Cardiometabolic diseases in patients with inflammatory bowel disease: An evidence-based review

Abstract

Metabolic syndrome-comprising central adiposity, dyslipidaemia, insulin resistance, and hypertension-is a major risk factor for cardiometabolic diseases such as ischaemic heart disease, stroke, and type 2 diabetes. Its global prevalence is rising, largely driven by urbanization, sedentary lifestyles, and dietary changes. These same factors are also associated with the increasing incidence of inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis. Emerging evidence supports a potential biological link between chronic gastrointestinal inflammation and the later development of cardiometabolic disorders; a connection that is particularly relevant for patients with IBD. Comparative studies examining cardiometabolic risk associated with Crohn’s disease versus ulcerative colitis have reported inconsistent findings, likely due to confounding factors such as age, lifestyle, and comorbidities. This review summarizes current evidence linking IBD and cardiometabolic disorders, and highlights the need for clinicians to recognize cardiometabolic risk in patients with IBD. Future research should investigate whether treat-to-target strategies focused on controlling intestinal inflammation can simultaneously improve both long-term IBD and cardiometabolic outcomes.

Key Words: Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis; Metabolic syndrome; Obesity; Cardiovascular disease; Stroke; Metabolic liver disease; Cardiometabolic diseases; Gastrointestinal inflammation

Core Tip: Emerging evidence supports a biological link between chronic gastrointestinal inflammation and the development of cardiometabolic diseases later in life. This is particularly relevant for inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, which are chronic immune-mediated disorders of the gastrointestinal tract. Observational studies indicate that IBD may increase the risk of cardiometabolic diseases. However, the role of uncontrolled intestinal inflammation in exacerbating this risk-and whether treat-to-target strategies aimed at controlling inflammation in IBD could mitigate these comorbidities-remains unclear. This review provides clinicians with an evidence-based summary of the associations between IBD and cardiometabolic diseases.

INTRODUCTION

The metabolic syndrome, characterised by a cluster of disorders including dyslipidaemia, insulin resistance, hypertension, and obesity, is associated with an increased risk of cardiometabolic disease and higher rates of all-cause mortality[1-3]. The global prevalence of metabolic syndrome continues to rise, with estimates ranging from 11% to 35%, depending on regional variations[4,5]. Higher rates are observed in the Americas and Europe, while lower prevalence is reported in Japan and south-east Asia[6]. Contributing factors to this growing prevalence include urbanization, lower socioeconomic status, dietary patterns, and more sedentary lifestyles[7-12]. Interestingly, many of these same factors are implicated in the rising incidence of inflammatory bowel diseases (IBD)[13,14].

Emerging evidence suggests a potential biological link between chronic gastrointestinal inflammation and the later development of cardiometabolic diseases. This connection is particularly relevant for patients with Crohn’s disease and ulcerative colitis, which are chronic immune-mediated disorders of the gastrointestinal tract. Observational studies have indicated that IBD may increase the risk of cardiometabolic comorbidities[15-17]. Furthermore, associations between active IBD, clinical flares, the need for surgical interventions, and progressive disease complications are well-established[18,19]. However, the impact of uncontrolled intestinal inflammation on the development of cardiometabolic disorders in IBD patients and whether targeted treatment strategies aimed at controlling inflammation can reduce these risks remains unclear[20,21].

This review aims to provide an evidence-based summary of the associations between IBD and cardiometabolic diseases, emphasising the need for further research and clinical awareness of the interconnected nature of these conditions.

DEFINING METABOLIC SYNDROME

In 2005, the International Diabetes Federation (IDF)[22,23] defined metabolic syndrome as the presence of central adiposity, identified by a body mass index (BMI) of more than 30 kg/m², or increased ethnicity-based waist circumference, in addition to two or more of the following criterion: Fasting glucose > 100 mg/dL (5.55 mmol/L) or on anti-hyperglycaemic therapy, triglycerides > 150 mg/dL (1.69 mmol/L) or on lipid lowering therapy or high density lipoprotein cholesterol (HDL-C) < 40 mg/dL (1.03 mmol/L) in men and HDL-C < 50 mg/dL (1.29 mmol/L) in women, blood pressure ≥ 130/80 mmHg or on antihypertensive therapy. The National Cholesterol Program Adult Treatment Panel III (NCEP ATP III)[1,23] subsequently proposed that central adiposity be changed from a mandatory to an optional inclusion criterion; thereby advocating that all metabolic risk factors be weighted equally, and that a diagnosis of metabolic syndrome require any three metabolic risk factors. This reflects heterogeneity in how metabolic syndrome has been defined (Table 1).

Table 1 Definitions of metabolic syndrome[22,199].

	NCEP ATP III (2005)[199]	IDF (2005)[22]
Criteria required	Three of five criteria below	Central obesity required plus two other required criteria
Obesity	Waist circumference: > 40 inches (101 cm) in men; > 35 inches (88 cm) in women	Waist circumference based on ethnicity1
Insulin resistance-serum glucose	Fasting serum glucose ≥ 100 mg/dL (≥ 5.6 mmol/L); or medical therapy for hyperglycaemia	Fasting serum glucose ≥ 100 mg/dL (≥ 5.6 mmol/L); or medical therapy for hyperglycaemia
Dyslipidaemia-serum triglycerides	Serum triglyceride level ≥ 150 mg/dL (> 1.7 mmol/L); or medical therapy for dyslipidaemia	Triglyceride level ≥ 150 mg/dL (> 1.7 mmol/L); or medical therapy for dyslipidaemia
Dyslipidaemia-serum HDL-C	Serum HDL-C: < 40 mg/dL (< 1.03 mmol/L) in men; < 50 mg/dL (< 1.29 mmol/L) in women; or medical therapy for dyslipidaemia	Serum HDL-C: < 40 mg/dL (< 1.03 mmol/L) in men; < 50 mg/dL (< 1.29 mmol/L) in women; medical therapy for dyslipidaemia
Hypertension	Systolic blood pressure ≥ 130 mmHg; or diastolic blood pressure ≥ 80 mmHg; or medical therapy for hypertension	Systolic blood pressure ≥ 130 mmHg; or diastolic blood pressure ≥ 80 mmHg; or medical therapy for hypertension

¹See Table 3 for reference details.

NCEP ATP III: National Cholesterol Program Adult Treatment Panel III; IDF: International Diabetes Federation; HDL-C: High density lipoprotein cholesterol.

The metabolic syndrome has been associated with unfavourable cardiometabolic sequalae such as ischaemic heart disease (IHD), ischaemic stroke, peripheral vascular disease (PVD), cirrhosis, and cancer. Several of these cardiometabolic disorders have been shown to occur more frequently in patients with IBD compared to the general population (Figure 1 and Table 2)[15,24-29]. These findings have also been replicated across other immune mediated inflammatory disorders (IMID), implying that a pro-inflammatory state may play a role in the development of metabolic syndrome[30].

Figure 1 Evidence-based associations between cardiometabolic disorders and inflammatory bowel disease. Positive association (+), negative associations (-) unknown association (?) [196-198].

Table 2 Observational studies examining prevalence of metabolic disorders in patients with inflammatory bowel disease[22,32-38,40,44,47,49,50,117,118,122,188,195,197,200-204].

