Introduction

Rheumatoid arthritis (RA) is a chronic immune-medi-ated inflammatory disease associated with a significantly increased metabolic and cardiovascular (CV) risk [1].

    Chronic systemic inflammation affects metabolic homeostasis by impairing insulin sensitivity and glucose and lipoprotein metabolism. Inflammation may influence and remodel conventional metabolic markers, leading to a paradoxical lipid profile and to potential underestimation of CV risk. Moreover, metabolic abnormalities can interact with immune and inflammatory pathways, contributing to disease-related mechanisms [2]. This two-way relationship between inflammation and metabolism has led to the con-cept of “immunometabolism”, in which metabolic pathways actively modulate immune responses.

    Recent integrative analyses have raised attention toward a new approach to cardiometabolic comorbidities in RA [3]. This narrative review provides an updated synthesis of mechanisms linking inflammation to metabolic dysfunction and discusses their impact on clinical practice.

    Pharmacological treatment further complicates this interplay. Anti-rheumatic therapies, including gluco-corticoids and disease-modifying anti-rheumatic drugs (DMARDs), exert heterogeneous effects on glucose and lipid metabolism, with a potential higher risk of type 2 Dia-betes Mellitus (T2DM) and CV diseases. Recently, atten-tion has also been raised toward the metabolic and potential immunomodulatory effects of new glucose-lowering agents in chronic inflammatory conditions [4].

    In this narrative review, we describe cardiometabolic changes in RA arising from three main directions: inflam-mation-driven mechanisms related to the underlying disease pathogenesis, patient-related cardiometabolic risk factors, and metabolic effects of antirheumatic therapies.

    We also integrate current evidence on immune-driven metabolic alterations in glucose and lipid metabolism in RA and their clinical effects on cardiometabolic risk assessment and management. Finally, we propose a practical cardiomet-abolic monitoring algorithm to support clinicians involved in the multidisciplinary care of patients with RA.

Methods

This narrative literature review was developed through a targeted, non-systematic search of PubMed/MEDLINE, focusing on articles published from 2000 to 2025. Search terms included: rheumatoid arthritis, insulin resistance, glu-cose metabolism, glycaemic control, dyslipidaemia, lipid profile, cardiovascular risk, inflammation, glucocorticoids, conventional DMARDs, biologic DMARDs, targeted syn-thetic DMARDs, GLP-1 receptor agonists, and SGLT2 inhibitors. Relevant publications were identified throughaccurate screening of the reference lists.

    Systematic review, meta-analyses, randomized con-trolled trials, large observational cohort studies, and posi-tion statements or guidelines from major scientific societies were prioritized. Mechanistic and preclinical studies were included to support biological plausibility and to contex-tualize clinical observations, particularly where high-level clinical evidence was limited.

    The selection of studies was guided by the relevance of metabolic outcomes, including insulin resistance (IR), glucose and lipid homeostasis, and CV risk. Another main purpose was to understand the interaction between chronic inflammation, antirheumatic therapies, and metabolic regu-lation. In line with the review’s narrative design, no sys-tematic selection process or quantitative quality assessment was applied.

Interplay between inflammatory and glucose dysregulation in RA

Mechanisms of inflammation-induced glucose changes in RA

Numerous studies have demonstrated a correlation among IR, T2DM, and the molecular mechanisms driving RA. Pro-inflammatory cytokines, such as Tumor Necrosis Fac-tor-alpha (TNF-α), Interleukin-6 (IL-6), and Interleukin-1 (IL-1), are central mediators of this interaction [5], by acting through an interconnected signalling network and amplify-ing each other’s effects on glucose metabolism.

    TNF-α plays a central role in the development of IR by directly interfering with insulin receptor signalling and glu-cose uptake. First, it induces post-translational modifica-tions of the insulin receptor and insulin receptor substrate-1 (IRS-1), functionally inhibiting the insulin signalling [6]. This altered phosphorylation pattern impairs activation of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt), reducing the translocation of glucose transporter type 4 (GLUT4) to the cell membrane in adipocytes and skeletal muscle cells [7] and thereby impairing glucose uptake. In parallel, TNF-α upregulates Suppressor of Cytokine Signal-ling 3 (SOCS-3), a known inhibitor of the insulin signalling pathway. Moreover, TNF-α inhibits the synthesis of peroxi-some proliferator-activated receptor gamma (PPARγ), com-promising adipocyte differentiation and insulin sensitivity. It also stimulates lipolysis and increases circulating free fatty acids (FA), thereby exacerbating IR [5].

