Management of Atherosclerotic Cardiovascular Risk in Inflammatory Bowel Disease: Current Perspectives

Abstract

Inflammatory bowel disease (IBD) is a complex condition characterized by inflammation of the gastrointestinal system, encompassing Crohn’s disease and ulcerative colitis. Patients diagnosed with IBD have an increased risk of atherosclerotic cardiovascular disease. This heightened risk can be attributed to a combination of mechanisms, including traditional risk factors, chronic inflammation, intestinal dysbiosis, increased risk of thrombosis, and the use of certain medications such as corticosteroids. There are significant gaps in current knowledge, particularly regarding the management of risk factors and the use of medications for cardiovascular disease prevention. Similarly, the cardiovascular effects of specific IBD therapies, particularly the newer ones, are not yet fully understood. This review focuses on the epidemiological evidence linking IBD with cardiovascular risk factors and cardiovascular disease. It describes the potential pathophysiological mechanisms underlying this association and examines the challenges involved in accurately assessing cardiovascular risk in these patients, including the utility of complementary tools such as subclinical atherosclerosis detection. Additionally, we consider the potential therapeutic implications for managing these patients. Finally, this review also underscores the importance of multidisciplinary collaboration. Effective teamwork among gastroenterologists, cardiologists, and general practitioners is essential for providing comprehensive care to patients with IBD.

Key Summary Points

Patients with inflammatory bowel disease (IBD) have an increased risk of atherosclerotic cardiovascular disease.

This increased risk is primarily due to a combination of traditional risk factors, chronic inflammation, intestinal dysbiosis, and thrombosis risk.

Stratifying cardiovascular risk in patients with IBD can be challenging when using only conventional risk scores.

There are notable gaps in current knowledge, especially in managing risk factors and using medications for cardiovascular disease prevention in these patients.

Effective teamwork among gastroenterologists, cardiologists, and general practitioners is essential for providing comprehensive care to patients with IBD.

Introduction

Inflammatory bowel disease (IBD) is a chronic digestive disorder of multifactorial origin, characterized by persistent inflammation in the gastrointestinal tract [1]. It has been calculated that approximately six million patients have IBD worldwide. Crohn disease (CD) and ulcerative colitis (UC) are the predominant forms of IBD. Although these conditions share some overlapping symptoms, they are distinct entities, each resulting from a combination of genetic, environmental, and immunological factors.

Multiple cardiovascular diseases, whether related to atherosclerosis or not, have been linked to chronic inflammatory diseases (Table 1). Patients diagnosed with IBD have an increased risk of several cardiovascular diseases, including coronary heart disease and cerebrovascular disease [2]. This association is not fully explained by traditional cardiovascular risk factors, such as smoking, hypertension, type 2 diabetes (T2D), and elevated cholesterol. It is believed that the proinflammatory state and changes in gut microbiome composition may contribute to a patient’s cardiovascular risk [3]. The increased cardiovascular risk observed in patients with IBD is also seen in other clinical conditions characterized by chronic inflammatory states, such as rheumatoid arthritis, systemic lupus erythematosus, human immunodeficiency virus infection, and psoriasis [4–6].

Table 1.

Different cardiovascular diseases associated with chronic inflammatory diseases

Cardiovascular disease
Atherosclerotic cardiovascular disease	Non-atherosclerotic cardiovascular disease
Coronary artery disease	Arrhythmia
Cerebrovascular disease	Pericarditis
Peripheral arterial disease	Myocarditis
Atherosclerotic renal artery stenosis	Vasculitis
Mesenteric ischemia	Non-atherosclerotic cardiomyopathy
Heart failure	Heart failure

This review aims to describe the epidemiological link between IBD and atherosclerotic cardiovascular disease (ASCVD), as well as the potential mechanisms underlying this association. Additionally, we will address the challenges of stratifying cardiovascular risk in these patients and explore supplementary prognostic tools. Finally, we will consider the potential therapeutic implications for managing these patients. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Potential Mechanisms Underlying the Link Between IBD and ASCVD

Various mechanisms that are persistently activated in patients with IBD have been linked to the pathogenesis of ASCVD. These include local and systemic inflammation, abnormalities in the gut microbiome, endothelial dysfunction, and thrombosis [7].

