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Background:
Systematic Review

Beyond the Gut: Inflammatory Bowel Disease as a Driver of Cardiovascular and Thromboembolic Risk—A Systematic Review and Meta-Analysis of 1.4 Million Patients

by
Aqsa Shoaib
1,
Mariam Shahabi
2,
Reyan Hussain Shaikh
3,
Mian Muinuddin Jamshed
3,
Syed Usama Ashraf
4,
Faryal Jahangir
3,
Faqeeha Arif
5,
Soha Ali
2,
Syed Adeel Hassan
6,*,
Waqas Rasheed
7,
Tooba Jabeen
8,
Fatima Mansoor
1,
Suhaira Khalid
2 and
Abubaker Khan
9
1
Department of Medicine, Karachi Medical and Dental College, Karachi 74700, Pakistan
2
Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
3
Department of Medicine, The Aga Khan University, Karachi 74800, Pakistan
4
Department of Medicine, Dow International Medical College, Karachi 74000, Pakistan
5
King Edward Medical University, Lahore 54890, Pakistan
6
Department of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, USA
7
Department of Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA
8
Bahria University of Health Sciences, Karachi 75340, Pakistan
9
Ayub Teaching Hospital, Abbottabad 22040, Pakistan
*
Author to whom correspondence should be addressed.
Gastrointest. Disord. 2025, 7(4), 78; https://doi.org/10.3390/gidisord7040078
Submission received: 26 October 2025 / Revised: 1 December 2025 / Accepted: 4 December 2025 / Published: 11 December 2025
Browse Figures
Versions Notes

Abstract

Background: Inflammatory bowel disease (IBD) is associated with systemic inflammation and potential cardiovascular complications. This meta-analysis evaluates long-term cardiovascular risks in IBD. Methods: Electronic databases were searched for studies examining cardiovascular, cerebrovascular, and thromboembolic risks in IBD. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Results: Fifty-three studies comprising 1,406,773 patients were analyzed. IBD was linked to increased risk of ischemic heart disease (aHR 1.25; p = 0.001) myocardial infarction (aHR 1.25; p = 0.01), acute coronary syndrome (aHR 1.43; p < 0.00001), heart failure (aHR 1.24; p < 0.00001), atrial fibrillation (aHR 1.20; p < 0.00001), and stroke (aHR 1.13; p < 0.00001). Elevated risks were also observed for peripheral arterial disease (aHR 1.41; p < 0.00001), diabetes mellitus (aHR 1.40; p < 0.00001), venous thromboembolism (aHR 1.98; p < 0.00001), deep vein thrombosis (aHR 2.85; p = 0.0004), and pulmonary embolism (aHR 1.98; p = 0.03). Importantly, IBD was associated with increased cardiovascular (aHR 1.14; p = 0.03) and all-cause mortality (aHR 1.53; p < 0.00001). Conclusions: IBD patients face higher risk for adverse cardiovascular outcomes, thromboembolic disease, and mortality, necessitating early cardiovascular risk assessment and targeted interventions in this population.

1. Introduction

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), presents a significant global health burden. The prevalence of IBD has been rising worldwide, with an estimated 4.9 million cases in 2019 [1]. Its incidence is increasing in newly industrialized countries but has plateaued in high-income nations [2]. The relapsing-remitting nature of IBD leads to persistent symptoms, frequent medical visits, and the need for ongoing treatment, all of which contribute to a reduced quality of life [3,4]. Patients often face challenges such as managing daily activities, maintaining social relationships, and coping with the psychological burden of the disease [5]. Moreover, systemic inflammation, as occurs in IBD and other chronic autoimmune diseases including psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis, has been implicated in the pathogenesis of atherosclerotic cardiovascular disease and chronic inflammation has been linked to an increased risk for developing cholangiocarcinoma and colorectal cancer [6,7].
Multiple studies have reported an increased risk of new-onset cardiovascular disease (CVD) in patients with IBD [8,9,10]. The systemic inflammation caused by IBD, particularly during flare-ups, involves the release of proinflammatory cytokines like tumor necrosis factor (TNF) alpha, interleukins-1,6,8 and 12, generation of reactive oxygen species, endothelial dysfunction, and platelet activation [11]. These processes ultimately contribute to atherosclerotic changes, such as arterial stiffening, coronary microcirculatory dysfunction, and increased carotid intima-media thickness, as well as a hypercoagulable state. Moreover, certain IBD medications such as 5-aminosalicylates, glucocorticoids, and the JAK inhibitor tofacitinib have associated cardiovascular adverse effects [12,13,14,15].
Previous meta-analyses have reported conflicting results on the association between IBD and cardiovascular and cerebrovascular diseases [8,16,17]. Newer data from more recent longitudinal cohorts also warrant an update to these previous reviews [10,18,19,20,21,22]. Therefore, we sought to conduct a comprehensive, up-to-date meta-analysis on the long-term risk of incident cardiovascular, cerebrovascular, and thromboembolic events among patients with IBD, compared with healthy controls.

