of data on humans [60].
In the clinical setting, DPP4 seems to be overexpressed in patients with T2DM, while cellular and serum DPP4 expression correlates well with glucose control [61]. In a cohort of diabetic patients treated with sitagliptin, a decrease in the levels of proinflammatory biomarkers such as CRP and IL-6 was observed [62]. Regarding the expression of DPP4 on peripheral blood monocytes, treatment with sitagliptin led to a reduction in DPP4 expression on their surface, while the unfavorable proinflammatory (M1)/anti-inflammatory (M2)-like phenotypes were improved [62]. The anti-inflammatory effect of DPP4i has also been recognized in patients with coronary artery disease and uncontrolled glucose levels. DPP4 seems to improve arterial stiffness measured via PWV as well as peripheral endothelial dysfunction [63]. Finally, in light of these complex effects of DPP4i, improvement in the inflammatory status of patients with sterile inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease have been documented [64,65].

3.2. GLP-1 Receptor Agonists

GLP-1 is a peptide hormone that presents 50% amino acid homology with glucagon. GLP-1 is mainly expressed by the intestinal L-cells as well as by brain cells after the degradation of proglucagon by prohormone convertase enzymes in response to nutrient ingestion [66,67]. Despite their high degree of sequence similarity, glucagon and GLP-1 have opposing effects on glucose homeostasis [68]. Glucagon causes a rise in glycemia, whereas GLP-1 causes a decrease in blood glucose levels. GLP-1’s hypoglycemic activity is linked to increased glucose-dependent insulin secretion, suppression of glucagon synthesis, and modulation of islet cell proliferation, differentiation, and survival. Furthermore, GLP-1 regulates satiety and decreases gastric emptying, which is consequently linked to weight reduction. As a result, GLP-1 has been extensively researched as a potential therapy for T2DM, while GLP-1 receptor antagonists and DPP4i are currently frequently used in the clinical setting [67,69].
GLP-1 receptor is widely expressed, suggesting that it may have additional roles other than glucose level regulation (Table 1). Evidence showed an anti-inflammatory effect on the cardiovascular system as well as on the pancreas, kidneys, and lungs [70]. In vitro studies revealed a downregulation in the expression of inflammatory genes such as NFκB1(p105), NFκB2(p100), RelA (also termed p65), TNF receptor superfamily member 1A, and receptor-interacting serine/threonine kinase 2 when treatment with a GLP-1 receptor agonist was applied in cultured human cells [71]. Exendin-4, a GLP-1 receptor antagonist, seems to suppress C-X-C motif chemokine 10 production, leading to decreased cytotoxic T lymphocyte cell recruitment in subjects with DM type I [72]. Another study showed that exenatide can induce the expression of serine protease inhibitor-9 in pancreatic islets, constituting a determining role in the survival of those cells against the attack from natural killers and cytotoxic T cells [73]. However, a hallmark in the pathophysiology of T2DM is the insulin resistance of adipose tissue. The main contributors to this phenomenon seem to be the infiltration of proinflammatory cytokines and chemokines in the tissue [74,75]. The administration of a recombinant adenovirus-producing GLP-1 to mice leads to the inhibition of NF-κB activation and phosphorylation of ERK1/2 and c-Jun N-terminal kinases. More particularly, the levels of common proinflammatory biomarkers (TNF-a, MCP-1, IL-6) were reduced [76]. As a result, in addition to glucose-lowering effects, GLP-1 receptor antagonists assist in the reduction in an individual’s inflammation grade, while also providing additional advantages such as islet preservation and potentially improved insulin sensitivity.
Regarding the anti-inflammatory properties of this drug category in the vascular bed, liraglutide seems to be the most widely studied. It was shown that administration of 100μM liraglutide resulted in a significant reduction in adhesion molecules’ gene expression [77,78]. More specifically, liraglutide’s anti-inflammatory effect is based on the activation of adenosine monophosphate-activated protein kinase (AMPK) and calcium/calmodulin-dependent protein kinase β (CAMKKβ), which are cAMP/Ca2+ signaling pathways [77,78]. Furthermore, an overexpression of sirtuin 6 (SIRT6) in endothelial cells and asymptomatic atherosclerotic plaques was observed. A SIRT6 level increase has been previously associated with the downregulation of proinflammatory genes expression [79,80]. The GLP-1 receptor’s beneficial effect extends to the reduction of oxidative stress. Indeed, the treatment of liraglutide to mice with high levels of catalase and glutathione peroxidase-3—important enzymes for regulating oxidative stress—increased their circulation levels [81,82]. A recent meta-analysis strongly supports the clinically relevant anti-inflammatory and antioxidant effects of GLP-1 receptor antagonists. An analysis of GLP-1 receptor antagonists versus standard diabetes therapies or placebo revealed significant reductions in CRP, TNFα, and malondialdehyde, and significant increases in adiponectin [83]. Finally, GLP-1 receptor antagonists seem to protect against contractile dysfunction in experimental animal models, as well as in diabetic cardiomyopathy [84,85]. Probably, GLP-1 receptor antagonists’ anti-inflammatory properties may be used to treat a wide range of conditions, including neurodegenerative brain disorders, kidney disease, nonalcoholic steatohepatitis, and pulmonary inflammatory diseases. However, certain uncommon incidents of acute pancreatitis and neoplasms have been recorded; consequently, the safety of GLP-1-based treatment should be evaluated in additional studies [86,87].
Probably, GLP-1 receptor antagonists’ anti-inflammatory properties may be used to treat a wide range of conditions, including neurodegenerative brain disorders, kidney disease, nonalcoholic steatohepatitis, and pulmonary inflammatory diseases. Regarding Alzheimer’s disease, recent studies illustrate that administration of liraglutide can reduce the inflammatory status in the cortex while restoration effects were observed [88,89]. Kim et al. highlighted the inhibitory effect of exendin-4 on microglial activation, suggesting that it may have therapeutic potential for the treatment of Parkinson’s disease [90]. Diabetic nephropathy is characterized by low-grade inflammation in the glomerular microvasculature of the kidney [91]. Studies showed that GLP-1-based treatments can reduce macrophage infiltration and inflammatory molecules in diabetic nephropathy models [92]. Anti-inflammatory efficiency has been proved not only in diabetic nephropathy but in nondiabetic as well. Generally, GLP-1-based treatments seem to reduce the infiltration of CD68-positive inflammatory macrophages in the kidney [93]. In individuals with nonalcoholic fatty liver disease, GLP-1 receptor agonists reduced alanine aminotransferase and aspartate aminotransferase levels, improving lipid metabolism [94]. In addition, a significant reduction in CRP and TNF-a circulating levels was observed in this special patient population [95,96]. However, certain uncommon incidents of acute pancreatitis and neoplasms have been recorded; consequently, the safety of GLP-1-based treatment should be evaluated in additional studies [86,87].