The natural history of IBD is characterized by episodes of acute inflammation interspersed with periods of quiescence, during which mucosal healing occurs. It is primarily during these active phases that local and systemic inflammation is most pronounced. In IBD, alterations in both the innate and adaptive immune systems trigger an exaggerated immune response to dietary and self-antigens, leading to inflammation [8]. Several inflammatory biomarkers, including high-sensitivity C-reactive protein (hsCRP), serum amyloid A, tumor necrosis factor alpha (TNFα), interleukin (IL)-1b, IL-6, IL-8, IL-12, and calprotectin, are significantly increased in patients with IBD. In addition, microbiota dysbiosis is considered a pivotal step in causing intestinal mucosal damage and is a key factor in the development of IBD [9]. Indeed, the latter results in apoptosis of intestinal epithelial cells and disruption of the barrier, allowing translocation of lipopolysaccharides and triggering an inflammatory cascade. However, there is still debate about whether the changes in microbiota observed in IBD are causative or simply a consequence of inflammation [7].

Inflammation plays a crucial role in the development and progression of atherosclerosis and its cardiovascular complications [10]. The role of inflammation in the pathophysiology of atherosclerosis is intricate and likely not completely understood, though significant advancements have paved the way for new therapeutic possibilities [11]. The JUPITER trial was groundbreaking as it demonstrated that rosuvastatin reduced the incidence of cardiovascular events in patients with “normal” low-density lipoprotein cholesterol (LDL-C) but elevated hsCRP [12]. Given that statins reduce hsCRP levels, this finding provided support for the inflammatory hypothesis of cardiovascular disease and emphasized inflammation as a potential target for future treatments. In the CANTOS trial, canakinumab—a monoclonal antibody that targets the inflammatory cytokine IL-1β—was found to prevent recurrent cardiovascular events in patients with a history of cardiovascular disease and elevated hsCRP levels [13]. Indeed, it was the first trial to demonstrate that a medication specifically targeting inflammation could improve cardiovascular outcomes.

Another example is how the inflammatory pathway may help explain the cardiovascular benefits observed in large clinical trials involving semaglutide [14]. Nevertheless, findings from studies on other anti-inflammatory drugs, such as colchicine, remain inconsistent [15–17], and we must await the results of ongoing trials for greater clarity. Additionally, other studies currently underway that are investigating drugs targeting IL-6 are contributing valuable information [18].

Another interesting aspect is the role of the melanocortin system in IBD. The melanocortin system is a complex network of molecular mediators and receptors involved in various physiological and homeostatic processes. It has been observed that melanocortins play a key role in modulating inflammatory processes [19]. In fact, the closely related G-protein-coupled receptors MC3-R and MC5-R correlate with disease activity. Additionally, the melanocortin system contributes to the regulation of both energy balance and blood pressure, and also has an impact on hunger and obesity.

On the other hand, patients with IBD have increased risk of developing systemic thrombosis compared to the general population [20, 21]. This heightened risk may be attributed to abnormalities in coagulation, fibrinolysis, and platelet function, which are partly driven by the action of proinflammatory cytokines. This data is highly relevant, as thrombosis is a consequence of plaque rupture or erosion rather than a key factor in the progression of atherogenesis. Its role is critical in precipitating acute ischemic events [22, 23].

Figure 1 provides a graphical representation of the key mechanisms contributing to the increased cardiovascular risk in patients with IBD.

Fig. 1.

Mechanisms underlying the increased cardiovascular risk observed in patients with inflammatory bowel disease. ASCVD atherosclerotic cardiovascular disease

Conventional Risk Factors in Patients with IBD

The prevalence of traditional cardiovascular risk factors in patients with IBD varies compared to control groups: some studies report lower frequencies, others show similar frequencies, and some indicate a higher prevalence of certain risk factors. Despite these conflicting findings, several key traditional risk factors have been reported with a high prevalence in the IBD population.