Ref.	Country	Study type	Reference criteria	Total number of IBD patients (CD/UC/IBD-U)	Prevalence in IBD (%)	Prevalence in CD (%)	Prevalence in UC (%)
Metabolic syndrome
Nagahori et al[32]	Japan	Prospective, cross-sectional cohort	NCEP-ATP III[188]	102 (28/74/-)	18.6	7.1	23.0
Yorulmaz et al[38]	Turkey	Prospective cross-sectional cohort	IDF[22]	177 (62/115/-)	25.4	17.7	29.5
Sourianarayanane et al[34]	United States	Retrospective cohort	NCEP-ATP III[188]	217 (110/107/-)	16.6
Fitzmorris et al[200]	United States	Retrospective cohort	IDF[22]	868 (868/-/-)		4.3
Carr et al[35]	United States	Retrospective cohort	NCEP-ATP III[188]	84 (60/24/-)	23.0	20.0	29.0
Sartini et al[201]	Italy	Retrospective cohort	NCEP-ATP III[188]	78 (42/36/-)	23.1
Dragasevic et al[37]	Serbia	Prospective, cross-sectional cohort	NCEP-ATP III[188] and IDF[22]	104 (50/54/-)	32.7	36.0	29.6
Magrì et al[36]	Italy	Prospective cohort	NCEP-ATP III[188]	178 (83/95/-)	19.1
Jovanovic et al[202]	Serbia	Retrospective cohort	NCEP-ATP III[188]	89 (-/89/-)			81.0
Kang et al[33]	Korea	Retrospective cohort	NCEP-ATP III[188]	443 (274/169/-)	10.6
Obesity
Long et al[44]	United States	Prospective cross-sectional cohort	BMI ≥ 30 kg/m2	1598 (paediatric population) (1027/571/-)	23.6	20.0	30.1
Nic Suibhne et al[50]	Ireland	Prospective case-control study	BMI ≥ 30 kg/m2	100 (100/-/-)		17.0
Flores et al[49]	United States	Retrospective cohort	BMI ≥ 30 kg/m2	581 (297/284/-)	32.7	30.3	35.2
Seminerio et al[47]	United States	Retrospective cohort	BMI ≥ 30 kg/m2	1494 (860/634/-)	31.5	27.0	32.0
Elangovan et al[40]	United States	Retrospective cohort	BMI ≥ 30 kg/m2	286, 760 (-/-/-)	37.3	36.9	38.5
Metabolic fatty liver disease
Martínez-Domínguez et al[117]	Spain	Prospective cross-sectional cohort	MASLD[197]	646 (-/-/-)	45.7
Zhang et al[122]	United Kingdom	Prospective cross-sectional cohort	MASLD[197]	4203 (1217/2642/344)	36.4
Oliveira et al[203]	Brazil	Prospective cross-sectional cohort	MASLD[197]	140 (89/51/-)	50.7	44.9	43.1
McHenry et al[118]	United States	Prospective cross-sectional cohort	NAFLD[195]	363 (363/-/-)			39.7
Hyun et al[204]	Korea	Prospective cross-sectional cohort	NAFLD[195]	3356 (1129/2227/-)	16.7	11.8	19.2
Zhang et al[123]	United Kingdom	Prospective cross-sectional cohort	MASLD[197]	4622 (1313/2914/-)	38.1

IBD: Inflammatory bowel disease; CD: Crohn’s disease; UC: Ulcerative colitis; IBD-U: Inflammatory bowel disease unclassified; NAFLD: Non-alcoholic fatty liver disease; MAFLD: Metabolic dysfunction associated fatty liver disease, MASLD: Metabolic dysfunction associated steatotic liver disease; NCEP ATP III: National Cholesterol Program Adult Treatment Panel III; IDF: International Diabetes Federation; BMI: Body mass index.

METABOLIC SYNDROME AND IBD

A 2024 systematic review and meta-analysis by Shen et al[31] estimated the pooled prevalence of metabolic syndrome in patients with IBD patient to be 21.9% [95% confidence interval (CI): 18.0% to 25.8%] on the basis of 273 cases of metabolic syndrome among 1544 patients with IBD derived from nine studies. This suggests that 1 in 5 patients with IBD had features of metabolic syndrome in this study[31]. These data were derived from nine studies, comprising IBD patients across North America, Europe and Asia, with lower rates of metabolic syndrome described across Asian [Japan (18.6%); Korea (10.6%)][32,33] compared to North American (16.6%-23%)[34,35] and European (19.1%-32.7%)[36,37] cohorts. This implies that factors beyond IBD, perhaps related to environmental, lifestyle and patient factors, may contribute to the development and sequelae of metabolic syndrome. Although the majority of studies applied the NCEP ATP III definition of metabolic syndrome, heterogeneity in how metabolic syndrome was defined, in conjunction with the relatively modest number of IBD patients included in the calculation of pooled prevalence, reflect obvious limitations. Nevertheless, the pooled prevalence reported by Shen et al[31] remains comparable with geographical variability data across non-IBD cohorts which have also documented lower rates of metabolic syndrome across Asian (ranging between 8.4% to 19.4%) relative to North American and European (ranging between 9.7% to 41.9%) cohorts[6].

Several studies have also sought to examine whether the risk of developing metabolic syndrome differs between patients with Crohn’s disease and ulcerative colitis. Carr et al[35] observed no differences (20.00% vs 29.16%, P = 0.36) in the prevalence of metabolic syndrome between patients with Crohn’s disease (n = 60) and ulcerative colitis (n = 24), respectively, with co-existing non-alcoholic fatty liver disease (NAFLD). Nagahori et al[32], examined 107 patients with quiescent IBD and demonstrated a non-significant difference between the frequencies of metabolic syndrome between patients with ulcerative colitis compared to Crohn’s disease, respectively 23.0% vs 7.1% (P = 0.089). These findings contrast with a Turkish cohort comprising 177 patients with IBD (62 Crohn’s disease, 115 ulcerative colitis), which documented that patients with ulcerative colitis were more likely to develop metabolic syndrome compared to patients with Crohn’s disease (29.5% vs 17.7%, P < 0.01)[38]. Of note, patients with ulcerative colitis were noted to be older than those with Crohn’s disease across the latter two studies, perhaps implying that age may confound the association between metabolic syndrome being more common in patients with ulcerative colitis[32,38,39]. On the basis of current data, a biological basis for differences in the prevalence of metabolic syndrome between patients with Crohn’s disease and ulcerative colitis remains unclear, but may be related to differences in disease biology, age of onset, and other factors[32].

A 2022 retrospective analysis of United States of America population-level data between 2010 to 2019 documented that the proportion of adult patients with IBD who had co-existing metabolic co-morbidities was reported to have increased between 2010 to 2019[40]. This was characterised by proportional increases in obesity (19.7%-30.1%), sleep apnoea (4.1%-10.8%), hypertension (25.1%-33.9%), type II diabetes (8.3%-12.5%), and hyperlipidaemia (22.1%-32.2%, all P < 0.0001)[40]. This emphasises the need to evaluate the impact of individual cardiometabolic disorders in patients with IBD which will be the focus of the following section.

Obesity

Obesity represents a key component of metabolic syndrome and is typically characterised by central adiposity, defined on the basis of either waist circumference or BMI. The World Health Organization defines obesity as a BMI above 30 kg/m² which does not account for body composition[41]. This contrasts with both the IDF and NCEP ATP III definitions of metabolic syndrome which include assessments of waist circumference (Table 3), which provides a better account of visceral adiposity than BMI alone, in their definitions of central adiposity[42]. This is of particular importance given that visceral adiposity has been shown to be key driver of morbidity and mortality, including cardiometabolic complications[42,43].

Table 3 Definitions of obesity based on waist circumference in men and women stratified by reference population[199,205-210].

Reference population	Reference criteria	Waist circumference threshold for men	Waist circumference threshold for women
Europoid	IDF[199]	≥ 94 cm	≥ 80 cm
Caucasian	WHO[205]	≥ 94 cm = increased risk; ≥ 102 cm = higher risk	≥ 80 cm = increased risk; ≥ 88 cm = higher risk
United States of America	ATP III[206]	≥ 102 cm	≥ 88 cm
Canada	Health Canada[207,208]	≥ 102 cm	≥ 88 cm
European	European Cardiovascular Societies[209]	≥ 102 cm	≥ 88 cm
Asian	IDF[199] and WHO[205]	≥ 90 cm	≥ 80 cm
Japanese	Japanese Obesity Society[210]	≥ 85 cm	≥ 90 cm
China	Cooperative Task Force	≥ 85 cm	≥ 90 cm
Middle East/Mediterranean	IDF[199]	≥ 94 cm	≥ 80 cm
Sub-Saharan Africa	IDF[199]	≥ 94 cm	≥ 80 cm
Ethnic Central and South American	IDF[199]	≥ 90 cm	≥ 80 cm

IDF: International diabetes federation; WHO: World Health Organization, ATP III: Adult Treatment Panel III.

Table adapted from Alberti et al[23]. Citation: Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr; International Diabetes Federation Task Force on Epidemiology and Prevention; Hational Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120: 1640-1645. Copyright ©American Heart Association, Inc 2025. The authors have obtained the permission for table using (Supplementary material).

Population-level data which examined temporal trends in the diagnosis of obesity in patients with IBD, documented an increase in rates of obesity between 2010 (19.7%) and 2019 (37.3%) amongst patients with IBD [ulcerative colitis (38.5%) vs Crohn’s disease (36.9%), P < 0001][40]. These findings are corroborated by cross-sectional studies which have reported that between 15%-40% of IBD patients are obese, with an additional 20%-40% considered overweight[44-50]. Collectively, these data dispel the premise that IBD is a malabsorptive disorder that cannot summarily be associated with obesity.