2. Materials and Methods

2.1. Data Resources and Search Strategy

We reported this meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [23]. The study protocol was not submitted to PROSPERO. Search methods also included publication language restrictions. Only English-language studies were included. Two independent reviewers (R.H.S and M.M.J) conducted an electronic search of PubMed, Embase, and Cochrane Central from inception till 30 November 2025 using the search string: (“inflammatory bowel disease” OR “IBD” OR “ulcerative colitis” OR “Crohn’s disease”) AND (“cardiovascular” OR “myocardial infarction” OR “MI” OR “angina” OR “acute coronary syndrome” OR “ischemic heart disease” OR “coronary heart disease” OR CHD OR “coronary artery disease” OR CAD OR atherosclero* OR “ASCVD” OR “heart failure” OR HF OR “atrial fibrillation” OR arrhythm* OR “peripheral arterial disease” OR PAD OR “peripheral vascular disease” OR PVD OR “cerebrovascular” OR stroke OR “hemorrhagic stroke” OR “ischemic stroke” OR “transient ischemic attack” OR thrombo* OR VTE OR “deep vein thrombosis” OR “pulmonary embolism” OR PE OR emboli* OR “death” OR “cardiovascular death” OR “mortality” OR “cardiovascular mortality” OR “cerebrovascular death” OR “cerebrovascular mortality”) AND (risk OR inciden* OR “new onset” OR “de novo”). In addition, the references in each study, previous meta-analyses and review articles were also manually screened to prevent the omission of any relevant studies during the electronic search.

2.2. Inclusion and Exclusion Criteria

The inclusion criteria for our meta-analysis were: (1) cohort studies, (2) IBD patients as the exposure group, (3) non-IBD patients as the control group, and (4) reported outcomes of interest. Studies lacking valid controls or not reporting our outcomes of interest were excluded as were cross-sectional studies, review articles, case reports, letters, and editorials.

2.3. Study Selection and Data Extraction

The articles obtained from the systematic search were exported to the Mendeley Reference Library software v2.130.2, where duplicates were screened and removed. Two reviewers (R.H.S and M.M.J) individually evaluated if a study satisfied the inclusion criteria. A third reviewer (M.S) was consulted to resolve any discrepancies. When two or more studies reported data from the same patient population for a particular outcome, the study with the larger sample size was preferred, to avoid patient overlap. Outcomes extracted were ischemic heart disease (IHD), myocardial infarction (MI), atrial fibrillation (AF), heart failure (HF), stroke, peripheral arterial disease (PAD), diabetes mellitus (DM), venous thromboembolism (VTE), deep vein thrombosis (DVT), pulmonary embolism (PE), and cardiovascular and all-cause mortality.

2.4. Quality Assessment

We used the Newcastle–Ottawa scale [24] for the quality assessment of observational studies.

2.5. Statistical Analysis

Statistical analysis was performed using Review Manager (version 5.4.1; Copenhagen, Denmark. The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Adjusted hazard ratios (aHR) with 95% confidence intervals were pooled for all outcomes using a random effects model. A separate unadjusted analysis was conducted to include studies reporting incidence rate ratios, odds ratios, standardized incidence ratios, or other measures of effect that cannot be pooled with HRs. Raw event rates were extracted from these studies, if available, and pooled as risk ratios (RR).
Forest plots were generated to visually assess the pooled results. Subgroup differences were assessed using a Chi-square test. Publication bias was evaluated using Begg’s test and visual inspection of the funnel plot. The I2 statistic was used to assess heterogeneity across studies, and an I2 value of 25–50% was considered mild, 50–75% as moderate, and I2 > 75% as severe heterogeneity [25]. To explore heterogeneity, we used the leave-one-out method by consecutively omitting one study at a time to identify the study contributing the most to heterogeneity. A p-value < 0.05 was considered statistically significant in all cases.

3. Results

3.1. Literature Search Results

A total of 5170 articles were identified after searching electronic databases. After duplicate removal and screening titles and abstracts, 188 full-text articles were assessed for eligibility. Of these, 53 studies matched our inclusion criteria and were ultimately included in the analysis [10,18,19,20,21,22,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72]. The PRISMA flowchart summarizing the literature search and study selection procedure is presented in Supplementary Figure S1.

3.2. Study Characteristics and Quality Assessment

The 53 studies encompassed a total of 1,406,773 patients with IBD. 619,490 patients with UC and 398,612 patients with CD were included in the analysis. The mean follow-up time ranged from 4.1 years to 13.7 years. The average age of IBD patients ranged from 12.6 years to 58 years. The proportion of females across our included studies ranged from 30.2% to 60%. The baseline patient and study characteristics are summarized in Table 1.
All the studies included were of a reasonably high methodological quality. The results of the risk of bias assessment are presented in Supplementary Table S1. Symmetry in the funnel plot (Supplementary Figure S2) suggests the absence of a small study and publication bias.

