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28 October 2026

14 Pages

SGLT2 Inhibitors as Endothelial Protectors: Mechanisms of Vascular Restoration in Type 2 Diabetes

,
and
Grupo de Investigación en Enfermedades Cardiorrenales y Metabólicas, Departamento de Medicina y Cirugía, Facultad de Ciencias de la Salud, Universidad Cardenal Herrera-CEU, CEU Universities, C/Santiago Ramón y Cajal S/N, 46115 Valencia, Spain
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Metabolites2026, 16(11), 824;https://doi.org/10.3390/metabo16110824
This article belongs to the Special Issue Management of Diabetes and Its Metabolic Complications
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Abstract

Endothelial dysfunction is a fundamental catalyst of atherosclerosis and cardiovascular mortality in type 2 diabetes mellitus (T2DM). While sodium-glucose co-transporter 2 inhibitors (SGLT2is) provide robust cardioprotection, whether these benefits stem from direct vasculature effects or from secondary systemic hemodynamics remains an active translational frontier. At the cellular level, preclinical data suggests that SGLT2is may modulate homeostatic pathways by suppressing NADPH oxidase-mediated oxidative stress, attenuating NF-κB/NLRP3-driven inflammatory cascades, and preserving endothelial nitric oxide synthase (eNOS) activity. In clinical cohorts, these molecular actions correlate with heterogeneous changes in flow-mediated dilation (FMD) and reductions in arterial stiffness. However, translating these cellular findings to macrovascular outcomes is highly confounded by concurrent volume contraction, blood pressure lowering and metabolic shifts.

1. Introduction

In patients with type 2 diabetes mellitus (T2DM), vascular health is severely compromised by chronic hyperglycemia, insulin resistance, and lipotoxicity, which disrupt the homeostatic balance of the endothelium, shifting it towards a pro-inflammatory and pro-thrombotic phenotype [1,2,3]. This endothelial impairment serves to further accelerate the progression of atherosclerosis, increasing the risk of cardiovascular complications. Landmark cardiovascular and renal outcome trials have established the efficacy of sodium-glucose cotransporter 2 inhibitors (SGLT2i), demonstrating significant reductions in major adverse cardiovascular events (MACE), heart failure hospitalizations and chronic kidney disease (CKD) [4,5,6,7,8,9].
While traditional therapeutic strategies focus solely on intensive glycemic control, macrovascular residual risk frequently persists [10]. This observation suggests that the clinical utility of SGLT2is may extend beyond proximal renal tubular glucose clearance [11]. Emerging translational evidence hints at a potential role for these agents in modulating endothelial signaling pathways [12,13,14,15]. SGLT2is appear to exert pleiotropic endothelial-protective properties, potentially acting as auxiliary vascular modifiers. However, whether these localized vascular actions occur fully independent of systemic metabolic improvements or represent a subordinate phenomenon remains a topic for future investigations.
In this communication, we explore the connection between laboratory data and clinical observations by evaluating how SGLT2i therapy modulates oxidative stress, localized in-flammation, and eNOS coupling. Furthermore, we contextualize how these cellular modifications contribute to observable human macrovascular and microvascular findings, specifically changes in conduit artery flow-mediated dilation, indices of arterial stiffness, and long-term cardiorenal outcomes.

2. Methodology

A comprehensive literature search was conducted using PubMed/MEDLINE, Scopus and Web of Science databases for articles published until August 2026, using combinations of terms including ‘SGLT2 inhibitors’, ‘endothelial dysfunction’, ‘FMD’, and ‘arterial stiffness’, prioritizing peer-reviewed primary cell models, meta-analyses, and clinical trials. Boolean operators (AND, OR) were used to refine the search. Original peer-reviewed research articles, encompassing in vitro primary cell lines, in vivo animal models, human observational data, and clinical trials, along with comprehensive meta-analyses, were prioritized for inclusion. Studies were selected if their primary outcomes detailed the molecular, cellular, microvascular, or macrovascular cardiorenal consequences of SGLT2 inhibitor intervention. Exclusion criteria consisted of non-English language publications and studies that did not explicitly focus on cardiovascular, metabolic, or renal outcomes. The final selection, evaluation, and data extraction process were performed independently by the authors, focusing on mapping key mechanistic pathways and evaluating the translation of preclinical observations into clinical outcomes.