3.3. SGLT2-Inhibitors

Because they are responsible for the reabsorption of the bulk of filtered glucose by the glomeruli, SGLT1 and SGLT2, which are found on the proximal convoluted tubule of nephrons, are essential mediators of glucose homeostasis. The high-capacity, low-affinity SGLT2 absorbs 90% of the glucose, with a sodium turnover ratio of 1:1 [97,98]. As a result, facilitative glucose transporters (GLUTs) situated in the epithelial lining of proximal tubules unleash glucose into the blood [97]. Overexpression of glucose transporter genes in diabetic individuals has been described, leading to upregulation of SGLT2 and consequently enhanced reabsorption [99]. The particular processes involved are unknown, although they appear to be linked to the underlying hyperglycemia [99].
The impact of SGLT inhibition on diabetes was first observed in 1987 with the use of phlorizin, a nonspecific SLGT1 and SGLT2 inhibitor [100]. Its treatment resulted in reduced hyperglycemia and increased glycosuria in an animal model of T2DM, along with normal insulin sensitivity. However, there were intrinsic limits that had to be solved. The simultaneous inhibition of SGLT1 on the intestinal mucosa resulted in diarrhea [101], whereas phlorizin’s hydrolysis to phloretin, which inhibits GLUT1, might result in poor glucose uptake in numerous tissues [102]. However, specific SGLT2 inhibitors have yet to be produced. Dapagliflozin [103] was the first high-potency SLGT2-i to be created, followed by canagliflozin [104], empagliflozin [105], and ertugliflozin [106]. Other compounds of this family, such as ipragliflozin, tofogliflozin, and luseogliflozin, have also been explored, but less thoroughly. In terms of hypoglycemic impact, all licensed medications have shown efficacy in decreasing glucose levels and HbA1c in randomized clinical studies.
Despite being first used to treat T2DM [107], SGLT2 inhibition has been at the center of scientific research in recent years due to its favorable cardiorenal profile. Recently completed clinical trials have shown significant improvements in individuals with heart failure and chronic kidney disease (CKD) [108,109,110,111]. Notably, the results were similar regardless of the presence of DM [112]. Furthermore, SGLT2 inhibitors have emerged lately as the sole pharmacologic treatment with proven effectiveness in individuals with heart failure and retained ejection fraction [113]. It should also be stressed that various additional offset effects, such as a lower incidence rate of atrial fibrillation and an improvement in nonalcoholic liver disease indices after therapy with an SGLT2 inhibitor, have been documented [114,115].
Their pleiotropic mechanism of action is believed to be accountable for these beneficial actions, including the management of inflammation (Table 2). In fact, inflammation could be contributing to incident endothelial dysfunction, oxidative stress, and platelet activation, among others [33,116]. However, clinical evidence of their impact on these parameters, notably inflammation, is sparse. SGLT2 inhibitors may reduce levels of inflammatory markers such as CRP, IL1, IL-6, and TNF-α in the few cohort studies that have been published [117,118,119,120]. Furthermore, a 6-month therapy with dapagliflozin 5 mg once daily resulted in a substantial decrease in plasma TNF-α in a small-scale RCT of 35 patients with T2DM and coronary artery disease [121].
A recent hypothesis for the probable mechanism involved in this anti-inflammatory action includes the restoration of autophagy, which leads to antiapoptotic, antioxidant, and anti-inflammatory effects. In this context, SGLT2 inhibitors may induce a state of perceived energy deprivation, leading to an increase in the autophagy-stimulating SIRT1/hypoxia-inducible factor/AMPK pathway [130], while decreasing the autophagy-inhibiting Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway [131]. As a result, restoring autophagy may mitigate the aforementioned negative effects, including inflammation.
The anti-inflammatory effect of SGLT2 inhibitors has also been assessed in preclinical models. Beginning with diabetic animal models, several contemporary studies have pointed towards an anti-inflammatory effect, evidenced by the lowering of inflammatory marker expression (MCP-1, IL-6, p38) [122,123,124]. In models of CKD, empagliflozin ameliorated IL-1β-induced inflammation in normoglycemic human proximal tubular cells, indicating a glucose-independent anti-inflammatory action of SGLT2 inhibitors through targeting CXCL8/IL8, LOX, NOV, PTX3, and SGK1 genes [132]. The SGLT2 inhibitor dapagliflozin resulted in attenuation of renal inflammation and apoptosis in a diabetic rat model [125]. Moreover, dapagliflozin led to itaconate-mediated NLRP3 inflammasome downregulation in an animal model of progressive CKD [133]. Empagliflozin diminished the renal expression of inflammatory markers (TNF-α, MCP-1) by acting on the HMGB1-TLR4 axis in an experiment involving rats with streptozocin-induced diabetes [126]. These findings may partly explain the attenuated glomerular and tubulointerstitial injury observed in CKD following treatment with an SGLT2 inhibitor [134]. In models of cardiovascular disease, Quaqliarriello et al. demonstrated the anti-inflammatory potential of empagliflozin in an animal model of doxorubicin-induced cardiotoxicity through the downregulation of NF-κB, NLRP3 inflammasome, and inflammatory interleukins. Empagliflozin also attenuated interleukin-17A-induced human aortic smooth muscle cell proliferation and migration by targeting TRAF3IP2/ROS/NLRP3/Caspase-1-dependent IL-1beta and IL-18 secretion [135]. SGLT2 inhibitors may exert anti-inflammatory effects in nonalcoholic steatohepatitis, since ipragliflozin and empagliflozin administration reduced lobular inflammation and inflammatory marker expression [128,129,136]. Lastly, recent studies have documented the anti-inflammatory potential of dapagliflozin in animal models of experimental colitis through inhibition of NADPH oxidase 2 and the NF-κB/AMPK/NLRP3 axis, among others [137,138].

4. Future Directions

The scientific interest in the management of not only T2DM but also obesity via the use of GLP-1 receptor agonist and the older one, glucose-dependent insulinotropic polypeptide (GIP), led to the development of newer agents [139,140,141]. The dual GIP/GLP-1 receptor agonist has outperformed dulaglutide and semaglutide, two highly selective GLP-1 receptor agonists, in terms of lowering plasma glucose and glycated hemoglobin (HbA1c). Until now, the main representative of this drug category has been Tirzepatide, which combines the antiglycemic benefits of both, augmenting insulin secretion [142]. However, in previous studies on diabetic patients, GIP did not influence the overall effect of the combination in type 2 diabetes patients. Rather, the combination of GIP and GLP-1 was less insulinotropic than the sum of the individual effects of GIP and GLP-1 given separately [142]. A potential explanation could be provided by the GIP resistance that diabetic patients present. Recently, the antiatherosclerotic effect of GIP, reducing oxidative stress in human endothelial cells and inflammatory cytokine release in visceral adipose tissue, was shown [143,144]. Moreover, the latest evidence suggests a significant improvement in glycemic control and obesity with tirzepatide compared to placebo, GLP1 receptor agonists, and insulin [145,146,147,148]. In addition, tirzepatide could ameliorate liver fat compared to insulin degludec, as recently shown in the SURPASS-3 MRI substudy [149]. The available data are sparse regarding the anti-inflammatory effect of GIP. Tirzepatide could induce reductions in hsCRP and ICAM-1 within 4 weeks of treatment in patients with T2DM [150]. According to the above-mentioned findings, it could be assumed that there is a possible synergistic anti-inflammatory role of dual GIP/GLP-1 receptor agonists, which has to be validated in future studies.
Subjects with and without T2DM benefit from SGLT2 inhibitors in terms of cardiac and renal outcomes. SGLT1 transporters are expressed in the intestines, kidney, brain, heart, trachea, testis, and prostate gland [151,152]. They control glucose absorption in the small intestine as well as the reabsorption of roughly 10% of filtered glucose in the upper section of the renal proximal tubule [151,152]. The development of dual SGLT1/SGLT2 inhibitors was a challenge for physicians trying to combine the benefits provided by the two substances [153]. Sotagliflozin, a first-in-class dual SGLT1 and SGLT2 inhibitor, has recently been evaluated in two trials of patients with T2DM: the Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial and the Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening HF (SOLOIST-WHF) trial [154,155]. A recent meta-analysis showed the efficiency of sotagliflozin in terms of decreasing the risk of all-cause mortality, cardiovascular mortality, and hospitalization for heart failure, myocardial infarction, and kidney disease progression in patients with T2DM [156,157]. At present, however, no studies have been performed comparing the anti-inflammatory potential of dual SGLT1/SGLT2 inhibitors to highly selective SGLT2 inhibitors. Therefore, there is a need for both preclinical and clinical evidence to determine whether the combined inhibition of SGLT1/SGLT2 may promote more potent anti-inflammatory actions.

5. Conclusions

Inflammation appears to be the main contributor in the development of a variety of comorbidities. It is well known that DM is a multifactorial disease consisting of complex pathophysiological pathways driven by low-grade inflammation. Currently, antidiabetic drugs are at the forefront of scientific research, not only for their glucose control effect but also their anti-inflammatory potential. In this review, we highlighted the anti-inflammatory effects of widely administered antidiabetic drugs and we presented their importance in mitigating an individual’s inflammatory status. Moreover, we foresee their potential application in other chronic sterile inflammatory diseases, whether or not DM is present.