3.3. Results of Meta-Analysis

3.3.1. Coronary Atherosclerosis and Acute Coronary Syndromes

Ischemic heart disease
Six studies [20,28,37,50,63,69] were included in the adjusted analysis (Figure 1). There was a significantly increased risk of IHD among IBD patients, compared with controls (aHR: 1.25, 95% CI: 1.09–1.43; p = 0.001; I2 = 77%). This finding was consistent across subgroups (p-value for subgroup difference = 0.65). Sensitivity analysis by excluding Kirchgesner et al. [50] reduced heterogeneity to 56% (Supplementary Figure S3).
An unadjusted analysis of four studies [29,39,43,61] revealed no significant difference in the risk of IHD between IBD and controls (RR: 0.57, 95% CI: 0.26–1.25; p = 0.16; I2 = 100%; Supplementary Figure S4).
Myocardial infarction
Six studies [20,27,32,33,58,63] were included in the adjusted analysis (Figure 1). There was a significantly increased risk of MI among IBD patients, compared with controls (aHR: 1.25, 95% CI: 1.05–1.50; p = 0.01; I2 = 87%). This finding was consistent across subgroups (p-value for subgroup difference = 0.97). Sensitivity analysis by excluding Aniwan et al. [27] reduced heterogeneity to 78% (Supplementary Figure S5).
An unadjusted analysis of three studies [41,51,62] also revealed a significantly increased risk of MI among IBD patients, compared with controls (HR: 1.29, 95% CI: 1.12–1.49; p = 0.0005; I2 = 82%; Supplementary Figure S6). There was a significantly higher risk of MI in the UC subgroup compared with CD (p = 0.04).
Acute coronary syndrome
Three studies [19,67,69] were included in the adjusted analysis (Figure 1). There was a significantly increased risk of ACS among IBD patients, compared with controls (aHR: 1.43, 95% CI: 1.29–1.58; p < 0.00001; I2 = 86%). This finding was consistent across subgroups (p-value for subgroup difference = 0.39). Sensitivity analysis by excluding Tsai et al. [67] reduced heterogeneity to 0% (Supplementary Figure S7).

3.3.2. Cardiac Dysfunction and Arrhythmia

Heart failure
Four studies [10,18,27,59] were included in the adjusted analysis (Figure 2). There was a significantly increased risk of HF among IBD patients, compared with controls (aHR: 1.24, 95% CI: 1.15–1.34; p < 0.00001; I2 = 71%). This finding was consistent across subgroups (p-value for subgroup difference = 0.86). Sensitivity analysis by excluding Aniwan et al. [27] slightly reduced heterogeneity to 68% (Supplementary Figure S8).
Atrial fibrillation
Three studies [22,34,64] were included in the adjusted analysis (Figure 2). There was a significantly increased risk of AF among IBD patients, compared with controls (aHR: 1.20, 95% CI: 1.11–1.30; p < 0.00001; I2 = 72%). This finding was consistent across subgroups (p-value for subgroup difference = 0.19). Sensitivity analysis by excluding Choi et al. [34] reduced heterogeneity to 0% (Supplementary Figure S9).

3.3.3. Cerebrovascular and Peripheral Vascular Disease

Stroke
Nine studies [10,20,28,32,33,45,48,50,65] were included in the adjusted analysis (Figure 3). There was a significantly increased risk of stroke among IBD patients, compared with controls (aHR: 1.13, 95% CI: 1.08–1.19; p < 0.00001; I2 = 47%). This finding was consistent across subgroups (p-value for subgroup difference = 0.62).
An unadjusted analysis of five studies [26,29,51,52,62] also revealed a significantly increased risk of stroke among IBD patients, compared with controls (RR: 1.29, 95% CI: 1.22–1.36; p < 0.00001; I2 = 47%; Supplementary Figure S10).
Peripheral arterial disease
Three studies [20,50,55] were included in the adjusted analysis (Figure 3). There was a significantly increased risk of PAD among IBD patients, compared with controls (aHR: 1.41, 95% CI: 1.26–1.58; p < 0.00001; I2 = 75%). This finding was consistent across subgroups (p-value for subgroup difference = 0.39). Sensitivity analysis by excluding Kirchgesner et al. [50] reduced heterogeneity to 0% (Supplementary Figure S11).
Diabetes mellitus
Three studies [10,37,46] were included in the adjusted analysis (Figure 4). There was a significantly increased risk of DM among IBD patients, compared with controls (aHR: 1.40, 95% CI: 1.12–1.75; p < 0.00001; I2 = 91%). This finding was consistent across subgroups (p-value for subgroup difference = 0.63). Sensitivity analysis by excluding Kang et al. [46] slightly reduced heterogeneity to 88% (Supplementary Figure S12).

3.3.4. Venous Thromboembolic Events

Venous thromboembolism
Seven studies [35,40,42,44,49,70,71,72] were included in the adjusted analysis (Figure 5). There was a significantly increased risk of VTE among IBD patients, compared with controls (aHR: 1.98, 95% CI: 1.77–2.21; p < 0.00001; I2 = 91%). This finding was consistent across subgroups (p-value for subgroup difference = 0.06). Sensitivity analysis by excluding Fang et al. [42] slightly reduced heterogeneity to 89% (Supplementary Figure S13).
An unadjusted analysis of four studies [47,60,62,68] also revealed a significantly increased risk of VTE among IBD patients, compared with controls (RR: 1.91, 95% CI: 1.66–2.20; p < 0.00001; I2 = 91%; Supplementary Figure S14).
Deep vein thrombosis
Three studies [36,44,72] were included in the adjusted analysis (Figure 5). There was a significantly increased risk of DVT among IBD patients, compared with controls (aHR: 2.85, 95% CI: 1.59–5.11, p = 0.0004; I2 = 90%).
An unadjusted analysis of four studies [40,47,62,68] also revealed a significantly increased risk of DVT among IBD patients, compared with controls (RR: 1.73, 95% CI: 1.50–1.99; p < 0.00001; I2 = 87%; Supplementary Figure S15).
Pulmonary embolism
Three studies [36,44,72] were included in the adjusted analysis (Figure 5). There was a significantly increased risk of PE among IBD patients, compared with controls (aHR: 1.98, 95% CI: 1.07–3.67, p = 0.03; I2 = 74%).
An unadjusted analysis of four studies [40,47,62,68] also revealed a significantly increased risk of PE among IBD patients, compared with controls (RR: 1.78, 95% CI: 1.53–2.06; p < 0.00001; I2 = 83%; Supplementary Figure S16).

