Relationship between statin use and inflammatory bowel disease: Exploring possible implications

Abstract

Inflammatory bowel diseases (IBD) have a chronic, relapsing, remitting course and impose a substantial clinical impact and economic burden. Despite the expansion of therapeutic options, a significant proportion of patients continue to fail to achieve relevant outcomes, representing a difficult-to-overcome therapeutic ceiling and highlighting the need to explore complementary pharmacological strategies. In this context, statins, widely used in cardiovascular prevention, have attracted increasing attention for their anti-inflammatory and immunomodulatory effects, independent of their lipid-lowering action. This review summarizes the available data on the relationship between statin use and IBD, including preclinical data, observational studies and clinical trials. Experimental studies demonstrate that statins modulate key pathways of intestinal inflammation, reducing pro-inflammatory cytokine production, improving epithelial barrier function and influencing both innate and adaptive immune responses. Large-scale epidemiological studies further suggest an association between statin use and a reduced risk of IBD onset, as well as a less aggressive clinical course in patients with established disease, with a lower need for corticosteroids, hospitalizations and surgery. Preliminary evidence also indicates a potential role in reducing the risk of colorectal carcinoma associated with chronic inflammation. Although the current data do not yet justify the adoption of statins as a specific treatment for IBD, these findings demonstrate a clear potential for these pharmacological agents to enter the therapeutic armamentarium of IBD.

Key Words: Statins; Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis; Immunomodulation; Anti-inflammatory effects; Cardiovascular comorbidity; Disease activity; Colorectal cancer; Complementary therapy

Core Tip: Beyond their lipid-lowering action, statins exert anti-inflammatory and immunomodulatory effects that may influence the onset and course of inflammatory bowel diseases, reducing inflammatory activity and the risk of complications, and positioning themselves as potential complementary therapies.

INTRODUCTION

Inflammatory bowel disease (IBD) represents a group of chronic, immune-mediated conditions that include ulcerative colitis (UC) and Crohn’s disease (CD). Although they share some common pathogenic mechanisms, UC and CD differ significantly in location, extent of intestinal involvement, clinical manifestations, and response to treatment[1,2].

IBD is associated with a significant disease burden, with profound socio-economic consequences for both affected individuals and healthcare systems; nonetheless, IBD has also exhibited epidemiological and treatment-related sex-specific differences[3]. Recent meta-analyses estimate a global prevalence of approximately 3.8 million people, with an annual incidence ranging from 1.4 to 11.6 cases per 100000 and over 40000 deaths in 2021, posing a significant challenge to healthcare systems worldwide[4].

In recent decades, the range of available treatments for UC and CD has significantly expanded as a result of the consistent introduction of new advanced therapies (i.e., biologic drugs and small molecules[5]), which have complemented conventional therapy of gut-targeting anti-inflammatory drugs (e.g., mesalazine) and classical immunomodulators (e.g., steroids, azathioprine)[6].

Although these novel medications have substantially transformed the therapeutic management of patients with IBD, contributing to reduced rates of hospitalization and surgery, the risk of treatment failure remains elevated, with a 10-year cumulative risk of surgery of nearly 10% for UC and approximately 26% for CD[7]. In this setting, the need for additional therapeutic options capable of reducing this risk is driving research towards the development of new molecules and the investigation of potential anti-inflammatory and immunomodulatory effects of drugs used for indications other than IBD therapy.

This latter group includes statins, medications currently used for the treatment of hypercholesterolemia. Moreover, within the context of other metabolic pharmacological strategies, glucagon-like peptide 1 agonists have also been shown to possess anti-inflammatory properties in the setting of gut inflammation[8]. The homeostasis of body cholesterol is maintained through the regulation of endogenous biosynthesis (primarily hepatic), exogenous uptake, storage, and exportation. Endogenous synthesis is a complex process that ultimately leads to cholesterol production from acetyl-coenzyme A (CoA) molecules. Statins work by blocking the endogenous cholesterol biosynthetic pathway. More precisely, their structural similarity to the substrate allows statins to compete for the binding site of the enzyme hydroxymethylglutaryl-CoA reductase (HMG-CoAR), which is responsible for the production of mevalonate through the reduction of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). By inhibiting HMG-CoA reductase, statins reduce mevalonate and downstream metabolite concentrations, thereby reducing cholesterol availability[9,10]. In addition to directly inhibiting cholesterol production, reduced hepatic cholesterol concentrations increase expression of the low-density lipoprotein (LDL) receptor on the surface of hepatocytes, enhancing LDL clearance from the bloodstream[11].

Beyond their well-known lipid-lowering function, statins have demonstrated significant immunomodulatory effects on various pro-inflammatory pathways, making these drugs potential allies in the treatment of chronic inflammation and, by extension, IBD. The anti-inflammatory effects are primarily attributable to reduced isoprenoid synthesis via the mevalonate pathway. This leads to inhibition of intracellular signaling pathways involving nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, resulting in decreased circulating levels of cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, as well as inflammatory markers including C-reactive protein (CRP)[12,13].

Furthermore, several studies have highlighted a potential antitumor effect of statins, attributed to reduced cellular GTPase activation and decreased reactive oxygen species production. These changes exert multiple effects on tumor cells, including the induction of apoptosis and cell cycle arrest, as well as inhibition of proliferation, colony formation, invasion and angiogenesis[14,15].

Besides their beneficial pleiotropic effects, statin therapy carries various adverse events like myopathy and rhabdomyolysis (the most common), as well as drug-induced liver injury, acute kidney injury, hemorrhagic stroke, cognitive decline, peripheral neuropathy, depression, memory issues, tendinitis and tendon ruptures[16].

Based on the above, this review summarizes the current evidence concerning the potential effects of statins in IBD.

CARDIOVASCULAR DISEASE IN IBD: EXTRA-INTESTINAL MANIFESTATION OR COMORBIDITY?

CD and UC have traditionally been viewed as disorders confined to the gastrointestinal tract. However, the systemic nature of their inflammatory processes has become increasingly evident, and in recent years, growing interest has focused on their potential role in cardiovascular complications. This has raised an important question: Should cardiovascular involvement in patients with IBD be considered merely a comorbidity, or a true extraintestinal manifestation of the disease? The answer carries significant clinical implications, influencing monitoring, risk stratification, and therapeutic strategies.

The increased incidence of arterial and coronary thrombotic events reported in several studies is not, by itself, sufficient to clarify the nature of this association. Notably, these events often occur in patients without a high burden of traditional cardiovascular risk factors, suggesting an independent role for systemic inflammation and the endothelial dysfunction characteristic of IBD[17-19].

IBD is characterized by a strong inflammatory component involving a wide range of mediators, including CRP, serum amyloid A, TNF-α, IL-1β, IL-6, IL-8, IL-12, and fecal calprotectin, all of which are known to contribute to atherosclerotic processes. Elevated CRP levels, for example, are associated with an increased risk of coronary events, while cytokines such as TNF-α and IL-6 play central roles in endothelial dysfunction. Beyond its established role as a marker of intestinal inflammation, calprotectin, particularly in its circulating forms and when transported by extracellular vesicles, has been proposed as an emerging biomarker of cardiovascular risk and poor prognosis in peripheral artery disease, as it is associated with a higher risk of adverse events and amputation[20-22].