3. Mechanistic Insights

3.1. Oxidative Stress Suppression

At the cellular level, the endothelium of the blood vessels in T2DM patients is heavily affected by the presence of free radicals, primarily mediated by the overactivation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) isoforms, particularly NOX2 and NOX4, alongside increased mitochondrial superoxide generation [14,16]. This excessive production of reactive oxygen species (ROS) outpaces antioxidant defenses, giving rise to lipid peroxidation, protein oxidation, and the activation of downstream detrimental signaling cascades [17,18]. Preclinical models indicate that SGLT2i intervention may help break this cycle of oxidative injury [19]. Experimental evidence demonstrates that use of empagliflozin or dapagliflozin correlates with a transcriptional downregulation of key NOX sub-units, thereby reducing baseline cytosolic ROS production [20]. Concurrently, SGLT2is have been observed to optimize mitochondrial efficiency and preserve mitochondrial membrane potential, mitigating the leakage of premature electrons and subsequent mitochondrial superoxide formation [21,22]. By dampening both enzymatic and organelle-sourced oxidative bursts, SGLT2i therapy preserves endothelial structural integrity and maintains a more favorable intracellular redox equilibrium, providing a clear mechanistic basis for direct vascular protection.

3.2. Inflammatory Attenuation

Chronic metabolic stress within the vessels initiates an inflammatory response that accelerates vascular remodeling and plaque vulnerability. Central to this process is the activation of the nuclear factor-kappa B (NF-κB) signaling pathway, which is upregulated by upstream oxidative stress and advanced glycation end-products (AGEs) [23,24]. Upon activation, NF-κB translocates to the nucleus, driving the transcription of pro-inflammatory cytokines such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) alongside endothelial adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) [25,26]. These adhesion molecules facilitate the tethering, rolling, and transendothelial migration of circulating leukocytes into the subendothelial space, a foundational step in atherogenesis (Figure 1).
Figure 1. Mechanisms of Vascular ROS-Driven Endothelial Dysfunction and Leukocyte Migration in Type 2 Diabetes. Chronic metabolic stress upregulates NOX2/NOX4 isoforms and damages mitochondrial structures, expanding the intracellular reactive oxygen species (ROS) pool. This oxidative stress drives the nuclear translocation of NF-κB, inducing the genomic transcription and surface expression of endothelial adhesion molecules VCAM-1 and ICAM-1. Concurrently, cytosolic ROS triggers NLRP3 inflammasome assembly, while uncoupled eNOS homodimers generate further superoxide (O2∙−), ultimately leading to cell junction disruption, leukocyte rolling, and subendothelial lipid plaque development. Black arrows indicate activation or pathways; T-bar lines indicate inhibition; cell types and tissue layers are color-coded for visual distinction.
Accumulating translational data suggest that SGLT2i treatment may attenuate this inflammatory cascade. In endothelial cell lines and diabetic rodent models, SGLT2i administration has been associated with suppression of NF-κB phosphorylation and nuclear translocation [27,28,29]. This molecular inhibition correlates with a downstream reduction in the expression of VCAM-1 and ICAM-1, thereby limiting leukocyte-endothelial interactions [30,31]. Emerging evidence indicates that SGLT2is modulate NLRP3 inflammasome activation, a key macromolecular complex responsible for IL-1β maturation, via systemic substrate shifts [32,33]. By inducing a state of fasting-mimicry, SGLT2is stimulate hepatic ketogenesis, mildly elevating circulating beta-hydroxybutyrate (β-HB) [34]. Within vascular cells, β-HB acts as an active signaling modifier that upregulates SIRT1, which subsequently deacetylates and inactivates the p65 subunit of NF-κB to suppress cytokine transcription [35,36]. Additionally, β-HB prevents the structural assembly of the NLRP3 inflammasome [32,37]. By suppressing these pathways, SGLT2is may blunt the chronic vascular inflammation that underpins accelerated macrovascular disease in T2DM [15,16].