Data on the prevalence of dyslipidemia in IBD are somewhat contradictory; however, it is generally accepted that individuals with IBD tend to have lower levels of LDL-C and total cholesterol compared to healthy controls [24–26]. A meta-analysis revealed that, compared to healthy controls, patients with IBD had significantly lower levels of total cholesterol (weighted mean difference [WMD] − 0.51; 95% confidence interval [CI], − 0.67 to − 0.34) and LDL-C (WMD − 0.37; 95% CI − 0.55 to − 0.19) [27]. However, these observations should be interpreted with caution, as they may be reflective of the “lipid paradox” seen in other inflammatory conditions, such as rheumatoid arthritis. This concept posits that patients with lower cholesterol levels, resulting from the inflammatory impact on their metabolism, paradoxically show a higher cardiovascular risk. Furthermore, treatment with anti-inflammatory therapies may lead to an increase in cholesterol levels, despite reducing the risk of cardiac events [28]. However, the inflammatory process can affect both the particle concentration (e.g., small, dense LDL) and the functional integrity of certain lipoproteins, such as high density lipoprotein (HDL) [29]. Another interesting lipid marker is lipoprotein (a) [Lp(a)], which has been linked to an increased cardiovascular risk. High levels of Lp(a) are an independent risk factor for ASCVD through mechanisms linked to increased atherogenesis, inflammation, and thrombosis [30]. Elevated Lp(a) levels have also been associated with various inflammatory conditions [31]. There is a bidirectional relationship between Lp(a) and inflammation, which may be particularly relevant in patients with IBD. Lp(a) may enhance or perpetuate inflammation through bound oxidized phospholipids, while inflammatory conditions, likely mediated by cytokines, may promote its synthesis, although the underlying mechanisms are not yet fully understood. Interestingly, this pathway appears to be independent of LDL, as inflammation may promote the expression of the LPA gene [31]. However, there is limited information regarding its role in patients with IBD, although some preliminary reports suggest that individuals with CD may exhibit elevated levels of this marker [32]. Additionally, a Chinese study found that patients with active CD had higher Lp(a) levels compared to those with inactive disease [33]. Consequently, it would be more appropriate to conduct a qualitative rather than a purely quantitative analysis when evaluating the lipid profile in patients with IBD.

To date, no specific treatments are available to lower Lp(a) levels. Promising new therapies for Lp(a) include antisense oligonucleotides and small interfering RNA that specifically target the mRNA encoding apolipoprotein (a) [34]. However, their potential role in treating patients across various clinical settings, including those with IBD, remains unclear, and additional clinical studies are necessary.

Hypertension is a key modifiable risk factor for cardiovascular disease. It is commonly seen in patients with immune-mediated conditions like rheumatoid arthritis and psoriasis [35, 36]. However, there is limited data on the prevalence of hypertension in individuals with IBD. Two cross-sectional studies found that patients with IBD had a higher prevalence of hypertension. The first study, which included adults aged 18 years and older without established ASCVD (786 patients with IBD), showed that IBD was associated with an increased likelihood of hypertension (odds ratio [OR] 1.71; 95% CI 1.39–2.09) [25]. The second study, involving 235 patients with IBD over the age of 45 years matched with 829 controls, also found higher odds of hypertension (OR 1.67; 95% CI 1.19–2.32) [26]. Additionally, in a large cohort study of the general population (with a median follow-up of 8 years), He et al. found that, compared to patients without IBD, those with UC had a higher risk of developing hypertension (hazard ratio [HR] 1.3; 95% CI 1.11–1.52) during follow-up, while patients with CD did not [37]. Mechanisms specific to IBD, such as chronic inflammation or the use of disease-specific medications, may help explain these findings (Table 1).

One of the cross-sectional studies previously discussed also identified an association between IBD and the presence of T2D (OR 1.68; 95% CI 1.22–2.32) [25]. Similarly, Dregan et al. conducted a study using data from patients with UC in the UK, which revealed a 50% increased risk of T2D among individuals with IBD [38]. Additionally, Jess et al. conducted a cohort study in Denmark that demonstrated an increased risk of developing T2D in individuals with IBD compared to those without it (standardized incidence ratio [SIR] 1.54; 95% CI 1.49–1.60) [39]. These findings were consistent with a cohort study from South Korea, which also reported an association between IBD and T2D (HR 1.14; 95% CI 1.05–1.23) [40]. A recent two-sample Mendelian randomization study indicated that IBD may increase the risk of T2D in the European population (OR 1.02; 95% CI 1.01–1.04) [41]. Although not fully resolved, mechanisms involving shared genetic pathways, chronic inflammation, dysbiosis, and the use of glucocorticoids have been proposed to explain the relationship between T2D and IBD [42]. Finally, both metabolic syndrome and T2D have adverse effects on the overall quality of life and place an increased financial burden on the IBD population [43]. Moreover, T2D might negatively affect the course of IBD by increasing the risk of hospitalization and infections [44].