3.3.5. Mortality

Cardiovascular mortality
Six studies [21,27,30,32,54,57] were included in the adjusted analysis. There was a significantly increased risk of cardiovascular mortality among IBD patients, compared with controls (aHR: 1.14, 95% CI: 1.02–1.29, p = 0.03; I2 = 72%). This finding was consistent across subgroups (p-value for subgroup difference = 0.14). Sensitivity analysis by excluding Bernstein CN [30] reduced heterogeneity to 61% (Supplementary Figure S17).
All-cause mortality
Eight studies [27,28,30,31,33,38,54,57] were included in the adjusted analysis. There was a significantly increased risk of all-cause mortality among IBD patients, compared with controls (HR: 1.53, 95% CI: 1.34–1.75; p < 0.00001; I2 = 97%). This finding was consistent across subgroups (p-value for subgroup difference = 0.46). Sensitivity analysis by excluding Olen et al. [57] slightly reduced heterogeneity to 94% (Supplementary Figure S18).
An unadjusted analysis of two studies [41,56] also revealed a significantly increased risk of all-cause mortality among IBD patients, compared with controls (RR: 1.24, 95% CI: 1.10–1.39; p < 0.003; I2 = 34%; Supplementary Figure S19).

4. Discussion

Our systematic review and meta-analysis assessed the long-term risk of CVD, stroke, and thromboembolic events in 1.4 million IBD patients, compared with healthy controls. Our pooled analysis revealed an increased risk of IHD, MI, AF, HF, stroke, PAD, DM, VTE, DVT, PE, and cardiovascular and all-cause mortality in IBD patients, compared with non-IBD controls.
Our results are largely consistent with previous meta-analyses [8,73,74,75]. However, the larger sample size of the present study imparts greater statistical power to our results. We synthesized evidence from 53 studies, including several recently published, large, population-based studies [10,18,19,20,22,70,71,72]; hence our meta-analysis represents the most comprehensive and updated review on this topic, to the best of our knowledge. We excluded studies that used overlapping patient data, which increases the credibility of our estimates. Further, to obtain the most accurate estimate of long-term risk, we pooled hazard ratios, specifically those that were adjusted for the greatest possible confounders. For this reason, we also excluded cross-sectional and survey-based studies that reported prevalent cases of CVD, rather than incident cases.
There is extensive literature focusing on the link between IBD and IHD. While the exact mechanism for the association remains unclear, it is believed that thrombosis and atherosclerosis are promoted by the systemic proinflammatory state in IBD, which is characterized by high levels of cytokines such as TNF-alpha, IL-12, IL-23, and possibly IL-17 and interferon-gamma [76,77]. IBD is also associated with an atherogenic lipoprotein profile, including reduced HDL-C and increased LDL-C, although it is not well-understood whether lipid malabsorption or systemic inflammation plays a bigger role as the key mediator of these changes [78]. Nevertheless, evidence from large, prospective cohort studies and meta-analyses is still equivocal. Many of our included studies do not report a significant long-term risk of IHD among IBD patients [28,30,37,43,61,62]. In two studies, the risk of IHD was in fact lower in the IBD groups than in controls [43,61]; one of these studies (Rungoe et al.) [61] had a relatively long follow-up duration of 13 years and utilized data on nearly 28,000 IBD patients from Danish National Patient Registers. On the contrary, another prospective cohort study [50] of nearly 200,000 IBD patients from the French National Hospital Discharge database, revealed an elevated risk of IHD in both UC and CD patients. The median follow-up was 3.4 years [50].
In our analysis, UC, but not CD patients, were at a heightened risk of developing IHD, although subgroup differences were not significant. However, preceding meta-analyses [16,73] report an elevated risk of IHD in both UC and CD subgroups. A differential cardiovascular risk in the two subtypes of IBD is also evidenced by Alayo et al.’s [20] cohort study, which utilized data from 5000 IBD patients enrolled in the UK Biobank. The risk of composite acute arterial events, IHD, and MI was significantly increased in the UC group, but not in CD [20]. Similarly, Rungoe et al. [61] also reported a higher incidence of IHD in UC but not in the CD subgroup. The reasons for this difference in risk are not well understood. These discrepancies between individual studies arise from variations in study populations, follow-up durations, and adjustments for confounding factors. Therefore, while our findings add to the growing body of evidence linking IHD and IBD, they also highlight the need for larger prospective cohorts to gain more robust insights.
Goyal et al. [75] recently reported an elevated risk of AF among patients with IBD, in their meta-analysis of seven studies (UC RR: 1.29; 95% CI: 1.08–1.53; p = 0.004]; CD RR: 1.30; 95% CI: 1.07–1.58; p = 0.008). Our findings corroborate this, further supporting the notion that chronic inflammation in IBD plays a critical role in increasing cardiovascular risk, particularly for arrhythmic events like AF. This is consistent with other studies linking systemic inflammation in IBD to AF through pathways involving oxidative stress and endothelial dysfunction [79].
Similar to Li et al. [16], our meta-analysis also reports a heightened risk of diabetes in patients with IBD. Proinflammatory cytokines may interfere with insulin signaling by disrupting the activation of insulin receptors, promoting insulin resistance [80,81]. Dysbiosis in IBD, characterized by reduced microbial diversity and an overrepresentation of proinflammatory species in the gut microbiome, may further exacerbate metabolic dysregulation [82,83]. Additionally, the impaired secretion of incretin hormones from the ileum, which is commonly affected in Crohn’s disease, may disrupt the enteropancreatic axis and contribute to beta-cell dysfunction and glucose intolerance [84,85].
The risk of incident HF was higher in IBD, among both CD (HR: 1.35, 95% CI: 1.05–1.70, p = 0.0004) and UC subgroups (1.14, 95%: 1.09–1.18, p < 0.00001). The strongest evidence to this end is provided by Sun and colleagues [18], on account of their long follow-up duration (median: 12.4 years), and large sample size (n = 81,749). They reported an adjusted HR of 1.19 (95% CI 1.15–1.23). Another nationwide cohort study by Kristensen et al. [86] reported a 37% increased risk of hospitalization for HF among IBD patients, particularly during flares or persistent activity. This study was not included in our formal analysis, because they reported incident rate ratios, which, owing to differences in definitions and underlying statistical assumptions, could not be reasonably pooled with the hazard ratios reported by our other studies [87]. Chronic inflammation and IBD medication are likely mediators of HF pathogenesis in IBD. Proinflammatory cytokines such as TNF-alpha, IL-1, and IL-6, which are chronically elevated in both IBD and HF, contribute to hemodynamic instability and cardiac remodeling [77,88]. Compelling evidence also exists for the risk of cardiotoxicity with many of the prevalent medications approved for use in IBD, including TNF-alpha inhibitors, Janus kinase inhibitors, and mesalamine [89,90,91,92]. In one pharmacovigilance study, HF constituted 0.6% of all adverse events reported with the use of infliximab, adalimumab, vedolizumab, ustekinumab, natalizumab, tofacitinib, certolizumab, and risankizumab in CD [89].
Consistent with preceding meta-analyses, we also report an increased risk of stroke and thromboembolic events such as VTE, DVT, and PE among IBD patients [8,70,71,72,93,94], in both UC and CD. This can be partly attributed to the hypercoagulable state induced by systemic inflammation and endothelial dysfunction [95]. Gut microbiome dysfunction is another feature of IBD, which may predispose patients to a heightened risk of thromboembolism [96,97].
While the pooled analysis revealed a high risk of cardiovascular death in IBD, subgroup analysis did not yield a significant result in either UC or CD. Nonetheless, epidemiological studies have reported a high burden of cardiovascular morbidity and mortality in IBD [98,99]. The risk of all-cause mortality was also significantly increased, which is a plausible finding, given the numerous intestinal and extraintestinal manifestations of IBD.
Large prospective studies are needed to gain more comprehensive insights into the pathophysiologic mechanisms underlying IBD-associated CVD, particularly the role of systemic inflammation, dysbiosis, and IBD medications, which may independently exacerbate cardiovascular risk. Additionally, exploring the differential cardiovascular risks associated with UC and CD is crucial, as our findings suggest possible variations between these two subtypes. The interaction of IBD with comorbid conditions, such as diabetes and hypertension, also warrants attention, as it may compound cardiovascular risk. Treatment for IBD patients should integrate cardiovascular risk assessment and management, including routine screening for traditional risk factors such as hypertension, diabetes, and dyslipidemia, alongside targeted strategies to address inflammation, optimize gut health, and mitigate the potential cardiotoxic effects of IBD medications.

Limitations

Despite its merits, our study also has certain limitations. Firstly, we did not employ meta-regression to analyze the impact of mediating factors such as age, sex, smoking, obesity, and IBD medication. Secondly, to ensure statistical homogeneity, we intentionally excluded studies that did not report adjusted HRs or raw event rates, potentially limiting the generalizability of our pooled estimates. Thirdly, we observed high heterogeneity for many outcomes. Despite undertaking leave-one-out analyses, heterogeneity remained high for IHD, MI, VTE, and all-cause mortality, which may stem from regional and population-level differences in environmental factors, genetic predispositions, healthcare systems, and diagnostic criteria among our included studies. Finally, all observational studies are, by nature, prone to residual bias from unmeasured confounders, hence our meta-analysis cannot confirm a direct causal link between IBD and incident CVD.