    The impact of IL-6 on glucose metabolism is variable: acute IL-6 elevation may enhance insulin sensitivity; how-ever, chronic exposure and overproduction observed in RA promote IR through SOCS-3 upregulation and altered IRS-1 phosphorylation [8].

    IL-1β exerts a similarly dual effect on glucose metabo-lism: at low concentrations, it enhances insulin secretion, whereas chronic exposure induces β-cell dysfunction and apoptosis via activation of the Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen-acti-vated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) signalling pathways, with subsequent nitric oxide and reactive oxygen species production and higher oxida-tive stress. Moreover, hyperglycaemia itself amplifies IL-1β expression and inhibits IL-1 receptor antagonist production in pancreatic islets [9].

    Finally, activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which has a key role in RA pathogenesis, has been linked to upreg-ulation of pro-apoptotic mediators and progressive loss of β-cells [10] (Fig. 1).

Glucose metabolism in RA pathogenesis

The relationship between glucose metabolism and RA is not unidirectional; rather, hyperglycaemia and T2DM may act as catalysts that accelerate RA progression, enhanc-ing systemic inflammation, exacerbating structural joint damage, and significantly impacting therapeutic efficacy. Metabolic Syndrome (MetS), particularly obesity, alters

the pharmacokinetics of various medications, sustaining a chronic inflammatory state and it has been associated with reduced therapeutic response to TNF inhibitors in several studies [11].

     At the molecular level, chronic hyperglycaemia facili-tates the accumulation of advanced glycation end products (AGEs). These compounds function as pro-inflammatory ligands that activate specific immune receptors, amplifying TNF-α and IL-6 production. Within the joint microenviron-ment, AGEs enhance synovial inflammation and activate degradative pathways, accelerating cartilage consumption and bone erosion [12].

    This structural decline is also associated with increased oxidative stress, which favours osteoclast differentiation and hyperactivity, resulting in more aggressive radiographic progression [13].

    IR further promotes systemic inflammation, reducing the clinical response to both conventional synthetic (cs) DMARDs and biologics. Consequently, patients with IR often exhibit higher disease activity scores, poorer clinical outcomes, and increased rates of long-term disability [14].

    hese findings are also confirmed by the Cardiovascular, Obesity and Rheumatic Diseases Italian Study (CORDIS) group, which highlighted that RA patients with diabetes suf-fer from significantly higher functional disability. Further-more, these individuals are more likely to require escalation to biologic (b)DMARDs compared to the others, suggesting that metabolic dysfunction resembles a more refractory dis-ease phenotype [15] .

Impact of RA therapies on glucose metabolism

    Glucocorticoids (GC) stimulate hepatic glucogenesis, reduce insulin secretion, and induce IR. Prolonged treat-ment with moderate-to-high doses increases T2DM risk, while short-term high-dose therapy carries lower diabe-togenic effects, with predominance of the beneficial anti-inflammatory benefits [16].

    Methotrexate (MTX), a first-line csDMARD in RA, is linked to lower MetS prevalence and improved glucose  control. In a study of 400 RA patients, MTX use was associ-ated with reduced MetS and fasting blood glucose (FBG) [17]. Other csDMARDs, such as leflunomide and sulfasala-zine, do not significantly affect glucose metabolism. Hydroxychloroquine (HCQ), an antimalarial drug com-monly used as a csDMARD in RA, improves insulin sensi-tivity and reduces the risk of T2DM [18].