Author Contributions

Conceptualization, D.T.; investigation, P.T. and M.S.; visualization, P.T. and M.S.; supervision, D.T.; original draft—writing, P.T. and M.S.; original draft—reviewing and editing, E.O., A.S.A., G.S., K.T. and D.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Oikonomou, E.; Leopoulou, M.; Theofilis, P.; Antonopoulos, A.S.; Siasos, G.; Latsios, G.; Mystakidi, V.C.; Antoniades, C.; Tousoulis, D. A link between inflammation and thrombosis in atherosclerotic cardiovascular diseases: Clinical and therapeutic implications. Atherosclerosis 2020, 309, 16–26. [Google Scholar] [CrossRef] [PubMed]
  2. Sagris, M.; Theofilis, P.; Antonopoulos, A.S.; Oikonomou, E.; Paschaliori, C.; Galiatsatos, N.; Tsioufis, K.; Tousoulis, D. Inflammation in Coronary Microvascular Dysfunction. Int. J. Mol. Sci. 2021, 22, 13471. [Google Scholar] [CrossRef] [PubMed]
  3. Sagris, M.; Theofilis, P.; Antonopoulos, A.S.; Tsioufis, C.; Oikonomou, E.; Antoniades, C.; Crea, F.; Kaski, J.C.; Tousoulis, D. Inflammatory Mechanisms in COVID-19 and Atherosclerosis: Current Pharmaceutical Perspectives. Int. J. Mol. Sci. 2021, 22, 6607. [Google Scholar] [CrossRef] [PubMed]
  4. Adamo, L.; Rocha-Resende, C.; Prabhu, S.D.; Mann, D.L. Reappraising the role of inflammation in heart failure. Nat. Rev. Cardiol. 2020, 17, 269–285. [Google Scholar] [CrossRef] [PubMed]
  5. Murphy, S.P.; Kakkar, R.; McCarthy, C.P.; Januzzi, J.L., Jr. Inflammation in Heart Failure: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 2020, 75, 1324–1340. [Google Scholar] [CrossRef]
  6. Sagris, M.; Katsaros, I.; Giannopoulos, S.; Rosenberg, R.D.; Altin, S.E.; Rallidis, L.; Mena-Hurtado, C.; Armstrong, E.J.; Kokkinidis, D.G. Statins and statin intensity in peripheral artery disease. Vasa 2022, 51, 198–211. [Google Scholar] [CrossRef]
  7. Guzik, T.J.; Touyz, R.M. Oxidative Stress, Inflammation, and Vascular Aging in Hypertension. Hypertension 2017, 70, 660–667. [Google Scholar] [CrossRef]
  8. Messner, B.; Bernhard, D. Smoking and cardiovascular disease: Mechanisms of endothelial dysfunction and early atherogenesis. Arterioscler. Thromb. Vasc. Biol. 2014, 34, 509–515. [Google Scholar] [CrossRef] [Green Version]
  9. Franceschi, C.; Garagnani, P.; Parini, P.; Giuliani, C.; Santoro, A. Inflammaging: A new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 2018, 14, 576–590. [Google Scholar] [CrossRef]
  10. Tsalamandris, S.; Antonopoulos, A.S.; Oikonomou, E.; Papamikroulis, G.A.; Vogiatzi, G.; Papaioannou, S.; Deftereos, S.; Tousoulis, D. The Role of Inflammation in Diabetes: Current Concepts and Future Perspectives. Eur. Cardiol. 2019, 14, 50–59. [Google Scholar] [CrossRef]
  11. Mahajan, A.; Tabassum, R.; Chavali, S.; Dwivedi, O.P.; Bharadwaj, M.; Tandon, N.; Bharadwaj, D. High-sensitivity C-reactive protein levels and type 2 diabetes in urban North Indians. J. Clin. Endocrinol. Metab. 2009, 94, 2123–2127. [Google Scholar] [CrossRef] [PubMed]
  12. Bahceci, M.; Tuzcu, A.; Ogun, C.; Canoruc, N.; Iltimur, K.; Aslan, C. Is serum C-reactive protein concentration correlated with HbA1c and insulin resistance in Type 2 diabetic men with or without coronary heart disease? J. Endocrinol. Investig. 2005, 28, 145–150. [Google Scholar] [CrossRef] [PubMed]
  13. Alzamil, H. Elevated Serum TNF-alpha Is Related to Obesity in Type 2 Diabetes Mellitus and Is Associated with Glycemic Control and Insulin Resistance. J. Obes. 2020, 2020, 5076858. [Google Scholar] [CrossRef] [Green Version]
  14. Patel, S.; Santani, D. Role of NF-kappa B in the pathogenesis of diabetes and its associated complications. Pharmacol. Rep. 2009, 61, 595–603. [Google Scholar] [CrossRef]
  15. Sagris, M.; Theofilis, P.; Antonopoulos, A.S.; Oikonomou, E.; Tsioufis, K.; Tousoulis, D. Genetic Predisposition and Inflammatory Inhibitors in COVID-19: Where Do We Stand? Biomedicines 2022, 10, 242. [Google Scholar] [CrossRef]
  16. Sun, S.C. The non-canonical NF-kappaB pathway in immunity and inflammation. Nat. Rev. Immunol. 2017, 17, 545–558. [Google Scholar] [CrossRef]
  17. Li, X.; Wu, Y.; Song, Y.; Ding, N.; Lu, M.; Jia, L.; Zhao, Y.; Liu, M.; Chen, Z. Activation of NF-kappaB-Inducing Kinase in Islet beta Cells Causes beta Cell Failure and Diabetes. Mol. Ther. 2020, 28, 2430–2441. [Google Scholar] [CrossRef]
  18. Malle, E.K.; Zammit, N.W.; Walters, S.N.; Koay, Y.C.; Wu, J.; Tan, B.M.; Villanueva, J.E.; Brink, R.; Loudovaris, T.; Cantley, J.; et al. Nuclear factor kappaB-inducing kinase activation as a mechanism of pancreatic beta cell failure in obesity. J. Exp. Med. 2015, 212, 1239–1254. [Google Scholar] [CrossRef]
  19. Xiao, P.; Takiishi, T.; Violato, N.M.; Licata, G.; Dotta, F.; Sebastiani, G.; Marselli, L.; Singh, S.P.; Sze, M.; Van Loo, G.; et al. NF-kappaB-inducing kinase (NIK) is activated in pancreatic beta-cells but does not contribute to the development of diabetes. Cell Death Dis. 2022, 13, 476. [Google Scholar] [CrossRef]
  20. Chen, X.; Zhang, D.; Li, Y.; Wang, W.; Bei, W.; Guo, J. NLRP3 inflammasome and IL-1beta pathway in type 2 diabetes and atherosclerosis: Friend or foe? Pharmacol. Res. 2021, 173, 105885. [Google Scholar] [CrossRef]
  21. Lv, S.; Wang, H.; Li, X. The Role of the Interplay between Autophagy and NLRP3 Inflammasome in Metabolic Disorders. Front. Cell Dev. Biol. 2021, 9, 634118. [Google Scholar] [CrossRef] [PubMed]
  22. Shen, Z.; Zhu, C.; Quan, Y.; Yang, J.; Yuan, W.; Yang, Z.; Wu, S.; Luo, W.; Tan, B.; Wang, X. Insights into Roseburia intestinalis which alleviates experimental colitis pathology by inducing anti-inflammatory responses. J. Gastroenterol. Hepatol. 2018, 33, 1751–1760. [Google Scholar] [CrossRef] [PubMed]
  23. Chang, Y.C.; Ching, Y.H.; Chiu, C.C.; Liu, J.Y.; Hung, S.W.; Huang, W.C.; Huang, Y.T.; Chuang, H.L. TLR2 and interleukin-10 are involved in Bacteroides fragilis-mediated prevention of DSS-induced colitis in gnotobiotic mice. PLoS ONE 2017, 12, e0180025. [Google Scholar] [CrossRef] [Green Version]
  24. Plovier, H.; Everard, A.; Druart, C.; Depommier, C.; Van Hul, M.; Geurts, L.; Chilloux, J.; Ottman, N.; Duparc, T.; Lichtenstein, L.; et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat. Med. 2017, 23, 107–113. [Google Scholar] [CrossRef] [Green Version]
  25. Li, X.; Wang, N.; Yin, B.; Fang, D.; Jiang, T.; Fang, S.; Zhao, J.; Zhang, H.; Wang, G.; Chen, W. Effects of Lactobacillus plantarum CCFM0236 on hyperglycaemia and insulin resistance in high-fat and streptozotocin-induced type 2 diabetic mice. J. Appl. Microbiol. 2016, 121, 1727–1736. [Google Scholar] [CrossRef]
  26. Chen, P.; Zhang, Q.; Dang, H.; Liu, X.; Tian, F.; Zhao, J.; Chen, Y.; Zhang, H.; Chen, W. Antidiabetic effect of Lactobacillus casei CCFM0412 on mice with type 2 diabetes induced by a high-fat diet and streptozotocin. Nutrition 2014, 30, 1061–1068. [Google Scholar] [CrossRef]
  27. Dagdeviren, S.; Jung, D.Y.; Friedline, R.H.; Noh, H.L.; Kim, J.H.; Patel, P.R.; Tsitsilianos, N.; Inashima, K.; Tran, D.A.; Hu, X.; et al. IL-10 prevents aging-associated inflammation and insulin resistance in skeletal muscle. FASEB J. 2017, 31, 701–710. [Google Scholar] [CrossRef] [Green Version]
  28. Liu, W.C.; Yang, M.C.; Wu, Y.Y.; Chen, P.H.; Hsu, C.M.; Chen, L.W. Lactobacillus plantarum reverse diabetes-induced Fmo3 and ICAM expression in mice through enteric dysbiosis-related c-Jun NH2-terminal kinase pathways. PLoS ONE 2018, 13, e0196511. [Google Scholar] [CrossRef]