5. Conclusions

Our meta-analysis confirms that patients with IBD face an elevated long-term risk of cardiovascular and thromboembolic disease, compared with individuals without IBD. These findings underscore the need for greater emphasis on cardiovascular risk assessment and management in patients with IBD.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/gidisord7040078/s1. Table S1: Quality assessment of included studies, using the Newcastle-Ottawa scale. Figure S1: PRISMA flowchart summarizing the results of the literature search. Figure S2: Funnel plot. Figure S3: Sensitivity analysis of ischemic heart disease. Figure S4. Unadjusted risk of ischemic heart disease. Figure S5: Sensitivity analysis of myocardial infarction. Figure S6: Unadjusted risk of myocardial infarction. Figure S7: Sensitivity analysis of acute coronary syndrome. Figure S8: Sensitivity analysis of heart failure. Figure S9: Sensitivity analysis of atrial fibrillation. Figure S10: Unadjusted risk of stroke. Figure S11: Sensitivity analysis of peripheral arterial disease. Figure S12: Sensitivity analysis of diabetes mellitus. Figure S13: Sensitivity analysis of venous thromboembolism. Figure S14: Unadjusted risk of venous thromboembolism. Figure S15: Unadjusted risk of deep vein thrombosis. Figure S16: Unadjusted risk of pulmonary embolism. Figure S17: Sensitivity analysis of cardiovascular mortality. Figure S18: Sensitivity analysis of all-cause mortality. Figure S19: Unadjusted risk of all-cause mortality.

Author Contributions

A.S. conceptualization, supervision, editing. M.S. data extraction, formal analysis, writing—draft and editing. R.H.S. data extraction, formal analysis, writing. M.M.J. data extraction, formal analysis. S.U.A. data extraction, writing. F.J. data extraction. F.A. writing—draft. S.A., S.A.H. and W.R. conceptualization, data extraction. T.J., F.M., S.K. and A.K. writing—draft. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

IRB approval was not needed because this study utilized only previously published, aggregate data and involved no interaction with human subjects or access to identifiable patient information.

Informed Consent Statement

Patient consent was waived due to the nature of the study being observational.

Data Availability Statement

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

Acknowledgments

The authors would like to acknowledge the Research Council of Pakistan (RCOP) for their support along all aspects of conducting this study.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
IBDInflammatory bowel disease
CDCrohn’s disease
UCUlcerative colitis
IBD-UIBD unclassified
IHDIschemic heart disease
MIMyocardial infarction
AFAtrial fibrillation
HFHeart failure
PADPeripheral arterial disease
DMDiabetes mellitus
VTEVenous thromboembolism
DVTDeep vein thrombosis
PEPulmonary embolism
CVDCardiovascular disease