Obesity itself has been described as a pro-inflammatory state, and has thus been suggested as a possible co-factor in the pathogenesis of IBD, albeit data remains conflicting[14]. When examining studies using BMI as a measure of obesity, a pooled analysis of five prospective cohorts encompassing 601009 individuals, isolated an increased risk of Crohn’s disease, but not ulcerative colitis, amongst obese (BMI ≥ 30 kg/m²) individuals [adjusted hazard ratio (aHR) = 1.34, 95%CI: 1.05-1.71] compared to those with a BMI ≥ 18 kg/m² and < 30 kg/m²[51]. These findings were reproduced in a large 2019 meta-analysis that included one million pooled individuals, primarily from European and North American cohorts, reported an increased risk of Crohn’s disease but not ulcerative colitis in those with a BMI above 30 kg/m² (aHR = 1.42, 95%CI: 1.18-1.71)[52]. Similarly, a United States based study of 111489 women within the general population found a similar association between obesity and Crohn’s disease incidence (aHR = 2.33, 95%CI: 1.15-4.69) irrespective of age (aHR = 1.58, 95%CI: 1.01-2.47)[53]. A more recent study across a United Kingdom population reported statistically significant increased risk of both Crohn’s disease [increased BMI hazard ratio (HR) = 1.16, P < 0.001, increased waist circumference HR = 1.17, P < 0.001] and ulcerative colitis (increased BMI HR = 1.09, P < 0.001, increased waist circumference = 1.09, P < 0.001) in patients with increased BMI and waist circumference[54]. Conversely, other smaller studies have found no association, including a Danish study of 75008 women from the general population, identifying no increased risk of Crohn’s disease with obesity (HR = 1.00, 95%CI: 0.96 to 1.04, P_trend = 0.89)[55]. Similarly, a Norwegian study, encompassing 334 IBD cases from a population 55896 participants, documented that there was no increased risk of either Crohn’s disease or ulcerative colitis associated with increases in BMI over a 10 year period[56]. On the basis of these studies, it remains difficult to attribute a direct relationship between obesity and the subsequent development of IBD.

Nevertheless, the presence of obesity has been shown to have deleterious effects on IBD outcomes. A 2023 systematic review, which evaluated associations between radiological body composition measurements in patients with Crohn’s disease and disease related outcomes, described a higher incidence of unfavourable outcomes, including disease recurrence, need for surgical treatment, and higher rates of post-operative complications, in 4219 patients with Crohn’s disease[57]. These findings were replicated in a retrospective study, conducted between 2010 and 2022, with patients included if they had a disease flare, with subsequent computed tomography imaging and colonoscopy performed within 30 days of this index flare. The primary outcome was the time to next disease flare, with a significantly higher risk of flare in those with higher visceral to subcutaneous fat; visceral fat to subcutaneous fat ratio > 1, [HR = 4.8 (95%CI: 1.7-13, P < 0.01)][58]. The limited data available does not suggest a higher risk of worsening perianal disease with obesity, with a cross-sectional study of 704 Crohn’s disease patients, finding no association between obesity, defined by BMI ≥ 30 kg/m², and the risk of perianal fistulas (20.6% of obese, 19.4% of non-obese, P = 0.719), complex fistulising disease (88.9% in obese, 78.7% in non-obese, P = 0.144), or need for perianal surgery[59]. Though this study is limited by several factors including its retrospective nature, and the use of BMI as a measure of obesity.

Obesity appears to be associated with a higher rate of post-operative complications in IBD[60]. A 2023 study identified that visceral fat, evaluated on the basis of body composition imaging, increased the risk of post-operative venous thromboembolism [odds ratio (OR) = 1.02, P = 0.028] in patients with Crohn’s disease[61]. Similarly, a large retrospective study of 6601 non-obese and 671 obese (defined by BMI ≥ 30 kg/m²) IBD patients, reported increased rates of post-operative complications following bowel resection in obese patients with IBD. This included higher rates of acute kidney injury (6.7% in obese vs 3.0% in non-obese individual, P = 0.006) and higher rates of post operative intensive care unit admission (6.1% in obese vs 2.7% in non-obese)[62]. However, another study failed to document an increased risk of post-operative complications, anastomotic recurrence or anastomotic leak associated with increased visceral fat across 223 patients with Crohn’s disease following ileocaecal resection over a 10 year period of follow-up[63].

Though a direct correlation between obesity and IBD is unfounded, there is sufficient data to observe that patients with IBD are not immune to the increased rates of obesity as seen among the general population with the current obesity epidemic. Undoubtably, this will lead to poorer general health outcomes for IBD patients, but may also lead to significant IBD related complications.

Insulin resistance and type 2 diabetes

Data pertaining to the prevalence of insulin resistance in patients with IBD remains limited. In fact, the largest study to-date, included 151 patients with IBD, and noted no differences in characteristics of insulin resistance, defined on the basis of elevated C-peptide and glucose levels, between IBD patients and non-IBD patients[64]. However, among IBD patients that did have evidence of insulin resistance, traditional metabolic risk factors such as elevated waist circumference, hypertension and elevated serum triglycerides were associated with an increased risk of insulin resistance[64]. Though not shown in an IBD population, studies using similar methodologies have demonstrated higher rates of insulin resistance in patients with other autoimmune conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA)[65,66]. Both SLE and RA demonstrated independent disease specific associations with insulin resistance, even after traditional metabolic risk factors and steroid exposure were accounted for, so it is plausible that a similar association between IBD and insulin resistance exists although more studies are needed. This is under the guise that chronic inflammation can stimulate insulin resistance, indirectly via inflammatory cytokines that modulate insulin receptors[67].

Despite studies having not demonstrated associations between IBD and insulin resistance, a greater incidence of type 2 diabetes mellitus has been reported among IBD patients compared to the general population. A Danish IBD population-based study, that applied coding data from the entire population (n = 6028844), with 65180 IBD patients, documented a higher incidence rate of type 2 diabetes mellitus in IBD (4.67 per 1000 years) compared to the population incidence rate of 3.02 per 1000 years[68]. The study reported a higher incidence of type 2 diabetes in IBD patients who were diagnosed with IBD over the age of 40, but did not document any differences in the incidence of type 2 diabetes between IBD-subtypes and between corticosteroid naïve and experienced patients[68]. However, the study’s design limited identification of metabolic risk factors such as increased BMI and waist circumference, which may have contributed to the development of diabetes. A Taiwanese population-based study, applied a similar approach to identify patients with co-existing type 2 diabetes mellitus and IBD, found no differences between the incidence rates of diabetes among IBD and non-IBD (1.34 vs 1.30 per 100 person-years; 95%CI: 0.94-1.14; P = 0.531) populations, respectively[69].

A 2023 United Kingdom based biobank study, consisting of prospectively collected data of over 500000 United Kingdom citizens aged between 37 and 73 years of age between 2006 and 2010, documented an association between type 2 diabetes and both IBD subtypes, specifically Crohn’s disease (HR = 2.11, 95%CI: 1.67-2.67, P < 0.001) and ulcerative colitis (HR = 1.76, 95%CI: 1.47-2.11, P < 0.01)[16]. This study also illuminated a possible bidirectional relationship between type II diabetes and IBD, implying that the risk of developing IBD may be increased in patients with type 2 diabetes (HR = 1.61, 95%CI: 1.26-2.06, P < 0.001), and vice versa[16].

A meta-analysis of observational studies documented that co-existing type 2 diabetes was not associated with an increased risk of IBD related complications (OR = 1.12, 95%CI: 0.52-2.45) or all-cause mortality (OR = 1.52, 95%CI: 0.61-3.81), though was associated with a higher frequency of IBD related hospitalisation (OR = 2.54, 95%CI: 2.17-2.98)[70]. However, infectious complications such as pneumonia (OR = 1.71, 95%CI: 1.38-2.14), urinary tract infections (OR = 1.93, 95%CI: 1.51-2.47) and sepsis (OR = 1.56, 95%CI: 1.06-2.29) were noted to be higher amongst IBD patients with co-existing diabetes relative to those who did not[70].

Based on the above literature, it is unclear if IBD predilects the development of insulin resistance and type 2 diabetes. Overall, the data is scant in this regard, and at present clinicians should be aware of the potential development of insulin resistance and diabetes among the IBD subpopulation, due to many being exposed to medications that may contribute to diabetes development such as corticosteroids.