3.3. eNOS Stabilization and NHE1 Inhibition

A defining hallmark of diabetic vasculopathy is the loss of endothelial nitric oxide synthase (eNOS) activity, which reduces nitric oxide (NO) and impairs endothelial vasodilation. Under physiological conditions, eNOS produces basal levels of NO, maintaining vascular tone, inhibiting platelet aggregation, and suppressing smooth muscle cell proliferation [38,39]. However, in the high-oxidative environment of T2DM, excessive reactive oxygen species (ROS) particularly superoxide (O2−) rapidly react with NO to form peroxynitrite (ONOO−) [39,40]. This highly reactive nitrogen species oxidizes tetrahydrobiopterin (BH4), an essential cofactor for eNOS [41]. Deprived of BH4, the eNOS enzyme undergoes “uncoupling,” a dysfunctional enzymatic state wherein it paradoxically generates further superoxide instead of NO, creating a feedback loop of endothelial injury [41,42] (Figure 2).
Figure 2. Cellular Cascade of Coupled eNOS Homeostasis Versus Peroxynitrite-Induced eNOS Uncoupling. (Left Panel) Under physiological conditions, the coupled eNOS homodimer utilizes the essential cofactor tetrahydrobiopterin (BH4) within endothelial caveolae to produce basal nitric oxide (NO), promoting smooth muscle cell vasodilation. (Middle Panel) Under diabetic oxidative stress, excessive superoxide (O2−) rapidly reacts with NO to form highly reactive peroxynitrite (ONOO−). (Right Panel) Peroxynitrite oxidizes and depletes local BH4 reserves, causing functional enzymatic uncoupling of the eNOS enzyme; uncoupled eNOS paradoxically generates further superoxide instead of NO, impairing vasodilation and driving vascular injury. Grey shading contrasts coupled vs. uncoupled states; red/purple spheres denote reactive radical species; arrows trace biochemical progression; muscle cells are represented in light red.
Experimental models suggest that SGLT2i therapy may disrupt this uncoupling cascade and support eNOS function [43,44,45,46]. By suppressing upstream NOX activation, SGLT2is reduce consumption of BH4, stabilizing the functional state of eNOS [44]. Furthermore, molecular studies indicate that SGLT2is stimulate eNOS enzymatic activity via the activation of the adenosine monophosphate-activated protein kinase (AMPK) and protein kinase B (Akt) pathways, promoting the regulatory phosphorylation of eNOS at its activating site [47,48]. The resulting restoration of NO has been proposed to normalize local vasodilation and reinforce the integrity of the vessel wall [49]. Nevertheless, because these laboratory findings are mapped in isolated myocardial, renal or lymphocyte models, uniform replication in the human blood vessels remains unproven. Translational evidence points towards inhibition of the sodium-hydrogen exchanger 1 (NHE1) as a parallel pathway for vascular preservation [50,51,52]. In diabetes, endothelial NHE1 hyperactivation prompts intracellular sodium and calcium overload, driving mitochondrial dysfunction and apoptosis [53,54]. Preclinical models indicate that specific gliflozins, particularly empagliflozin, inhibit vascular NHE1, restoring ion homeostasis [52]. This pathway, however, varies significantly across individual SGLT2i agents. Individual gliflozins manifest highly divergent affinity profiles for different NHE isoforms, thus NHE modulation represents a compound-specific pharmacodynamic trait rather than a uniform class effect [51,55]. A consolidated overview of these molecular pathways and cellular mechanisms under diabetic conditions is summarized in Table 1.
Table 1. An overview of the interplay between diabetic vascular damage and SGLT2i intervention.

4. Clinical Implications

The translational bridge between cellular modifications and macrovascular preservation is clinically evaluated through non-invasive surrogates of vascular health, primarily flow-mediated dilation (FMD) and indices of arterial stiffness. While early landmark outcome trials like EMPA-REG OUTCOME and DECLARE-TIMI 58 established systemic macrovascular benefits, granular physiological sub-studies and dedicated prospective cohorts have provided direct insight into localized conduit and elastic artery dynamics [4,5]. To interpret these data accurately, translational research requires a clear distinction between basic science pathways and long-term clinical outcomes. While these domains provide overlapping insights, a favorable shift in one cannot be interpreted as a confirmation in the other. Thus, although the clinical efficacy of SGLT2is in non-diabetic cohorts suggests that their effects go beyond proximal tubule inhibition, these outcomes reflect an integrated response heavily driven by systemic fluid and pressure changes rather than isolated endothelial cell protection (Table 2).