  29. Inan, M.S.; Rasoulpour, R.J.; Yin, L.; Hubbard, A.K.; Rosenberg, D.W.; Giardina, C. The luminal short-chain fatty acid butyrate modulates NF-kappaB activity in a human colonic epithelial cell line. Gastroenterology 2000, 118, 724–734. [Google Scholar] [CrossRef]
  30. Hall, A.B.; Yassour, M.; Sauk, J.; Garner, A.; Jiang, X.; Arthur, T.; Lagoudas, G.K.; Vatanen, T.; Fornelos, N.; Wilson, R.; et al. A novel Ruminococcus gnavus clade enriched in inflammatory bowel disease patients. Genome Med. 2017, 9, 103. [Google Scholar] [CrossRef]
  31. Yang, Y.; Weng, W.; Peng, J.; Hong, L.; Yang, L.; Toiyama, Y.; Gao, R.; Liu, M.; Yin, M.; Pan, C.; et al. Fusobacterium nucleatum Increases Proliferation of Colorectal Cancer Cells and Tumor Development in Mice by Activating Toll-Like Receptor 4 Signaling to Nuclear Factor-kappaB, and Up-regulating Expression of MicroRNA-21. Gastroenterology 2017, 152, 851–866.e24. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Tousoulis, D.; Oikonomou, E.; Oikonomou, E.K.; Crea, F.; Kaski, J.C. Inflammatory cytokines in atherosclerosis: Current therapeutic approaches. Eur. Heart J. 2016, 37, 1723–1732. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Theofilis, P.; Sagris, M.; Oikonomou, E.; Antonopoulos, A.S.; Siasos, G.; Tsioufis, C.; Tousoulis, D. Inflammatory Mechanisms Contributing to Endothelial Dysfunction. Biomedicines 2021, 9, 781. [Google Scholar] [CrossRef] [PubMed]
  34. Di Marco, E.; Gray, S.P.; Jandeleit-Dahm, K. Diabetes alters activation and repression of pro- and anti-inflammatory signaling pathways in the vasculature. Front. Endocrinol. 2013, 4, 68. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Yamagishi, S.; Matsui, T. Advanced glycation end products, oxidative stress and diabetic nephropathy. Oxidative Med. Cell. Longev. 2010, 3, 101–108. [Google Scholar] [CrossRef] [Green Version]
  36. Klessens, C.Q.F.; Zandbergen, M.; Wolterbeek, R.; Bruijn, J.A.; Rabelink, T.J.; Bajema, I.M.; DHT, I.J. Macrophages in diabetic nephropathy in patients with type 2 diabetes. Nephrol. Dial. Transplant. 2017, 32, 1322–1329. [Google Scholar] [CrossRef] [Green Version]
  37. Wang, X.; Chen, J.; Xu, J.; Xie, J.; Harris, D.C.H.; Zheng, G. The Role of Macrophages in Kidney Fibrosis. Front. Physiol. 2021, 12, 705838. [Google Scholar] [CrossRef]
  38. Nguyen, D.; Ping, F.; Mu, W.; Hill, P.; Atkins, R.C.; Chadban, S.J. Macrophage accumulation in human progressive diabetic nephropathy. Nephrology 2006, 11, 226–231. [Google Scholar] [CrossRef]
  39. Moon, J.Y.; Jeong, K.H.; Lee, T.W.; Ihm, C.G.; Lim, S.J.; Lee, S.H. Aberrant recruitment and activation of T cells in diabetic nephropathy. Am. J. Nephrol. 2012, 35, 164–174. [Google Scholar] [CrossRef]
  40. Araujo, L.S.; Torquato, B.G.S.; da Silva, C.A.; Dos Reis Monteiro, M.L.G.; Dos Santos Martins, A.L.M.; da Silva, M.V.; Dos Reis, M.A.; Machado, J.R. Renal expression of cytokines and chemokines in diabetic nephropathy. BMC Nephrol. 2020, 21, 308. [Google Scholar] [CrossRef]
  41. Woroniecka, K.I.; Park, A.S.; Mohtat, D.; Thomas, D.B.; Pullman, J.M.; Susztak, K. Transcriptome analysis of human diabetic kidney disease. Diabetes 2011, 60, 2354–2369. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Sinha, S.K.; Nicholas, S.B.; Sung, J.H.; Correa, A.; Rajavashisth, T.B.; Norris, K.C.; Lee, J.E. hs-CRP Is Associated with Incident Diabetic Nephropathy: Findings from the Jackson Heart Study. Diabetes Care 2019, 42, 2083–2089. [Google Scholar] [CrossRef] [PubMed]
  43. Niewczas, M.A.; Pavkov, M.E.; Skupien, J.; Smiles, A.; Md Dom, Z.I.; Wilson, J.M.; Park, J.; Nair, V.; Schlafly, A.; Saulnier, P.J.; et al. A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes. Nat. Med. 2019, 25, 805–813. [Google Scholar] [CrossRef] [PubMed]
  44. Ohnuma, K.; Hosono, O.; Dang, N.H.; Morimoto, C. Dipeptidyl peptidase in autoimmune pathophysiology. Adv. Clin. Chem. 2011, 53, 51–84. [Google Scholar] [CrossRef] [PubMed]
  45. Zhong, J.; Rao, X.; Rajagopalan, S. An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: Potential implications in cardiovascular disease. Atherosclerosis 2013, 226, 305–314. [Google Scholar] [CrossRef]
  46. Gorrell, M.D. Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. Clin. Sci. 2005, 108, 277–292. [Google Scholar] [CrossRef]
  47. Yazbeck, R.; Howarth, G.S.; Abbott, C.A. Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease? Trends Pharmacol. Sci. 2009, 30, 600–607. [Google Scholar] [CrossRef]
  48. Chen, J.J.; Wu, C.Y.; Jenq, C.C.; Lee, T.H.; Tsai, C.Y.; Tu, H.T.; Huang, Y.T.; Yen, C.L.; Yen, T.H.; Chen, Y.C.; et al. Association of Glucagon-Like Peptide-1 Receptor Agonist vs. Dipeptidyl Peptidase-4 Inhibitor Use with Mortality among Patients with Type 2 Diabetes and Advanced Chronic Kidney Disease. JAMA Netw. Open 2022, 5, e221169. [Google Scholar] [CrossRef]
  49. Singh, T.P.; Vangaveti, V.N.; Malabu, U.H. Dipeptidyl peptidase-4 inhibitors and their potential role in the management of atherosclerosis—A review. Diabetes Metab. Syndr. 2015, 9, 223–229. [Google Scholar] [CrossRef]
  50. Donath, M.Y.; Shoelson, S.E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 2011, 11, 98–107. [Google Scholar] [CrossRef]
  51. Hotamisligil, G.S. Inflammation and metabolic disorders. Nature 2006, 444, 860–867. [Google Scholar] [CrossRef] [PubMed]
  52. Tomovic, K.; Lazarevic, J.; Kocic, G.; Deljanin-Ilic, M.; Anderluh, M.; Smelcerovic, A. Mechanisms and pathways of anti-inflammatory activity of DPP-4 inhibitors in cardiovascular and renal protection. Med. Res. Rev. 2019, 39, 404–422. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Ta, N.N.; Li, Y.; Schuyler, C.A.; Lopes-Virella, M.F.; Huang, Y. DPP-4 (CD26) inhibitor alogliptin inhibits TLR4-mediated ERK activation and ERK-dependent MMP-1 expression by U937 histiocytes. Atherosclerosis 2010, 213, 429–435. [Google Scholar] [CrossRef]
  54. Ta, N.N.; Schuyler, C.A.; Li, Y.; Lopes-Virella, M.F.; Huang, Y. DPP-4 (CD26) inhibitor alogliptin inhibits atherosclerosis in diabetic apolipoprotein E-deficient mice. J. Cardiovasc. Pharmacol. 2011, 58, 157–166. [Google Scholar] [CrossRef] [PubMed]
  55. Ferreira, L.; Teixeira-de-Lemos, E.; Pinto, F.; Parada, B.; Mega, C.; Vala, H.; Pinto, R.; Garrido, P.; Sereno, J.; Fernandes, R.; et al. Effects of sitagliptin treatment on dysmetabolism, inflammation, and oxidative stress in an animal model of type 2 diabetes (ZDF rat). Mediators. Inflamm. 2010, 2010, 592760. [Google Scholar] [CrossRef] [Green Version]
  56. Liu, X.; Men, P.; Wang, B.; Cai, G.; Zhao, Z. Effect of dipeptidyl-peptidase-4 inhibitors on C-reactive protein in patients with type 2 diabetes: A systematic review and meta-analysis. Lipids Health Dis. 2019, 18, 144. [Google Scholar] [CrossRef] [Green Version]
  57. Dobrian, A.D.; Ma, Q.; Lindsay, J.W.; Leone, K.A.; Ma, K.; Coben, J.; Galkina, E.V.; Nadler, J.L. Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice. Am. J. Physiol. Endocrinol. Metab. 2011, 300, E410–E421. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Vittone, F.; Liberman, A.; Vasic, D.; Ostertag, R.; Esser, M.; Walcher, D.; Ludwig, A.; Marx, N.; Burgmaier, M. Sitagliptin reduces plaque macrophage content and stabilises arteriosclerotic lesions in Apoe (−/−) mice. Diabetologia 2012, 55, 2267–2275. [Google Scholar] [CrossRef] [Green Version]
  59. Sato, N.; Nakamura, Y.; Yamadera, S.; Inagaki, M.; Kenmotsu, S.; Saito, H.; Oguchi, T.; Tsuji, M.; Chokki, H.; Ohsawa, I.; et al. Linagliptin Inhibits Lipopolysaccharide-Induced Inflammation Concentration-Dependently and -Independently. J. Inflamm. Res. 2019, 12, 285–291. [Google Scholar] [CrossRef] [Green Version]