We lack robust data demonstrating significant differences in smoking prevalence between patients with and without IBD. Tobacco use is associated with detrimental effects in CD, including an increased risk of disease onset, progression, and poor response to both medical and surgical treatments [45]. Conversely, it appears to have protective effects in UC [46]. It has been suggested that nicotine may inhibit the production of certain cytokines, and smoking could also impact endothelial function through the modulation of nitric oxide production. Additionally, it may alter gut barrier integrity. However, smoking remains one of the primary risk factors for cardiovascular events, making smoking cessation an essential priority [47].

Finally, some studies have reported reduced physical activity [25, 48] and higher levels of intra-abdominal obesity [26] in patients with IBD. Despite the potential cardiovascular and metabolic benefits, patients with IBD appear less likely to engage in physical activity. The BE-FIT-IBD study showed that a large proportion of patients with IBD (42.9%) were classified as inactive, while only a minority (4.1%) participated in health-enhancing physical activity [49]. Several barriers (e.g., fear of flare-ups after physical activity) and specific factors, such as the sarcopenia frequently observed in these patients, may partly explain these findings. Moreover, in contrast to the high prevalence of malnutrition previously observed in patients with IBD due to inflammation and malabsorption, the current prevalence of obesity in this population is substantial, with an estimated 15–40% of adult patients with IBD being obese and 20–40% being overweight [50].

Epidemiological Links Between IBD and ASCVD

A study conducted in the USA, which evaluated a population with various types of chronic inflammatory diseases, found that the prevalence of ASCVD was higher than in the general population across all age groups and races studied [51]. African American adults with chronic inflammatory diseases had an ASCVD prevalence of 29.7%, 3.1 times higher than in control African American adults. Additionally, white patients with chronic inflammatory diseases had an ASCVD prevalence of 14.7%, 1.8 times higher than in reference white adults. A large Israeli cohort study included a total of 14,768 patients with IBD and 120,338 matched non-IBD individuals [52]. During a mean follow-up of 10.5 years, the cumulative incidence rates of ischemic heart disease among patients with IBD and the reference group were 1.9% and 1.0%, respectively. The incidence density (per 100,000 patient-years) for ischemic heart disease was 178, 152, and 216 for IBD, CD, and UC, respectively.

Several meta-analyses have combined and analyzed the published data on the association between IBD and the risk of cardiovascular disease. Feng et al. conducted a meta-analysis that included 10 cohort studies and found a multivariate-adjusted, independent association between IBD and incident ischemic heart disease (relative risk [RR] 1.24; 95% CI 1.14–1.36) [53]. A subsequent, larger meta-analysis that included 27 studies reported consistent associations between IBD and cardiovascular disease [54]. The pooled relative risks were 1.25 (95% CI 1.08–1.44) for cerebrovascular disease, 1.17 (95% CI 1.07–1.27) for coronary heart disease, and 1.12 (95% CI 1.05–1.21) for myocardial infarction. Notably, the pooled relative risk was significantly higher in female patients. Recently, another meta-analysis that included 12 retrospective cohort studies involving 225,248 patients with IBD found that IBD was associated with an increased risk of acute coronary syndrome (ACS) (adjusted HR 1.23; 95% CI 1.08–1.41) [55]. Subgroup analysis by age indicated a stronger association of ACS in patients with IBD under 40 years of age (HR 1.50; 95% CI 1.15–1.96). Similarly, Wan et al. recently published a meta-analysis on IBD and stroke [56]. Based on the analysis of 10 studies, the pooled incidence of cerebrovascular accidents in patients with IBD was higher than that in the general population (incidence rate ratio [IRR] 1.21; 95% CI 1.09–1.34). Risk factors for stroke in patients with IBD included age, disease flares, and chronic disease activity, among others. Finally, another meta-analysis included a total population of 515,455 controls and 77,140 individuals with IBD [57]. Pooled results from multivariate adjustments showed that, after a 5-year follow-up, both CD and UC were associated with an increased risk of myocardial infarction (HR 1.36 [95% CI 1.12–1.64] and HR 1.24 [95% CI 1.05–1.46], respectively), death (HR 1.55 [95% CI 1.27–1.90] and HR 1.29 [95% CI 1.01–1.64]), and stroke (HR 1.22 [95% CI 1.01–1.49] and HR 1.09 [95% CI 1.03–1.15]).