4.1. Flow-Mediated Dilation (FMD)

Clinical assessment of endothelium-dependent vasodilation via brachial artery FMD serves as a proxy marker of real-time endothelial nitric oxide (NO) bioavailability [47,48]. In patients with T2DM, who characteristically manifest blunt or absent hyperemic reactive dilation, SGLT2i therapy has demonstrated heterogeneous functional results.
In the DEFENCE Trial, which evaluated dapagliflozin versus metformin in early-stage T2DM over 16 weeks, there was no statistically significant difference in the primary endpoint of overall baseline-adjusted change in brachial artery FMD between the two groups [56]. However, a pre-specified analysis revealed a significant improvement in FMD exclusively in patients with poorly controlled diabetes (baseline HbA1c > 7%) [56]. This specific benefit correlated with a significant reduction in urinary 8-OHdG markers, suggesting that SGLT2i-mediated oxidative mitigation is most functionally relevant in states of severe metabolic and oxidative stress [56]. Parallel subacute trends were described by Balleza-Alejandri et al. (2024) in a double-blind trial demonstrating that an acute, 7-day administration of empagliflozin or dapagliflozin significantly increased brachial artery FMD from baseline in patients with T2DM [57]. While these findings suggest a rapid class effect on the dynamic, shear-stress-responsive properties of the endothelial wall, interpretation remains restricted by the brief study duration, sample size, and notable baseline clinical imbalances [57]. More broadly, systematic reviews confirm that across unselected clinical cohorts, SGLT2is yield modest and highly heterogeneous FMD modifications, underscoring a low-to-moderate overall certainty of evidence [58,59,60].
Clinical FMD responses are not uniform across trial populations. The landmark EMPA-HEART CardioLink-6 trial evaluated the impact of empagliflozin (10 mg/day) over 6 months in patients with T2DM and established coronary artery disease, failing to demonstrate a statistically significant improvement in brachial artery FMD compared to placebo [61]. This discrepancy suggests that while gliflozins may modulate dynamic, shear-stress-responsive endothelial properties in early-stage metabolic dysfunction or lower-risk cohorts, they do not consistently override or reverse structural macrovascular damage in advanced, established atherothrombotic disease where intensive cardioprotective medications and mechanical hemodynamic loading fluctuations drive vascular behavior [62,63].

4.2. Arterial Stiffness and Wave Reflection

Concurrently, structural and functional stiffening of the large elastic arteries, quantified via the gold-standard carotid-femoral pulse wave velocity (cfPWV) and the cardio-ankle vascular index (CAVI), represents an independent predictor of incident heart failure and cardiovascular mortality [64,65]. The therapeutic use of SGLT2is has shown an association with reductions in central vascular impedance. For instance, a pooled analysis of Phase III trials specifically scrutinized the acute and intermediate effects of empagliflozin on arterial stiffness parameters in patients with T2DM. While the primary findings demonstrated consistent shifts in central hemodynamics over 12-week and 24-week timelines, parallel findings indicated a stabilizing or reducing effect on peripheral vascular resistance and ambulatory arterial stiffness [66,67,68].
However, the capacity of these agents to achieve true structural destiffening remains highly debated. A systematic review and meta-analysis by Wei et al. (2022) demonstrated that while SGLT2i therapy significantly improved peripheral vascular resistance, it failed to identify a statistically significant overall reduction in the cfPWV [59]. This underscores that clinical improvements in vascular impedance may stem primarily from acute mechanical volume contraction and blood pressure reduction, rather than true structural matrix remodeling (such as reductions in advanced glycation end-products or active vascular smooth muscle cell modulation) of the elastic arterial wall [59,63,69,70,71].