  60. Katsiki, N.; Ferrannini, E. Anti-inflammatory properties of antidiabetic drugs: A “promised land” in the COVID-19 era? J. Diabetes Complicat. 2020, 34, 107723. [Google Scholar] [CrossRef]
  61. Lee, S.A.; Kim, Y.R.; Yang, E.J.; Kwon, E.J.; Kim, S.H.; Kang, S.H.; Park, D.B.; Oh, B.C.; Kim, J.; Heo, S.T.; et al. CD26/DPP4 levels in peripheral blood and T cells in patients with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 2013, 98, 2553–2561. [Google Scholar] [CrossRef] [PubMed]
  62. Makdissi, A.; Ghanim, H.; Vora, M.; Green, K.; Abuaysheh, S.; Chaudhuri, A.; Dhindsa, S.; Dandona, P. Sitagliptin exerts an antinflammatory action. J. Clin. Endocrinol. Metab. 2012, 97, 3333–3341. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Matsubara, J.; Sugiyama, S.; Akiyama, E.; Iwashita, S.; Kurokawa, H.; Ohba, K.; Maeda, H.; Fujisue, K.; Yamamoto, E.; Kaikita, K.; et al. Dipeptidyl peptidase-4 inhibitor, sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes. Circ. J. 2013, 77, 1337–1344. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Ellingsen, T.; Hornung, N.; Moller, B.K.; Hjelm-Poulsen, J.; Stengaard-Pedersen, K. In active chronic rheumatoid arthritis, dipeptidyl peptidase IV density is increased on monocytes and CD4(+) T lymphocytes. Scand. J. Immunol. 2007, 66, 451–457. [Google Scholar] [CrossRef]
  65. Hildebrandt, M.; Rose, M.; Ruter, J.; Salama, A.; Monnikes, H.; Klapp, B.F. Dipeptidyl peptidase IV (DP IV, CD26) in patients with inflammatory bowel disease. Scand. J. Gastroenterol. 2001, 36, 1067–1072. [Google Scholar] [CrossRef]
  66. Campbell, J.E.; Drucker, D.J. Islet alpha cells and glucagon—Critical regulators of energy homeostasis. Nat. Rev. Endocrinol. 2015, 11, 329–338. [Google Scholar] [CrossRef]
  67. Lee, Y.S.; Jun, H.S. Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control. Mediat. Inflamm. 2016, 2016, 3094642. [Google Scholar] [CrossRef] [Green Version]
  68. Day, J.W.; Li, P.; Patterson, J.T.; Chabenne, J.; Chabenne, M.D.; Gelfanov, V.M.; Dimarchi, R.D. Charge inversion at position 68 of the glucagon and glucagon-like peptide-1 receptors supports selectivity in hormone action. J. Pept. Sci. 2011, 17, 218–225. [Google Scholar] [CrossRef]
  69. Kim, W.; Egan, J.M. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol. Rev. 2008, 60, 470–512. [Google Scholar] [CrossRef] [Green Version]
  70. Viby, N.E.; Isidor, M.S.; Buggeskov, K.B.; Poulsen, S.S.; Hansen, J.B.; Kissow, H. Glucagon-like peptide-1 (GLP-1) reduces mortality and improves lung function in a model of experimental obstructive lung disease in female mice. Endocrinology 2013, 154, 4503–4511. [Google Scholar] [CrossRef]
  71. Velmurugan, K.; Balamurugan, A.N.; Loganathan, G.; Ahmad, A.; Hering, B.J.; Pugazhenthi, S. Antiapoptotic actions of exendin-4 against hypoxia and cytokines are augmented by CREB. Endocrinology 2012, 153, 1116–1128. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Pugazhenthi, U.; Velmurugan, K.; Tran, A.; Mahaffey, G.; Pugazhenthi, S. Anti-inflammatory action of exendin-4 in human islets is enhanced by phosphodiesterase inhibitors: Potential therapeutic benefits in diabetic patients. Diabetologia 2010, 53, 2357–2368. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Cechin, S.R.; Perez-Alvarez, I.; Fenjves, E.; Molano, R.D.; Pileggi, A.; Berggren, P.O.; Ricordi, C.; Pastori, R.L. Anti-inflammatory properties of exenatide in human pancreatic islets. Cell Transplant. 2012, 21, 633–648. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Kanda, H.; Tateya, S.; Tamori, Y.; Kotani, K.; Hiasa, K.; Kitazawa, R.; Kitazawa, S.; Miyachi, H.; Maeda, S.; Egashira, K.; et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Investig. 2006, 116, 1494–1505. [Google Scholar] [CrossRef] [PubMed]
  75. Winer, S.; Chan, Y.; Paltser, G.; Truong, D.; Tsui, H.; Bahrami, J.; Dorfman, R.; Wang, Y.; Zielenski, J.; Mastronardi, F.; et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 2009, 15, 921–929. [Google Scholar] [CrossRef]
  76. Lee, Y.S.; Park, M.S.; Choung, J.S.; Kim, S.S.; Oh, H.H.; Choi, C.S.; Ha, S.Y.; Kang, Y.; Kim, Y.; Jun, H.S. Glucagon-like peptide-1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes. Diabetologia 2012, 55, 2456–2468. [Google Scholar] [CrossRef] [Green Version]
  77. Krasner, N.M.; Ido, Y.; Ruderman, N.B.; Cacicedo, J.M. Glucagon-like peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism. PLoS ONE 2014, 9, e97554. [Google Scholar] [CrossRef] [Green Version]
  78. Shiraki, A.; Oyama, J.; Komoda, H.; Asaka, M.; Komatsu, A.; Sakuma, M.; Kodama, K.; Sakamoto, Y.; Kotooka, N.; Hirase, T.; et al. The glucagon-like peptide 1 analog liraglutide reduces TNF-alpha-induced oxidative stress and inflammation in endothelial cells. Atherosclerosis 2012, 221, 375–382. [Google Scholar] [CrossRef]
  79. Balestrieri, M.L.; Rizzo, M.R.; Barbieri, M.; Paolisso, P.; D’Onofrio, N.; Giovane, A.; Siniscalchi, M.; Minicucci, F.; Sardu, C.; D’Andrea, D.; et al. Sirtuin 6 expression and inflammatory activity in diabetic atherosclerotic plaques: Effects of incretin treatment. Diabetes 2015, 64, 1395–1406. [Google Scholar] [CrossRef] [Green Version]
  80. Lappas, M. Anti-inflammatory properties of sirtuin 6 in human umbilical vein endothelial cells. Mediat. Inflamm. 2012, 2012, 597514. [Google Scholar] [CrossRef]
  81. Liljedahl, L.; Pedersen, M.H.; McGuire, J.N.; James, P. The impact of the glucagon-like peptide 1 receptor agonist liraglutide on the streptozotocin-induced diabetic mouse kidney proteome. Physiol. Rep. 2019, 7, e13994. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Winiarska, A.; Knysak, M.; Nabrdalik, K.; Gumprecht, J.; Stompor, T. Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists. Int. J. Mol. Sci. 2021, 22, 10822. [Google Scholar] [CrossRef] [PubMed]
  83. Bray, J.J.H.; Foster-Davies, H.; Salem, A.; Hoole, A.L.; Obaid, D.R.; Halcox, J.P.J.; Stephens, J.W. Glucagon-like peptide-1 receptor agonists improve biomarkers of inflammation and oxidative stress: A systematic review and meta-analysis of randomised controlled trials. Diabetes Obes. Metab. 2021, 23, 1806–1822. [Google Scholar] [CrossRef] [PubMed]
  84. Cai, Y.; Hu, X.; Yi, B.; Zhang, T.; Wen, Z. Glucagon-like peptide-1 receptor agonist protects against hyperglycemia-induced cardiocytes injury by inhibiting high mobility group box 1 expression. Mol. Biol. Rep. 2012, 39, 10705–10711. [Google Scholar] [CrossRef]
  85. Du, X.; Hu, X.; Wei, J. Anti-inflammatory effect of exendin-4 postconditioning during myocardial ischemia and reperfusion. Mol. Biol. Rep. 2014, 41, 3853–3857. [Google Scholar] [CrossRef]
  86. Franks, A.S.; Lee, P.H.; George, C.M. Pancreatitis: A potential complication of liraglutide? Ann. Pharmacother. 2012, 46, 1547–1553. [Google Scholar] [CrossRef]
  87. Butler, P.C.; Elashoff, M.; Elashoff, R.; Gale, E.A. A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care 2013, 36, 2118–2125. [Google Scholar] [CrossRef] [Green Version]
  88. McClean, P.L.; Holscher, C. Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer’s disease. Neuropharmacology 2014, 76 Pt A, 57–67. [Google Scholar] [CrossRef]
  89. McClean, P.L.; Parthsarathy, V.; Faivre, E.; Holscher, C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J. Neurosci. 2011, 31, 6587–6594. [Google Scholar] [CrossRef] [Green Version]
  90. Kim, S.; Moon, M.; Park, S. Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson’s disease. J. Endocrinol. 2009, 202, 431–439. [Google Scholar] [CrossRef]