Epidemiological studies further support this association. Population-based analyses have demonstrated a significantly higher incidence and prevalence of ischemic heart disease, chronic coronary artery disease, and vascular events in patients with IBD compared with controls, with particularly pronounced effects observed in specific subgroups, such as women and certain age groups[23,24]. Notably, this increased risk persists even after adjustment for traditional cardiovascular risk factors.

A particularly noteworthy finding is the discrepancy between the metabolic profile of patients with IBD and their observed cardiovascular risk. In several cohorts, diabetes, obesity and hypercholesterolemia are no more prevalent than in the general population and, in some studies, are even less common[25,26]. Despite this, the risk of cardiovascular events remains elevated[25,26]. Hypertension appears to be the only traditional risk factor consistently associated with coronary events, whereas smoking, obesity and dyslipidemia do not seem to account for the excess risk[26,27]. This imbalance supports the hypothesis that IBD directly contributes to vascular disease through its own biological mechanisms.

Recent findings further support the presence of specific metabolic changes in patients with IBD. A cross-sectional study demonstrated that patients with IBD have significantly lower levels of apolipoprotein C-III (ApoC3), a key regulator of triglyceride metabolism implicated in atherosclerotic pathogenesis[28]. This reduction was independent of conventional cardiovascular risk factors, medication use such as statins, and disease activity, suggesting an intrinsic metabolic alteration in IBD[28]. The stable downregulation of ApoC3 may explain why patients with IBD develop cardiovascular events even in the absence of typical dyslipidemia or other traditional risk factors, thereby strengthening the hypothesis of a distinct vascular phenotype that may constitute an extraintestinal manifestation of the disease.

An additional element supporting the non-random nature of the relationship between IBD and cardiovascular disease comes from a recent Swedish population-based case-control study investigating whether atherosclerosis represents not only a comorbidity of IBD, but even a predisposing factor for its development. In this extensive analysis, over 56000 patients with newly diagnosed IBD were compared with more than 530000 matched controls according to age, sex and geographical area, assessing the presence of clinical conditions attributable to atherosclerosis, including myocardial infarction, ischemic stroke, peripheral artery disease and documented atherosclerosis, before the onset of IBD[29]. The results showed a strong, consistent association: A history of atherosclerotic disease significantly increased the likelihood of developing IBD [odds ratio (OR) = 1.30; 95% confidence interval (CI): 1.24-1.37], with a slightly stronger association for CD (OR = 1.37) than for UC (OR = 1.27). The risk increased further in individuals with more than one atherosclerotic manifestation, suggesting a cumulative effect of systemic vascular disease. Significantly, this association could not be attributed to surveillance bias or increased healthcare contact in the period immediately preceding diagnosis: The risk of IBD remained elevated even when the atherosclerosis diagnosis had occurred more than 5 years earlier. The association persisted after adjustment for numerous confounders, including smoking, obesity, diabetes, hypertension, dyslipidemia, other immune-mediated comorbidities and prior use of potentially protective drugs, such as aspirin and statins.

Taken together, these data suggest a broader and more integrated view of the link between IBD and cardiovascular disease. Instead of being a condition that occurs in parallel, atherosclerosis may serve as an indicator or a contributing factor to a systemic inflammatory predisposition, thereby increasing the risk of IBD. Such evidence is consistent with a pathophysiological framework in which IBD emerges as a systemic disease characterized by profound immune and vascular alterations rather than a disorder confined to the gastrointestinal tract. The existence of a bidirectional relationship, whereby IBD increases cardiovascular risk, while atherosclerotic inflammation may precede its onset, further supports the hypothesis of a shared inflammatory continuum in which the vascular system and the intestine represent two distinct components of the same pathobiological network.

The link between IBD and venous thromboembolism (VTE) is particularly robust. Extensive cohort studies and national registries have demonstrated that patients with IBD have a significantly increased risk of deep vein thrombosis and pulmonary embolism, with a particularly marked increase in younger patients and during disease flares[30]. Moreover, the risk appears higher in women than in men[31], and several studies confirm greater female vulnerability, even for acute arterial thrombotic events[32-34]. Active inflammation amplifies risk by altering the balance between pro-coagulant and anticoagulant factors and reducing fibrinolysis[35].

The link between chronic inflammation and a prothrombotic state in IBD can be framed within the broader model of “inflammation-induced thrombosis” described by Aksu et al[36]. According to this model, pro-inflammatory cytokines induce increased expression of tissue factor on endothelial cells and monocytes, thereby activating the extrinsic coagulation pathway. Concurrently, inflammation leads to a marked reduction in key physiological anticoagulant systems, particularly the protein C/protein S axis, antithrombin and tissue factor pathway inhibitor, thereby contributing to a persistent shift towards hypercoagulability. Another key mechanism is inhibition of fibrinolysis, primarily mediated by increased plasminogen activator inhibitor-1, which limits fibrin degradation and stabilizes the thrombus. In parallel, endothelial dysfunction and platelet activation promote leukocyte adhesion and the formation of a highly thrombogenic vascular microenvironment. In turn, activated coagulation further amplifies the inflammatory response: Through protease activated receptor activation, thrombin stimulates the release of cytokines and growth factors, reinforcing the inflammation coagulation loop. Platelets also contribute to this process through immune activation and interactions with neutrophils and monocytes. This vicious cycle has been described in many systemic inflammatory diseases, including IBD, which is characterized by a true “inflammatory thrombophilia,” in which thrombosis is not merely a coincidental complication but rather a potential systemic manifestation of the disease.

Cardiovascular involvement in IBD is not limited to thrombotic events. Cardiac arrhythmias represent another emerging concern. An extensive analysis of more than 800000 patients showed a significantly higher prevalence of atrial fibrillation, atrial flutter, ventricular tachycardia and ventricular fibrillation in patients with IBD compared with controls, with a robust association during periods of disease activity[37,38].

Endothelial dysfunction also appears to be tightly linked to IBD. Both microvascular and macrovascular alterations have been described using techniques such as peripheral arterial tonometry, with increased arterial stiffness correlating with levels of systemic inflammation[39,40]. Processes such as smooth muscle cell hyperplasia and extracellular matrix remodeling, both induced by inflammation, contribute to this altered vascular profile[41,42].

Regarding cerebrovascular risk, data are not entirely uniform. Still, many analyses suggest increased stroke risk in patients with IBD, particularly in the presence of other comorbidities or during treatments such as corticosteroids, which may worsen hypertension and dyslipidemia[43-45]. Studies by Keller et al[46,47] confirmed an increased risk of stroke in patients with IBD in the Taiwanese population. Further support for cerebrovascular involvement in IBD comes from clinical observations, suggesting a possible role for non-traditional thrombotic factors. Calabrò et al[48] described a patient with UC who developed recurrent ischemic strokes despite markedly elevated lipoprotein(a), a well-established independent atherothrombotic risk factor. Although based on a single case, this report illustrates how, within the context of the chronic systemic inflammation characteristic of IBD, pro-atherogenic factors such as elevated lipoprotein(a) may acquire significant clinical relevance, contributing to increased cerebrovascular risk even in patients without a classical cardiovascular risk profile. This observation fits within the broader framework of a “non-conventional” vascular vulnerability in individuals with IBD, in whom genetic and metabolic factors combine with chronic inflammation to modulate stroke risk.