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Gastrointestdisord 07 00078 g001
Figure 1. Forest plot of coronary atherosclerosis and acute coronary syndromes.
Figure 1. Forest plot of coronary atherosclerosis and acute coronary syndromes.
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Figure 2. Forest plot of cardiac dysfunction and arrhythmias.
Figure 2. Forest plot of cardiac dysfunction and arrhythmias.
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Figure 3. Forest plot of cerebrovascular and peripheral vascular disease.
Figure 3. Forest plot of cerebrovascular and peripheral vascular disease.
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Figure 4. Forest plot of diabetes mellitus.
Figure 4. Forest plot of diabetes mellitus.
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Figure 5. Forest plot of venous thromboembolic events.
Figure 5. Forest plot of venous thromboembolic events.
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Table 1. Baseline characteristics of included patients and studies.
Table 1. Baseline characteristics of included patients and studies.
StudyFollow-Up Duration (Years)UC
(n = 619,490)		CD
(n = 398,612)		Total No. of pts with IBD (n = 1,406,773)Total No. of Individuals Without IBD (n = 12,608,263)Dataset UsedCountryDuration of StudyGender (Female %)Age of Non-IBD Patients, y ± SDAge of IBD Patients, y ± SD
1Alayo 2023
[20]		12.4 years1928915509420,376UK BiobankUK2006–202113,905 (54.6)56.7 ± 7.956.0 ± 8.1
2Andersohn 2010
[26]		5.4 years882882176418,214UK General Practice Research DatabaseUnited Kingdom1987–200510,064 (52.8)--
3Aniwan 2018
[27]		14.3 years3973397361472Rochester Epidemiology ProjectUnited States1980–2010993 (45)--
4Baena-Diez 2017
[28]		---9544952,489SIDIAPCatalonia (Spain)2007–2012524,052 (52.9)52 ± 1356 ± 14
5Bernstein 2008
[29]		-38794193807280,489Manitoba Health administrative databasesCanada1984–200348,407 (30.2)--
6Bernstein CN 2015
[30]		 5502528610,788101,860University of Manitoba IBD Epidemiology Database
(UMIBDED)		Canada1 April 1984–31 March 2010-37.6 (18.2)43.6 (19.1)
7Card 2003
[31]		 8301596016,55082,917General Practice Research Database (GPRD) United KingdomUnited Kingdom-53,364 (53.7)46.346.16
8Card 2021
[32]		5.9 years16,73410,90331,175154,412Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) data and Office for National Statistics (ONS) mortality data.UKApril 1997–June 201716 292 (52.3)45.4 ± 17.145.2 ± 17.2
9Choi 2018
[33]		8.4 ± 1.7 years26,76910,70837,477112,431National Health Insurance Service (NHIS)South Korea2006–200916,184 (43.2)40.4 ± 16.640.4 ± 16.6
10Choi YJ 2019
[34]		 25,34712,34937,696113,088National Health Insurance Service (NHIS) databaseSouth Korea1 January 2010–31 December 201458,844 (39%)39.42 ± 16.439.4 ± 16.4
11Chu 2018
[35]		- 23,046106,795Clinical Practice Research Datalink (CPRD)United KingdomJanuary 1987–January 201161,166 (47.1)--
12Chung 2015
[36]		- 11,44545,780National Health Insurance Research
Database (NHIRD)		Taiwan2000–201026,095 (45.6)53.0 (19.5)53.5 (19.5)
13Dregan 2014
[37]		≥12 months12,203762819,831373,851Clinical Practice Research Datalink (CPRD)UK1 January 2002–31 January 201310,212 (51.5) 47 ± 18
14Dregan A 2017
[38]		-149426594153483,559UK BiobankUnited Kingdom-263,837 (54.1)57 (8)37.9 (13.4)
15Eriksson C 2024
[19]		8 years42,19422,73276,517757,141Nationwide registersSweden2003–2021411,985 (49%)42.58 (20.34)42.8 (20.45)
16Fang 2022
[39]		-50992614351588Chines IBD Elite Union comprising 12 IBD centersChina2013–20181141 (37.7)38.6 (25–51)38.9 (26–51)
17Galloway 2020
[40]		-14,182948923,671213,512Royal College of General Practitioners Research (RCGP) and Surveillance Centre (RSC) databaseEngland, UK1999–2018192,303 (60.0)45.0 (16.8)51.7 (17.8)
18Gill 2021
[41]		4.4 years6658940615,29215,292MedStar Health systemUnited States-8955 (59)51 (18)50 (18)
19Grainge 2010
[42]		-6765483513,75671,672General Practice Research Database (GPRD)United KingdomNovember 1987–July 2001.45,295 (53)46·6 (18·1)46·1 (17·9)
20Ha 2009
[43]		4.1 years9968748017,48769,958MarketScan Commercial Claims and Encounters database (Thomson Reuters)United StatesJuly 2001–September 200648,787 (56)43.2 (18–59)43.3 (18–59)
21Heo MC 2021
[44]		-989323,19933,131198,825Health Insurance and Review Agency (HIRA) databaseSouth Korea2012–201613,013 (39.3)--
22Huang 2014
[45]		---18,39273,568National Health Insurance Research Database (NHIRD)Taiwan1998–201150,510 (54.9)44.5 (16.8)44.8 (16.6)
23Sun 2024
[18]		10 years46,85624,954206,455399,904Swedish National Patient Register (NPR), 1 biopsy record indicating IBD in the ESPRESSOSweden1969–2017263,992 (66)--
24Kang 2019