    Treatment with TNF-α inhibitor has been associated with a reduced IR and T2DM incidence, particularly among normal-weight patients [19]. Additionally, a recent meta-analysis reported a significant increase in Insulin Sensi-tivity, measured by the Quantitative Insulin Sensitivity Check Index (QUICKI), in patients treated with different anti-TNF-α regimens. According to the results, the QUICKI increased with minimal variability across the three drugs, suggesting comparable clinical efficacy [20]. Finally, the CORRONA study, a large multicentre cohort, evaluated the development of T2DM in RA patients. After adjustment for BMI, disease activity, and GC therapy, TNF-α inhibi-tors were associated with reduced IR and a reduced risk of T2DM [21].

    Among other bDMARDs considered for RA treatment, anakinra, an IL-1 inhibitor, improved HbA1c, proinsulin-to-insulin ratio, β-cell function, and inflammatory markers in patients with T2DM. On the other side, tocilizumab, an IL-6 receptor antagonist, was associated with reduced HbA1c in RA patients, with no hypoglycaemia events. Given that serum IL-6 levels rise before IR and T2DM onset, targeting this pathway could also be promising in improving patients’ metabolic profile [22].

    Finally, JAK inhibitors are highly effective in managing synovial inflammation, and clinical data showed minimal impact on glucose metabolism [23].

Interplay between inflammatory and lipid dysregulation in RA 

Mechanisms of inflammatory-induced lipid changes

Dyslipidaemia is observed in approximately 55–65% of RA patients and may already be detectable during the preclini-cal phase of the disease, preceding overt joint involvement. RA patients carry an increased CV risk, mainly due to accel-erated atherosclerosis. However, lipid abnormalities in RA differ substantially from those observed in the general popu-lation and are strongly related to the chronic inflammation characterizing the disease. During high disease activity, RA patients frequently show reduced levels of total cholesterol and low-density lipoprotein cholesterol (LDL), a phenome-non commonly referred to as the “lipid paradox”, since these lower lipid concentrations are paradoxically associated with increased CV risk [24]. This pattern is secondary to altera-tions in lipid turnover induced by inflammatory cytokines, such as TNF-α, IL-6 and IL-1β, rather than a truly protective lipid profile [25].

    Beyond quantitative changes, chronic inflammation alters lipoprotein composition and function. Inflammatory microenvironment impairs high-density lipoprotein (HDL) maturation by inhibiting lecithin–cholesterol acyltransfer-ase (LCAT) activity. Particularly, HDL shifts toward a dys-functional, pro-inflammatory phenotype characterized by reduced cholesterol efflux capacity and loss of antioxidant properties [26]. Apolipoprotein A-I (ApoA-I), which con-stitutes the major protein component of HDL and plays a central role in reverse cholesterol transport, is reduced in RA due to decreased hepatic synthesis and increased degra-dation [27]. In addition, oxidative modifications of ApoA-I driven by elevated myeloperoxidase (MPO) activity impair its interaction with ATP-binding cassette transporter A1 (ABCA1), further limiting cholesterol efflux [28].

    Oxidative stress represents a key amplifier of lipid altera-tions in RA. Increased production of reactive oxygen spe-cies and MPO promotes LDL oxidation in both serum and synovial fluid, favouring macrophage uptake and foam cell formation [29]. In parallel, inflammatory cytokines modu-late hepatic lipid handling, enhancing LDL clearance from the circulation and facilitating lipid deposition within the arterial wall [30]. Role of triglycerides (TG) has not been completely elucidated; however, their levels appear to be elevated in early active disease and reduced in the chronic phases [31] (Fig. 2).

Lipid metabolism in RA pathogenesis

Current evidence in RA suggests that lipid metabolic altera-tions may also actively contribute to disease pathogenesis. Lipidomic analyses identified a distinct metabolic signature in RA, characterized by an imbalance in FA composition, particularly a reduction in omega-3 polyunsaturated FA and an increase of pro-inflammatory lipid metabolites [32]. Higher levels of omega-3 FA have been associated with a lower prevalence of autoantibodies in individuals at risk of RA, suggesting their protective role in the early phases of the disease [33].

    Altered lipid metabolism also promotes oxidative stress and the generation of lipid peroxidation products, further amplifying immune activation. Elevated levels of reac-tive aldehydes derived from peroxidised polyunsaturated FA have been detected in serum, synovial fluid, and eryth-rocytes of RA patients, linking lipid oxidation to chronic inflammation [34]. Moreover, arachidonic acid-derived lipid mediators, including prostaglandins and leukotrienes, have been detected in inflamed joints and seem to contribute

directly to synovitis, cartilage degradation and bone erosion[35].

    Immune cells have shown a metabolic reprogram-ming that induces pro-inflammatory differentiation and persistence in the synovium. First, T lymphocytes display impaired mitochondrial respiration and increased FA syn-thesis, enhancing migratory capacity and tissue invasiveness [36]. Fibroblast-like synoviocytes (FLS) showed impaired mitochondrial function and altered FA metabolism, promot-ing an aggressive, tissue-invasive phenotype [37]. In resi-dent joint cells, lipid mediators also promote chondrocyte apoptosis and extracellular matrix degradation, enhance osteoclast differentiation, and inhibit osteoblast function, contributing to bone resorption [35, 38] (Fig. 3). These find-ings demonstrate that lipid metabolic dysfunction is tightly integrated into RA pathogenesis, representing both a con-sequence and an active driver of chronic inflammation and articular damage, supporting the use of metabolic pathways as an adjunctive strategy to modulate disease activity in RA.

Impact of RA therapies on lipid metabolism

The reduction of systemic inflammation represents one of the main targets in CV risk reduction in RA patients. How-ever, antirheumatic therapies show heterogeneous effects on lipid metabolism, underlining the need to carefully interpret lipid changes observed during treatment.

    GC remain widely used for disease control, particularly in the acute phases, but their metabolic effects on lipids are mainly unfavourable. First, they enhance hepatic lipogen-esis and impair lipid clearance, increasing circulating levels of TG and LDL cholesterol; on the other hand, prolonged GC treatment contributes to endothelial dysfunction and oxidative stress, further amplifying atherosclerotic risk [39]. These effects reinforce the need to limit cumulative steroid exposure whenever possible.

    Among csDMARDs, methotrexate displays the most favourable cardiometabolic profiles. It consistently corre-lates with reduced CV morbidity and mortality, likely medi-ated by control of inflammation and improved lipoprotein handling rather than by direct lipid lowering. Importantly, methotrexate appears to enhance macrophage cholesterol

efflux, supporting its anti-atherogenic potential despite min-imal changes in standard lipid measurements [40, 41].

    Biologic and targeted synthetic DMARDs profoundly influence lipid metabolism, largely by reversing inflam-mation-driven hypocholesterolaemia. Particularly, TNF inhibitors and IL-6 receptor antagonists are more strongly associated with increases in total and LDL cholesterol levels [42].

    A large cohort study showed a reduced incidence of CV events among RA patients receiving TNF inhibitors com-pared with biologic-naïve patients [43]. Moreover, a recent meta-analysis reported no difference in the incidence of CV events in patients treated with abatacept compared to TNF inhibitors, while a significantly reduced risk was observed with IL-6 inhibitors, suggesting a general cardioprotective effect despite lipid elevations [44].

    IL-1 inhibitors, such as anakinra and canakinumab, are rarely used in RA. However, the role of IL-1 in atheroscle-rosis has been largely studied, since IL-1 blockade reduces endothelial activation, leukocyte recruitment and downreg-ulates the IL-6 signalling. The CANTOS trial demonstrated a reduction in recurrent CV events with IL-1β inhibition among patients with prior myocardial infarction, supporting the validity of targeting inflammation for CV risk reduction [45].

    Rituximab, an anti-CD20 monoclonal antibody indicated in severe RA, appear metabolically neutral, with no relevant adverse effects on lipid levels and CV risk.

    Finally, the influence of JAK inhibitors on CV risk remains to be further understood. It has been observed that JAK inhibitors initially increase lipid levels, particularly LDL and HDL, while generally maintaining a stable LDL/ HDL ratio [46]. These changes occur mainly in the early phase after treatment initiation and tend to stabilise over time. From a pathogenetic perspective, the anti-inflamma-tory effect of JAK inhibitors could reverse the lipid paradox, thereby increasing cholesterol levels.

    Beyond lipid levels, JAK inhibitors have been associated with a higher incidence of CV and thromboembolic events compared to TNF inhibitors. Data from real-world evidence linked the overall increased risk to the presence of baseline CV risk factors [47]. The European Medicines Agency has therefore recommended careful patient selection and risk stratification, limiting their prescription in patients aged 65 years or more and in the presence of other CV risk factors.

    In this context, a recent analysis proposed that subopti-mal management of LDL‑cholesterol may contribute to part of the safety signal observed with JAK inhibitors [48]. This hypothesis highlights the potential importance of proactive lipid monitoring and optimization of lipid‑lowering therapy in selected patients receiving JAK inhibitors.

    Overall, lipid alterations observed during RA treatment should not be viewed as isolated adverse effects but rather as part of an interaction between inflammation, immune modulation, and metabolic regulation.

Strategies for cardiometabolic risk assessment and monitoring in RA

In patients with RA, cardiometabolic risk assessment requires a structured and dynamic approach that accounts for traditional CV risk factors, disease activity, inflamma-tory burden, and treatment-related metabolic effects. From a clinical practice perspective, routine metabolic screening should be integrated into rheumatologic care and adapted over time.

    Currently, specific monitoring strategies from the Euro-pean League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) for glucose monitoring in patients with rheumatic diseases are limited and largely follow those applied to the general population. Standard screening tests include fasting FBG, an oral glu-cose tolerance test (OGTT), and HbA1c determination and the current consensus recommends screening for T2DM in individuals with known risk factors [49]. This may be par ticularly important in pregnant patients with inflammatory arthritis, where early screening for gestational diabetes is mandatory to reduce maternal and foetal risks [50].

     Screening for prediabetes and T2DM should be initiated at age 25. However, in adults with a BMI indicating over-weight or obesity, screening is recommended regardless of age, if at least one other risk factor is present [49].

    As previously discussed, the RA lipid profile shows a paradoxical, non-linear correlation with inflammation, especially in active disease. Therefore, its monitoring needs to be contextualized in the clinical setting.

    EULAR guidelines advocate assessing total cholesterol (TC) and HDL to stratify CV risk once the patient has reached a stable disease state. Evidence suggests that the TC/HDL ratio is a more sensitive predictor of CV disease in RA than lipid components evaluated separately [51].

    Finally, lipid profile monitoring needs to be implemented according to ongoing treatments

    The Systematic Coronary Risk Estimation 2 (SCORE2) system has been developed to estimate 10-year CV risk in the general population. However, this tool in RA carries a high risk of underestimation since it does not account for specific disease-related risk factors. EULAR recommenda-tions suggested a 1.5 multiplication factor for RA patients to improve risk prediction [51], though the risk of underes-timation remains considerable.

    A more specific risk stratification has been proposed by the working group of cardiovascular pharmacothera-pies of the European Society of Cardiology (ESC). They stratified RA patients into Low-risk (LR-RA) and High-risk (HR-RA) groups based on disease activity, disease-related negative prognostic factors, and cumulative steroid treat-ment [52]. Finally, both EULAR and ESC recommend the integrated use of carotid ultrasound to detect subclinical EULAR recommends a CV risk assessment at least once every five years, with reassessment following any signifi-cant changes in antirheumatic therapy, while the Italian CORDIS group proposed a new algorithm based on a dis-ease-specific CV risk stratification. Patients are stratified in low, medium and high-risk, accounting for disease activity, disease-related prognostic factors, ongoing antirheumatic treatments and presence of traditional CV risk factors.

    While low-risk patients follow the EULAR guidelines, CV risk in medium and high-risk patients should be assessed at the time of the visit. Carotid ultrasound is always recom-mended for medium-risk patients, while a cardiologic refer-ral is mandatory for high-risk patients [53].

    Given the lack of a defined timing for integrating inflam-mation, antirheumatic therapies, and metabolic monitor-ing in RA, we recognize that cardiometabolic management must be implemented through the coordination of a clearly defined multidisciplinary panel, as recently outlined [3].

    Therefore, we propose an algorithm derived from a syn-thesis of current recommendations and scientific literature examined in this review, reporting the highest level of evi-dence available (Table 1). We defined different clinical set-tings commonly encountered not only by rheumatologists but also by other specialists, such as cardiologists, diabe-tologists, and internists, when managing patients with RA and multiple comorbidities.

    ADA American Diabetes Association, ApoB Apolipo-protein B, BMI Body Mass Index, CORDIS Cardiovascu-lar, Obesity and Rheumatic Diseases Italian Study, EAS European Atherosclerosis Society, EMA European Medi-cal Agency, ESC European Society of Cardiology, EULAR European League Against Rheumatism, FBG Fasting Blood Glucose, FDA Food and Drug Administration, GC gluco-corticoids, GDM Gestational Diabetes Mellitus, HbA1c  IL-6i Interleukin-6 inhibitors, JAKi Janus Kinase inhibi-tors, LDL Low-Density Lipoprotein, Lp(a) Lipoprotein (a), OGTT Oral Glucose Tolerance Test, RA Rheumatoid Arthritis, SCORE2 Systematic Coronary Risk Evaluation 2, T2DM Type 2 Diabetes Mellitus, TC Total Cholesterol, TG Glycated Hemoglobin, HDL High-Density Lipoprotein, Triglycerides, CV / CVD Cardiovascular / Cardiovascular

    *Defined according to the ACR/EULAR (Studenic P et al. 2022): Boolean 2.0 remission (tender joint count≤1, swollen joint count ≤, C-reactive protein≤1 mg/dL, Patient Global Assessment≤2 cm) or Simplified Disease Activ-ity Index (SDAI)≤3.3 or Clinical Disease Activity Index (CDAI)≤2.8.

Cardiometabolic risk management in RA

Following these recommendations, CV risk management in these patients should primarily focus on optimal disease control and minimizing systemic GC use.

    Regarding pharmacological treatment, the use of anti-diabetic agents in RA follows the recommendations for the general population, although their role in inflammatory dis-eases has yet to be fully elucidated. In fact, therapies as met-formin and, more recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, have also demonstrated anti-inflamma-tory and cardioprotective properties [55].

    Lipid-lowering therapy for primary prevention in RA should be guided by a comprehensive CV risk assessment that accounts for disease activity, inflammatory burden and traditional risk factors. According to the ESC guidelines, LR-RA patients can follow the general population guide-lines, with LDL<115 mg/dL for all individuals at low to-moderate CV risk, whereas HR-RA patients should be classified into a one-level higher ESC category, implying stricter LDL targets [56].

Focus on: dietary and vitamin D supplementation

An appropriate management also includes lifestyle changes, such as a healthy diet, smoking cessation, and regular physi-cal activity. Micronutrient deficiency has been documented in inflammatory arthritis and linked to higher disease activ-ity [57]. Beyond its well-known function in calcium metab-olism, vitamin D exerts important immunomodulatory effects through the vitamin D receptors (VDRs) expressed in several immune cell populations. Results from experi-mental and translational studies indicate that vitamin D signalling may regulate inflammatory responses in many immune-mediated diseases, including RA, by modulating cytokine production, inhibiting pro-inflammatory pathways, and promoting immune tolerance. Different molecular path-ways have been identified, including their role in T-cell maturation, leading to a transition from a pro-inflammatory to an anti-inflammatory phenotype. It also showed reduced macrophage and dendritic cell activation and NF-κB inhi-bition, a key signalling pathway in RA pathogenesis [58].

Several other mechanisms have been proposed, including interactions between vitamin D signalling and oxidative stress, mitochondrial function, and epigenetic regulation of immune-related genes. However, whether these pathways are recognized in RA and contribute to its pathogenesis remains to be established [58]. Finally, more recent studies suggest that vitamin D reduces IR through both protective effects on pancreatic beta cells and actions on metabolically relevant tissues, including insulin-sensitive tissues such as skeletal muscle and adipose tissue [59]. In RA, dietary supplementation with omega-3 FA and vitamin D in combi-nation with standard therapy showed improved clinical out-comes compared to pharmacological treatment alone [60] and correlated with lower arterial stiffness in RA patients, emphasizing their on both disease activity and CV risk [61].

Focus on: glucagon-like peptide-1 receptor agonists

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs used to treat T2DM and obesity. More recently, tirzepatide, an agonist of glucose-dependent insu-linotropic peptide (GIP) and GLP-1 receptors, has been approved for clinical use [62]. GLP-1 is an incretin hormone secreted by intestinal endocrine cells, which starts its signal-ling cascade through binding to the GLP-1 receptor (GLP- 1R). After binding to the GLP-1 receptor (GLP-1R), GLP-1 directly enhances glucose-dependent insulin secretion from pancreatic β-cells, thereby modulating glucose metabolism. In addition, GLP-1 promotes satiety and delays gastric emp-tying, leading to significant body weight reduction [63].

    Beyond its metabolic effects, available data suggest that GLP-1 plays a role in regulating systemic inflammation  and immune regulation. GLP-1R is expressed in several immune cell types, including macrophages, T and B lym phocytes. GLP-1RA has been shown to reduce the produc-tion of pro-inflammatory cytokines, such as TNFα, IL-1β, and IL-6, both in vitro and in vivo models [64]. GLP-1R has also been identified in chondrocytes, and its activation resulted in suppressing inflammatory pathways involved in osteoarthritis, including the NFk-B and the production of IL-6 and TNFα. Based on this evidence, GLP-1 RAs are under evaluation as potential disease-modifying drugs in autoimmune diseases [65].

    Whether GLP-1 RAs reduce RA disease activity through immune modulation, metabolic improvement, and weight loss, or both remains to be defined. Preclinical studies dem-onstrate anti-inflammatory and cytoprotective effects of GLP-1RA on FLS stimulated with pro-inflammatory cyto-kines (Table 2) [66–68]. However, well-designed random-ized controlled trials are needed to confirm their therapeutic role in RA.

    Basic science studies demonstrate that GLP-1 receptor agonists, including lixisenatide, exenatide, and dulaglutide, reduce oxidative stress, mitochondrial dysfunction, and pro-inflammatory cytokine production in fibroblast-like synovi-ocytes (FLS) stimulated with pro-inflammatory mediators, while inhibiting key inflammatory signaling pathways (JNK, AP-1, NF-κB, p38/MAPK).

Conclusion

RA represents a model of interplay between metabolic dysfunction and inflammation, in which glucose and lipid abnormalities must be interpreted in the context of underly-ing disease mechanisms.

    Clinicians have to be aware that chronic systemic inflam-mation profoundly reshapes cardiometabolic risk, frequently masking high-risk profiles. Alterations in glucose and lipid metabolism should be considered part of RA-associated metabolic disease rather than incidental comorbidities.

    This has clear implications for cardiometabolic screening strategies, which in these subjects should incorporate dis-ease activity, inflammatory burden, and treatment exposure.

    From a metabolic perspective, RA also challenges the validity of traditional CV risk calculators, which may sub-stantially underestimate risk in the presence of active inflam-mation and qualitative lipoprotein dysfunction. Moreover, anti-inflammatory therapies commonly used in RA exert heterogeneous effects on glucose and lipid metabolism. Therefore, their values should be interpreted in the context of disease activity, inflammatory burden, lipoprotein func-tion, and ongoing treatments.

    In conclusion, incorporating inflammatory status into metabolic assessment represents a critical step toward more accurate CV risk stratification and personalized prevention in RA. These considerations also support the need for a mul-tidisciplinary approach to cardiometabolic risk management in RA, involving rheumatologists, endocrinologists, cardi-ologists, internal medicine, and primary care.

Funding Open access funding provided by Università degli Studi di Roma Tor Vergata within the CRUI-CARE Agreement. None.

Declarations

Conflict of interest The authors declare that they have no conflict of

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 This article is excerpted from the 《Acta Diabetologica》 by Wound World.