Dyslipidaemia

A 2023 systematic review identified 36 studies that evaluated lipid profiles in patients with IBD[71]. These studies documented significantly lower total cholesterol [weighted mean difference (WMD) = -0.506, P < 0.001] in patients with IBD compared to healthy controls[71]. HDL-C (WMD = -0.122, P < 0.004) and low density lipoprotein cholesterol (LDL-C) (WMD = -0.371 P < 0.001) levels were also significantly lower in IBD patients across 29 studies, while there were no significant differences in triglyceride (WMD = -0.077, P = 0.161) levels between IBD and non-IBD patients across 33 studies[71]. Though both IBD and healthy control patients appeared to have relatively normal lipid profiles, subgroup analysis, undertaken on the basis of IBD-subtype, was suggestive of lower total cholesterol levels in patients with Crohn’s disease compared to ulcerative colitis (WMD = -0.349, P < 0.0001)[71]. No significant differences were observed across other lipid parameters such as HDL-C, LDL-C and triglyceride levels[71]. The activity of IBD, through cycles of activity and remission, may also impact the lipid profile of patients with IBD. Studies have documented reductions in total cholesterol (WMD = -0.454, P = 0.001) and LDL-C (WMD = -0.225 P = 0.045) levels during periods of clinically active IBD relative to periods of remission, although similar differences were not observed in HDL-C (WMD = -0.248, P = 0.099) and triglycerides (WMD = -0.129, P = 0.08)[71]. However, dyslipidaemia may also be associated with more severe IBD, defined on the basis of clinical and endoscopic disease activity, and elevated high sensitivity C-reactive protein[72]. The pathological mechanisms behind alterations in lipid profiles in IBD, and chronic inflammation, is poorly understood. Hence associations between dyslipidaemia and disease activity in patients with IBD still remain to be clarified.

Despite largely favourable lipid profiles, patients with IBD have been documented to have a higher risk of cardiovascular complications[73]. This paradox, termed the “lipid paradox”, insinuate that cardiovascular complications in patients with IBD may be driven by non-traditional atherosclerotic pathways. The recent evaluation of metabolomic profiles of patients with IBD indicated that smaller LDL particles, such as LDL-6, may be associated with an increased risk of unstable atherosclerotic plaques[74,75]. This indicates that higher concentrations of smaller LDL molecules, as yet unmeasured via traditional assays of LDL, may account for increased cardiovascular risk in patients with IBD.

Cardiovascular diseases in patients with IBD

A higher incidence of cardiovascular events has been reported in patients with autoimmune disorders, including IBD (Table 4). A United Kingdom based study, encompassing 22 million individuals, reported a higher incidence of cardiovascular events in patients with an autoimmune disorder (HR = 1.56, 95%CI: 1.52-1.59)[76]. A 2020 meta-analysis of IBD patients documented increased rates of cardiovascular disease; specifically cerebrovascular disease (HR = 1.25, 95%CI: 1.08-1.44), coronary heart disease (HR = 1.17, 95%CI: 1.07-1.27) and myocardial infarction (HR = 1.12, 95%CI: 1.05-1.21)[77]. A 2023 study evaluated the impact of IBD subtype on cardiovascular outcomes using Mendelian randomisation in over 5000 IBD patients, reporting differences in the cardiovascular complication profiles of patients with Crohn’s disease and ulcerative colitis compared to a cohort of healthy controls[16]. Crohn’s disease was associated with higher rates of heart failure (HR = 1.72, 95%CI: 1.22-2.42, P = 0.002) compared to healthy controls, while patients with ulcerative colitis were observed to have a higher associated risk of myocardial infarction (HR = 1.29, 95%CI: 1.03-1.62, P = 0.027), ischaemic stroke (HR = 1.59, 95%CI: 1.16-2.14, P = 0.003) and heart failure (HR = 1.38, 95%CI: 1.07-1.80, P = 0.015) compared to healthy controls[16].

Table 4 Observational studies examining the risk of cardiovascular disorders in patients with inflammatory bowel disease[16,98,99].

Ref.	Country	Study type	Total number of IBD patients (CD/UC/IBD-U)	Risk in IBD vs non-IBD HR (95%CI)	Risk in CD vs non-IBD HR (95%CI)	Risk in UC vs non-IBD HR (95%CI)
Ischaemic heart disease
Zhu et al[16]	United Kingdom	Prospective cross-sectional cohort	5496 (1861/3635)		HR = 0.93 (0.64-1.36)	HR = 1.29 (1.03-1.62)
Heart failure
Aniwan et al[99]	United States	Retrospective cohort	736 (339/397/-)	aHR = 2.03 (1.36-3.03)	aHR = 1.73 (0.98-3.07)	aHR = 2.06 (1.18-3.65)
Zhu et al[16]	United Kingdom	Prospective cross-sectional cohort	5496 (1861/3635/-)		HR = 1.72 (1.22-2.42)	HR = 1.38 (1.07-1.80)
Sun et al[98]	Sweden	Prospective cross-sectional cohort	81749 (24303/45709/11737)	aHR = 1.19 (1.15-1.23)	aHR = 1.28 (1.20-1.36)	aHR = 1.14 (1.09-1.19)
Ischaemic stroke
Zhu et al[16]	United Kingdom	Prospective cross-sectional cohort	5496 (1861/3635/-)		HR = 1.32 (0.82-2.12)	HR = 1.59 (1.16-2.14)

IBD: Inflammatory bowel disease; CD: Crohn’s disease; UC: Ulcerative colitis; IBD-U: Inflammatory bowel disease unclassified; HR: Hazard ratio; aHR: Adjusted hazard ratio; CI: Confidence interval.

Whether atherosclerotic-related inflammation may confer a higher risk of subsequent IBD has been studied. A large Swedish nationwide case-control study that included 56212 individuals with IBD and 531014 controls, sought to determine whether patients who experienced an atherosclerotic-related condition, defined as a myocardial infarction, thromboembolic stroke, or atherosclerosis itself, were more likely to develop IBD over a 19 year follow-up period[78]. This study documented that patients who were exposed to an atherosclerotic-related condition were more likely to develop IBD (OR = 1.30, 95%CI: 1.24-1.37), including Crohn’s disease (OR = 1.37, 95%CI: 1.26-1.48) and ulcerative colitis (OR = 1.27, 95%CI: 1.20-1.35), particularly among older adults.

The following sections will evaluate associations between IBD and common cardiovascular complications such as IHD, congestive cardiac failure, ischaemic stroke, and PVD.

IHD: The general mechanism of IHD is the formation of atherosclerotic plaques, which occur in the context of traditional cardiovascular risk factors including hypertension, diabetes, and hyperlipidaemia[79]. In IBD, additional risk factors are proposed to increase the burden of IHD including; activation of prothrombotic protein plasminogen activator inhibitor-1, increased production of radical oxygen species and nitric oxide leading to endothelin dysfunction, and increases in circulating lipopolysaccharides due to gut mucosal barrier breakdown promoting atherosclerosis, and overexpression of matrix metalloproteinases causing coronary vessel stiffening[80-84].

Although the prevalence of IHD in patients with IBD remains unclear, several studies support the notion that IBD patients remain at higher risk of atherosclerotic complications such as acute coronary syndromes. This is supported by a 2023 meta-analysis which observed rates of acute coronary syndrome, defined as either unstable angina or myocardial infarction, to be slightly increased in patients with IBD (HR = 1.23, 95%CI: 1.08-1.41)[85]. In the same year, another meta-analysis evaluated the risk of myocardial infarction in patients with IBD, reporting that there was an increased risk of myocardial infarction across both IBD subtypes [Crohn’s disease (HR = 1.36, 95%CI: 1.12-1.64); ulcerative colitis (HR = 1.24, 95%CI: 1.05-1.46)][86]. In 2024, Takagi et al[87] studied the incidence rates of major adverse cardiac events (MACE) in Japanese patients with ulcerative colitis using Japanese administrative claims data, reporting a cumulative incidence rate of MACE of 2.86% (95%CI: 1.89-4.32) over 120 months.

Traditional risk factors are associated with the development of IHD in patients with IBD. A Japanese study identified older age (> 65 years) (HR = 4.56, 95%CI: 2.79-7.45), presence of diabetes (HR = 1.71, 95%CI: 1.03-2.84) and atrial fibrillation (HR = 2.76, 95%CI: 1.19-6.41) to be associated with increased cumulative incidence rate of MACE[87]. Similar findings were also described in a retrospective multi-centre Chinese cohort study of 1435 patients with IBD, which documented that the risk of IHD in patients with IBD was higher in Crohn’s disease (OR = 2.69, 95%CI: 2.02-3.57) and ulcerative colitis (OR = 1.73, 95%CI: 1.20-2.51) across all ages compared to matched non-IBD patients[88]. Notably, the risk of IHD was observed to peak in IBD patients between the ages of 18-35 years across both Crohn’s disease (OR = 6.33, 95%CI: 3.29-12.16) and ulcerative colitis (OR = 3.00, 95%CI: 1.18-7.60) relative to matched non-IBD subjects[88]. Contrary to general population data, smoking was not associated with an increased risk of IHD, and female patients with Crohn’s disease (OR = 3.15, 95%CI: 1.77-5.61) and ulcerative colitis (OR = 7.35, 95%CI: 4.52-11.96) were noted to have a higher risk of IHD, in this study[88]. Similarly, IBD appears to increase the risk of atherosclerosis even at younger ages. This observation has also been identified in a large registry study of patients with IBD, with a higher prevalence of premature (age ≤ 55) or extremely premature (age < 40) ischaemic atherosclerotic events in patients with IBD compared to healthy controls; premature (OR = 1.14, 95%CI: 1.08-1.21) and extremely premature (OR = 1.82, 95%CI: 1.52-2.17)[89].