Risk Stratification in Patients with IBD

Stratifying cardiovascular risk in patients with IBD presents a significant challenge. The traditional risk scores used to assess cardiovascular risk have considerable limitations, as they were not designed specifically for IBD and tend to underestimate the true risk [58]. Certain mechanisms through which IBD increases ASCVD risk may not be fully captured by conventional clinical risk scores. Moreover, patients with IBD are often young adults who fall below the age threshold for a 10-year ASCVD risk assessment. Additionally, traditional ASCVD risk prediction scores have not been validated for use in patients with IBD. In the PESA study [59], the majority of participants from the general population with high cardiovascular risk, as estimated by risk scores, exhibited subclinical atherosclerosis. However, extensive atherosclerosis was also observed in a significant number of low-risk individuals, emphasizing the added value of imaging for diagnosis and prevention. This may be particularly relevant for patients with IBD, where traditional risk scores often classify many individuals as low risk.

In this complex context, the use of additional tools to enhance risk stratification becomes a key consideration, such as screening for subclinical vascular atherosclerosis (carotid and femoral) via ultrasound or assessing the coronary artery calcium (CAC) score through computed tomography. In other words, a patient with IBD classified as “low” or “moderate risk” by traditional scores, but who presents with carotid or femoral plaques or an elevated CAC score, might be a candidate for statins to lower their LDL-C and, consequently, reduce their cardiovascular risk.

A cross-sectional study involving 186 patients with IBD and 175 controls assessed cardiovascular risk using the SCORE system and evaluated the presence of carotid plaques through ultrasonography [60]. Regarding carotid ultrasound assessments, 33% of patients with IBD had carotid plaques compared to 25% of controls (p = 0.07). Notably, carotid ultrasound assessments revealed a significantly higher rate of reclassification in patients with IBD compared to controls (34% vs. 24%, p = 0.03). When this analysis was restricted to individuals in the Systematic Coronary Risk Assessment (SCORE) low-risk category, 21% of patients with IBD were reclassified into the very high-risk category, compared to 11% of controls (p = 0.03). Recently, a study evaluated the performance of two cardiovascular risk algorithms in patients with IBD: the QRESEARCH risk estimator version 3 (QRISK3) calculator and the SCORE [61]. The discrimination ability of QRISK3 for subclinical atherosclerosis was optimal and comparable to that of SCORE in patients with IBD. However, QRISK3 showed a trend toward better discrimination of carotid plaque (QRISK3 area under the ROC curve (AUROC) 0.81 [95% CI 0.75–0.88] vs. SCORE 0.79 [95% CI 0.72–0.86], p = 0.05).

Similarly, some studies have assessed the utility of CAC score in patients with IBD. Naami et al. retrospectively included 369 patients with IBD and found that 41% had a CAC score of 0, 29% had a score between 1 and 99, 17% had a score between 100 and 399, and 13% had a score of ≥ 400 [62]. Approximately half of the patients with IBD had a 10-year estimated ASCVD risk of 7.5% or higher (estimated by the American College of Cardiology/American Heart Association [ACC/AHA] pooled cohort equation). Among patients with an ASCVD risk of < 7.5% (n = 163), 18% had a CAC score of ≥ 100, whereas among those with an ASCVD risk of ≥ 7.5% (n = 178), 57% had a CAC score of < 100. The CAC score (AUROC 0.67 [95% CI 0.56–0.78]) was predictive of major adverse cardiovascular events (MACE). Additionally, a small pilot prospective study (n = 13) showed that 38.5% had a CAC score of 0, 38.5% had a score between 1 and 99, 23.1% had a score between 100 and 399, and none had a score of ≥ 400 [63].