[46]		5.1 years--807040,350National Health Insurance (NHI) databaseSouth Korea2010–201416,169 (33.4)44.9 ± 13.145.0 ± 12.8
25Kappelman 2011
[47]		-35,29914,21149,799477,504Danish National Patient Registry (DNPR)Denmark1980–2007289,541 (55)--
26Keller JJ 2014
[48]		-516--2063Longitudinal
Health Insurance Database 2000 (LHID2000)		Taiwan1 January 2001 and 31 December 2005 --
27Kim 2022
[49]		5.03 ± 2.94 years31,18713,85045,037133,019Korean NHISKorea2004–201537.80%--
28Kirchgesner 2017
[50]		3.4 years (IQR:1.8–4.0)112,45497,708210,162-French National Hospital Discharge DatabaseFrance2008–2013113,157 (53.8)-40 years (28–53)
29Kristensen 2013
[51]		6.04 years13,622473220,795199,978National Patient Register, Danish Register of Medicinal Product Statistics, National Cause of Death RegisterDenmark1996–2009120,879 (54.7)43.1 (18.7)43.8 (18.7)
30Kristensen 2014
[52]		6.8 years 24,499236,275National Patient Register, Danish Register of Medicinal Product Statistics, Danish civil Registration SystemDenmark1996–2011140,557 (53.9)43.2 (18.7)43.1 (18.7)
31Lee MT 2021
[53]		 147516199485-Veterans wIth premaTure AtheroscLerosis (VITAL) registryUnited States2014–2015220,219 (13.8%)--
32Li 2023
[54]		13.7 years416621125789496,624UK BiobankUK2006 to 2010273,301 (54.0)56.5 ± 8.157.3 ± 7.9
33Lin TY 2015
[55]		---11,06743,765National Health Insurance Research Database
(NHIRD)		Taiwan2000–201025,099 (45.8)53.0(19.3)-
34Malham 2024
[21]		11.1 years (IQR: 5.9–18.0)2558264411,58199,665Danish healthcare registersDenmark1980–201861,923 (56)12.4 (7.7–15.3)12.6 (7.9–15.5)
35Nocerino A 2019
[56]		-841112919707880New York state death recordsUnited States1993–20105670 (57.56%)75.36 (16.87)72.85 (15.02)
36Olén O 2019
[57]		138,690 person-years467137809442-Swedish National Patient RegistrySweden1964–20144219 (44.7)-15.2 (5.4)
37Osterman 2011
[58]		4.6–4.7 years15,498982925,327144,605General Practice Research DatabaseUnited Kingdom-82,933 (51.8)49.150
38Prasada S 2020
[59]		3.6 years 507819,358Northwestern Medicine Enterprise Data Warehouse (NMEDW) (Northwestern University Clinical and Translational Sciences Institute, Chicago, Illinois) electronic health record dataUnited States2000–201910,446 (42.7%)48.60 (16.65)44.55 (16.49)
39Rothberg 2011
[60]		- 814241,924Premier’s PerspectiveUnited States1 January 2004–30 June 2005---
40Rungoe C
[61]		13 years19,990752128,8334,541,987Danish National Patient
Register (NPR)		Denmark1997–20092,222,553 (51.1)40.9 (19.5)38.3 (18.6)
41Setyawan 2021
[62]		- 34,68734,687MarketScan Commercial and Medicare Supplemental DatabasesUnited States2014–201818,880 (54.4)49.0 ± 16.149.0 ± 16.1
42Sinha A 2021
[63]		4.4 years 129010,289Northwestern Medicine Enterprise Data Warehouse (NMEDW) (Northwestern University Clinical and Translational Sciences Institute, Chicago, Illinois) electronic health record dataUnited States2000–201955.70%50.6 ± 15.647.9 ± 15.9
43Sun 2023
[64]		12.2 (6.8–18.7) years47,35425,25785,006406,987Swedish National Patient RegisterSweden1969–2019238,947 (48.6)42.3 ± 18.743.3 ± 19.2
44Sun 2024
[65]		12.4 years45,70924,30311,73781,749Swedish National Patient
Register (NPR)		Sweden1969–2017218,636 (47.1)41.6 ± 18.442.7 ± 18.9
45Tanislav 2021
[66]		- 11,94711,947from several general practicesGermany2000–201554.347.2 (16.2)47.2 (16.2)
46Tilly 2023
[22]		-406720616128-UK BiobankUK2006–2022270,804 (54.8)-58.0 (13) median age
47Tsai MS 2014
[67]		6.78 (3.59) years 11,82247,288National Health Insurance Research Database
(NHIRD)		Taiwan1998–201026,970 (45.6)52.3 (19.2)52.8 (19.3)
48Weng 2018
[68]		-2492686317831,780Tokyo Medical and Dental University (TMDU; Japan),
Asan Medical Center (AMC; South Korea),
National Taiwan University Hospital (NTUH; Taiwan)		Japan, South Korea, Taiwan2010–201513,004 (37.2)--
49Yarur AJ 2011
[69]		52 months183173356712Jackson Memorial Hospital medical recordsUnited StatesJanuary 1995–December 2009556 (51.69)45.11 (16.02)44.62 (15.82)
50Yuan 2023
[70]		12.0 years420522766481-UK BiobankUK2006–2010 --
51Zhu 2024
[10]		-186136355496-UK BiobankUKFrom 2006–2010 up until December 2019255,600 (56.2)-56.2 ± 8.1
52Bröms 2025
[71]		6.530,88116,24355,252536,067Swedish Healthcare RegistersSweden2007–202149.7%46 (19)
53Fang 2025
[72]		5.94--12,12612,126Taiwan National Health Insurance Research Database (NHIRD)Taiwan-44.69%49.19
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Shoaib, A.; Shahabi, M.; Shaikh, R.H.; Jamshed, M.M.; Ashraf, S.U.; Jahangir, F.; Arif, F.; Ali, S.; Hassan, S.A.; Rasheed, W.; et al. Beyond the Gut: Inflammatory Bowel Disease as a Driver of Cardiovascular and Thromboembolic Risk—A Systematic Review and Meta-Analysis of 1.4 Million Patients. Gastrointest. Disord. 2025, 7, 78. https://doi.org/10.3390/gidisord7040078