Beyond traditional risk factors, IBD disease activity may also be associated with the development of IHD. This was described by a Danish study in which IBD flares (risk ratio = 1.49, 95%CI: 1.16-1.93) and periods of persistent disease activity (risk ratio = 2.05, 95%CI: 1.58-2.56) were observed to be associated with an increased risk of myocardial infarction (risk ratio = 1.17, 95%CI: 1.05-1.31) in patients with IBD[90]. Clinically active IBD was also described to increase the frequency of acute arterial events, defined as myocardial infarction or ischaemic stroke, among a cohort of 30 French patients with IBD (OR = 12.3, 95%CI: 2.8-53.6)[91]. The study also suggested that an elevated C-reactive protein (> 5 mg/L) was associated with an increased risk of ischaemic stroke or myocardial infarction (OR = 3.2, 95%CI: 1.2-8.5). The post-event course of IBD patients who encounter an ischaemic cardiac event does not appear to differ from that of non-IBD patients. This was demonstrated by a French case-control study, with 246 IBD patients and 1470 age-sex matched controls, which reported all-cause mortality (9% vs 8.3%, P = 0.729) and frequency of rehospitalisation with heart failure (0.3% vs 3.5%, P = 0.846) following an ischaemic cardiac event to be similar between IBD and non-IBD patients[92]. However, a 2021 study of 70 patients with IBD who underwent percutaneous coronary intervention for IHD, indicates that patients with IBD may be subject to more frequent readmission for acute coronary syndrome within 12 months compared to non-IBD individuals (34.3% vs 25.5% P < 0.0001)[93]. This may indicate that the severity and complexity of IHD may differ between IBD and non-IBD patients.

The literature is forthcoming in suggesting a higher risk of IHD among patients with IBD. Notably, beyond traditional cardiovascular risk factors, IBD disease activity correlates with higher rate of IHD events. This is supported by studies in the cardiovascular space that have suggested that systemic and local inflammation may play a significant role in the development of IHD[94,95]. This may suggest that a treat-to-target approach focused on improving IBD outcomes may also dampen the risk cardiovascular complications.

Heart failure: Heart failure can occur as a complication of IHD as well as via other pathogenic mechanisms. There is an association between dysregulation of immune and inflammatory responses in the pathogenesis of heart failure which may place individuals with IBD at higher risk of this condition. This is mediated via inflammatory cytokines that can subjugate cardiac remodelling[96,97]. Data regarding the prevalence of heart failure in patients with IBD remains limited, however several studies have evaluated whether an association between IBD and heart failure exists. A large Swedish nationwide cohort of 81 749 patients with IBD reported that IBD was associated with a moderately increased risk of heart failure compared to patients without IBD (aHR = 1.19, 95%CI: 1.15-1.23)[98]. The study calculated an incident rate of 50.3 per 10000 person years for patients with IBD, compared to 37.9 per 10000 person years among non-IBD controls over 12.4 years of median follow-up[98]. This increased risk was observed across all IBD subtypes, including Crohn’s disease [incidence rate = 46.9 vs 34.4; aHR = 1.28 (95%CI: 1.20-1.36)], ulcerative colitis [incidence rate = 50.1 vs 39.7; aHR = 1.14 (95%CI: 1.09-1.19)], and IBD-unclassified [incidence rate = 60.9 vs 39.0; aHR = 1.28 (95%CI: 1.16-1.42)][98]. A smaller study that included 736 IBD patients documented that the relative risk of heart failure was increased among patients with ulcerative colitis (aHR = 2.06; 95%CI: 1.18-3.65) but not Crohn’s disease, as well as IBD patients exposed to systemic corticosteroids (aHR = 2.51; 95%CI: 1.93-4.57)[99]. The cumulative incidence of heart failure in IBD patients across this study was higher than age and sex-matched controls, and similar to a Swedish study, in which IBD was identified as an independent risk factor for heart failure development with an aHR = 2.03 (95%CI: 1.36-3.03)[99].

Few studies have evaluated whether the presence of heart failure is associated with less favourable IBD outcomes. A United States based study that utilised a large institutional database, consisting of 2449 patients with IBD and an additional 271 with IBD and concomitant heart failure, sought to evaluate the impact of heart failure on IBD outcomes and disease course[100]. This study indicated that IBD patients with co-existing heart failure had higher risk of requiring an IBD-related hospitalisation [HR = 1.42 (95%CI: 1.2-1.69)], experiencing an IBD flare [HR = 1.32 (95%CI: 1.09-1.58)] and complications [HR = 1.7 (95%CI: 1.33-2.17)], compared to IBD patients without heart failure[100]. These findings reflect that IBD patients with co-existing heart failure are likely to experience more unfavourable IBD outcomes than those without heart failure. Moreover, the mortality risk of IBD patients with co-existing heart failure was shown to be higher than IBD patients without heart failure, but similar to those of patients with heart failure without IBD[100]. This may imply that the increased mortality is more likely to be conferred by heart failure rather than co-existing IBD.

It is difficult to determine whether the higher incidence of heart failure in patients with IBD is due to the disease itself. Indeed, a plausible pathophysiological mechanism exists that may underpin the higher incidence, though these findings may also occur in the context of higher rates of IHD amongst individuals with IBD.

Ischaemic stroke: In view of the shared pathophysiology with IHD, patients with IBD have also been suggested to have a higher risk of atherosclerotic and thromboembolic ischaemic stroke than the general population. This was demonstrated in a 2025 meta-analysis, that included pooled outcomes from 2.8 million patients across 13 studies, which reported that patients with IBD had an increased risk of ischaemic stroke [pooled HR = 1.3 (95%CI: 1.21-1.39, P < 0.001)] compared to non-IBD patients, with no differences observed between sexes[101]. This risk was also observed across IBD subtypes of Crohn’s disease [HR = 1.35 (95%CI: 1.22-1.49 P < 0.001)] and ulcerative colitis [HR = 1.15 (95%CI: 1.09-1.22, P < 0.001)][101]. These findings reflect that IBD patients are at increased risk of stroke, particularly ischaemic stroke, irrespective of IBD-subtype. The risk of ischaemic stroke has been shown to be highest immediately following the diagnosis of IBD, and plateaus after several years; perhaps implying that early active disease around the time of IBD diagnosis may potentiate the risk of thromboembolic ischaemic stroke rather than disease duration[102]. This is supported by data from two studies included in a recent meta-analysis which suggested that there may be higher risk of ischaemic stroke during IBD disease flares [incidence rate ratio (IRR) = 1.70 (95%CI: 1.36-2.12, P < 0.0001)], and also during periods of chronic persistent disease activity [IRR = 2.20 (95%CI: 1.38-3.52, P = 0.001)][103]. Nevertheless, the increased risk of ischaemic stroke in patients with IBD was shown to persist for up to 25 years following IBD diagnosis, highlighting the need for ongoing clinical vigilance.

PVD: There is limited data evaluating associations between PVD in patients with IBD. A large retrospective observational study of French insurance data, consisting of more than 170000 patients, sought to evaluate the impact that exposure to thiopurines and anti-tumour necrosis factor (TNF) therapies had on the risk of acute arterial events, comprising IHD, stroke, and PVD, in patients with IBD[104]. This study reported an incidence rate of 5.4, 2.8, 1.7 and 0.9 per 1000 person-years across all arterial events, IHD, stroke, and PVD, respectively, although comparisons with a non-IBD cohort were not reported[104]. Another retrospective observational study of a large United States based claims database, comprising 17487 IBD patients and 69948 controls, documented no significant differences in the adjusted risks of PVD events in IBD patients compared to controls (HR = 1.0), including across IBD subtypes of Crohn’s disease (HR = 0.9) and ulcerative colitis (HR = 1.1)[105]. Similar findings were reported in a large prospective study that used data from the United Kingdom Biobank to evaluate the risk of acute arterial events in patients with IBD[106]. This study documented no significant difference in the incidence of PVD in patients with IBD compared to those without IBD (55.1 vs 39.8 per 1000 years, P = 0.098), respectively, including premature PVD [HR = 1.05, (P = 0.889)], defined as that occurring before the age of 55 years in men and 65 years in women[106].

Though similar pathological mechanisms to coronary vessel disease may potentiate the development of PVD, data in this area is lacking, leading to uncertainty regarding its significance among patients with IBD.