  91. Saraheimo, M.; Teppo, A.M.; Forsblom, C.; Fagerudd, J.; Groop, P.H. Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients. Diabetologia 2003, 46, 1402–1407. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Gangadharan Komala, M.; Gross, S.; Zaky, A.; Pollock, C.; Panchapakesan, U. Saxagliptin reduces renal tubulointerstitial inflammation, hypertrophy and fibrosis in diabetes. Nephrology 2016, 21, 423–431. [Google Scholar] [CrossRef] [PubMed]
  93. Higashijima, Y.; Tanaka, T.; Yamaguchi, J.; Tanaka, S.; Nangaku, M. Anti-inflammatory role of DPP-4 inhibitors in a nondiabetic model of glomerular injury. Am. J. Physiol. Renal Physiol. 2015, 308, F878–F887. [Google Scholar] [CrossRef] [Green Version]
  94. Wang, X.C.; Gusdon, A.M.; Liu, H.; Qu, S. Effects of glucagon-like peptide-1 receptor agonists on non-alcoholic fatty liver disease and inflammation. World J. Gastroenterol. 2014, 20, 14821–14830. [Google Scholar] [CrossRef] [PubMed]
  95. Derosa, G.; Franzetti, I.G.; Querci, F.; Carbone, A.; Ciccarelli, L.; Piccinni, M.N.; Fogari, E.; Maffioli, P. Exenatide plus metformin compared with metformin alone on beta-cell function in patients with Type 2 diabetes. Diabet. Med. 2012, 29, 1515–1523. [Google Scholar] [CrossRef] [PubMed]
  96. Varanasi, A.; Patel, P.; Makdissi, A.; Dhindsa, S.; Chaudhuri, A.; Dandona, P. Clinical use of liraglutide in type 2 diabetes and its effects on cardiovascular risk factors. Endocr. Pract. 2012, 18, 140–145. [Google Scholar] [CrossRef]
  97. Bakris, G.L.; Fonseca, V.A.; Sharma, K.; Wright, E.M. Renal sodium-glucose transport: Role in diabetes mellitus and potential clinical implications. Kidney Int. 2009, 75, 1272–1277. [Google Scholar] [CrossRef] [Green Version]
  98. Lee, Y.J.; Lee, Y.J.; Han, H.J. Regulatory mechanisms of Na(+)/glucose cotransporters in renal proximal tubule cells. Kidney Int. Suppl. 2007, 72, S27–S35. [Google Scholar] [CrossRef] [Green Version]
  99. Rahmoune, H.; Thompson, P.W.; Ward, J.M.; Smith, C.D.; Hong, G.; Brown, J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 2005, 54, 3427–3434. [Google Scholar] [CrossRef] [Green Version]
  100. Rossetti, L.; Smith, D.; Shulman, G.I.; Papachristou, D.; DeFronzo, R.A. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J. Clin. Investig. 1987, 79, 1510–1515. [Google Scholar] [CrossRef]
  101. Wright, E.M.I. Glucose galactose malabsorption. Am. J. Physiol. 1998, 275, G879–G882. [Google Scholar] [CrossRef] [PubMed]
  102. Isaji, M. Sodium-glucose cotransporter inhibitors for diabetes. Curr. Opin. Investig. Drugs 2007, 8, 285–292. [Google Scholar] [PubMed]
  103. Meng, W.; Ellsworth, B.A.; Nirschl, A.A.; McCann, P.J.; Patel, M.; Girotra, R.N.; Wu, G.; Sher, P.M.; Morrison, E.P.; Biller, S.A.; et al. Discovery of dapagliflozin: A potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2008, 51, 1145–1149. [Google Scholar] [CrossRef] [PubMed]
  104. Nomura, S.; Sakamaki, S.; Hongu, M.; Kawanishi, E.; Koga, Y.; Sakamoto, T.; Yamamoto, Y.; Ueta, K.; Kimata, H.; Nakayama, K.; et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J. Med. Chem. 2010, 53, 6355–6360. [Google Scholar] [CrossRef]
  105. Grempler, R.; Thomas, L.; Eckhardt, M.; Himmelsbach, F.; Sauer, A.; Sharp, D.E.; Bakker, R.A.; Mark, M.; Klein, T.; Eickelmann, P. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: Characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes. Metab. 2012, 14, 83–90. [Google Scholar] [CrossRef] [PubMed]
  106. Mascitti, V.; Maurer, T.S.; Robinson, R.P.; Bian, J.; Boustany-Kari, C.M.; Brandt, T.; Collman, B.M.; Kalgutkar, A.S.; Klenotic, M.K.; Leininger, M.T.; et al. Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors. J. Med. Chem. 2011, 54, 2952–2960. [Google Scholar] [CrossRef]
  107. Shyangdan, D.S.; Uthman, O.A.; Waugh, N. SGLT-2 receptor inhibitors for treating patients with type 2 diabetes mellitus: A systematic review and network meta-analysis. BMJ Open 2016, 6, e009417. [Google Scholar] [CrossRef] [Green Version]
  108. Theofilis, P.; Sagris, M.; Oikonomou, E.; Antonopoulos, A.S.; Siasos, G.; Tsioufis, K.; Tousoulis, D. Pleiotropic effects of SGLT2 inhibitors and heart failure outcomes. Diabetes Res. Clin. Pract. 2022, 188, 109927. [Google Scholar] [CrossRef]
  109. Theofilis, P.; Antonopoulos, A.S.; Katsimichas, T.; Oikonomou, E.; Siasos, G.; Aggeli, C.; Tsioufis, K.; Tousoulis, D. The impact of SGLT2 inhibition on imaging markers of cardiac function: A systematic review and meta-analysis. Pharmacol Res. 2022, 180, 106243. [Google Scholar] [CrossRef]
  110. Zannad, F.; Ferreira, J.P.; Pocock, S.J.; Anker, S.D.; Butler, J.; Filippatos, G.; Brueckmann, M.; Ofstad, A.P.; Pfarr, E.; Jamal, W.; et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: A meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 2020, 396, 819–829. [Google Scholar] [CrossRef]
  111. Bae, J.H.; Park, E.G.; Kim, S.; Kim, S.G.; Hahn, S.; Kim, N.H. Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Renal Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Sci. Rep. 2019, 9, 13009. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Li, L.F.; Ding, L.L.; Zhan, Z.L.; Qiu, M. Meta-Analysis on the Safety and Cardiorenal Efficacy of SGLT2 Inhibitors in Patients without T2DM. Front. Cardiovasc. Med. 2021, 8, 690529. [Google Scholar] [CrossRef]
  113. Anker, S.D.; Butler, J.; Filippatos, G.; Ferreira, J.P.; Bocchi, E.; Bohm, M.; Brunner-La Rocca, H.P.; Choi, D.J.; Chopra, V.; Chuquiure-Valenzuela, E.; et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N. Engl. J. Med. 2021, 385, 1451–1461. [Google Scholar] [CrossRef] [PubMed]
  114. Li, H.L.; Lip, G.Y.H.; Feng, Q.; Fei, Y.; Tse, Y.K.; Wu, M.Z.; Ren, Q.W.; Tse, H.F.; Cheung, B.Y.; Yiu, K.H. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and cardiac arrhythmias: A systematic review and meta-analysis. Cardiovasc. Diabetol. 2021, 20, 100. [Google Scholar] [CrossRef] [PubMed]
  115. Wong, C.; Yaow, C.Y.L.; Ng, C.H.; Chin, Y.H.; Low, Y.F.; Lim, A.Y.L.; Muthiah, M.D.; Khoo, C.M. Sodium-Glucose Co-Transporter 2 Inhibitors for Non-Alcoholic Fatty Liver Disease in Asian Patients with Type 2 Diabetes: A Meta-Analysis. Front. Endocrinol. 2020, 11, 609135. [Google Scholar] [CrossRef]
  116. Theofilis, P.; Sagris, M.; Antonopoulos, A.S.; Oikonomou, E.; Tsioufis, C.; Tousoulis, D. Inflammatory Mediators of Platelet Activation: Focus on Atherosclerosis and COVID-19. Int. J. Mol. Sci. 2021, 22, 11170. [Google Scholar] [CrossRef]
  117. Heerspink, H.J.L.; Perco, P.; Mulder, S.; Leierer, J.; Hansen, M.K.; Heinzel, A.; Mayer, G. Canagliflozin reduces inflammation and fibrosis biomarkers: A potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease. Diabetologia 2019, 62, 1154–1166. [Google Scholar] [CrossRef] [Green Version]
  118. Iannantuoni, F.; de Marañon, A.M.; Diaz-Morales, N.; Falcon, R.; Banuls, C.; Abad-Jimenez, Z.; Victor, V.M.; Hernandez-Mijares, A.; Rovira-Llopis, S. The SGLT2 Inhibitor Empagliflozin Ameliorates the Inflammatory Profile in Type 2 Diabetic Patients and Promotes an Antioxidant Response in Leukocytes. J. Clin. Med. 2019, 8, 1814. [Google Scholar] [CrossRef] [Green Version]
  119. Sardu, C.; Massetti, M.; Testa, N.; Martino, L.D.; Castellano, G.; Turriziani, F.; Sasso, F.C.; Torella, M.; De Feo, M.; Santulli, G.; et al. Effects of Sodium-Glucose Transporter 2 Inhibitors (SGLT2-I) in Patients with Ischemic Heart Disease (IHD) Treated by Coronary Artery Bypass Grafting via MiECC: Inflammatory Burden, and Clinical Outcomes at 5 Years of Follow-Up. Front. Pharmacol. 2021, 12, 777083. [Google Scholar] [CrossRef]