However, a CAC score of 0 does not rule out the presence of non-calcified soft lipid plaques [64]. A cohort study found that the diagnostic value of a CAC score of 0 in ruling out obstructive coronary artery disease beyond clinical variables was age-dependent, with its added diagnostic value being smaller for younger patients [65]. In symptomatic patients under 60 years of age, a significant proportion of obstructive coronary artery disease was observed in those without CAC, and it was associated with an increased risk of myocardial infarction and all-cause mortality. This could represent an additional concern in the IBD population, which is typically younger.

Other markers of subclinical atherosclerosis and endothelial damage, less commonly used in clinical practice, such as carotid intima-media thickness, flow-mediated dilation, and carotid-femoral pulse wave velocity, have also been found to be more frequently altered in the IBD population compared to controls [66].

Finally, epicardial adipose tissue (EAT) has garnered significant attention. It is defined as a fat depot situated between the myocardial surface and the visceral layer of the pericardium. EAT is recognized as a metabolically active endocrine organ and has been proposed as an emerging risk factor for cardiovascular diseases. Moreover, systemic inflammatory conditions create an environment in which EAT can become detrimental to cardiovascular health [67]. A previous meta-analysis demonstrated that EAT is elevated in patients with systemic inflammatory diseases compared to healthy controls, and that EAT measurement is strongly correlated with subclinical atherosclerosis in these patients [68]. Notably, several studies have found that EAT thickness in patients with IBD was significantly greater than in the control group [69–71]. Although EAT thickness and volume can be assessed using echocardiography, computed tomography, or nuclear magnetic resonance, the cutoff values are not yet well established, limiting their clinical applicability. Future studies should explore how to incorporate this promising diagnostic tool into the cardiovascular risk stratification of patients.

Therapeutic Approaches to Cardiovascular Risk Management in IBD

Current guidelines on the prevention of cardiovascular disease in clinical practice recommend assessing cardiovascular risk, with more intensive interventions for patients at higher risk. However, cardiovascular risk algorithms designed for the general population are not accurate for patients with IBD.

The 2019 update of the ACC/AHA guidelines on primary prevention of cardiovascular disease identifies certain chronic inflammatory diseases, such as psoriasis, rheumatoid arthritis, lupus, and HIV, as risk-enhancing factors [72]. According to these guidelines, for patients with borderline or intermediate risk (5% to < 20% 10-year ASCVD risk), risk-enhancing factors should inform clinical decision-making for primary prevention strategies, including statin therapy. However, IBD is not mentioned in these guidelines.

Conversely, the 2021 guidelines published by the European Society of Cardiology recognize IBD, along with other proinflammatory conditions, as requiring more intensive risk screening, counseling, and management [73]. Nevertheless, specific recommendations for patients with IBD are still lacking.

The Consensus of the Argentine Society of Cardiology on cardiovascular risk in chronic inflammatory diseases states that information regarding the differential use of drugs for prevention in this population is limited and inconclusive. Consequently, the use of statins, antihyperglycemic agents, or antihypertensive medications should follow the recommendations for the general population [74].

A recent position paper from the Spanish Working Group on CD and UC (GETECCU) addresses cardiovascular disease in patients with IBD [75]. Among the recommended pharmacological interventions for cardiovascular disease prevention, the following are particularly noteworthy: (1) Statins are safe for use in patients with IBD and should be administered according to the same indications as in the general population; (2) There is no scientific evidence supporting the recommendation of a specific antihypertensive treatment for patients with IBD, so ACE inhibitors or angiotensin II receptor blockers, which are first-line drugs for treating hypertension in the general population, should also be the drugs of choice for patients with IBD; (3) The use of low-dose aspirin for primary or secondary cardiovascular prophylaxis does not appear to be associated with an increased risk of disease exacerbations. The latest European Crohn’s and Colitis Organisation (ECCO) evidence-based consensus on extraintestinal manifestations of IBD acknowledges the increased risk of ASCVD in patients with IBD, but does not provide specific recommendations for managing risk factors or administering preventive medications [76].