Metabolic fatty liver disease

Metabolic fatty liver disease consists of multiple disorders; NAFLD, metabolic dysfunction associated fatty liver disease (MAFLD) and metabolic dysfunction associated steatotic liver disease (MASLD) (Table 5). Despite varied nomenclature and definitions, these conditions represent similar patient populations that collectively represent metabolic fatty liver disease[107].

Table 5 Definitions of metabolic liver diseases[211-213].

	NAFLD[211]	MAFLD[212]	MASLD[213]
Required criteria	Radiological or Histological evidence of hepatic steatosis
Cardiometabolic risks required		At least 1 of the following 3 criteria required: (1) Obesity: BMI ≥ 25 kg/m2 in Caucasians; or BMI ≥ 23 kg/m2 in Asians; (2) Fasting glucose ≥ 100 mg/dL (≥ 5.6 mmol/L), or on treatment for hyperglycaemia; and (3) Two or more of the following: Elevated waist circumference (Table 2); Systolic blood pressure ≥ 130 mmHg; Diastolic blood pressure ≥ 85 mmHg; Serum triglycerides ≥ 150 mg/dL (> 1.7 mmol/L); HDL-C < 40 mg/dL (< 1.03 mmol/L); hsCRP > 2 mg/L; Insulin resistance-HOMA-IR ≥ 2.5; or On treatments for diabetes	At least 1 of the following 5 criteria required: (1) Obesity defined by BMI ≥ 25 kg/m2 in Caucasians; or BMI ≥ 23 kg/m2 in Asians; or elevated waist circumference: > 94 cm (males), > 80 cm (females); (2) Fasting glucose ≥ 100 mg/dL (≥ 5.6 mmol/L), or glucose level post glucose tolerance test ≥ 140 mg/dL (7.8 mmol/L), or HbA1c ≥ 5.7% (39 mmol/L) or on treatment for hyperglycaemia; (3) Systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 85 mmHg, or on anti-hypertensive treatment; (4) Serum triglycerides ≥ 150 mg/dL (> 1.7 mmol/L) or on lipid lowering therapy; and (5) HDL-C < 40 mg/dL (< 1.03 mmol/L) in men of < 50 mg/dL (< 1.29 mmol/L) in women or on treatment for dyslipidaemia
Additional criteria	Other causes of hepatic steatosis excluded

NAFLD: Non-alcoholic fatty liver disease; MAFLD: Metabolic dysfunction associated fatty liver disease; MASLD: Metabolic dysfunction associated steatotic liver disease; HOMA-IR: Homeostatic model assessment for insulin resistance; hsCRP: High sensitivity C-reactive protein; HDL-C: High density lipoprotein cholesterol; BMI: Body mass index; HbA1c: Glycated hemoglobin.

The global burden of metabolic fatty liver diseases are significant, affecting approximately 30% of the global population, and represent the most common cause of chronic liver disease[108]. Geographical variations are also observed, however similar prevalence rates are observed globally; 2024 data stating prevalence in Asia 30.9%, Europe 30.2%, North America 29.0% and South America 34.0%[109]. Complications are common, including potential progression to cirrhosis (estimated at around 3% over 15 years) and hepatocellular carcinoma (annual incidence of 0.5%-2.6% among cirrhotic patients, and estimated incidence amongst non-cirrhotic patients of 0.1-1.3 per 1000 patient years)[110,111].

Given that metabolic syndrome can be a pathogenic catalyst in the development of metabolic fatty liver disease, and the high prevalence of this syndrome among IBD patients, it can be postulated that metabolic liver disease may also be prevalent among this subpopulation. A 2023 metanalysis looking at NAFLD within the IBD population showed similar rates to the general population, with geographical variation[112]. Prevalences reported using any measure to define fatty liver revealed rates of 31.8% (95%CI: 22.1-42.4, 32 studies) among European nations, 27.7% (95%CI: 19.5-36.8, 10 studies) in East Mediterranean countries, 14.2% (95%CI: 12.5-16, 32 studies) in the Americas, 19.7% (95%CI: 10.8-30.4, 8 studies) in South East Asia, and 18.7% (95%CI: 12.2-26.2, 5 studies) in Western Pacific region[112]. Analysis of outcomes using transient elastography and controlled attenuation parameter, which are clinically recognised measures of liver fibrosis and steatosis, have also been undertaken[113]. These analysis identified a higher prevalence of liver steatosis in all geographical regions; 43.1% in Europe, 35.7% in the Americas and 28.6% in South East Asia[112]. Within a Spanish cohort of patients, MAFLD prevalence was significantly higher in patients with IBD than those without (349/831, 42.00% vs 563/1718, 32.77%; P < 0.001)[114].

IBD may hasten the development of metabolic fatty liver disease. Multitudinous factors may play a role, including systemic inflammation disrupting leptin signalling pathways causing alterations in fat metabolism and insulin resistance, and direct hepatoxic effects via reactive oxygen species[115,116]. A recent study of patients with MASLD and concomitant IBD showed a higher incidence of MASLD in lean IBD patients compared to lean non-IBD patients, 21.3% in the IBD group vs 10.0% in the non-IBD group (P = 0.022), with IBD independently being associated as a risk factor for MASLD in lean IBD patients; OR = 2.71 (95%CI: 1.05-7.01, P = 0.04)[117]. Another study similarly showed IBD as an independent risk factor for the development of MAFLD; OR = 2.00 (95%CI: 1.59-2.51, P < 0.001)[114]. The same study also identified IBD as an independent risk factor for the development of fibrosis diagnosed on liver biopsy; OR = 5.55 (95%CI: 2.69-11.47, P < 0.001)[114]. Despite this, associations between the development of fatty liver disease and IBD disease activity have been explored by few studies. A 2023 study found patients with quiescent Crohn’s disease had higher rates of liver steatosis based on magnetic resonance imaging compared to those with active disease[118]. In patients with Crohn’s disease a 2024 study revealed that disease duration was an independent predictor of fatty liver development, with an OR of 1.02 (95%CI: 1.001-1.04)[119], suggesting potential longer systemic inflammation, even low-grade, may have an influence on fatty liver disease. Older age and traditional metabolic risk factors such as obesity have also been identified as risk factors across multiple studies[114,118,120].

Conversely, liver steatosis may also be associated with the development of IBD. In a large Chinese cohort of 418721 participants, 160807 had a diagnosis of NAFLD. Within the population of NAFLD participants there was significantly higher risk of incident IBD (HR = 1.13, 95%CI: 1.04-1.24, P = 0.005), particularly a higher risk of incident Crohn’s disease (HR = 1.36, 95%CI: 1.17-1.58, P_trend < 0.001)[121].

Beyond hepatic complications, IBD patients with metabolic fatty liver disease may have increased risk of other metabolic disorders. One study found that patients with a combination of MASLD and IBD may be at a higher risk of cardiometabolic complications; higher risk of incident cardiovascular disease (HR = 1.77, 95%CI: 1.26-2.49, P = 0.001), increased risk of IHD (HR = 2.54, 95%CI: 1.62-3.98, P < 0.001) and heart failure (HR = 3.36, 95%CI: 1.53-7.38, P = 0.003) compared to those with IBD alone[122]. There may also be an increased risk of all-cause mortality, with a 2024 United Kingdom study independently associating the combination of IBD and MASLD, with higher rates of all-cause mortality compared to IBD patients without MASLD; HR = 1.58, 95%CI: 1.07-2.32[123]. Risk of mortality also increased with the presence of metabolic risk factors; 3 risk factors with (HR = 1.85, 95%CI: 1.20-2.85), 4 or more risk factors (HR = 1.83, 95%CI: 1.16-2.89)[123].

The rising global burden of metabolic fatty liver disease cannot be ignored among IBD patients. Often considered a disorder of obese individuals, the literature suggests a higher burden of metabolic fatty liver disease, even among lean IBD patients, potentially implicating non-traditional pathogenic mechanisms, such as systemic inflammation. Overall, clinicians should be aware and vigilant of the potential of metabolic fatty liver disease among patients with IBD; particularly, among those with metabolic risk factors, given poorer health outcomes observed in this cohort.

EXAMINING THE IMPACT OF IBD THERAPEUTICS ON CARDIOMETABOLIC RISK

Beyond the risks associated with IBD and the metabolic syndrome, the effect of treatments on the risk of metabolic complications is another important consideration for clinicians managing IBD. Corticosteroids are frequently used to induce clinical remission, however, a large proportion of patients with IBD require ongoing corticosteroid sparing therapies to maintain remission and achieve more stringent treatment targets as espoused by the STRIDE-II guidelines[20,124]. Maintenance IBD therapies include small molecule and biological therapies, and once initiated, patients with IBD frequently remain these therapies for extended periods. The following section will examine the cardiometabolic risk associated with commonly used IBD medications.