The intestinal microbiota represents another crucial element in IBD pathogenesis. The dysbiosis typical of IBD has been associated with increased cardiovascular risk through various mechanisms: Greater predisposition to VTE in patients with IBD and Clostridioides difficile infection[49]; impaired regulation of neutrophil extracellular trap formation[50]; increased systemic translocation of lipopolysaccharides (LPS), capable of damaging the endothelium and promoting foam cell formation[51-53]. An intriguing paradox is represented by specific microbial metabolites, such as trimethylamine-N-oxide, a pro-inflammatory and pro-atherogenic marker that, although typically associated with cardiovascular risk, is associated with reduced levels in patients with IBD[54], suggesting that cardiovascular pathways in IBD may not always follow classical metabolic risk patterns.

Overall, this body of evidence suggests that cardiovascular involvement in IBD cannot be interpreted as a mere parallel comorbidity. Instead, the clinical picture lies along a continuum in which risk factors shared with the general population overlap with IBD-specific risk factors, driven by systemic inflammation, endothelial dysfunction, and a prothrombotic state. This perspective calls for a more personalized and proactive approach to cardiovascular prevention in patients with IBD, with strategies particularly targeted at subgroups at the highest risk[55,56].

HOW CAN STATINS AMELIORATE THE INTESTINAL INFLAMMATORY BURDEN? A PATHOGENETIC WINDOW OFFERED BY PRECLINICAL EVIDENCE

Atorvastatin

Several studies have evaluated the gut-specific anti-inflammatory potential of statins in experimental colitis, predominantly in murine preclinical models. For example, one study by Rashidian et al[57] sought to verify whether atorvastatin improved intestinal inflammation through inhibition of the Toll-like receptor 4 NF-κB signaling pathway in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats. Acute colitis was induced by intrarectal administration of 100 mg/kg TNBS dissolved in 0.25 mL of 50% ethanol. Twenty-four hours after colitis induction, animals were orally administered saline solution, atorvastatin at 20 mg/kg and 40 mg/kg, and sulfasalazine at 100 mg/kg. Treatment was repeated daily for 1 week. Changes in body weight and macroscopic and microscopic lesions were assessed. Atorvastatin and sulfasalazine reduced body weight loss and macroscopic and microscopic lesions. In addition, both drugs decreased the expression of myeloperoxidase-positive and TNF-positive cells in colonic tissue. Furthermore, they inhibited TNBS-induced expression of Toll-like receptor 4, MyD88, and NF-κB p65. It was therefore hypothesized that the anti-inflammatory effect of atorvastatin on TNBS acid-induced colitis in rats may involve inhibition of the Toll-like receptor 4 NF-κB signaling pathway.

A further study by El-Mahdy et al[58] investigated whether the combination of mesalazine and atorvastatin could enhance anti-inflammatory effects and attenuate the progression of oxazolone-induced colitis in rats. Sixty male albino rats were used and divided into six groups: Control, an oxazolone-treated group to induce colitis, and groups treated with mesalazine alone, atorvastatin alone, or in combination. Colitis was induced by intrarectal administration of oxazolone. Disease progression was assessed by measuring colon length and body weight, recording the incidence of diarrhea and rectal bleeding, and performing histopathological examination of colonic tissue. In addition, several inflammatory, tight junction and apoptotic markers were measured, including IL-6, TNF-α, IL-13, signal transducer and activator of transcription 3, myeloperoxidase, reduced glutathione, and gene expression of IL-10, zonula occludens 1 and caspase-3. Combination therapy showed markedly superior effects compared with the use of individual drugs. In particular, it led to improvements in clinical and pathological parameters, including a reduction in the incidence of diarrhea compared with the untreated group (10% vs 100%) and a reduction in rectal bleeding (0% vs 80%).

Moreover, the combination group exhibited a 15.91% increase in body weight at the end of the 3-week study period, whereas the oxazolone group showed a significant 29.8% decrease. From a histopathological perspective, the study further revealed that combination therapy completely restored normal mucosa and submucosa, whereas the individual drugs showed only partial or minimal restoration. At the molecular level, combination therapy exerted its effects by targeting key mechanisms of intestinal inflammation and barrier dysfunction. Colitis caused significant damage to tight junction proteins, as evidenced by reduced zonula occludens 1 gene expression. The combination therapy strongly restored zonula occludens 1 levels, with a 433.33% increase compared with the oxazolone group, surpassing the effects of individual drugs and rendering levels comparable to controls. Expression of the anti-inflammatory cytokine IL-10 was significantly increased by combination treatment, with a 600% increase compared with the oxazolone group, again exceeding the effects of individual treatments. Combination therapy also significantly reduced levels of IL-6 and signal transducer and activator of transcription 3 by 86.76% and 82.26%, respectively, compared with the oxazolone group. It further showed a more pronounced reduction in TNF-α and IL-13, by 81.76% and 89.96% respectively. These effects are particularly relevant given that IL-6 and signal transducer and activator of transcription 3 signaling are key regulators of proliferation and pathogenesis in IBD. The combination also induced a potent antioxidant effect, as demonstrated by a 387.67% increase in reduced glutathione content. In addition, it significantly reduced myeloperoxidase activity by 83.79% and caspase-3 gene expression related to apoptosis by 66.21%, indicating reduced oxidative damage and cell death.

A study by Grip and Janciauskiene[59] followed 10 patients with CD who received a supplementary daily oral treatment of 80 mg atorvastatin for 13 weeks. Plasma levels of nine inflammatory chemokines, including CCL2, CCL4, CXCL8 and CXCL10, and four soluble endothelial cytokines, including soluble P-selectin and thrombomodulin, were measured before and after atorvastatin treatment. The results showed a specific reduction in CXCL10 in all 10 patients; in particular, plasma CXCL10 levels decreased by a mean of 34% (P = 0.026). Moreover, CXCL10 levels were closely correlated with CRP after atorvastatin treatment (r = 0.82, P < 0.01). Atorvastatin treatment also exerted a profound hypocholesterolemia effect, but there was no relationship identified between plasma CXCL10 levels and lipid parameters, including total cholesterol, apolipoprotein B or triglycerides. In conclusion, the study suggested that high-dose oral atorvastatin significantly reduces plasma CXCL10 levels in patients with CD.

Another interesting pathway under investigation is peroxisome proliferator-activated receptor-alpha (PPAR-α), which is thought to contribute to inflammation resolution. Basso et al[60] aimed to investigate whether the beneficial effects of atorvastatin in experimental colitis are mediated by the nuclear receptor PPAR-α and whether its activation has an anti-inflammatory effect. C57BL/6 mice with dextran sulfate sodium-induced colitis were used, and the mice were treated with oral atorvastatin at 10 mg/kg/day. The main findings of the study included reduced lymphocyte proliferation and decreased IL-6 production, accompanied by increased IL-10 levels, without inducing cell death in vitro. In vivo, in mice with dextran sulfate sodium-induced colitis, improvements in clinical and histological parameters were observed, along with reductions in circulating leukocyte counts and intestinal inflammatory infiltrates. These changes were associated with a shift in the intestinal immune response from T helper (Th) 17 to Th2, characterized by increased IL-4 and decreased IL-17.