AMA Style

Shoaib A, Shahabi M, Shaikh RH, Jamshed MM, Ashraf SU, Jahangir F, Arif F, Ali S, Hassan SA, Rasheed W, et al. Beyond the Gut: Inflammatory Bowel Disease as a Driver of Cardiovascular and Thromboembolic Risk—A Systematic Review and Meta-Analysis of 1.4 Million Patients. Gastrointestinal Disorders. 2025; 7(4):78. https://doi.org/10.3390/gidisord7040078

Chicago/Turabian Style

Shoaib, Aqsa, Mariam Shahabi, Reyan Hussain Shaikh, Mian Muinuddin Jamshed, Syed Usama Ashraf, Faryal Jahangir, Faqeeha Arif, Soha Ali, Syed Adeel Hassan, Waqas Rasheed, and et al. 2025. "Beyond the Gut: Inflammatory Bowel Disease as a Driver of Cardiovascular and Thromboembolic Risk—A Systematic Review and Meta-Analysis of 1.4 Million Patients" Gastrointestinal Disorders 7, no. 4: 78. https://doi.org/10.3390/gidisord7040078

APA Style

Shoaib, A., Shahabi, M., Shaikh, R. H., Jamshed, M. M., Ashraf, S. U., Jahangir, F., Arif, F., Ali, S., Hassan, S. A., Rasheed, W., Jabeen, T., Mansoor, F., Khalid, S., & Khan, A. (2025). Beyond the Gut: Inflammatory Bowel Disease as a Driver of Cardiovascular and Thromboembolic Risk—A Systematic Review and Meta-Analysis of 1.4 Million Patients. Gastrointestinal Disorders, 7(4), 78. https://doi.org/10.3390/gidisord7040078

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