Corticosteroids

Corticosteroids have multiple adverse metabolic effects that are related to dose and duration of exposure[125]. Short term metabolic effects include alterations in hepatic glucose metabolism, while medium to longer term effects can include diabetogenic complications, alterations in lipid metabolism, onset of central adiposity and increased cardiovascular risk[126].

From a metabolic perspective, corticosteroids have been associated with alterations in hepatic glucose metabolism and have been demonstrated to invoke insulin resistance through multiple mechanism, both of which can potentiating diabetogenic complications[127-129]. This risk is driven by the dose and length of exposure to corticosteroid therapy. This was illuminated in a 2020 meta-analysis that included 100722 patients with IMID, 28.2% of whom had IBD, which documented strong dose-related associations with diabetic events in those exposed to corticosteroids compared to those without exposure[130]. This was exemplified by corticosteroid doses of 25 mg daily or above (HR = 4.34, 95%CI: 3.83-4.91) having stronger associations with hyperglycaemic complications compared to doses of 5 mg or less (HR = 1.90, 95%CI: 1.73-2.09)[130].

Corticosteroids have also been shown to have a negative impact on lipid metabolism in a dose dependent manner that remains independent of duration of exposure[131-133]. Three studies have explored these associations within an IBD context, with a meta-analysis reporting a pooled mean increase in total cholesterol across 73 IBD patients exposed to corticosteroids of 1.25 mmol/L (95%CI: 0.31-2.39) during periods of steroid exposure during induction, and 1.29 mmol/L (95%CI: 0.40-2.38) when corticosteroids were used for maintenance[134]. A non-significant increase in triglycerides was observed during induction, with a pooled change of 0.08 (95%CI: -0.13 to 0.34), however, serum HDL-C and LDL-C were not evaluated[134].

Corticosteroid exposure has also been associated with increased cardiovascular risk in patients with IBD. This was evident in a large United Kingdom based population cohort study, that included 27739 patients with IBD, which documented 1937 cardiovascular events over 15 years; amounting to a dose-dependent increase in corticosteroid associated cardiovascular event risk [aHR = 4.35 (95%CI: 3.34-5.52)] associated with corticosteroid doses at or above 25 mg daily[135]. Cumulative exposure to corticosteroid therapy was also documented to contribute to cardiovascular event risk, particularly when exposed to a cumulative corticosteroid dose of 7300 mg or more [aHR = 1.50 (95%CI: 1.36-1.66)][135]. This was also reflected in a large Danish population study, that included 28833 patients with IBD, which observed that IBD patients exposed to corticosteroids had a higher incidence of IHD compared to unexposed patients[136]. However, a smaller retrospective United States study of 356 patients, documented no association between corticosteroid exposure and risk of IHD [HR = 0.8 (95%CI: 0.39-1.65)][137]. Nevertheless, in view of robust evidence linking corticosteroid exposure with cardiometabolic risk factors, it remains likely that steroid exposure has significant adverse cardiometabolic effects.

Monoclonal antibodies

Anti-TNF-adalimumab, certolizumab, golimumab, infliximab: Patients with heart failure and myocardial infarction have been documented to have higher circulating levels of TNF alpha, with reductions in TNF levels shown to improve heart failure in mouse models[138-140]. This provided the basis to evaluate the clinical utility of anti-TNF therapy to treat heart failure and myocardial infarction. However, owing to an increased risk of death, and worsening of heart failure of moderate to severe severity (New York Heart Association class 3 to 4) with very high doses of infliximab, anti-TNF therapy is generally avoided in this patient subset[141]. Notably, studies subsequent to this have not have not documented an increased risk of heart failure in patients with RA, perhaps indicating the risk may be limited to those who receive high doses of anti-TNF or have pre-existing risk factors[142,143]. In fact, several studies have reported that anti-TNF agents may proffer a protective cardiovascular effect in patients with RA and psoriatic arthritis, particularly if therapy is able to facilitate inflammatory disease control[144,145]. This was illuminated in a meta-analysis of RA patients on anti-TNF therapy which reported that patients who demonstrated a good clinical response to anti-TNF therapy had 50% lower risk of acute coronary syndrome compared to those who demonstrated moderate response or non-response[144]. Nevertheless, in patients with pre-existing heart failure, and those with traditional cardiovascular risk factors, caution should be applied when prescribing anti-TNF agents.

Several studies have sought to evaluate associations between anti-TNF therapy and cardiovascular risk. A large French cohort of 177827 IBD patients exposed to anti-TNF agents reported that exposure to this class of therapy was associated with a decrease in acute arterial events such as cerebrovascular disease, IHD, and PVD (HR = 0.79, 95%CI: 0.66-0.95)[104]. Exposure to anti-TNF therapy has also been associated with improved mortality in patients with Crohn’s disease (21.4 vs 30.1 per 1000 person-years, OR = 0.78, 95%CI: 0.65-0.93), albeit in comparison to prolonged corticosteroid exposure, with benefits attributed to reductions in major adverse cardiovascular events (OR = 0.68, 95%CI: 0.55-0.85)[146]. Anti-TNF therapy has also been associated with a decrease in arterial stiffness that closely approximates to controls after 4 years of exposure[147]. A 2023 meta-analysis by Shehab et al[148] indicated that biologic therapies, including anti-TNF, had no significant impact on the risk of MACE during periods of induction and maintenance in IBD randomised controlled trials. However, a 2024 network meta-analysis, that included 40 studies encompassing anti-TNF exposure across IBD (6 studies consisting of a cohort of 7463 IBD patients), dermatology, and rheumatology indications, demonstrated a higher risk of major cardiovascular events, including ischaemic stroke and heart failure, across all autoimmune conditions compared to placebo (OR = 2.49, 95%CI: 1.14-5.62)[149]. This may imply that differences in patient demographics, including pre-existing cardiovascular risk factors, in patients with IMID may contribute towards MACE events.

Anti-TNF agents have also been associated with dyslipidaemia, albeit in patients with RA[150]. Although short-term changes in lipid profiles have been reported in patients with IMID, the impact of these changes on future cardiovascular events remains to be clarified. A study that sought to evaluate risk factors for developing NAFLD among IBD patients indicated that patients not receiving anti-TNF therapy exhibited a higher occurrence of NAFLD (29.7% vs 17.1%, P = 0.048)[34]. These data indicate that exposure to anti-TNF therapy may have favourable associations with overall mortality and cardiometabolic risk; however whether these benefits are related to the drug’s mechanism, or simply as a consequence of a reduction in systemic inflammation and improved disease control, remains unclear.

Anti-interleukin-12/interleukin-23-ustekinumab, risankizumab, mirikizumab: Interleukin (IL)-12 has been implicated in the pathogenesis of atherosclerosis, with inhibition of IL-12 identified as a potential novel mechanism to address atherosclerosis on the basis of murine models[151,152]. However, studies of briakinumab, an IL-12/23 inhibitor, in patients with chronic plaque psoriasis documented an increased association with MACE events[153]. Similarly, a French cohort study suggested that patients with high cardiovascular risk (OR = 4.17, 95%CI: 1.19-14.59), were at increased risk of developing significant ischaemic events, unstable angina and myocardial infarction, within the first 6 months of commencing ustekinumab, with no comparable increase observed in patients with low cardiovascular risk (OR = 0.30, 95%CI: 0.03-3.13)[154]. This remains in keeping with current mechanistic models for atherosclerotic disease in which the period following initiation of anti-IL 12/23p40 may be associated with destabilisation of atherosclerotic plaque via inhibition of helper Th-17 cells[155-157]. A 2024 network meta-analysis, which examined cardiovascular events in patients with IMIDs, also demonstrated that exposure to ustekinumab for the management of IMIDs may be associated with an increased risk of major adverse cardiovascular events compared to placebo (OR = 3.15, 95%CI: 1.01 to 13.35)[149]. However, these findings have not been replicated in other studies, including pooled analysis of 3117 patients exposed to ustekinumab for the treatment of psoriasis or PsA which was suggestive of a trend toward decreased MACE events over at least 4 years of follow-up[153,158,159]. Similarly, data from IBD trials have not demonstrated any material change in the risk of cardiovascular events following up to two-years of ustekinumab exposure[160,161]. More recent IBD therapeutics such as risankizumab and mirikizumab, both of which selectively inhibit IL-23, have not demonstrated any significant signal for MACE[162,163]. Collectively, these data reflect that controversies regarding the association between exposure to anti–IL-12/23p40 therapies and cardiovascular atherosclerotic disease remain to be resolved[153,158,159]. However, no intrinsic effect of IL-23 has been reported on plaque vulnerability to-date.

Several case reports have documented potential temporal associations between the administration of ustekinumab and heart failure, with documented reversibility following discontinuation of ustekinumab in some cases[164-166]. However, unfavourable associations between ustekinumab and heart failure have not been widely reported across clinical trials and larger ‘real-world’ cohorts.

Anti-integrin-vedolizumab: Overall, vedolizumab does not appear to increase the risk of cardiometabolic complications, although data is limited. Real world data and registration studies for vedolizumab did not reveal any negative cardiometabolic outcomes[167-169]. A 2022 study examining the safety of vedolizumab in a matched cohort of elderly and non-elderly patients with IBD did not document any significant association between vedolizumab exposure and cardiovascular disease in the elderly cohort over the age of 65[170].

Small molecules

5-aminosalicylic acid: The impact that 5-aminosalicylic acid (5-ASA) therapies have on cardiovascular disease is inconsistent. A Danish study found that IBD patients exposed to 5-ASA therapy had lower risk of IHD compared to unexposed patients (IRR = 1.16 vs 1.36, P = 0.02)[136]. Conversely, a United Kingdom based study reported a negative association between 5-ASA exposure and the development of cardiovascular disease. This study examined a cohort of 18000 patients with IBD who had 1400 exposures to 5-ASA therapies, and reported exposure to 5-ASA was associated with an increased risk of cardiovascular events (unadjusted HR = 1.2, 95%CI: 1.1-1.3)[171]. It is important for clinicians to be aware of non-traditional cardiac manifestations of 5-ASA therapy such as the development of myocarditis and pericarditis[172]. There is no evidence that exposure to 5-ASA therapy has any negative metabolic effects in patients with IBD.

Thiopurines: Thiopurines, which inhibit purine synthesis, may provide benefit in patients with metabolic syndrome. A recent French cohort study in IBD patients with a prior history arterial thrombosis (cardiovascular event, cerebrovascular event or PVD) had lower rates of recurrence if treated with both anti-TNF therapy and thiopurines[173]. Though it is difficult to discern if the effect is due to thiopurine or anti-TNF exposure, or simply related to better IBD control. Another small study comprising of 111 patients with IBD and concomitant CVD, documented a statistically insignificant reduction in cardiovascular events; OR = 0.45 (95%CI: 0.19-1.06, P = 0.07) in patients exposed to thiopurines, though was potentially underpowered for this outcome[174].

Methotrexate: Data pertaining to the cardiometabolic impact that methotrexate may have in patients with IBD remains unclear. However, two meta-analyses of patients with rheumatic conditions have demonstrated that exposure to methotrexate may be associated with a reduced risk of cardiovascular events; relative risk = 0.72 (95%CI: 0.57-0.91) and relative risk = 0.79 (95%CI: 0.71-0.88)[145,175]. This has been attributed to methotrexate’s ability to reduce oxidative stress and reduce the burden of inflammatory cytokines. Methotrexate has also demonstrated associations with reductions in arterial blood pressure, improvements in lipid profile, and a decreased risk of type II diabetes[176].

Janus kinase inhibitors-tofacitinib, upadacitinib: Janus kinase inhibitors may have deleterious effects on the metabolic syndrome through increased lipid concentrations with proportionate, dose-related, increases in both HDL and LDL, with no significant alterations in lipid ratios[177-180]. These agents have been used in inflammatory arthropathies for a longer duration than IBD, with safety data suggesting a higher risk of all form cardiovascular disease in these cohorts, particularly if individuals had a pre-existing cardiovascular risk factor[181]. Though in patients without discernible cardiac risk factors, several cohort studies, including meta-analysis have shown no preponderance to develop IHD, including in those with IBD[182-184]. In light of these findings, clinicians should consider pre-existing cardiovascular risk at the time of prescribing JAK inhibitors.

Sphingosine-1-phosphate modulators-ozanimod, etrasimod: Sphingosine-1-phosphate (S1P) modulators have been shown to be relatively safe, with the main concern being the risk of significant hypertension[185]. S1P modulators can also interact with other medications including monoamine oxidase (MAO) inhibitors, and serotonin and norepinephrine modulators[186]. Concomitant use may increase the risk of hypertension and hypertensive crisis, particularly with MAO inhibitors[186]. These therapies are contraindicated in heart failure, and those with recent myocardial infarction, though data suggest that there is no increased risk of MACE developing de novo with exposure to S1P modulators[185,187].

Therapeutic considerations in obesity

Obesity has been suggested to impact the therapeutic effectiveness of several advanced IBD therapies, particularly monoclonal antibodies. A 2020 meta-analysis, identified a higher risk of treatment failure and loss of response (LOR) in obese patients treated with anti-TNF therapies such as adalimumab, certolizumab and infliximab, with a combined OR = 1.20, P = 0.015[188]. Similar findings were also observed in the personalised anti-TNF therapy in Crohn’s disease personalised anti-TNF therapy in Crohn’s disease study cohort study, which reported an increased risk of LOR (HR = 1.62, 95%CI: 1.08-2.42) in patients defined as obese on the basis of a BMI ≥ 30 kg/m²[189]. However, data from a paediatric cohort of IBD patients showed no significant differences in terms of anti-TNF treatment response between obese and non-obese patients; although obese patients were more likely to require dose escalation of either infliximab or adalimumab therapy within 6-months (30% vs 19.5%, P = 0.04)[190].

Other biologic agents, including vedolizumab and ustekinumab, have not demonstrated reduced clinical efficacy in obese individuals. This is exemplified by similar dose escalation requirements between obese and non-obese (48.9% and 42.0%, P = 0.4) IBD patients exposed to vedolizumab, and lower rate of vedolizumab discontinuation among obese patients (31.9% vs 53.2%, P = 0.01)[191]. Post-hoc analysis of the IM-UNITI trial did not identify differences in clinical response between Crohn’s disease patients categorised as normal, overweight and obese on the basis of BMI, who were exposed to ustekinumab[192]. However, ustekinumab trough levels were noted to be lower in patients classified as obese compared to those categorised as overweight and normal (obese: 2.98 mcg/mL vs overweight: 4.84 mcg/mL vs normal: 4.43 mcg/mL, P = 0.01). Risankizumab, an anti-IL-23 agent recently approved for use in IBD, has shown no differences in treatment responses in obese psoriasis patients derived from long term observational study data[193,194].

CONCLUSION

The relationship between cardiometabolic diseases and IBD is multifaceted. Cardiometabolic diseases are more prevalent in IBD patients compared to the general population; however, identifying which IBD patients are at the highest risk of developing these conditions later in life remains challenging. The European Society for Clinical Nutrition and Metabolism and United European Gastroenterology guidelines recommend measuring waist circumference and conducting non-invasive assessments of hepatic steatosis for patients with a BMI between 25-30 kg/m², and screening for insulin resistance in those with a BMI > 30 kg/m²[195]. However, IBD-specific guidance that incorporates non-traditional risk factors are yet to be defined. Emerging evidence suggests a biological link between chronic gastrointestinal inflammation and the development of cardiometabolic disorders, a concern for IBD patients given the typical early age of onset. Although associations between IBD disease activity and cardiometabolic risk have been observed, it remains unclear whether a treat-to-target approach aimed at eliminating bowel inflammation can reduce the risk of these disorders in the longer term. Current evidence linking IBD activity to cardiometabolic risk remains limited, primarily due to the reliance on national registry-based data, which often lacks the granularity necessary to establish robust associations. These data sources typically fail to capture key variables such as disease severity, treatment regimens, and lifestyle factors that may influence cardiometabolic outcomes in IBD patients. To better understand the medium- and longer-term effects of gastrointestinal inflammation on the development of cardiometabolic diseases, large-scale, prospective studies with extended follow-up are needed. Additionally, regional variability in the prevalence of cardiometabolic comorbidities among IBD patients underscores the necessity of conducting studies across diverse geographical populations. Such research is essential to elucidate the factors contributing to cardiometabolic risk in IBD and to develop more targeted prevention and management strategies. The growing number of IBD therapies that help achieve better disease control offers promising opportunities for reducing cardiometabolic risk. However, clinicians must remain cautious about the potential negative cardiometabolic effects of some therapies, particularly in patients with pre-existing cardiometabolic risk factors. This review highlights the clinically significant relationship between IBD and cardiometabolic disorders and emphasizes the importance of considering non-traditional risk factors, such as disease activity, in this context. While observational studies suggest a link, further research is needed to clarify the biological and pathogenic mechanisms underlying this relationship. This research is crucial for identifying which IBD patients are at highest risk with a view towards developing strategies to mitigate this risk. In the meantime, IBD clinicians should consider incorporating cardiometabolic risk assessments into clinical practice, particularly for patients with pre-existing cardiometabolic risk factors and in the context of therapy-related decisions. Future research should focus on whether treat-to-target strategies that control intestinal inflammation can simultaneously improve both long-term IBD and cardiometabolic outcomes.