  120. Xue, L.; Yuan, X.; Zhang, S.; Zhao, X. Investigating the Effects of Dapagliflozin on Cardiac Function, Inflammatory Response, and Cardiovascular Outcome in Patients with STEMI Complicated with T2DM after PCI. Evid. Based Complement. Altern. Med. 2021, 2021, 9388562. [Google Scholar] [CrossRef]
  121. Sato, T.; Aizawa, Y.; Yuasa, S.; Fujita, S.; Ikeda, Y.; Okabe, M. The Effect of Dapagliflozin Treatment on Epicardial Adipose Tissue Volume and P-Wave Indices: An Ad-hoc Analysis of The Previous Randomized Clinical Trial. J. Atheroscler. Thromb. 2020, 27, 1348–1358. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Madonna, R.; Doria, V.; Minnucci, I.; Pucci, A.; Pierdomenico, D.S.; De Caterina, R. Empagliflozin reduces the senescence of cardiac stromal cells and improves cardiac function in a murine model of diabetes. J. Cell. Mol. Med. 2020, 24, 12331–12340. [Google Scholar] [CrossRef] [PubMed]
  123. Ganbaatar, B.; Fukuda, D.; Shinohara, M.; Yagi, S.; Kusunose, K.; Yamada, H.; Soeki, T.; Hirata, K.I.; Sata, M. Empagliflozin ameliorates endothelial dysfunction and suppresses atherogenesis in diabetic apolipoprotein E-deficient mice. Eur. J. Pharmacol. 2020, 875, 173040. [Google Scholar] [CrossRef]
  124. Radlinger, B.; Hornsteiner, F.; Folie, S.; Salvenmoser, W.; Haubner, B.J.; Schuetz, T.; Haas, S.; Ress, C.; Adolph, T.E.; Salzmann, K.; et al. Cardioprotective effects of short-term empagliflozin treatment in db/db mice. Sci. Rep. 2020, 10, 19686. [Google Scholar] [CrossRef]
  125. Elkazzaz, S.K.; Khodeer, D.M.; El Fayoumi, H.M.; Moustafa, Y.M. Role of sodium glucose cotransporter type 2 inhibitors dapagliflozin on diabetic nephropathy in rats; Inflammation, angiogenesis and apoptosis. Life Sci. 2021, 280, 119018. [Google Scholar] [CrossRef]
  126. Ashrafi Jigheh, Z.; Ghorbani Haghjo, A.; Argani, H.; Roshangar, L.; Rashtchizadeh, N.; Sanajou, D.; Nazari Soltan Ahmad, S.; Rashedi, J.; Dastmalchi, S.; Mesgari Abbasi, M. Empagliflozin alleviates renal inflammation and oxidative stress in streptozotocin-induced diabetic rats partly by repressing HMGB1-TLR4 receptor axis. Iran J. Basic Med. Sci. 2019, 22, 384–390. [Google Scholar] [CrossRef] [PubMed]
  127. Quagliariello, V.; De Laurentiis, M.; Rea, D.; Barbieri, A.; Monti, M.G.; Carbone, A.; Paccone, A.; Altucci, L.; Conte, M.; Canale, M.L.; et al. The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin. Cardiovasc. Diabetol. 2021, 20, 150. [Google Scholar] [CrossRef]
  128. Perakakis, N.; Chrysafi, P.; Feigh, M.; Veidal, S.S.; Mantzoros, C.S. Empagliflozin Improves Metabolic and Hepatic Outcomes in a Non-Diabetic Obese Biopsy-Proven Mouse Model of Advanced NASH. Int. J. Mol. Sci. 2021, 22, 6332. [Google Scholar] [CrossRef] [PubMed]
  129. Tahara, A.; Takasu, T. Therapeutic Effects of SGLT2 Inhibitor Ipragliflozin and Metformin on NASH in Type 2 Diabetic Mice. Endocr. Res. 2020, 45, 147–161. [Google Scholar] [CrossRef]
  130. Faridvand, Y.; Kazemzadeh, H.; Vahedian, V.; Mirzajanzadeh, P.; Nejabati, H.R.; Safaie, N.; Maroufi, N.F.; Pezeshkian, M.; Nouri, M.; Jodati, A. Dapagliflozin attenuates high glucose-induced endothelial cell apoptosis and inflammation through AMPK/SIRT1 activation. Clin. Exp. Pharmacol. Physiol. 2022, 39, 643–651. [Google Scholar] [CrossRef]
  131. Packer, M. Critical examination of mechanisms underlying the reduction in heart failure events with SGLT2 inhibitors: Identification of a molecular link between their actions to stimulate erythrocytosis and to alleviate cellular stress. Cardiovasc. Res. 2021, 117, 74–84. [Google Scholar] [CrossRef] [PubMed]
  132. Pirklbauer, M.; Sallaberger, S.; Staudinger, P.; Corazza, U.; Leierer, J.; Mayer, G.; Schramek, H. Empagliflozin Inhibits IL-1beta-Mediated Inflammatory Response in Human Proximal Tubular Cells. Int. J. Mol. Sci. 2021, 22, 5089. [Google Scholar] [CrossRef] [PubMed]
  133. Ke, Q.; Shi, C.; Lv, Y.; Wang, L.; Luo, J.; Jiang, L.; Yang, J.; Zhou, Y. SGLT2 inhibitor counteracts NLRP3 inflammasome via tubular metabolite itaconate in fibrosis kidney. FASEB J. 2022, 36, e22078. [Google Scholar] [CrossRef] [PubMed]
  134. Li, Z.; Murakoshi, M.; Ichikawa, S.; Koshida, T.; Adachi, E.; Suzuki, C.; Ueda, S.; Gohda, T.; Suzuki, Y. The sodium-glucose cotransporter 2 inhibitor tofogliflozin prevents diabetic kidney disease progression in type 2 diabetic mice. FEBS Open Bio 2020, 10, 2761–2770. [Google Scholar] [CrossRef] [PubMed]
  135. Sukhanov, S.; Higashi, Y.; Yoshida, T.; Mummidi, S.; Aroor, A.R.; Jeffrey Russell, J.; Bender, S.B.; DeMarco, V.G.; Chandrasekar, B. The SGLT2 inhibitor Empagliflozin attenuates interleukin-17A-induced human aortic smooth muscle cell proliferation and migration by targeting TRAF3IP2/ROS/NLRP3/Caspase-1-dependent IL-1beta and IL-18 secretion. Cell. Signal. 2021, 77, 109825. [Google Scholar] [CrossRef]
  136. Honda, Y.; Imajo, K.; Kato, T.; Kessoku, T.; Ogawa, Y.; Tomeno, W.; Kato, S.; Mawatari, H.; Fujita, K.; Yoneda, M.; et al. The Selective SGLT2 Inhibitor Ipragliflozin Has a Therapeutic Effect on Nonalcoholic Steatohepatitis in Mice. PLoS ONE 2016, 11, e0146337. [Google Scholar] [CrossRef] [Green Version]
  137. Morsy, M.A.; Khalaf, H.M.; Rifaai, R.A.; Bayoumi, A.M.A.; Khalifa, E.; Ibrahim, Y.F. Canagliflozin, an SGLT-2 inhibitor, ameliorates acetic acid-induced colitis in rats through targeting glucose metabolism and inhibiting NOX2. Biomed. Pharmacother. 2021, 141, 111902. [Google Scholar] [CrossRef]
  138. El-Rous, M.A.; Saber, S.; Raafat, E.M.; Ahmed, A.A.E. Dapagliflozin, an SGLT2 inhibitor, ameliorates acetic acid-induced colitis in rats by targeting NFkappaB/AMPK/NLRP3 axis. Inflammopharmacology 2021, 29, 1169–1185. [Google Scholar] [CrossRef]
  139. Holst, J.J.; Orskov, C.; Nielsen, O.V.; Schwartz, T.W. Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett. 1987, 211, 169–174. [Google Scholar] [CrossRef] [Green Version]
  140. Mojsov, S.; Weir, G.C.; Habener, J.F. Insulinotropin: Glucagon-like peptide I (7–37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J. Clin. Investig. 1987, 79, 616–619. [Google Scholar] [CrossRef] [PubMed]
  141. Flint, A.; Raben, A.; Astrup, A.; Holst, J.J. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J. Clin. Investig. 1998, 101, 515–520. [Google Scholar] [CrossRef] [PubMed]
  142. Mentis, N.; Vardarli, I.; Kothe, L.D.; Holst, J.J.; Deacon, C.F.; Theodorakis, M.; Meier, J.J.; Nauck, M.A. GIP does not potentiate the antidiabetic effects of GLP-1 in hyperglycemic patients with type 2 diabetes. Diabetes 2011, 60, 1270–1276. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Ojima, A.; Matsui, T.; Maeda, S.; Takeuchi, M.; Yamagishi, S. Glucose-dependent insulinotropic polypeptide (GIP) inhibits signaling pathways of advanced glycation end products (AGEs) in endothelial cells via its antioxidative properties. Horm. Metab. Res. 2012, 44, 501–505. [Google Scholar] [CrossRef] [PubMed]
  144. Varol, C.; Zvibel, I.; Spektor, L.; Mantelmacher, F.D.; Vugman, M.; Thurm, T.; Khatib, M.; Elmaliah, E.; Halpern, Z.; Fishman, S. Long-acting glucose-dependent insulinotropic polypeptide ameliorates obesity-induced adipose tissue inflammation. J. Immunol. 2014, 193, 4002–4009. [Google Scholar] [CrossRef] [Green Version]