4.3. Nephrology Outcome Trials

While localized measurements like FMD and cfPWV reflect subacute changes in vascular physiology, landmark large-scale outcome trials within the nephrology sector indicate that pathways correspond to microvascular and macrovascular preservation in the kidneys. This cardiorenal protective class effect has been mapped across three major clinical trials. The CREDENCE Trial, evaluating canagliflozin in patients with T2DM and diabetic nephropathy, was the first dedicated renal outcome trial to demonstrate a significant 30% reduction in the risk of the primary composite cardiorenal endpoint (progression to end-stage kidney disease, doubling of serum creatinine, or renal/cardiovascular death) [7].
The DAPA-CKD Trial expanded the therapeutic horizon by including chronic kidney disease (CKD) patients with and without T2DM [8]. Dapagliflozin demonstrated a significant 39% reduction in the primary composite renal endpoint alongside significant reductions in all-cause mortality and cardiovascular hospitalizations, indicating that the foundational mechanisms of SGLT2i-mediated vascular and tissue preservation can operate independently of ambient baseline glycemic states [8]. Finally, the EMPA-KIDNEY Trial scrutinized a broad spectrum of CKD populations, showing that empagliflozin reduced the risk of kidney disease progression or cardiovascular death by 28% [9]. Notably, EMPA-KIDNEY included patients with lower baseline kidney function (eGFR down to 20 mL/min/1.73 m2) and lower levels of albuminuria, supporting the agent’s role as a broad-spectrum vascular stabilizer [9].
The cardiorenal protection highlighted in these trials is reinforced at the microvascular level through the preservation of the endothelial filtration barrier, specifically the endothelial glycocalyx (Figure 3). The glycocalyx regulates the permeability of the endothelium and limits leukocyte adhesion [72,73]. In T2DM, chronic glucotoxicity degrades the barrier, giving rise to protein leakage, podocyte loss and worsening glomerular injury [74,75]. Emerging preclinical data indicate that SGLT2i therapy helps prevent glycocalyx shedding and supports its structural thickness [76]. By shielding this endothelial gel layer, SGLT2is mitigate microvascular permeability, directly contributing to the observable reductions in albuminuria and long-term filtration decline demonstrated across the CREDENCE and DAPA-CKD cohorts [7,8].
Figure 3. Pleiotropic Pathways and Macrovascular Benefits of SGLT2i-Mediated Endothelial Protection. This diagram maps the multi-targeted systemic impacts of SGLT2i therapy, organizing them into four distinct functional axes: organelle homeostasis (mitochondrial rejuvenation via mitophagy and fusion balance), nitric oxide bioavailability (eNOS activation and enhanced NO generation), barrier shield integrity (endothelial glycocalyx fortification and stabilization), and macrovascular compliance (enhanced vasodilation paired with a reduction in arterial wall stiffness). The diagram features four color-coded quadrants, blue, orange, purple, and green, representing distinct therapeutic axes; outward block arrows indicate downstream effects of central SGLT2i action, while small black arrows denote increased or decreased parameters.
Ultimately, these cumulative macrovascular and nephrology outcomes demonstrate that the molecular hallmarks of SGLT2i action, which encompass oxidative, inflammatory, and enzymatic pathways, correlate favorably with overall macrovascular compliance and endothelial responsiveness (Figure 3).

4.4. Limitations and Clinical Confounders

The translational evidence connecting SGLT2is to direct endothelial protection possesses several distinct boundaries. Mechanistically, primary basic science data exhibit notable variability across individual agents; for example, specific pathway interactions (such as NHE1 inhibition) represent compound-specific traits rather than uniform class effects [51,52]. Clinically, human studies evaluating vascular surrogate markers are severely constrained by small sample sizes and brief treatment durations, leaving long-term structural changes in the arterial wall largely unverified. Most importantly, non-invasive clinical vascular measurements like FMD, cfPWV, and CAVI are highly sensitive to acute fluctuations in blood pressure, volume status, systemic glycemic control, and body weight [77]. Because SGLT2i therapy simultaneously modulates all of these metabolic and fluid parameters via osmotic diuresis and natriuresis, isolating an intrinsic, direct endothelial stabilization effect in human cohorts remains a complex clinical challenge.
Table 2. Stratification of clinical trials and systematic evidence evaluating SGLT2i vascular and cardiorenal endpoints.

5. Conclusions

Accumulating translational and clinical evidence suggests that SGLT2 inhibitors possess vascular-modulating properties, potentially complementing their established systemic cardiorenal effects. Mechanistically, preclinical models demonstrate that these agents sustain nitric oxide bioavailability by suppressing oxidative stress, NF-κB-mediated inflammation, and eNOS uncoupling. In human cohorts, these cellular actions correlate with changes in flow-mediated dilation and reduced arterial stiffness, underpinning some of the macrovascular and renal protection observed in landmark outcome trials. However, to definitively isolate these direct endothelial benefits from systemic hemodynamic confounders, such as osmotic diuresis and blood pressure reduction, the cardiorenal research community should transition toward more targeted clinical trial designs. Specifically, future protocols should prioritize flow-mediated dilation and pulse wave velocity assessments conducted under strictly volume- and blood pressure-clamped conditions. Furthermore, head-to-head mechanistic trials comparing SGLT2is directly against pure loop or thiazide diuretics are essential to differentiate mechanical volume unloading from active endothelial cell stabilization. Elucidating these precise pathways remains vital to addressing the high residual cardiorenal risk persisting in this population.

Author Contributions

Conceptualization, L.D. and A.C.-R.; methodology, L.D., A.C.-R. and O.-J.O.; writing—original draft, L.D., A.C.-R. and O.-J.O.; writing—review and editing, A.C.-R. and O.-J.O. 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.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

During the preparation of this work, the authors used ChatGPT version 5.2 strictly for English copy-editing, syntax refinement, and clarity improvement of text originally drafted by the authors. The authors reviewed, verified, edited all outputs manually and take full academic responsibility for the integrity of the scientific content.

Conflicts of Interest

The authors declare no conflicts of interest.

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