Finally, a recent population-based cohort study that included 10,855 patients with immune-mediated inflammatory diseases (1562 of whom had IBD) and T2D found that exposure to glucagon-like peptide 1 receptor agonists was associated with a lower risk of all-cause mortality and MACE, compared to a cardiologically neutral active comparator [77]. Emerging evidence from a retrospective cohort study indicates that semaglutide is effective in achieving sustained weight loss in patients with obesity and IBD, without increasing the risk of IBD-specific complications, such as steroid use or hospitalization [78]. These findings support its safety and efficacy as a weight management strategy for this population. However, further research is necessary to evaluate the effectiveness and safety of new medications for managing T2D and obesity in these patients. According to a recently published position paper, obesity medications—excluding orlistat—can be used in patients with IBD, considering their mechanisms of action and associated gastrointestinal side effects. However, no specific anti-obesity drug is recommended for these patients because of the absence of controlled studies involving individuals with IBD [50].

At first glance, specific treatments for IBD, by reducing disease activity and systemic inflammation, are expected to positively impact cardiovascular risk. Furthermore, disease activity serves as a significant risk marker for ASCVD [79, 80], and optimizing IBD management in all patients, especially during active flares, should be a priority. Therefore, uncontrolled inflammation in IBD represents a potentially modifiable risk factor for cardiovascular disease, according to the ECCO evidence-based consensus on extraintestinal manifestations of IBD [76]. However, the net effect of an IBD medication on cardiovascular risk will depend not only on its influence on inflammatory burden but also on its potential effects on traditional risk factors, such as hypertension, glycemic control, lipid profiles, as well as its possible actions on coagulation and thrombosis. A summary of the main cardiovascular effects related to the medication used in IBD can be seen in Table 2.

Table 2.

Key cardiovascular safety concerns to consider with specific IBD treatments

Drug	Dyslipidemia	Dysglycemia	High blood pressure	Thrombosis	Worsening heart failure	High CV risk	Bradycardia
Corticosteroids [93–96]	✔	✔	✔	✔	✘	✘	✘
Cyclosporine [97, 98]	✔	✘	✔	✘	✘	✘	✘
Tacrolimus [98]	✔	✘	✔	✘	✘	✘	✘
Anti-TNFα [99]	✘	✘	✘	✘	✔	✘	✘
Tofacitinib [84, 100]	✔	✘	✘	✘	✘	✔ *	✘
S1P receptor inhibitors [101]	✘	✘	✔	✘	✘	✘	✔

CV cardiovascular, SIP sphingosine-1-phosphate, TNF tumor necrosis factor

*Increased cardiovascular risk is observed in patients with rheumatoid arthritis over the age of 65, especially those with additional risk factors, such as a history of cardiovascular disease or smoking [84]

The findings from two observational studies indicated promising outcomes. First, a large Danish cohort study demonstrated that the risk of ischemic heart disease was lower among patients with IBD who used 5-aminosalicylic acids (RR 1.16; 95% CI 1.06–1.26) compared to non-users (RR 1.36; 95% CI 1.22–1.51) (p = 0.02), particularly among those using oral corticosteroids, which served as a proxy for disease severity [81]. Second, a French observational study involving 177,827 patients found that the use of anti-TNFα agents was associated with a reduced risk of acute arterial events, including CAD, stroke, and peripheral artery disease [82]. However, other studies in different patient populations have raised some concerns. The Oral Rheumatoid Arthritis Trial (ORAL) Surveillance, which assessed MACE in rheumatoid arthritis patients over 50 years of age with at least one pre-existing cardiovascular risk factor, found potential risks associated with Janus kinase (JAK) inhibitors, specifically tofacitinib, compared to anti-TNF therapies [83]. Similarly, another study reported an increased risk of cardiovascular events after initiating ustekinumab, an anti-IL-12/23 agent, particularly in patients with high cardiovascular risk [84].

Although not statistically significant in direct comparisons, a recent network meta-analysis indicated that anti-IL-12/23 inhibitors, JAK inhibitors, and anti-TNFα drugs were associated with an increased risk of MACE compared to placebo in a large population of individuals with immune-mediated inflammatory disorders, including 7463 subjects with IBD [85]. However, another meta-analysis of randomized controlled trials suggests that the use of biologic therapies and small molecules in adult patients with IBD does not significantly affect the risk of MACE during either the induction or maintenance phases [86].