  145. Heise, T.; Mari, A.; DeVries, J.H.; Urva, S.; Li, J.; Pratt, E.J.; Coskun, T.; Thomas, M.K.; Mather, K.J.; Haupt, A.; et al. Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: A multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial. Lancet Diabetes Endocrinol. 2022, 10, 418–429. [Google Scholar] [CrossRef]
  146. Karagiannis, T.; Avgerinos, I.; Liakos, A.; Del Prato, S.; Matthews, D.R.; Tsapas, A.; Bekiari, E. Management of type 2 diabetes with the dual GIP/GLP-1 receptor agonist tirzepatide: A systematic review and meta-analysis. Diabetologia 2022, 65, 1251–1261. [Google Scholar] [CrossRef]
  147. Jastreboff, A.M.; Aronne, L.J.; Ahmad, N.N.; Wharton, S.; Connery, L.; Alves, B.; Kiyosue, A.; Zhang, S.; Liu, B.; Bunck, M.C.; et al. Tirzepatide once Weekly for the Treatment of Obesity. N. Engl. J. Med. 2022, 387, 205–216. [Google Scholar] [CrossRef]
  148. Inagaki, N.; Takeuchi, M.; Oura, T.; Imaoka, T.; Seino, Y. Efficacy and safety of tirzepatide monotherapy compared with dulaglutide in Japanese patients with type 2 diabetes (SURPASS J-mono): A double-blind, multicentre, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 2022, 10, 623–633. [Google Scholar] [CrossRef]
  149. Gastaldelli, A.; Cusi, K.; Fernandez Lando, L.; Bray, R.; Brouwers, B.; Rodriguez, A. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): A substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol. 2022, 10, 393–406. [Google Scholar] [CrossRef]
  150. Wilson, J.M.; Lin, Y.; Luo, M.J.; Considine, G.; Cox, A.L.; Bowsman, L.M.; Robins, D.A.; Haupt, A.; Duffin, K.L.; Ruotolo, G. The dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide improves cardiovascular risk biomarkers in patients with type 2 diabetes: A post hoc analysis. Diabetes Obes. Metab. 2022, 24, 148–153. [Google Scholar] [CrossRef]
  151. Cefalu, W.T.; Riddle, M.C. SGLT2 inhibitors: The latest “new kids on the block”! Diabetes Care 2015, 38, 352–354. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Garg, S.K.; Henry, R.R.; Banks, P.; Buse, J.B.; Davies, M.J.; Fulcher, G.R.; Pozzilli, P.; Gesty-Palmer, D.; Lapuerta, P.; Simo, R.; et al. Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes. N. Engl. J. Med. 2017, 377, 2337–2348. [Google Scholar] [CrossRef] [PubMed]
  153. Powell, D.R.; Zambrowicz, B.; Morrow, L.; Beysen, C.; Hompesch, M.; Turner, S.; Hellerstein, M.; Banks, P.; Strumph, P.; Lapuerta, P. Sotagliflozin Decreases Postprandial Glucose and Insulin Concentrations by Delaying Intestinal Glucose Absorption. J. Clin. Endocrinol. Metab. 2020, 105, e1235–e1249. [Google Scholar] [CrossRef]
  154. Bhatt, D.L.; Szarek, M.; Pitt, B.; Cannon, C.P.; Leiter, L.A.; McGuire, D.K.; Lewis, J.B.; Riddle, M.C.; Inzucchi, S.E.; Kosiborod, M.N.; et al. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. N. Engl. J. Med. 2021, 384, 129–139. [Google Scholar] [CrossRef]
  155. Bhatt, D.L.; Szarek, M.; Steg, P.G.; Cannon, C.P.; Leiter, L.A.; McGuire, D.K.; Lewis, J.B.; Riddle, M.C.; Voors, A.A.; Metra, M.; et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. N. Engl. J. Med. 2021, 384, 117–128. [Google Scholar] [CrossRef] [PubMed]
  156. Salah, H.M.; Al’Aref, S.J.; Khan, M.S.; Al-Hawwas, M.; Vallurupalli, S.; Mehta, J.L.; Mounsey, J.P.; Greene, S.J.; McGuire, D.K.; Lopes, R.D.; et al. Effects of sodium-glucose cotransporter 1 and 2 inhibitors on cardiovascular and kidney outcomes in type 2 diabetes: A meta-analysis update. Am. Heart J. 2021, 233, 86–91. [Google Scholar] [CrossRef]
  157. Sagris, M.; Antonopoulos, A.S.; Theofilis, P.; Oikonomou, E.; Siasos, G.; Tsalamandris, S.; Antoniades, C.; Brilakis, E.S.; Kaski, J.C.; Tousoulis, D. Risk factors profile of young and older patients with myocardial infarction. Cardiovasc. Res. 2022, 118, 2281–2292. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Anti-inflammatory effects of glucagon-like peptide-1 (GLP-1)-based drugs.
Table 1. Anti-inflammatory effects of glucagon-like peptide-1 (GLP-1)-based drugs.
GLP-1-Based DrugsSubstanceDisease/Organ TargetMain Effect
GLP-1 Receptor AgonistsExenatide
Liraglutide
Lixisenatide
Albiglutide
Taspoglutide
Dulaglutide		Diabetes
Atherosclerosis–Cardiovascular disease
Asthma
Alzheimer’s disease
Parkinson’s disease
Nonalcoholic Steatohepatitis
(NASH)
Nephropathy
Testis
Psoriasis
▪
Levels of CRP, TNF-α, IL-1β, IL-6, MCP-1, and soluble adhesion molecules
▪
Suppress C-X-C motif chemokine 10 production
▪
Inhibit of nuclear factor-kappa B (NF-κB)
▪
Increase of SIRT6 levels
DPP4 InhibitorsSitagliptin
Des-fluoro-sitagliptin
Alogliptin
Linagliptin
Vildagliptin
NVP-DPP728
Anagliptin
Saxagliptin		Diabetes
Vascular Disease
Nephropathy
Neurodegenerative brain disorder
▪
Levels of IL-1β, IL-6, MCP-1, and soluble Adhesion Molecules
▪
Suppress toll-like receptor 4 mediated extracellular signal-regulated kinase
▪
Inhibition of NF-kappaB p65 nuclear translocation
▪
Improve arterial stiffness and peripheral endothelial dysfunction
DPP4: dipeptyl peptidase-4, CRP: C-reactive protein, IL: interleukin, MCP-1: monocyte chemoattractant protein-1, TNF-a: tumor necrosis factor alpha, SIRT6: sirtuin 6.
Table
Table 2. Selected preclinical studies demonstrating the anti-inflammatory effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors.
Table 2. Selected preclinical studies demonstrating the anti-inflammatory effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors.
StudyPreclinical ModelDiseaseSGLT2 InhibitorFinding
Madonna et al. [122]Male C57BL/6 miceDMEmpagliflozin↓ p38
Ganbaatar et al. [123]Male ApoE/miceDMEmpagliflozin↓ aortic expression of MCP-1, VCAM-1, NOX2 and p22phox
↓ PVAT expression of MCP-1, ICAM-1, VCAM-1, CD68, p47phox, and p22phox
Radlinger et al. [124]Male db/db miceDMEmpagliflozin↓ cardiac IL-6, CCL2, CCR2
↑ cardiac IL-10
Elkazzaz et al. [125]Male albino ratsDMDapagliflozin↑ PTX-3
↓ TNF-α
Ashrafi Jigheh et al. [126]Male Wistar ratsDMEmpagliflozin↓ NF-κB in renal cortex
↓ renal TNF-α and MCP-1
↓ urinary IL-6
Quaqliariello et al. [127]Female C57Bl/6 miceDoxorubicin-induced cardiotoxicityEmpagliflozin↓ IL-6, IL-8, NF-κB, NLRP3
Perakakis et al. [128]Male C57BL/6JRj miceNASHEmpagliflozin↓ hepatic lobular inflammation
Tahara et al. [129]KK/Ay miceDM + NASHIpragliflozin↓ plasma and liver IL-6, MCP-1, TNF-α, and CRP
MCP-1: monocyte chemoattractant protein-1, VCAM-1: vascular cell adhesion molecule-1, NOX2: NADPH oxidase 2, ICAM-1: intercellular adhesion molecule-1, IL: interleukin, CCL2: chemokine ligand 2, CCR2: chemokine receptor 2, PTX-3: pentraxin-3, TNF-α: tumor necrosis factor-alpha, Ay: lethal yellow, CRP: C-reactive protein.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Theofilis, P.; Sagris, M.; Oikonomou, E.; Antonopoulos, A.S.; Siasos, G.; Tsioufis, K.; Tousoulis, D. The Anti-Inflammatory Effect of Novel Antidiabetic Agents. Life 2022, 12, 1829. https://doi.org/10.3390/life12111829

AMA Style

Theofilis P, Sagris M, Oikonomou E, Antonopoulos AS, Siasos G, Tsioufis K, Tousoulis D. The Anti-Inflammatory Effect of Novel Antidiabetic Agents. Life. 2022; 12(11):1829. https://doi.org/10.3390/life12111829

Chicago/Turabian Style

Theofilis, Panagiotis, Marios Sagris, Evangelos Oikonomou, Alexios S. Antonopoulos, Gerasimos Siasos, Kostas Tsioufis, and Dimitris Tousoulis. 2022. "The Anti-Inflammatory Effect of Novel Antidiabetic Agents" Life 12, no. 11: 1829. https://doi.org/10.3390/life12111829

APA Style

Theofilis, P., Sagris, M., Oikonomou, E., Antonopoulos, A. S., Siasos, G., Tsioufis, K., & Tousoulis, D. (2022). The Anti-Inflammatory Effect of Novel Antidiabetic Agents. Life, 12(11), 1829. https://doi.org/10.3390/life12111829

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop