Cardiovascular risk in systemic lupus erythematosus: beyond Framingham to emerging risk prediction tools and therapeutic approaches

Introduction

Understanding CVD and its associated risk factors is essential in the management of systemic lupus erythematosus (SLE), as individuals with SLE experience a higher incidence of both clinical and subclinical atherosclerosis, along with an increased risk of myocardial infarction (MI) and stroke, particularly at a younger age. Traditional risk factors for atherosclerosis—such as smoking, diabetes, dyslipidemia, and hypertension—are commonly incorporated into prediction tools like the FRS. However, SLE-specific factors, including disease activity measured by the systemic lupus erythematosus disease activity index (SLEDAI), inflammatory markers, and autoantibodies, also contribute to cardiovascular risk and are not captured by traditional risk scores. Collectively, current evidence supports a paradigm shift toward integrated cardiovascular risk assessment in SLE, in which traditional risk factors are complemented by disease-specific and immune-mediated determinants, as reliance on conventional risk models alone substantially underestimates cardiovascular risk and limits accurate identification of high-risk patients in clinical practice. Chronic inflammation remains a central driver in creating an atherogenic substrate, and further research is required to clarify these mechanisms and inform future therapeutic strategies.

In this review, we examine the incidence of cardiovascular disease, briefly review pathogenic mechanisms, explore selected existing and emerging cardiovascular risk prediction tools, and summarize the evidence supporting the use of hydroxychloroquine, statins, and ASA, as well as newer therapies such as SGLT2i and GLP-1 receptor agonists, in reducing adverse cardiovascular outcomes. The aim of this review is to synthesize and contextualize foundational and emerging evidence related to cardiovascular risk factors in SLE, and it is not intended to represent a systematic appraisal of the literature.

Methods

This narrative review integrates evidence from landmark and high-impact publications, including epidemiological, translational, mechanistic, and clinical studies, identified through targeted searches of PubMed and Embase from 1976 through the most recent updates in 2025. Search terms included combinations of “cardiovascular disease,” “systemic lupus erythematosus,” “atherosclerosis,” “subclinical atherosclerosis,” “risk stratification,” “risk prediction,” and “risk score,” as well as specific tools such as the Framingham Risk Score and alternative risk models [e.g., the atherosclerotic cardiovascular disease (ASCVD) risk estimator and QRISK]. Terms related to cardiovascular risk management and prevention (e.g., “primary prevention” and “treatment”), early vascular disease (e.g., “endothelial dysfunction,” “carotid intima-media thickness,” and “coronary artery calcium”), and SLE-related immune and inflammatory mechanisms of vascular injury were also incorporated, with attention to studies evaluating the performance and limitations of traditional cardiovascular risk models in SLE populations. In addition, reference lists from key reviews and seminal studies were manually reviewed to identify additional relevant publications. Priority was given to randomized controlled trials where available, large observational cohort studies, and major international guideline statements.

Prevalence of cardiovascular disease in SLE

The seminal work by Urowitz et al. in 1976 (1) first described a bimodal pattern in mortality in patients with SLE. This study included 81 patients (12 men and 69 women) with a mean age at disease onset of 32 years and an average disease duration of approximately 6 years. The authors identified two distinct mortality peaks: early deaths, which occurred in 6 patients and were primarily attributed to active SLE or infectious complications, and late deaths, reported in 5 patients approximately 8.6 years after diagnosis, which were predominantly due to cardiovascular causes. These late deaths were associated with MI resulting from atherosclerosis, confirmed by post-mortem examination revealing atheromatous occlusion of the coronary arteries, rather than ongoing disease-related activity. This study thus highlighted the critical importance of accelerated atherosclerosis in patients with SLE.

Subsequent work by Manzi et al. (2) examined a cohort of 498 women with SLE, compared to 2,208 age-matched women from the Framingham Offspring Study. Women were stratified into different age groups, and incidence rates of first cardiovascular events (MI, angina, or both) were calculated for each group. The study identified a total of 33 cardiovascular events among women with SLE, with approximately two-thirds occurring in those under 55 years of age. Notably, women aged 35–44 years with SLE had a rate ratio of 52.4 for MI compared to Framingham controls, representing more than a 50-fold higher risk. This elevated risk and the overall burden of premature cardiovascular disease were particularly pronounced in younger, premenopausal women with lupus compared to the control population. This landmark study revealed that cardiovascular risk in SLE, particularly among young women, exceeds predictions based on Framingham risk factors, highlighting the need for alternative strategies for identifying and managing these patients.

In a prospective cohort study by Hak et al. (3), 119,332 Caucasian female participants were followed over a span of 28 years. During this period, 148 women developed SLE (confirmed by medical records), and 20 of those patients experienced a cardiovascular event (fatal or non-fatal MI, stroke, coronary artery bypass grafting, or angioplasty). The relative risk of a cardiovascular event among women with SLE was 2.26 (95% CI 1.45–3.52) after adjustment for age, race, traditional cardiovascular risk factors [hypertension, diabetes, hyperlipidemia, body mass index (BMI), smoking, physical activity], and medication use (corticosteroids, but no information on dose or duration of treatment). The mean age at diagnosis in this cohort was approximately 52.6 years, comparable to findings from the Framingham Offspring Heart Study cited above, where women aged 45–54 years had a relative risk of MI of approximately 2.47 (2). This study underscored the importance of disease-related factors—such as inflammation, endothelial dysfunction, prothrombotic states, and medication exposure—in addition to traditional risk factors, as the elevated risk of cardiovascular events persisted even after adjustment for conventional determinants.

Building on these results, Urowitz et al. (4) evaluated 250 patients with SLE and compared them to 250 age-matched controls. The SLE group included a lower proportion of White patients. Among women with SLE, the prevalence of hypertension was higher (33% vs. 13%, P < 0.01), as was the prevalence of diabetes mellitus (5% vs. 1%, P < 0.01). Calculation of the 10-year risk for a cardiac event using the Framingham risk factors—which includes hypertension, hypercholesterolemia, low high-density lipoprotein (HDL), smoking status, diabetes, and family history of premature CVD—revealed no significant difference between the SLE and control groups. Given that the prevalence of coronary heart disease [sometimes used interchangeably with coronary artery disease (CAD) in epidemiologic studies, though coronary heart disease (CHD) looks at clinical outcomes] can be up to 3- to 8-fold higher in patients with SLE as compared with the general population (4–6), the Framingham equation clearly underestimates risk, particularly as a primary prevention tool. This finding was corroborated by Esdaile et al. (7), who similarly demonstrated that the substantial increase in coronary heart disease (10.1-fold higher risk of non-fatal MI, 7.5-fold higher risk for overall CHD) and stroke risk among patients with SLE was not predicted by the Framingham score. Since then, many newer studies have shown similar findings. In a large population-based registry (1,285 patients), 13.9% experienced a cardiovascular event, defined as either MI or stroke, and this was more pronounced in younger, male, Hispanic/Latino, or non-Hispanic Black patients (8). In the systematic review and meta-analysis by Li et al. the pooled risk ratio of CAD was 3.39 (95% CI: 2.15–5.35) in patients with SLE and this risk was the same in male and females with SLE. Similarly, Yazdani et al. found a pooled relative risk of 2.99 (95% CI 2.34–3.82) for MI in patients with SLE (9) Lastly, in a large cohort of patients from Korea (8,568 SLE patients and 34,272 controls), there was a 2.4-fold higher adjusted risk of major adverse cardiovascular events (MACE) as compared to the general population and that risk was approximately 12-fold in the younger population, with no sex differences observed (6). Similar observations were reported in the systematic review and meta-analysis by Bello et al. (10).

Therefore, given the persistently higher prevalence of cardiovascular events and the significant burden of early-onset cardiovascular disease, particularly among younger patients with SLE (with sex differences that may be race-dependent), it is imperative to improve understanding of the underlying mechanisms and to develop strategies that address both traditional and SLE-related risk factors to reduce the risk of cardiovascular disease.

Accelerated atherosclerosis in SLE

The increased incidence of cardiovascular events in patients with SLE has brought attention to the phenomenon of accelerated atherosclerosis, which develops earlier and progresses more rapidly than in the general population. As alluded to earlier, this excess risk cannot be fully explained by traditional cardiovascular risk factors, suggesting that SLE-specific mechanisms also play a critical role.

Atherosclerosis is often detected through imaging, such as B-mode ultrasound for assessing carotid intima-media thickness (CIMT), non-contrast computed tomography (CT) for calculating coronary artery calcium score, or flow-mediated dilation (FMD), where a reduced FMD indicates impaired endothelial-dependent vasodilation which serves as an indicator of endothelial dysfunction. Roman et al. (11) looked at extracranial plaque using carotid ultrasonography, which revealed a substantially higher prevalence of plaque among SLE patients compared to matched controls (37.1% vs. 15.2%, P < 0.001). Using multivariate analysis and adjusting for traditional cardiovascular risk factors—including hypertension, diabetes status, smoking status, fasting cholesterol level—as well as age and sex, SLE itself remained a strong independent predictor of plaque, with an odds ratio of 4.8 (95% CI: 2.6–8.7).

Within the SLE cohort, predictors of plaque included longer disease duration, higher damage index scores, and the absence of cyclophosphamide use or anti-Smith antibodies. These findings suggest that the burden of atherosclerosis in SLE is driven primarily by chronic inflammation and cumulative disease activity rather than traditional cardiovascular risk factors. Consistent with this, Yu et al. (12) showed that premature coronary artery disease in SLE as evidenced by coronary artery calcification detected by electron-beam CT is significantly more prevalent in patients with SLE compared with the general population (12). In this study, HDL and LDL (low-density lipoprotein) levels did not differ between SLE patients and controls, although higher triglyceride and homocysteine levels were observed in the SLE cohort. A systematic review and meta-analysis of 80 studies (6,085 SLE patients and 4,794 controls) found that CIMT and carotid plaque measurement are effective tools for identifying patients with increased cardiovascular risk in SLE (13). Age, HDL, triglycerides, disease duration, erythrocyte sedimentation rate (ESR), and SLEDAI score were significantly associated with CIMT, while greater steroid exposure and higher triglyceride levels correlated with prevalence of carotid plaque. Although it should be noted that not all studies included in this meta-analysis controlled for blood pressure, diabetes, smoking, and dyslipidemia which are some of the core Framingham inputs. Overall, higher SLEDAI scores and elevated ESR highlighted the contribution of inflammation and disease activity to cardiovascular risk in SLE.

Pathogenesis of atherosclerosis in SLE

The pathogenesis of atherosclerosis in SLE is complex and multifactorial, involving chronic systemic inflammation, endothelial dysfunction, immune-mediated vascular injury, and SLE-associated abnormalities in lipid handling and HDL function (14). Accumulating evidence suggests that type I interferon (IFN-I) contributes to endothelial dysfunction by impairing endothelial progenitor cell function, reducing their circulating levels, and promoting endothelial cell apoptosis, thereby shifting the balance from vascular repair toward vascular injury (14, 15). Additionally, IFN signaling has been implicated in the regulation of macrophage lipid handling through effects on scavenger receptor expression. In experimental systems, IFN-I enhances oxidized LDL uptake and foam cell formation by upregulating Scavenger Receptor class A (SR-A) on monocytes and macrophages (16). Consistent with these findings, increased SR-A expression has been reported in peripheral blood mononuclear cells from patients with SLE (17) and has been shown to correlate with a heightened IFN signature. Together, these observations support a mechanistic association between IFN-driven immune activation and pro-atherogenic macrophage phenotypes, although direct evidence linking this pathway to clinical cardiovascular outcomes in SLE remains limited (17–19).

Additional immune mechanisms implicated in SLE include neutrophil activation with the release of neutrophil extracellular traps (NETs), which are large extracellular structures composed of chromatin, histones, and granular and cytoplasmic proteins (20). NETs promote immune activation and type I interferon production in SLE and have been implicated in endothelial injury and atherosclerosis through direct cytotoxic effects (21), propagation of vascular inflammation, and amplification of innate and adaptive immune responses (22, 23). Although NETs may contribute to a pro-atherogenic immune milieu via effects on dendritic cells and lymphocytes, the precise mechanisms linking NET formation to accelerated atherosclerosis in SLE remain incompletely understood. Nonetheless, reciprocal amplification between NET formation and IFN-I signaling (24) provides a biologically plausible pathway through which chronic immune activation may drive sustained vascular injury in SLE.

Consistent with these mechanistic observations, clinical evidence showed that in a cohort of SLE patients, serum IFN-I activity was independently associated with increased CIMT, reduced vascular repair capacity, and greater severity of coronary calcification, even after adjusting for conventional cardiovascular risk factors, underscoring its role in premature vascular injury (25). Given its ability to modulate cardiometabolic risk factors (26), it remains of interest whether anifrolumab (a type I IFN receptor blocker) could influence cardiovascular outcomes. However, to date, no clinical trial has been powered or designed to demonstrate a reduction in adverse cardiovascular events with this therapy. Beyond IFN-I-mediated pathways, additional factors have also been implicated in vascular homeostasis in SLE. Fibroblast growth factor 21 (FGF21), a vasculoprotective mediator thought to be upregulated as a compensatory response to inflammatory stress, reduces endothelial cell apoptosis and may represent an adaptive mechanism aimed at mitigating inflammation-induced vascular injury. Elevated FGF21 levels have been associated with subclinical atherosclerosis, as measured by CIMT (27). This paradox likely suggests that despite its elevation, FGF21 remains insufficient to counteract the highly pro-atherogenic environment in SLE. Similarly, epidermal growth factor receptor (EGFR) signaling has been identified as pro-atherogenic, with increased activity driving vascular smooth muscle cell proliferation, activation, and oxidative stress. In experimental models, EGFR expression is upregulated within atherosclerotic plaques, where it promotes macrophage infiltration, pro-inflammatory cytokine production, and smooth muscle activation, collectively contributing to early atherosclerosis (28). Finally, other cytokines, such as interleukin-6 (IL-6), have also been implicated in SLE-associated atherogenesis. While IL-6 may serve as a marker of inflammatory vascular risk, findings in this area have been inconsistent (14).

In parallel with cytokine and interferon mediated pathways, autoantibodies are also linked to the development of atherosclerosis in SLE through multiple mechanisms. Notable examples include anti-oxidized LDL, anti-apolipoprotein A-1, and anti-beta2 glycoprotein 1 antibodies. Anti-beta2 glycoprotein 1 antibodies, a subset of anti-phospholipid antibodies, facilitate the uptake of beta2 glycoprotein 1–oxidized LDL complexes by macrophages, thereby accelerating foam cell and plaque formation and promoting an atherogenic environment (29). Additional mechanisms include activation of vascular smooth muscle cells and the induction of a prothrombotic state, both of which further contribute to atherosclerosis.

Patients with SLE also exhibit characteristic lipid abnormalities, including increased total cholesterol, LDL, and triglycerides, along with reduced HDL and apolipoprotein A1 (30, 31). Chronic inflammation is a central driver of these changes, disrupting lipid metabolism and impairing HDL function. Inflammatory pathways promote the formation of dysfunctional HDL with diminished atheroprotective capacity and enhanced pro-inflammatory properties, while simultaneously increasing LDL susceptibility to oxidative modification. Oxidized LDL facilitates macrophage uptake and foam cell formation, thereby accelerating atherogenesis.

Collectively, the interaction between chronic inflammation (including inflammatory cytokines and autoantibodies), dyslipidemia, endothelial dysfunction, and vascular injury creates a pro-atherogenic environment in SLE, contributing to the accelerated development of atherosclerosis observed in this population.

More recently, emerging hypotheses have further implicated the gut microbiota as a potential modulator of cardiovascular risk in SLE. Gut microbiota dysbiosis—defined as an imbalance between beneficial and pathogenic bacterial communities—has been shown in broader atherosclerosis research to influence systemic inflammation, lipid metabolism, and the production of microbial metabolites such as trimethylamine N-oxide (TMAO), which affect endothelial function and immune activation (32, 33). Although recent reviews in SLE have described gut microbial alterations and proposed immunometabolic links to cardiovascular risk, direct evidence specifically linking dysbiosis to SLE-associated atherosclerosis remains limited (34, 35) and is beyond the scope of this review.

Modified risk assessment tools

Given the importance of accurately identifying patients at increased cardiovascular risk and the well-recognized tendency of the FRS to underestimate risk in SLE, Urowitz et al. (36) proposed a modified version, the 2FRS, which doubles the weight of each component. While the individual variables (e.g., systolic blood pressure, total cholesterol) remain unchanged, their relative contributions are multiplied by two, thereby more accurately reflecting the heightened CAD risk in SLE and reclassifying a greater proportion of patients into moderate- or high-risk categories. This score has been validated in SLE cohorts, with its highest predictive accuracy observed in adult SLE patients without a prior history of CAD or diabetes. Nonetheless, its overall performance remains limited, as it does not incorporate SLE-related factors—an important limitation, since younger SLE patients with few traditional risk factors but active disease may not be adequately identified.

Several other risk scores have since been developed, including QRISK3, SLECRISK, and the adjusted Global Antiphospholipid Syndrome Score (aGAPSS) (summarized in Table 1). QRISK3 was developed in the UK to predict 10-year cardiovascular risk in the general population and incorporates additional variables such as SLE, corticosteroid use, atypical antipsychotic use, severe mental illness, migraine, chronic kidney disease (CKD) stage 3–5, and ethnicity (37). By explicitly including SLE and corticosteroid use, QRISK3 is better suited to capture autoimmune-related risk factors contributing to CVD and has been shown to classify a greater proportion of SLE patients as high risk as compared with the FRS (38).

Table 1. Selected cardiovascular risk assessment tools and performance in SLE.

AUC reflects discrimination; calibration is reported as observed-to-predicted event ratios. Performance estimates in SLE are derived from heterogeneous cohorts and should be interpreted accordingly.

2FRS, modified Framingham Risk Score; ACC/AHA, American College of Cardiology/American Heart Association; aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; ASCVD, atherosclerotic cardiovascular disease; AUC, area under the curve; BMI, body mass index; CKD, chronic kidney disease; CVD, cardiovascular disease; dsDNA, double-stranded DNA; eGFR, estimated glomerular filtration rate; FRS, Framingham Risk Score; HbA1c, glycated haemoglobin; HF, heart failure; MACE, major adverse cardiovascular events; PREVENT, Predicting Risk of CVD EVENTs score; QRISK3, QRISK3 cardiovascular risk score; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; SLECRISK, SLE-specific cardiovascular risk score; UACR, urine albumin-to-creatinine ratio; aGAPSS, adjusted Global Antiphospholipid Syndrome Score.

In SLE cohorts, QRISK3 has demonstrated fair discrimination, with reported area under the curve (AUC) values ranging from 0.76 to 0.77, and reasonable calibration (39–41), with an observed-to-predicted risk ratio of approximately 0.85 (39). Accordingly, an AUC in the range of 0.7–0.8 suggests an adequate ability to rank patients by cardiovascular risk, although limitations in absolute risk estimation persist. Importantly, studies evaluating QRISK3 in SLE suggest that optimal risk thresholds may differ from those used in the general population. In a validation cohort of 143 patients with SLE from France, Azoulay et al. identified an optimal risk threshold of 9.4% for predicting clinical events, rather than the standard 10% threshold commonly used for 10-year atherosclerotic cardiovascular disease (ASCVD) risk in American College of Cardiology/American Heart Association (ACC/AHA) primary prevention guidelines (39). This modestly lower threshold improved identification of higher-risk patients who may benefit from preventive interventions. Nevertheless, QRISK3 still underestimates CVD risk, particularly when compared to imaging-based strategies (42). Furthermore, despite evaluation in multiple small SLE cohorts, its predictive accuracy has not been validated in large, dedicated SLE populations, and true external validation remains limited (39).

To address the limitations of general-population models that include SLE as a variable but do not capture disease heterogeneity, a disease-specific risk score—SLECRISK was developed in 2024 by Choi et al. (43). In addition to traditional risk factors, SLECRISK incorporates SLE-specific variables such as disease duration (since diagnosis), disease activity (remission/mild vs. moderate/severe), autoantibody profile, low C4, and creatinine. This score appears more effective at identifying high-risk patients who might otherwise be missed by traditional models. At a clinical threshold of ≥7.5% 10-year-risk, SLECRISK sensitivity was 0.74 (95% CI 0.65–0.83) compared with 0.38 (95% CI 0.28–0.48) for the ACC/AHA and Framingham-based scores (43). However, in a separate cohort of 128 patients with SLE, post-hoc analysis revealed a sensitivity of only 30.8% for detecting abnormal coronary artery calcification, despite high specificity (95%–100%), indicating that SLECRISK failed to identify a substantial proportion of patients with subclinical atherosclerosis (44), At present, SLECRISK has undergone only internal validation in a single-center cohort and requires further external validation. Importantly, it has demonstrated higher sensitivity for detecting moderate- to high-risk patients, particularly younger women with severe SLE, compared with ACC/AHA and Framingham-based scores. Identification of this subgroup is critical, as young women with SLE (ages 35–44 years) are more than 50 times more likely to experience myocardial infarction than age-matched participants in the Framingham Offspring study.

At this stage, no direct head-to-head comparison between SLECRISK and QRISK3 has been performed. Given that both scores incorporate SLE as a variable, they may be viewed as complementary; however, further studies are required before SLECRISK can be recommended for widespread clinical use.

In contrast to these broader cardiovascular risk tools, the aGAPSS score may be particularly useful in patients with antiphospholipid antibodies (aPL), who are at the highest risk of arterial and venous thrombosis, stroke, and cardiovascular disease. In a study by Barinotti et al., QRISK3 and aGAPSS were compared in SLE patients with and without secondary antiphospholipid syndrome (APS). aGAPSS outperformed QRISK3 in identifying patients at heightened risk for cerebrovascular and coronary events (45).

Most recently, the PREVENT score has been introduced as a contemporary cardiovascular risk model for the general population, although it was not specifically developed for patients with SLE (46). While PREVENT incorporates estimated glomerular filtration rate (eGFR) and predicts total cardiovascular outcomes, including heart failure, it lacks SLE-specific disease variables. To date, only one published validation study has evaluated PREVENT in an SLE cohort from France (39). In this study, PREVENT demonstrated fair discrimination for ASCVD events (AUC∼0.80), comparable to QRISK3; however, calibration was poor, with a mean observed-to-predicted risk ratio of 2.8, indicating substantial misestimation of absolute risk. In addition, application of PREVENT in SLE required a lower optimal risk threshold of 4.3%. Although PREVENT offers advantages in the general population, including incorporation of kidney function and removal of race from the model (promotes health equity and uses social deprivation index instead), the absence of SLE-specific disease markers and suboptimal calibration currently limit its utility in SLE, and further validation in dedicated SLE cohorts is required.

Overall, these clinical risk scores highlight the importance of incorporating SLE-specific factors such as disease activity, duration, and autoantibody profile to improve cardiovascular risk estimation. While modified scores such as QRISK3, SLECRISK, and aGAPSS provide promising advances, limitations in calibration, sensitivity—particularly among younger patients—and external validation remain key challenges.

Beyond modified clinical scores, emerging mechanistic evidence supports the use of biomarkers as adjunctive tools for cardiovascular risk prediction in SLE. These include inflammatory markers such as proinflammatory HDL (piHDL), soluble TNF-like weak inducer of apoptosis (sTWEAK)—which is a marker of endothelial activation—and leptin, as well as lipid and metabolic markers such as homocysteine and oxidized LDL (47). A composite biomarker panel, the PREDICT score, incorporates piHDL, leptin, sTWEAK, and homocysteine in addition to clinical risk factors such as diabetes. Patients with more than three positive biomarkers had 28-fold increased odds of longitudinal presence of carotid plaque or progression (48). However, this score was evaluated only for subclinical atherosclerosis, without assessment of MACE, and lacks external validation. Accordingly, while biomarker-based approaches are promising, they are not yet ready for routine clinical application and are not the primary focus of this review.

Taken together, the optimal strategy for cardiovascular risk stratification in SLE may ultimately require integration of clinical risk scores with carotid US imaging, potentially complemented by selected biological or immunological markers in the future (Figure 1). This approach is particularly relevant for patients with SLE and atherosclerotic plaque who may still be classified as low- to moderate-risk by clinical scores alone. At present, QRISK3 (which explicitly incorporates SLE) and SLECRISK (which integrates SLE-specific disease factors) represent the most promising tools, whereas aGAPSS may be particularly valuable in the presence of APS features. There are other risk scores that are beyond the scope of this review.

Treatment considerations in SLE

Benefits of hydroxychloroquine

Hydroxychloroquine is a cornerstone of therapy in patients with SLE and has been associated with multiple clinical benefits. Among these, reduction in CVD risk is particularly important, especially considering the drug's favorable safety profile and wide accessibility.

In a recent (2024) French cohort study of 52,883 patients with SLE (mean age: 44 years; 86.6% women), including 1,981 patients with eligible cardiovascular (CV) events (experienced a qualifying CV event and were included as cases in the study) and 16,892 matched controls, hydroxychloroquine use was associated with a lower risk of MI, stroke/ transient ischemic attack (TIA), and other thromboembolic events. The composite CV outcome demonstrated an odds ratio of 0.63 (95% CI, 0.57–0.69), corresponding to an approximate 37% risk reduction (53). Of note, remote hydroxychloroquine use (discontinuation of treatment 91–365 days before the CV event) was not associated with a reduction in CV events, underscoring the importance of continuous therapy to achieve sustained cardiovascular benefit. In this context, multiple cohort and case-control studies have likewise demonstrated benefit (54–57), though one cohort study showed no vascular protective benefit (58). To date, no clinical trials have directly evaluated the effectiveness of hydroxychloroquine in reducing CV events. However, existing evidence supports its beneficial effects. Therefore, conducting a placebo-controlled trial would raise ethical concerns, given the numerous well-established benefits of hydroxychloroquine in patients with SLE and especially in those patients with severe disease.

The proposed mechanism of beneficial effects of hydroxychloroquine in this setting involves controlling SLE disease activity and reducing inflammation through interference with Toll-like receptor signaling, leading to decreased production of type I interferons (59). Additional effects include reduced proinflammatory cytokine production [interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-α)] and decreased autoantibody generation through inhibition of B cell activation (60, 61). Chronic hydroxychloroquine use has also been shown to improve endothelial dysfunction by increasing nitric oxide (NO) bioavailability in a mouse model of SLE (62, 63). Additionally, in vitro studies show that hydroxychloroquine and its parent compound, chloroquine, stimulate NO synthase (NOS) activity in murine, porcine, and human endothelial cells (64) and prevent endothelial NOS uncoupling (65). By preserving endothelial NOS coupling, hydroxychloroquine promotes NO production over superoxide generation, thereby increasing NO bioavailability. These effects directly improve endothelial function and provide a mechanistic basis by which hydroxychloroquine may reduce atherosclerosis and CVD risk.

Notably, the beneficial effect of hydroxychloroquine in preventing a first cardiovascular event was found to be more pronounced when hydroxychloroquine was used for more than 5 years (HR: 0.26; 95% CI: 0.08–0.82; p = 0.021) (66). Similar findings were reported in a recent study by Glasin et al., in which treatment of SLE patients with hydroxychloroquine was associated with reduced progression of atherosclerotic plaque, as assessed by CIMT using high-frequency ultrasound at 3-year follow-up (67). Additionally, in the study by Roman et al. (11), patients with SLE and carotid plaque had lower rates of hydroxychloroquine use, suggesting a potential protective association between hydroxychloroquine and plaque formation. In their logistic regression analysis of independent predictors of atherosclerosis, the odds ratio for hydroxychloroquine use was 0.49; however, this did not reach statistical significance (P = 0.09).

Of note, hydroxychloroquine can influence traditional CVD risk factors by modifying lipid metabolism. A systematic review and meta-analysis demonstrated that treatment with hydroxychloroquine was associated with reductions in total cholesterol [weighted mean difference (WMD): −0.18 mmol/L], LDL (WMD: −0.21 mmol/L), and triglycerides, as well as an increase in HDL (WMD: +0.03 mmol/L) (68). Although these changes are modest, they remain statistically significant. Similar findings have been reported in multiple studies of patients with SLE (69–71).

In another systematic review and meta-analysis of SLE cohorts, hydroxychloroquine use was associated with a mean reduction in LDL of 24.4 mg/dL (0.63 mmol/L) (72). While this reduction is moderate and less pronounced than that typically achieved with statins (1–2 mmol/L), the improvement in lipid profile nonetheless represents an added benefit for patients with SLE. Potential mechanisms include enhanced cholesterol transport to HDL (73), along with modulation of adipokines and inflammatory cytokines (74).

Other important effects of hydroxychloroquine involve improvement in thrombotic risk by reducing platelet activation and aggregation. A systematic review and meta-analysis which looked at 13 clinical trials found that hydroxychloroquine decreased the risk of thromboembolic events by 49% (RR 0.51, 95% CI 0.31–0.84) (75). This antithrombotic risk is especially important in patients with antiphospholipid syndrome where it further lowers the risk of thrombosis (76).

Given the numerous benefits of hydroxychloroquine—particularly its ability to modify both SLE-related risk factors and traditional risk factors such as dyslipidemia and potentially insulin resistance (77)—continued use with the appropriate monitoring is strongly recommended in patients with SLE.

Role of corticosteroids

When evaluating the role of glucocorticoids in CVD among patients with SLE, two main aspects must be considered. The first relates to their essential role in suppressing inflammation during acute flares or periods of increased disease activity. The second, which contributes to atherogenesis, involves long-term exposure, particularly at higher doses. Given this potential dual effect, several studies have attempted to evaluate whether corticosteroid exposure contributes to cardiovascular risk in patients with SLE.

However, the overall quality of evidence linking corticosteroid exposure to cardiovascular disease in SLE remains limited. A recent umbrella review including nine systematic reviews identified glucocorticoid use, higher disease activity, organ damage, presence of antiphospholipid antibodies (aPL), and lupus nephritis as potential risk factors for CVD in SLE; however, the overall quality of evidence across these studies was judged to be critically low due to methodological limitations (78). In light of these limitations, the evidence specifically relating to corticosteroid exposure remains uncertain, as conflicting findings across studies may, in part, reflect underlying biases and study design constraints rather than true differences in effect. Accordingly, much of the current understanding of corticosteroid-associated cardiovascular risk in SLE is derived primarily from observational studies, which are inherently susceptible to confounding and have yielded heterogeneous results.

Several studies have evaluated steroid exposure as a potential risk factor for atherosclerosis, with variable findings. Roman et al. (11) reported that patients with plaque had a lower average 5-year daily prednisone dose compared with controls (6.9 ± 6.8 vs. 11.9 ± 6.9 mg/day, P = 0.002), although the duration of use was longer but not statistically significant (91 ± 94 vs. 67 ± 75 months, P = 0.24). Patients with plaque also had longer disease duration, greater damage index scores, and less frequent use of immunosuppressives such as cyclophosphamide and azathioprine, which may be suggestive of inadequate disease control in this group. Other cohorts, including those of Yu et al. (12) and Ammirati et al. (79), found no association between corticosteroid therapy and subclinical atherosclerosis. In contrast, Manzi et al. (2) observed longer cumulative steroid exposure in SLE patients with CV events (11 vs. 7 years, P = 0.002). However, disease severity was not assessed with validated activity scores such as Safety of Estrogens in Lupus Erythematous National Assessment-SLEDAI (SELENA-SLEDAI), limiting interpretation, though disease duration and major organ involvement (renal disease) were considered. A key challenge in interpreting these findings is that glucocorticoid exposure is closely linked to disease activity, making it difficult to disentangle cardiovascular risk attributable to corticosteroids from risk driven by underlying inflammatory disease.

In addition, subsequent studies have suggested a potential dose-dependent effect of steroids on CVD risks. Magder et al. (80) demonstrated that current prednisone use >20 mg/day was associated with a five-fold increase in risk of cardiovascular events (e.g., MI, thrombotic event, percutaneous coronary event or bypass procedure), while past exposure was not associated with adverse outcomes. In their multivariable analysis, they adjusted for disease activity (including SELENA-SLEDAI score, serum creatinine, and traditional FRS factors) and overall cardiovascular events were not associated with SLE disease duration. A systematic review and meta-analysis by Wu et al., which included 80 studies (6,084 SLE patients and 4,795 controls) further supported this association, with meta-regression showing that steroid therapy had a significant influence on prevalence of carotid plaque and CIMT. One proposed mechanism for this finding is that chronic corticosteroid use—particularly at higher doses—exacerbates dyslipidemia, hypertension, hyperglycemia, and obesity (metabolic risk factors), thereby accelerating atherosclerosis. However, interpretation remains challenging, given the close interplay between steroid exposure and underlying disease activity.

Collectively, these findings emphasize the central role of chronic inflammation in driving atherosclerosis, while highlighting the delicate balance between achieving adequate disease control and avoiding excessive steroid exposure. Importantly, higher prednisone exposure may, in some cases, reflect more severe disease, which itself contributes to vascular risk. Discrepancies across studies may reflect variation in how steroid exposure is quantified (cumulative vs. daily use or maximum dose during follow-up), how disease activity is captured, and whether adherence is assessed. Furthermore, outcome measures differ, with some studies evaluating surrogate markers such as CIMT and others focusing on clinical outcomes such as MI or stroke. This heterogeneity in study design and outcome assessment further complicates interpretation of the existing literature. It is possible that corticosteroids, depending on dose, exert a greater effect on subclinical atherosclerosis than on hard clinical endpoints.

At present, while additional research is needed, accurate risk attribution in SLE (especially with regards to steroids) must incorporate markers of disease activity such as dsDNA, complement levels, serum albumin, and renal parameters, to enable a comprehensive assessment of disease severity. Ultimately, the therapeutic goal should be to achieve complete remission, as prolonged remission (>5 consecutive years) has been associated with less damage accrual and lower rates of cardiovascular events (81). Following remission, minimizing corticosteroid exposure—using the lowest effective dose in combination with steroid-sparing agents and hydroxychloroquine—remains essential.

An intriguing unresolved question in this area is, whether more aggressive short-term glucocorticoid dosing to effectively suppress inflammation may confer greater long-term vascular and endothelial benefit despite higher cumulative exposure. Additionally, future observational studies of glucocorticoid-associated cardiovascular risk should employ analytic approaches that appropriately address time-dependent confounding affected by prior treatment (where disease activity both influences glucocorticoid prescribing and is itself modified by earlier therapy), rather than relying solely on conventional survival models with time-updated covariates. In SLE, disease activity functions as a time-varying confounder and mediator, such that standard Cox models with time-dependent covariate adjustment may yield biased estimates and fail to reliably distinguish cardiovascular risk attributable to glucocorticoid exposure from risk driven by underlying disease severity.

Role of statins

Among pharmacologic agents that improve cardiovascular outcomes, statins are widely used in the general population to slow the progression of atherosclerosis. Owing to their anti-inflammatory and lipid-lowering properties, they have been expected to confer similar benefits in SLE. However, the available evidence has been mixed, drawing from both randomized controlled trials (RCT) and observational studies. In an RCT of 200 SLE patients, atorvastatin 40 mg daily was compared with placebo and 43% of participants had coronary artery calcification at baseline (82). After two years, no significant differences were observed in CIMT, plaque burden, or coronary calcium score, and disease activity (SLEDAI) remained comparable between groups. The lack of an effect on subclinical atherosclerosis may, in part, reflect the relatively short duration of follow-up. Overall, the limited number of trials in this area and the lack of benefit observed in statin trials in SLE may be explained by several methodological and population-related factors, including short follow-up duration, reliance on surrogate measures of subclinical atherosclerosis, enrollment of relatively low-risk populations, and confounding from disease activity and concurrent immunosuppressive therapies.

In terms of anti-inflammatory activity, systematic reviews and meta-analyses did not show a change in SLEDAI score, although reductions in high-sensitivity C-reactive protein (CRP) have been observed (83, 84). In terms of improvement in cardiovascular outcomes the results have been inconsistent (66, 82). In an observational cohort study by Yu et al. (85) which included 4,095 patients with SLE, and hyperlipidemia high dose statin use was associated with a reduced risk of mortality, cardiovascular disease, and end-stage renal disease (ESRD).

Given these limitations, further research is required to clarify the role of statins in SLE, ideally through adequately powered studies with longer follow-up and improved cardiovascular risk stratification to better identify high-risk SLE subgroups who may derive the greatest benefit from lipid-lowering therapy. At present, based on current expert opinion and European Alliance of Associations for Rheumatology (EULAR) guidelines (86), lipid-lowering therapy in SLE should still follow general population cardiovascular prevention guidelines, guided by traditional risk factors and overall CVD risk. At this stage there is insufficient evidence to recommend statins solely for primary prevention on the basis of SLE alone, and further studies are needed in this area. However, there should be heightened awareness about the overall higher risk of CVD in patients with SLE and its use should be considered, especially when conventional indications are present (e.g., in patients with hyperlipidemia or elevated ASCVD risk).

Role of acetylsalicylic acid

When considering ASA to reduce cardiovascular events, two strategies are considered: primary prevention of atherosclerotic CVD and secondary prevention after an established event such as MI/TIA/ischemic stroke or after coronary revascularization.

Given the high prevalence of cardiovascular events in patients with SLE, it is important to determine whether low-dose ASA can modify this risk. To date, no RCTs have specifically evaluated the role of ASA for primary prevention of cardiovascular events in SLE, and available evidence is limited to small observational studies. In a retrospective cohort study by Iudici et al. (87), 167 patients with SLE without a prior history of ischemic coronary events were followed for a median of 8 years (range 1–14). Among them, 146 regularly used low-dose ASA, while 21 did not. During follow-up, nine cardiovascular events occurred: five in the ASA group (one stroke, three TIAs, and one MI) and four in the non-ASA group (one TIA and three MIs). The study population was predominantly female (approximately 92%) with a mean age of 35.3 years.

On closer analysis, cardiovascular events were more common (in these 9 patients with SLE) in women aged 22–53 years and were more frequently associated with aPL positivity, hypertension, dyslipidemia, and an eGFR <90 mL/min. Kaplan–Meier analysis demonstrated a higher cardiovascular event–free rate among ASA users, and no major adverse effects were reported with ASA use. Overall, low-dose ASA (100 mg/day) appeared to have a protective effect, however, the small, single-center observational design limits the strength and generalizability of these findings.

In a study by Fasano et al., 291 patients with SLE (no prior cardiovascular events) from two Italian centers were evaluated. Of these, 93% were women, with a median age of 33 years; 54.2% had severe SLE, defined as the presence of glomerulonephritis, central nervous system (CNS) involvement, heart or lung parenchymal manifestations, or haemolytic/aplastic anemia. The median follow-up was 8 years. Sixteen patients experienced a thrombotic/ischemic event: 2 strokes, 5 TIA, 7 acute MI, and 2 episodes of peripheral gangrene. Similar to the Iudici study, the ASA-treated group demonstrated a higher CV event-free rate, with the effect more pronounced among patients receiving both ASA and hydroxychloroquine, particularly with a cumulative hydroxychloroquine dose >600 g (≥5 years of therapy) (66). Fasano et al. had similar findings in another study of a smaller Italian cohort (88). Conversely, Bertoli et al. reported that low-dose ASA was associated with an increased HR of ∼2.46 (95% CI 1.71–3.53) for arterial vascular events in their univariable model, though the authors cautioned that this association should not be interpreted as predictive given the limitations in the study design (89).

Importantly, the potential role of ASA in patients with aPL antibodies relates primarily to prevention of arterial and venous thrombosis rather than prevention of atherosclerotic cardiovascular disease. This represents a distinct clinical indication, as thrombosis in aPL-positive patients is largely mediated by autoimmune and prothrombotic mechanisms rather than atherosclerotic plaque rupture. Consistent with this, Tektonidou et al. demonstrated that longer duration of low-dose ASA treatment was associated with protection against both arterial and venous thrombosis in SLE patients with positive aPL (90). Furthermore, a meta-analysis of patient-level data from five international cohorts found that low-dose ASA reduced the risk of arterial thrombotic events in SLE patients with aPL (91). Taken together, these findings suggest a potential benefit in selected high-risk populations, although the overall evidence remains limited and heterogeneous, and decisions regarding initiation depend heavily on individual risk profiles (e.g., triple-positive status, high anticardiolipin titers), which is beyond the scope of this review.

In contrast, evidence supporting ASA for primary prevention of atherosclerotic cardiovascular disease in SLE is lacking. Randomized controlled trials are not available, and existing data are limited to small observational studies. Accordingly, treatment decisions should therefore be individualized, taking in to count cardiovascular risk factors, comorbidities, aPL status and bleeding risk. Nevertheless, current EULAR recommendations support the use of low-dose ASA for primary thrombosis prevention in patients with a high-risk aPL profile (asymptomatic), particularly in those with SLE, with or without traditional risk factors (92). In contrast, ASA use for secondary prevention of cardiovascular disease should follow general population guidelines. Importantly, the possibility of ASA resistance or reduced efficacy in subsets of SLE patients (e.g., those with metabolic syndrome, obesity, or active disease) should be considered, as this may necessitate alternative antiplatelet strategies (93, 94).

Thus, while ASA may have a role in selected high-risk patients—particularly those with antiphospholipid antibodies—current evidence does not support its routine use for primary prevention of atherosclerotic cardiovascular disease in patients with SLE.

Emerging therapies

Sodium glucose transport inhibitors (SGLT2i)

With regard to newer therapies in patients with SLE, SGLT2i have demonstrated cardiovascular and renoprotective benefits in patients with concomitant diabetes, although studies in this area have not specifically evaluated atherosclerosis progression. In a propensity-matched cohort study by Yen et al. including 1,775 matched pairs of SGLT2i users, SGLT2i use (with follow-up of up to 5 years) was associated with a significantly lower risk of heart failure and all-cause mortality compared with non-users (HR 0.35, 95% CI 0.26–0.47) (95). In contrast, in a separate study by Ma et al., among 2,165 patients with SLE and diabetes treated with SGLT2i over a mean follow-up of 753.1 days, SGLT2i use was associated with a lower incidence of heart failure (HR 0.72, 95% CI 0.56–0.92), but no difference in all-cause mortality was observed (96). At present, there are no studies specifically addressing atherosclerotic burden in SLE patients treated with SGLT2i. In diabetic populations, studies have shown inconsistent effects on CIMT, and similarly, the impact of SGLT2i on endothelial function and arterial stiffness have been variable (97). As a result, the current evidence is insufficient to support a definitive anti-atherosclerotic effect (97). Importantly, the available data are derived almost entirely from patients with type 2 diabetes, with no dedicated studies in SLE, precluding firm conclusions regarding endothelial or atherosclerotic benefit in autoimmune populations. Nevertheless, as a drug class, SGLT2i remain promising therapies with established cardiovascular and renal outcome benefits and ongoing research is critically needed in this area.

Glucagon like peptide - 1 receptor (GLP-1) agonist

Similar to SGLT2i, GLP-1 receptor agonists have demonstrated cardioprotective and renoprotective benefits in patients with diabetes; however, evidence in patients with SLE remains limited. In a recent pragmatic trial, patients with SLE and type 2 diabetes treated with GLP-1 receptor agonists experienced a 34% reduction in MACE (HR: 0.66, CI: 0.48–0.91) compared with dipeptidyl peptidase-4 (DPP-4) inhibitors, along with a 74% reduction in all-cause mortality (HR: 0.26, CI: 0.10–0.68) (98). Although GLP-1 receptor agonists have been extensively studied in diabetes and obesity, their effects on atherosclerosis are less well defined. Some evidence suggests that exenatide therapy improves FMD, a surrogate of endothelial function, in patients with diabetes over an 8-month prospective study (99), with similar endothelial benefits reported for liraglutide (100). Consistent with these findings, multiple animal models have demonstrated improvements in endothelial function or attenuation of endothelial dysfunction with GLP-1 receptor agonists (101). Other beneficial effects are potentially mediated through reductions in oxidative stress, foam cell formation, and platelet activation (101) In the context of the chronic inflammatory milieu characteristic of SLE, these mechanisms suggest that GLP-1 receptor agonists may have a role in slowing atherosclerotic progression, although prospective studies are needed to confirm benefits beyond metabolic effects alone.

Selected biologics

Belimumab

Belimumab is a monoclonal antibody that targets soluble BLyS (B-lymphocyte stimulator, also known as BAFF), thereby inhibiting B-cell survival and differentiation into autoantibody-producing plasma cells. Despite its widespread use in SLE, no RCTs have evaluated its effects on hard cardiovascular endpoints such as MI or stroke, nor on direct measures of atherosclerosis (e.g., CIMT).

Available evidence suggests potential cardiovascular benefit through improvements in surrogate markers. In a prospective study of 35 patients with SLE (high disease activity), add-on belimumab therapy significantly improved cholesterol efflux and antioxidant capacity of HDL after 6 months, indicating enhanced HDL atheroprotective function (102). Yamato et al. reported improved lipid profile (LDL and triglyceride) after 2 years of subcutaneous belimumab therapy, likely mediated by reduced prednisone exposure (effect shown in patients with prednisolone reduction >5 mg/day) with improved disease control (103). Similarly, Liang et al. observed a 7.6% increase in HDL levels after 6 months of belimumab, with no significant changes in total cholesterol, triglycerides, or apolipoprotein B (ApoB) (104).

In a lupus-associated atherosclerosis mouse model, BAFF neutralization reduced atherosclerotic lesion burden in a low-cholesterol milieu (21% decrease) but had adverse effects under high-cholesterol conditions, underscoring the context-dependent vascular effects of anti-BAFF therapy (105). At this stage, any potential cardiovascular benefit of belimumab appears to be mediated indirectly through improvements in HDL function, lipid profile, disease control, and reduced cumulative steroid exposure rather than through demonstrated effects on clinical cardiovascular outcomes.

Anifrolimumab

As discussed in an earlier section, anifrolimumab (monoclonal antibody) is a type I interferon receptor antagonist. Given the established role of the IFN-I pathway in atherosclerosis, it has been hypothesized that anifrolimumab could confer cardiovascular benefit in patients with SLE. However, studies directly addressing this question remain limited. In this regard, Casey et al. (26) demonstrated that in patients with SLE and moderate-to-severe disease enrolled in the phase IIb MUSE trial, treatment with anifrolimumab resulted in a significant reduction in NET formation. In addition, treatment was associated with decreased tumour necrosis factor (TNF) and interleukin-10 (IL-10) levels, which correlated with IFN-I activity.

With respect to lipid function, patients with SLE exhibited impaired HDL function as assessed by cholesterol efflux capacity (CEC). Following inhibition of the IFN-I pathway with anifrolimumab, patients with impaired baseline CEC experienced a statistically significant improvement in HDL function, with a median relative increase of approximately 17%, compared with a modest and non-significant ∼5% increase in the placebo group (P < 0.001 for between-group comparison). Although these findings are promising, a key limitation is that the study did not evaluate effects on hard cardiovascular outcomes or progression of atherosclerosis.

In the phase III extension trial evaluating the long-term safety and tolerability of anifrolimumab in SLE, exposure-adjusted incidence rates of major acute cardiovascular events were low and similar between continuous anifrolumab and placebo, with no significant differences observed (106). Importantly, this study was not designed to evaluate cardiovascular efficacy. Furthermore, to date, no studies or trials have demonstrated anifrolumab-associated reductions in carotid plaque burden, CIMT progression, coronary artery calcification, or major adverse cardiovascular events. Accordingly, further prospective studies incorporating vascular imaging and cardiovascular endpoints are needed to determine whether IFN-I blockade with anifrolimumab translates into meaningful cardiovascular benefit in SLE.

Conclusion

In conclusion, patients with SLE carry a substantially increased risk of cardiovascular events that extends beyond traditional risk factors typically considered in clinical practice. This is particularly concerning, as conventional tools consistently underestimate cardiovascular risk in this population, and even SLE-specific models remain limited by incomplete external validation (particularly for newer tools), fair discrimination in independent cohorts and uncertainty regarding calibration across diverse populations and disease phenotypes. A recurring theme in the literature is the urgent need to better define the mechanisms driving accelerated atherosclerosis in SLE, which may inform the development of targeted preventive and therapeutic strategies. At present, limited disease-specific interventions exist for the primary prevention of cardiovascular events in SLE (current available evidence is summarized in Table 2). Nonetheless, optimal control of disease activity and systemic inflammation, along with prevention of irreversible organ damage (e.g., lupus nephritis), remain essential. Accordingly, treatment strategies should emphasize early recognition, aggressive modification of both traditional and lupus-related risk factors, and integration of comprehensive cardiovascular risk assessment into routine clinical care. In parallel, there is an emerging need for immunologic and metabolic biomarkers that are reproducible, affordable, and supported by standardized assays, which can complement existing risk scores and more accurately reflect disease activity and vascular risk.

Table 2. Selected guideline recommendations and SLE therapies with potential cardiovascular implications.

Table 2 The selected pharmacologic interventions presented in this table are based on currently available guideline statements for CVD risk prevention in SLE. Their limitations are discussed in detail within this review. Importantly, patients with SLE have additional disease-specific risk factors—including chronic inflammation, immune dysregulation, autoantibody profiles, and treatment-related effects—that extend beyond traditional cardiovascular risk factors and are not adequately captured by conventional risk prediction tools; therefore, the cardiovascular risk profile in SLE is not equivalent to that of the general population. As understanding of disease mechanisms continues to evolve, strategies for CVD risk reduction in SLE are also likely to change.

ACC/AHA, American College of Cardiology/American Heart Association; aPL, antiphospholipid antibodies; APS, antiphospholipid syndrome; ASA, acetylsalicylic acid; ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; CVR: cardiovascular risk; EULAR, European Alliance ofAssociations for Rheumatology; MI, myocardial infarction; RCTs, randomized controlled trials; SLE, systemic lupus erythematosus.

Data regarding corticosteroids and acceleration or mitigation of cardiovascular risk remain inconsistent; however, current evidence supports the use of the minimal effective dose to control disease activity. Hydroxychloroquine use is supported by multiple studies demonstrating cardioprotective benefits, although no RCTs have been performed in this area. The role of statins and ASA remains uncertain, with their use largely guided by lipid profile, aPL status, and the presence of additional high-risk features such as established coronary artery disease. Finally, newer cardiometabolic therapies, including SGLT2i and GLP-1 receptor agonists, represent promising avenues but require dedicated evaluation in SLE populations. Overall, high-quality prospective and interventional studies are urgently needed to define the cardiovascular benefits of existing therapies and to develop targeted strategies for cardiovascular risk reduction in SLE.

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Footnotes

Edited by: Mónica del Rosario Meza Meza, University of Guadalajara, Mexico

Reviewed by: Antonio La Cava, University of California, Los Angeles, United States

Emanuele Bizzi, Vita-Salute San Raffaele University, Italy