It is important to acknowledge the limitations of certain studies, as they may not always account for all confounding factors. The most significant of these include the concomitant use of medications (such as corticosteroids) and the presence of disease activity. These factors are often linked to the decision to start additional drug therapy and, independently, could contribute to an increased cardiovascular risk. Therefore, further randomized trials with longer follow-up periods are essential to gain a clearer understanding of the potential role of IBD-modifying therapies in reducing ASCVD risk. The final impact of specific IBD treatments on cardiovascular outcomes will depend on their anti-inflammatory properties, their effects on cardiovascular risk factors such as dyslipidemia, blood pressure, and blood glucose levels, as well as their neutrality in terms of adverse effects on the cardiovascular system. Several studies are currently ongoing and will evaluate as secondary objectives or as safety points the relationship between specific treatments for IBD and subclinical and clinical cardiovascular events [87–89].

Finally, an additional concern pertains to the potential inappropriate administration of preventive medications to patients with IBD. A study involving patients with chronic inflammatory diseases (excluding patients with IBD) found that lipid-lowering treatments and antihypertensive medications were prescribed in only 36.1% and 52.6% of cases, respectively [90]. Furthermore, even when therapies were initiated, 50% of patients still failed to reach guideline-recommended treatment targets. Similarly, other studies suggest that patients with IBD receive suboptimal ASCVD prevention care, which is even worse than that provided to individuals without IBD [91, 92].

Therefore, it is essential to design an algorithm for managing cardiovascular risk in a multidisciplinary manner. Initially, patient education and screening for cardiovascular risk factors should be conducted by the gastroenterologist or general practitioner overseeing the patient’s care. Additionally, it would be highly beneficial to perform an initial cardiovascular risk stratification using a score designed for this purpose. In the presence of risk factors or if the patient is at moderate or higher risk, they should be referred to a professional with expertise in this area, such as a cardiologist. Together, they should address the risk factors and implement specific treatments. Statins are the cornerstone of preventive therapy, and their use will depend not only on LDL-C levels but also on the overall risk as ultimately estimated. Figure 2 presents a schematic flowchart illustrating a proposed multidisciplinary care model for managing cardiovascular risk in patients with IBD.

Fig. 2.

Schematic flowchart illustrating a proposed multidisciplinary care model for managing cardiovascular risk in patients with inflammatory bowel disease. Lp(a) lipoprotein (a), HDL-C high density lipoprotein cholesterol, LDL-C low density lipoprotein cholesterol, IBD inflammatory bowel disease

Conclusion

Patients diagnosed with IBD have an increased risk of ASCVD. This heightened risk is driven by variables beyond traditional cardiovascular risk factors, with chronic inflammation and intestinal dysbiosis likely playing a significant role. There are considerable gaps in current knowledge, particularly regarding the management of risk factors and the use of medications for cardiovascular disease prevention. As a result, clinical practice guideline recommendations on this issue are limited or non-existent.

In addition to managing the underlying inflammatory condition in line with current guidelines, it is essential to regularly evaluate individual cardiovascular risk factors to guide risk stratification and treatment decisions. Comprehensive risk assessment may, in certain cases, benefit from the inclusion of supplementary tools as an alternative approach. Effective collaboration among gastroenterologists, cardiologists, and general practitioners is essential for providing holistic care to these patients. Further high-quality research is needed to bridge existing knowledge gaps and provide clarity on these unresolved issues.

Author Contributions

Walter Masson and Gonzalo Fernández-Villar participated in the conception and design of the research. Waler Masson and Gonzalo Fernández-Villar participated in the data collection. The interpretation and final selection of the data was done by Walter Masson and Solange Martinez-Elhelou. Walter Masson and Gonzalo Fernández-Villar drafted the manuscript. All authors performed a critical review of the final document. All authors have read and agreed to the published version of the manuscript.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Walter Masson, Gonzalo Fernández-Villar, and Solange Martinez-Elhelou have nothing to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.