PPAR-α expression decreased in experimental colitis and in patients with IBD. In PPAR-α^-/- mice, the beneficial effects of atorvastatin, including symptom reduction and cytokine modulation, were abolished, demonstrating that atorvastatin’s efficacy depends on PPAR-α. In conclusion, atorvastatin appears to improve experimental colitis through PPAR-α-dependent mechanisms, modulating intestinal immunity and promoting an anti-inflammatory Th2 IL-4 response, thereby emerging as a potential biomarker of therapeutic response in IBD.

Simvastatin

Research has also focused on the anti-inflammatory and immunomodulatory effects of other statins, including simvastatin. Bereswill et al[61] used a murine model to induce acute ileitis of the small intestine by peroral infection with Toxoplasma gondii. This hyperacute Th1-type ileitis model reproduces key immunological features of acute IBD episodes in humans. Simvastatin was shown to possess anti-inflammatory and immunomodulatory properties beyond its primary function of modulating cholesterol levels. Mice treated with simvastatin were protected from ileitis. They survived the acute phase of inflammation, whereas all placebo-treated control animals died within 11 days after infection. Treated mice exhibited significantly milder macroscopic signs of intestinal inflammation, including less body weight loss and reduced small intestinal shortening the compared with placebo controls. Among the various cellular immunomodulatory effects, a significant increase in FOXP3-positive regulatory T cells was observed in the ileal mucosa of simvastatin-treated animals compared with placebo controls.

In contrast, reduced numbers of T lymphocytes, cluster of differentiation 3 positive, and neutrophil granulocytes, myeloperoxidase 7 positive, were detected in the mucosa of treated animals. Expression of pro-inflammatory cytokines, such as IL-23p19, interferon gamma, TNF-α, IL-6 and monocyte chemoattractant protein 1, was significantly lower in the ileum of treated animals compared with placebo controls. In contrast, levels of the anti-inflammatory cytokine IL-10 were significantly increased in the ileum, mesenteric lymph nodes and spleen.

Moreover, simvastatin appears to modulate the NF-κB pathway by inhibiting its signaling in intestinal epithelial cells and improving acute colitis in murine models. Sustained NF-κB activation is considered central to the pathophysiology of chronic intestinal inflammation[62]. Activation of NF-κB has been detected in the lamina propria of patients with CD and in murine models of TNBS-induced experimental colitis. In this context, Lee et al[63] used a human colon cancer cell line and observed that simvastatin significantly inhibited TNF-induced IL-8 gene expression. Simvastatin blocked TNF-induced NF-κB transcriptional activity in a dose-dependent manner. NF-κB activation, which was increased 4.2-fold by TNF-α, was significantly inhibited by pretreatment with simvastatin. In vivo experiments employed a murine model of acute colitis induced by dextran sulfate sodium. Simvastatin was administered orally once daily at doses of 5 mg/kg/day or 50 mg/kg/day, starting 2 days before exposure to dextran sulfate sodium and continuing for a total of 8 days. The results demonstrated a dose-dependent attenuation of colitis, characterized by reduced body weight loss, improved disease activity index scores, and histological improvement, demonstrating significant attenuation of experimental colitis.

Simvastatin has also been shown to be effective in combination with commonly used drugs for the treatment of IBD, such as sulfasalazine. One study investigated the effects of simvastatin combined with sulfasalazine by administering the two drugs from 5 days before and 7 days after acetic acid-induced UC[64]. Colonic mucosal inflammation was assessed both macroscopically and microscopically. In addition, TNF-α, IL-1 beta, NLRP3, malondialdehyde, reduced glutathione and superoxide dismutase levels in colonic tissue were analyzed, together with immunohistochemical evaluation of caspase-1 and cyclooxygenase-2. The results showed that simvastatin significantly improved macroscopic and histological scores in a dose-dependent manner, reduced colonic levels of IL-1 beta, TNF-α, NLRP3, malondialdehyde, caspase-1 and cyclooxygenase 2, and increased reduced glutathione and superoxide dismutase. These findings once again led to the conclusion that simvastatin exerts anti-inflammatory, cytoprotective and antioxidant effects that are not directly related to its cholesterol-lowering action.

Rosuvastatin

Finally, evidence for rosuvastatin’s beneficial effects on colonic mucosal damage and the inflammatory response in a murine model of dextran sulfate sodium-induced colitis is available. In this study by Naito et al[65], colitis severity was assessed using the disease activity index, colon length, histology and biochemical analyses. Disease activity index scores based on weight loss, stool consistency and fecal blood, were significantly lower in rosuvastatin-treated mice compared with control mice treated with dextran sulfate sodium alone. Rosuvastatin significantly reversed dextran sulfate sodium-induced colon shortening. While dextran sulfate sodium alone caused epithelial crypt loss, neutrophil infiltration, and ulceration, rosuvastatin treatment resulted in milder erosions and fewer neutrophils, the latter due to a significant inhibition of tissue-associated myeloperoxidase activity. In addition, rosuvastatin inhibited the increase in intestinal TNF-α protein levels and messenger RNA expression following dextran sulfate sodium administration. A fascinating finding was that rosuvastatin exerted anti-apoptotic effects by reducing the levels of caspase-3, caspase-7 and poly adenosine diphosphate ribose polymerase, an essential marker cleaved by caspases-3 and caspase-7.

STATIN USE AND IBD INCIDENCE AND ONSET

Statins are among the most widely prescribed drugs worldwide for cardiovascular prevention. In addition to their lipid-lowering effect, they are well documented to possess anti-inflammatory and immunomodulatory properties. They inhibit the mevalonate pathway, reduce isoprenoid availability, modulate NF-κB activation, lower TNF-α and IL-6 production, and improve endothelial function and the profile of lymphocyte subpopulations[66].

During the same period in which statins became widely used, the incidence of IBD has risen steadily in high-income regions, prompting a systematic search for modifiable environmental factors, including smoking, Western dietary patterns, antibiotics, nonsteroidal anti-inflammatory drugs, and other commonly used chronic medications. In this context, statins have emerged as potential protective agents, given their widespread population exposure and biological plausibility in modulating immunoinflammatory pathways, a hypothesis explored in several observational studies, a dedicated meta-analysis, and a recent Danish prospective cohort study[67-70].

An initial signal supporting this hypothesis comes from the case-control study by Ungaro et al[70], based on a large United States claims database. The investigators identified 9617 incident IBD cases and 46665 controls matched for age, sex, race, and geographic region. Cases were classified as “new onset” only when at least three International Classification of Diseases (ICD), ninth revision (ICD-9) codes for CD or UC were present, with no prior IBD-related codes or prescriptions, thereby minimizing the risk of including pre-existing disease. To reduce protopathic bias, statin exposure within the 6 months preceding diagnosis was excluded; sensitivity analyses extending this window to 12 and 24 months yielded similar results. In this context, any statin use was associated with a significantly lower risk of incident IBD diagnosis (OR = 0.68; 95%CI: 0.64-0.72), with comparable reductions observed for CD (OR = 0.64; 95%CI: 0.59-0.71) and UC (OR = 0.70; 95%CI: 0.65-0.76). The protective association was consistent across different statin agents and only modestly influenced by treatment intensity, with a stronger effect observed in older individuals, particularly for CD.

Additional evidence comes from the Swedish study by Lochhead et al[69], which used national registers to identify 7637 cases of CD and 15652 cases of UC, each matched to ten population controls. Statin exposure was determined from the prescribed drug register, with cumulative dose calculated in defined daily doses. In conditional logistic regression models adjusted for multiple comorbidities and primary indications for statin therapy, any statin use was associated with a reduced risk of CD (OR = 0.71; 95%CI: 0.63-0.79), whereas no significant association was observed for UC (OR = 1.03; 95%CI: 0.96-1.11). The strongest effect for CD was seen among current users (OR = 0.67; 95%CI: 0.60-0.75). Risk reduction was evident even at the lowest cumulative doses (31-325 defined daily doses, OR = 0.73; 95%CI: 0.61-0.88) and persisted at the highest exposure levels (> 1500 defined daily doses, OR = 0.66; 95%CI: 0.55-0.80), despite the absence of a statistically significant linear dose-response trend. For UC, estimates remained close to unity across all dose categories.

To synthesize these and other data, Bhagavathula et al[68] conducted a systematic meta-analysis comprising five retrospective studies (seven comparisons) that encompassed more than 10 million participants and 89324 incident IBD cases, with a mean follow-up of 8.6 years. Overall, statin use was associated with a hazard ratio (HR) of 0.81 (95%CI: 0.63-1.06) for new-onset IBD, a relative reduction of 19% although the CI crossed unity. When the two primary disease forms were examined separately, the HR was 0.94 (95%CI: 0.72-1.25) for CD and 0.89 (95%CI: 0.70-1.12) for UC, both of which were non-significant. Heterogeneity was high (I² > 80% for all endpoints), indicating substantial differences across studies in terms of populations, exposure definitions, temporal windows, and adjustment strategies. The authors cautiously conclude that the overall pattern is consistent with a potentially protective effect but does not yet provide definitive proof.

The Danish prospective cohort by Faye et al[67] represents a methodological step forward owing to its nationwide “new user” design. Individuals aged ≥ 40 years eligible for statin therapy for primary cardiovascular prevention were enrolled between 2008 and 2022: 110961 new statin users and 554805 non-users matched 1:5 for age, sex, calendar year, and cardiovascular risk factors. In multivariable Cox models, statin use was associated with a reduced risk of incident IBD [adjusted HR (aHR) = 0.84; 95%CI: 0.72-0.97], with similar estimates for CD (aHR = 0.84; 95%CI: 0.65-1.09) and UC (aHR = 0.83; 95%CI: 0.69-1.00). Expressed in absolute terms, this corresponds to a number needed to treat 2881 individuals over 5 years to prevent a single case of IBD. The effect remained essentially unchanged when patients were censored at treatment discontinuation, suggesting that the benefit is linked to ongoing exposure.

Taken together the United States case-control study, the Swedish case-control study, the meta-analysis, and the Danish cohort provide a reasonably comprehensive picture for a field still in an exploratory phase: On average, patients receiving statin therapy exhibit a 15%-30% lower risk of developing IBD compared with unexposed individuals. In some studies, the signal is more pronounced for CD, whereas in others, the effect appears similar for CD and UC. Importantly, none of these extensive studies suggests an increased risk; when the association is non-significant, estimates nevertheless remain < 1, and the CIs exclude significant risk increases[67-70].

Nevertheless, the intrinsic limitations of observational studies remain. Confounding by indication and healthy-user bias are difficult to rule out; individuals taking statins tend to receive more regular medical follow-up, show higher treatment adherence, and generally engage in healthier lifestyles than non-users, and these factors are never fully measurable. The primary studies attempted to mitigate these biases through different strategies, including exclusion of exposures immediately preceding diagnosis and extensive adjustment for medications and comorbidities in the study by Ungaro; explicit modeling of treatment indications in the Swedish analysis; and a new-user design with matching for cardiovascular risk in the Danish cohort. However, the high heterogeneity observed in the meta-analysis clearly indicates that context and methodological choices substantially influence the estimated effect size[67-70]. The temporal question also remains: At what point in the natural history of IBD do statins exert their potential protective effect? The observation in Ungaro’s study that the association persists even after excluding 6, 12, and 24 months of pre-diagnostic exposure, the finding by Lochhead of the lowest OR among current users, and the emergence of the signal over a multi-year horizon in the Danish cohort are all consistent with an effect distributed across the entire pre-clinical phase. However, these data do not allow for precise definition of the minimum exposure duration required[67-70].

On the biological front, these epidemiological data rest on robust literature documenting the effects of statins on both innate and adaptive immunity: Reduction of isoprenoids required for prenylation of small GTPases, attenuation of NF-κB, decreases in TNF-α and IL-6, and modulation of the Th/regulatory T cell balance. Cardiovascular clinical trials have shown rapid reductions in CRP and other inflammatory markers following treatment initiation, independent of the magnitude of cholesterol decrease. Altogether, this provides a plausible bridge between chronic systemic immunomodulation and a reduced risk of immune-mediated diseases such as IBD, albeit without trials directly demonstrating a primary preventive effect on IBD[66,67].

Further coherence comes from cohorts of patients with established IBD, in whom statin use has been associated with a less aggressive disease course. In the retrospective study by Crockett, statin exposure was associated with an 18% reduction in the rate of steroid initiation (HR = 0.82; 95%CI: 0.71-0.94), with a more substantial effect in UC than in CD; the large Swedish national cohort by Khalili likewise shows a lower risk of surgery in both disease forms and, in UC, reductions in hospitalizations and flares. These data pertain to disease trajectory rather than incidence, but they lend credibility to the notion that statins’ immunomodulatory mechanisms may be relevant both before and after clinical onset[71,72].

From a practical standpoint, the available evidence does not justify prescribing statins solely to prevent IBD. The absolute effect is modest (with numbers needed to treat in the thousands), and all supporting data derive from observational studies. Nonetheless, in patients with a clear cardiovascular indication, the potential additional benefit regarding IBD risk may be considered a non-trivial “bonus”, particularly in high-incidence settings or in individuals with a family history. The honest synthesis is that statins do not appear to increase the risk of IBD and may, in fact, modestly reduce it; however, progressing from a “drug with a protective signal” to an “intervention for targeted IBD prevention” requires higher levels of evidence, achievable only through dedicated prospective studies and randomized trials in high-risk populations. At present, such a level of evidence has not yet been reached[67-70].

STATIN USE AND MODULATION OF DISEASE ACTIVITY IN IBD: A TOOL FOR CONTAINING THE INFLAMMATORY BURDEN?

Interest in the potential use of statins to modulate disease activity in IBD has intensified over the last few years, supported by the hypothesis that these molecules may represent additional tools to control the inflammatory burden by modulating immune and metabolic pathways relevant to IBD pathogenesis. The first evidence derives from mouse models of experimental colitis, in which statins have been shown to reduce inflammatory infiltrates, diminish the production of pro-inflammatory cytokines, and modulate key immune pathways involved in the mucosal response[73]. In particular, Gou et al[73] demonstrated that atorvastatin improves dextran sulfate sodium-induced colitis by modulating microbiota-mediated tryptophan metabolism and activating the aryl hydrocarbon receptor (AhR) and IL-22 axis, thereby promoting intestinal epithelial regeneration and increasing the expression of tight junction proteins, which are crucial for maintaining epithelial barrier integrity. Protective effects were attenuated in germ-free models, confirming that the microbiota is crucial for modulating tryptophan metabolism and activating the AhR-IL-22 axis. Similarly, although most evidence derives from dextran sulfate sodium-induced colitis models, statin-treated mice showed reduced expression of pro-inflammatory markers, including TNF-α[63]. In another preclinical study using TNBS-induced colitis, simvastatin exerted anti-fibrotic effects, as demonstrated by a dose-dependent decrease in a fibrosis-associated growth factor[74]. Although obtained in experimental models, these results provide an initial biological rationale for a potential role of statins in controlling intestinal inflammation. An important translational contribution comes from an ex vivo study by Grip et al[75], which showed that atorvastatin decreases monocyte chemoattractant protein-1 and TNF-α secretion by monocytes in patients with active CD. This effect appears to be related to interference with signaling pathways activated by oxidative stress, particularly those activated by oxidized (ox) LDL[76]. Statins diminish the uptake and intracellular degradation of oxLDL in monocytes, attenuating one of the main stimuli for pro-inflammatory cytokine production[76]. Simultaneously, they reduce the oxidative modification of plasma LDL and the activation of the mitogen-activated protein kinase pathway mediated by oxLDL, as well as inhibit the synthesis of isoprenoids necessary for the prenylation of small GTPases (i.e., Rho, Ras, and Rac), which are crucial for the activation of pro-inflammatory pathways[77,78]. Because inhibition of stress-activated mitogen-activated protein kinases has already shown favorable clinical effects in moderate-to-severe CD[79], these results suggest that statins might modulate similar circuits, thereby limiting the recruitment/activation of monocytes in IBD. Despite the limitations of an ex vivo experiment, these findings represent an important step forward in understanding the potential role of statins in controlling systemic and mucosal inflammation. According to these results, the same group led the first in vivo clinical study in CD[80]. Indeed, 13 weeks of treatment with high-dose atorvastatin significantly reduced CRP (44%) and decreased monocytic expression of C-C motif chemokine receptor type 2 and C-X3-C motif chemokine receptor 1, suggesting modulation of their migratory capacity. Fecal calprotectin decreased in several patients but did not reach statistical significance and returned to basal values after drug discontinuation. Despite limitations associated with an open-label, uncontrolled, and small study, these findings represent the first clinical evidence consistent with previous ex vivo observations that statins may have a detectable effect on systemic and intestinal inflammatory burden[80].

On the other hand, extending the statin assessment to the acute phases of UC did not return positive findings. Indeed, in the randomized trial conducted by Dhamija et al[81], the use of atorvastatin in combination with conventional therapy did not improve clinical outcomes in patients with mild-to-moderate UC flare-ups, but was associated with a higher rate of discontinuation due to worsening disease activity. In agreement with these findings, the study by Voth et al[82] did not support a protective role of statins in the outcomes of Clostridioides difficile infection in IBD patients. Still, it did report an association with more severe forms. This finding might represent residual confounding, as patients on statin therapy were likely subjects with the most complex clinical profiles. However, a biological contribution cannot be excluded, as statins have been shown to modulate several aspects of the immune response[83,84]. A preliminary analysis has hypothesized a possible unfavorable interaction with Clostridioides difficile toxins A/B, promoted by Rho-dependent pathways[85]. Furthermore, the same work did not highlight any protective effect of statins on the recurrence and mortality risk associated with Clostridioides difficile infection, leaving uncertainty on their impact in the infectious context. Large-scale observational studies present a more favorable picture. In the United States cohort of Crockett et al[72], which counted almost 12000 patients with IBD, starting statin therapy significantly reduced the risk of corticosteroid use, adopted as a proxy for disease exacerbation. The association was more marked in UC, while it was weaker and not significant in CD. A favorable, although non-significant, trend toward lower risk was also observed for anti-TNF therapy, hospitalization, and surgery. Stratified analyses by dose and duration suggested a possible dose-dependent effect, with lower rates of steroid use in patients treated for longer times or with higher doses. Among individual molecules, atorvastatin had the strongest association. Without ignoring the inherent limitations of observational studies, these data represent the first large-scale epidemiological evidence supporting a potential steroid-sparing effect of statins in IBD, particularly in UC, and revive interest in their complementary action in reducing the inflammatory burden. These findings were corroborated and extended in the Swedish study by Khalili et al[71], based on a national cohort of over 32000 adults with IBD. Exposure to statins after diagnosis was associated with a significant reduction in the risk of surgery, hospitalization, and flare-ups in UC, while in CD, the effect seemed more confined to a reduction in surgical risk. Exploratory analyses suggested possible differences between statins, with stronger signals for atorvastatin, though without definitive evidence. Overall, the cohort by Khalili et al[71] provides a coherent signal of benefit, particularly in UC, reinforcing the hypothesis that statins may modify the disease course long-term. Previous evidence showed that statin use was associated with a lower risk of incident CD, but not UC[69]. Speculatively, this could indicate different effects of statins between IBD subtypes and between CD and UC, before and after disease onset. In the context of hepatobiliary diseases, several studies have reported an association between statin use and a reduced risk of liver failure and mortality[86-89]. The hypothesis has been raised that the drugs may also play a favorable role in cholestatic and immune-mediated conditions such as primary sclerosing cholangitis (PSC), especially in patients with PSC-IBD[90,91]. In a national cohort study of over 2900 patients with IBD-associated PSC, Stokkeland et al[90] reported reduced mortality and reduced transplantation risk among statin users, suggesting a possible benefit, even in hepatobiliary conditions characterized by a high inflammatory burden. The association remained significant after adjustment for concomitant ursodeoxycholic acid use and major metabolic comorbidities, suggesting an effect independent of confounding variables. Another emerging aspect of interest is the connection between statins and the gut microbiota. Vieira-Silva et al[92] demonstrated that statin use was associated with a lower prevalence of the dysbiotic Bacteroides 2 enterotype, commonly found in IBD and characterized by low microbial diversity along with a systemic pro-inflammatory profile. This association remained significant after adjustment for metabolic variables, suggesting that statins’ potential immunomodulatory role may also involve modulation of altered gut microbial ecosystems. The authors postulated that this association may have resulted from reduced bacterial LPS production or an increase in short-chain fatty acid-producing bacteria that are known for their anti-inflammatory properties. Overall, the available evidence suggests that statins modulate several aspects of inflammatory pathogenesis in IBD, including monocyte responses and systemic inflammation, as well as microbiota composition, leaving open the possibility of a complementary intervention in selected clinical settings. However, most evidence comes from observational or experimental studies using surrogate endpoints, and large-scale, prospective, controlled trials with robust clinical outcomes are lacking. It will therefore be important to define which statin molecules, dosages, duration, and clinical contexts might most benefit from this class of drugs and whether the response changes according to disease phenotype and individual microbial profile.

CAN STATINS SERVE AS A TOOL TO CONTAIN THE RISK OF COLITIS-ASSOCIATED COLORECTAL CARCINOGENESIS? AN OVERVIEW OF AVAILABLE DATA STARTING FROM PRECLINICAL EVIDENCE

IBD is associated with an increased risk of colorectal cancer (CRC). In general, the risk of CRC begins to rise approximately 8-10 years after the diagnosis of UC or CD[93], with a cumulative risk in patients with UC of 2% at 10 years and 8% and 18% at 20 and 30 years of disease, respectively[94]. According to a recent analysis, the risk of CRC has decreased over time[95], likely due to the more widespread use of maintenance therapy with 5-aminosalicylic acid (5-ASA) and high rates of endoscopic surveillance[95,96].

The pathophysiology of IBD-associated CRC differs from that of sporadic CRC. Whereas sporadic CRC is caused by a series of random mutations involving the APC or MSH gene pathways, IBD-associated CRC may be related to the chronic inflammatory state that characterizes these conditions. Recent data suggest that through the production of reactive oxygen species, chronic inflammation leads to DNA damage and to an environment conducive to carcinogenesis[97,98]. Tumor progression is also facilitated by an inflammatory milieu, as disturbances in immune surveillance mechanisms such as suppression of cytotoxic T cells, recruitment of regulatory T cells, and the expansion of myeloid-derived suppressor cells may promote tumor invasion and metastasis[98]. Finally, it has also been demonstrated that specific cytokines that are increased in chronic IBDs, such as IL-6 and IL-23, nuclear NF-κB, and TNF-α, are involved in cancer progression[99,100].

There are also clinical risk factors that support the hypothesis that chronic inflammation increases the risk of IBD-associated CRC, including long disease duration; disease extent, with a 14.8-fold higher risk in patients with pancolitis compared with the general population; a history of dysplastic lesions; PSC; and a family history of CRC[94,101-103]. It is therefore essential in patients with IBD to adopt strategies aimed at reducing the risk of CRC through the recognition of early lesions by means of surveillance colonoscopies and by reducing and/or halting the colorectal carcinogenesis driven by chronic inflammation through chemo-preventive strategies (i.e., 5-ASA and/or biologics and small molecules)[104].

Concerning endoscopic surveillance, the European Crohn’s and Colitis Organization guidelines suggest performing the first colonoscopy 8 years after the diagnosis of IBD and scheduling subsequent examinations according to the patient’s risk class: After 1 year in high-risk patients (with severe inflammation, dysplasia, colonic strictures, or PSC), after 2-3 years in patients with intermediate risk factors, and after 5 years in patients without high or intermediate risk[105].

In recent years, several meta-analyses and systematic reviews have reported a significant association between statin use and reduced CRC risk[106-109]. Additional anti-inflammatory, antiproliferative, pro-apoptotic, and antineoplastic effects associated with statin use have been demonstrated in in vitro and animal studies[110,111]. As HMG-CoAR is overexpressed in CRC and other tumors, statins appear to be rational chemo-preventive agents[106,112-114]. Although no strong studies specifically designed as CRC surveillance studies in the context of IBD are currently available, some observational studies have reported encouraging results regarding the use of statins as chemo-preventive agents, whereas others have not confirmed these findings.

A Swedish cohort study evaluated the association between statin use and the risk of CRC in patients with IBD[115]. A total of 5273 statin users and an equal number of non-users were identified and matched using propensity scores to minimize baseline confounding. The results, with a median follow-up of 5.6 years showed that statin use was associated with a significant reduction in CRC incidence [aHR = 0.56 (0.37-0.83)] and all-cause mortality [aHR = 0.63 (0.57-0.69)]. This risk reduction among statin users appeared to depend on treatment duration, with clear benefits after at least 2 years of continuous use. Moreover, the reduction in risk was mainly observed in patients with UC, in patients diagnosed with IBD before the age of 50 years, and in those with a disease duration greater than 10 years.

In another retrospective study conducted on a large cohort of 11001 patients with IBD, the association between statin use and CRC risk was assessed. During a median follow-up of 9 years, CRC occurred in 2% of statin users compared with 3% of non-users. In multivariable logistic regression analysis, statin use was independently associated with a 58% reduction in risk (OR = 0.42; 95%CI: 0.28-0.62), even after adjustment for age, sex, IBD type, smoking status, inflammatory markers, endoscopic surveillance practices, and medical therapies[116].

Similarly, in a case-control study conducted by Samadder et al[117], prolonged statin use showed a strong inverse association with CRC risk in the general population, which was even more pronounced in patients with IBD, suggesting statin use as a potentially promising chemo-preventive strategy in a high-risk population like patients with IBD.

By contrast, no significant protective effect emerged in an extensive Korean population-based study of 35189 patients with UC, in which statin use was associated with a chemo-preventive effect against overall malignancies but not against CRC[118]. Similarly, a Chinese cohort study based on the Hong Kong territory-wide registry evaluated cancer risk and the potential chemo-preventive effects of 5-ASA, statins, and aspirin in an IBD population. In multivariate analyses, neither 5-ASA, statins, nor aspirin was associated with a reduced risk of malignancy[119]. Likewise, in a study conducted by Shah et al[120], which assessed the association between statin exposure and the risk of dysplasia or CRC in a cohort of patients with IBD, the observed results did not demonstrate a significant chemo-preventive benefit related to statin use.

The differences in results across studies may reflect heterogeneity in study populations, variability in surveillance practices, and differences in the duration of statin exposure. Therefore, in the face of such heterogeneous and inconclusive findings, prospective studies are needed to confirm or refute causality and to understand better the role of statins in the prevention of IBD-associated CRC.

ONGOING CLINICAL TRIALS ON THE USE OF STATINS IN IBD: WHAT IS IN THE PIPELINE?

In recent years, evidence (in terms of clinical trials) investigating the potential role of statins in IBD has increased significantly. Large-scale cohort studies and meta-analyses have reported increasingly consistent associations between statin exposure and reduced disease activity, fewer complications, and a lower risk of CRC in patients with IBD. Simultaneously, several clinical trials have been initiated to investigate mechanistic hypotheses, including immunomodulation, modulation of the microbiota, prevention of fibrosis, and mucosal protection. Before this recent pipeline was launched, two small, pioneering studies provided the first clinical signals suggesting the therapeutic potential of statins in IBD. The open-label (No. NCT00454545) trial tested high-dose atorvastatin in patients with active CD, reporting reductions in circulating CXCL10 levels and alterations in the expression of the monocyte chemokine receptor, suggesting an early impact on systemic inflammatory pathways[59]. Similarly, the pilot (No. NCT00599625) study assessed the feasibility of adding pravastatin as therapy, confirming good tolerability and suggesting a potential effect on systemic inflammatory markers. Although limited in scale, these studies laid the conceptual groundwork for current clinical investigations. Within CD, the fibrostenotic phenotype remains one of the most complex presentations, characterized by progressive strictures often refractory to medical therapy[121]. Despite advances and the introduction of new therapies, strictures remain among the main indications for surgery[121]. However, surgery is often not a definitive solution: Approximately half of patients develop clinical recurrence within 10 years of intestinal resection[122]. Based on this rationale and supported by preclinical evidence of statins’ anti-fibrotic effects[74], the phase 1 trial (No. NCT06538649) is evaluating the perioperative use of rosuvastatin to reduce early postoperative recurrence in CD through an integrated assessment of clinical outcomes and immune, microbiomics, and metabolomic profiles. The results are expected to clarify whether statin-induced pharmacological modulation of pro-inflammatory and pro-fibrotic circuits may represent an effective strategy to prevent postoperative recurrence in CD. In UC, interest in the potential role of statins as therapeutic agents has led to the development of trials to define their efficacy as adjuncts to conventional therapy. The (No. NCT05561062 and No. NCT05567068) phase 2 trials tested atorvastatin 80 mg/day in addition to mesalazine in mild-to-moderate UC. Both studies showed improvements in clinical activity and quality of life, while significant reductions were recorded in CRP, erythrocyte sedimentation rate (ESR) and pro-inflammatory cytokines. In the first case, the primary endpoints included reductions in the partial Mayo score and improvements in quality of life (short form-36). In contrast, secondary endpoints included variations in IL-6, TNF-α, sphingosine 1-phosphate, nitric oxide, CRP, ESR, and fecal calprotectin. It showed that the addition of atorvastatin significantly improved clinical activity and inflammatory biomarkers[123]. The second trial used the simple clinical colitis activity index (SCCAI) and quality of life [32-item inflammatory bowel disease questionnaire (IBDQ-32)] as primary outcomes and, as secondary endpoints, variations in IL-18, CRP, and ESR. Findings confirmed significant improvements in SCCAI, IBDQ-32, and systemic inflammatory markers[124]. Therefore, preliminary data suggest that the addition of atorvastatin may be associated with improvements in symptoms and quality of life, and a reduction in systemic markers of inflammation, compared with mesalazine alone, providing evidence for statins’ anti-inflammatory effects. A similar approach, though focused on microbiota modulation, is provided by the ReMiDy study (No. NCT04883840), investigating the effect of 10 mg rosuvastatin on microbiota composition in patients with IBD in remission or with mild-to-moderate disease. The rationale is provided by evidence linking the Bact2 enterotype to dysbiosis and increased systemic inflammation[92]. The study uses a crossover design to determine whether rosuvastatin can modulate the Bact2 profile toward less pro-inflammatory microbial configurations. Secondary endpoints include assessing the impact of such modulation on disease activity. Results are pending, but the study will likely clarify whether statin-mediated modulation of the microbiota can influence the clinical course of IBD. Another area of emerging interest is the prevention of IBD-associated CRC, a complication that, in patients with long-standing UC, reflects a carcinogenic process driven by chronic inflammation. This is characterized by progressive accumulation of somatic and epigenetic mutations, genomic instability, and impairment of proliferative control systems and DNA repair mechanisms, ultimately predisposing the colonic epithelium to malignant transformation[125,126]. Consistent with evidence suggesting a potential effect of statins on colorectal carcinogenesis[127], the trial (No. NCT04767984) explores the potential chemo-preventive role of atorvastatin 40 mg/day for 12 months in reducing the proportion of colonic cells expressing mutant p53, assessed by immunohistochemistry on colorectal mucosal biopsies obtained before and after treatment. Secondary endpoints include modulation of Ki-67, apoptotic markers, and inflammatory pathways. Taken together, these data may support the possible use of statins as a targeted approach to reducing inflammation-driven oncogenesis in patients with long-standing UC. Previous studies have investigated the possible role of statins in hepatobiliary diseases associated with IBD, suggesting that statin use is associated with lower mortality in patients with PSC[90]. Based on these findings, the study (No. NCT05912387) investigates rosuvastatin in combination with a multiomic approach, globally assessing changes in bile acids, microbiome structure, bacterial transcriptomes, and metabolic pathways to clarify the biological mechanisms underlying PSC and to identify potential therapeutic targets. As a whole, such studies outline a research path to explore key pathophysiological aspects of IBD, intending to determine whether and in which clinical contexts statins may be repositioned as agents capable of modifying the course of the disease. Table 1 summarizes the principal studies described in this section.

Table 1 Collection of the principal clinical trials conducted on the use of statins in patients with inflammatory bowel disease.

Trial (NCT)1	Disease/setting	Intervention	Design/phase	Main objective	Status
NCT00454545	Moderate active CD	Atorvastatin 80 mg once daily for 13 weeks	Open-label, single-arm pilot	Effect on CXCL10 and immune markers	Completed
NCT00599625	Active CD (add-on to standard therapy)	Pravastatin (6 weeks)	Pilot, non-randomized	Feasibility and exploratory anti-inflammatory effects	Completed
NCT06538649	Stricturing CD after ileal resection	Rosuvastatin 10-20 mg daily vs placebo, 6-12 months	Randomized, placebo-controlled (phase 1)	Prevention of post-surgical stricture recurrence; immune-microbiome-metabolic profiling	Active
NCT05561062	Mild-to-moderate UC	Atorvastatin 80 mg plus mesalazine vs placebo plus mesalazine, 6 months	Randomized, placebo-controlled (phase 2)	Change in partial Mayo score and inflammatory markers	Active
NCT05567068	Mild-to-moderate UC	Atorvastatin 80 mg plus mesalazine vs placebo plus mesalazine	Randomized, placebo-controlled (phase 2)	Change in SCCAI, IBDQ-32, and systemic inflammation	Completed
NCT04883840 (ReMiDy)	UC and CD (remission or mild activity)	Rosuvastatin 10 mg daily vs placebo, cross-over design	Randomized, double-blind (phase 2/3)	Modulation of Bacteroides 2 enterotype and microbiota-inflammation link	Terminated; results pending
NCT04767984	Long-standing UC with TP53 mutation, high CRC risk	Atorvastatin 40 mg daily for 12 months vs placebo	Randomized, placebo-controlled (phase 2)	Effect on mutant TP53, proliferation and apoptosis markers	Active
NCT05912387	PSC (often IBD-associated)	Rosuvastatin 12 weeks plus 2-week washout	Single arm (phase 1)	Multiomic profiling of bile acids, microbiome and metabolism	Active

¹All data are extracted from the HYPERLINK https://clinicaltrials.gov portal.

NCT: National clinical trial; CD: Crohn’s disease; UC: Ulcerative colitis; CRC: Colorectal cancer; PSC: Primary sclerosing cholangitis; IBD: Inflammatory bowel disease; SCCAI: Simple clinical colitis activity index; IBDQ-32: 32-item inflammatory bowel disease questionnaire.

CONCLUSION

The high burden of disease associated with IBD encourages a constant search for new treatments, and statins could play a role in this context. Several studies have shown that the pleiotropic effects of statins reduce systemic inflammation, lowering circulating cytokine levels and reactive oxygen species formation. This makes statins potential allies in both the prevention and treatment of established IBD. Furthermore, some evidence shows that statins may be protective against IBD-associated CRC. Although some studies involving patients with UC or CD have already provided evidence in favor of their use in this population, other research casts doubt on these findings. Several issues affect the currently available evidence, which largely consists of observational studies burdened by the risk of selection and information biases, thus allowing only the assessment of potential associations, while the randomized controlled trials conducted to date are still few and often include small patient numbers. Moreover, there is marked heterogeneity among existing studies, both in methodological terms and in terms of interventions, including the use of different statins at different dosages, as well as in study duration, thereby precluding robust long-term conclusions. Finally, adequate profiling is lacking to identify which IBD patient phenotypes might truly benefit from a statin add-on therapeutic approach. Results from ongoing clinical trials (currently in phases 1 or 2) will shed light on some uncertainties surrounding statin treatment and provide a solid foundation for future trials. Lastly, in parallel with this, studies are warranted to better clarify, within the framework of statins’ pleiotropic anti-inflammatory and immunomodulatory potential, which mechanisms underpin their potential beneficial effects in IBD.