Metformin as a Potential Adjunct in the Treatment of Mild-to-Moderate Ulcerative Colitis: A Double-Blind, Randomized, Placebo-Controlled Pilot Study.

Metformin as a Potential Adjunct in the Treatment of Mild-to-Moderate Ulcerative Colitis: A Double-Blind, Randomized, Placebo-Controlled Pilot Study. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Metformin as a Potential Adjunct in the Treatment of Mild-to-Moderate Ulcerative Colitis: A Double-Blind, Randomized, Placebo-Controlled Pilot Study. Mahdi Molavi, Bahareh Amin, Mohammad Sahebkar This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7652190/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Dec, 2025 Read the published version in Internal and Emergency Medicine → Version 1 posted 4 You are reading this latest preprint version Abstract Managing relapsing ulcerative colitis (UC) remains a clinical challenge despite therapeutic advances. Metformin, primarily an antidiabetic agent with demonstrated anti-inflammatory properties, has been proposed as an adjunctive treatment for UC. This double-blind, randomized, placebo-controlled pilot trial evaluated the effectiveness of adjunctive Metformin in reducing disease activity among patients experiencing acute UC exacerbations. A total of 112 patients with UC were enrolled at Sabzevar, Iran, between 2017 and 2024. The mean age of participants was 34.52 ± 5.79 years, and 57 patients (50.1%) were male. Patients were randomly assigned to receive either 1000 mg Metformin tablets twice daily (after breakfast and dinner) in addition to routine treatment or placebo tablets with routine treatment for two months. The primary outcome was the change in UC Disease Activity Index (UCDAI) scores after the follow-up period. Ordinal logistic regression demonstrated that the odds of having a higher UCDAI score were approximately 54% lower in the Metformin group compared with the control group (OR: 0.46; 95% CI: 0.21–0.97; P = 0.044). Multiple linear regression further confirmed significantly lower mean UCDAI scores in the Metformin group (β = −1.11; 95% CI: −1.86 to − 0.37; P = 0.004). These findings suggest that adjunctive Metformin is associated with meaningful reductions in disease activity scores, supporting its potential therapeutic role in managing acute exacerbations of UC. While the results are promising, larger-scale clinical trials are needed to validate these outcomes and investigate the underlying mechanisms by which Metformin may exert its anti-inflammatory effects in UC management. Ulcerative colitis Metformin Ulcerative Colitis Disease Activity Index Figures Figure 1 Highlights • Efficacy in Disease Management: Metformin demonstrates a significant reduction in Ulcerative Colitis Disease Activity Index (UCDAI) scores compared to the control group, indicating its potential therapeutic benefit in managing disease activity. • Promising Therapeutic Potential: As a pilot study, the findings suggest that Metformin may offer beneficial anti-inflammatory effects in mild-to-moderate ulcerative colitis, providing preliminary evidence to support further investigation through larger clinical trials. • Safe Adjunctive Therapy: The results highlight Metformin’s safety and tolerability as an adjunct to routine treatment, suggesting its potential as a safe and effective addition in managing mild-to-moderate ulcerative colitis. Introduction Ulcerative colitis (UC) is a chronic inflammatory disease of the intestine, with an increasing incidence over the past five decades [ 1 ]. This condition is characterized by symptoms such as bloody diarrhea, abdominal pain, and weight loss, which vary in severity according to disease activity [ 2 ]. While severe UC is associated with high morbidity, including frequent hospitalization and surgery, patients with mild to moderate UC also experience substantial impairment in quality of life and ongoing disease management challenges [2; 3]. Pharmacological treatments for UC—including Mesalazine, corticosteroids, immunosuppressants, and biological agents—are effective for many patients, particularly those with mild to moderate disease; however, treatment response varies, and concerns remain regarding side effects and economic costs [ 4 ]. Metformin, a biguanide derivative, is widely utilized as a primary pharmacological agent in the treatment of type 2 diabetes [ 5 ]. Its primary mode of action involves the inhibition of hepatic glucose production and a reduction in peripheral tissue resistance to insulin, resulting in decreased circulating glucose and insulin levels [6; 7]. Beyond its hypoglycemic effects, recent research has highlighted its additional cardioprotective [ 8 – 10 ], antioxidant, and anti-inflammatory properties [ 11 ]. Notably, Metformin demonstrates the ability to attenuate lipopolysaccharide-induced inflammatory responses in cultured macrophages and endothelial cells, while also downregulating experimental inflammation in various organs [ 12 ]. Its use has been associated with a decreased risk of Parkinson's disease, and ongoing studies explore its potential anti-cancer properties [13; 14]. Furthermore, metformin has shown efficacy in mitigating lipopolysaccharide-induced inflammation in smooth muscle cells and improving intestinal epithelial barrier integrity in mice with inflammatory bowel disease (IBD) [ 15 ]. Despite the potential benefits of Metformin, there is a significant gap in the existing literature, as there is no comparison of its effectiveness in individuals with UC. This study aims to fill this gap by assessing the therapeutic impact of adding Metformin to the current treatment regimen for individuals with mild to moderate UC. Material and Methods Study Design This double-blind, randomized, parallel-group clinical trial was conducted to examine the efficacy of adding Metformin on the severity of Disease Activity Index (DAI) scores in patients presenting with acute exacerbation of UC between 2017 and 2024. Participants The study participants included all patients with UC referred to the endocrinology clinic of Vasei Hospital in Sabzevar, Iran, from March 2017 to December 2024. Inclusion criteria included adults aged 18 years or older with a confirmed diagnosis of UC affecting at least the rectosigmoid region, based on colonoscopy and physical examination at study entry. Eligible participants were required to have mild to moderate recurrent UC, defined by a Disease Activity Index (DAI) score of 3 to 8, with symptom recurrence within 4 weeks prior to enrollment. Although moderate UC is often defined as a DAI score up to 10, we used a 3–8 range to ensure a more homogeneous study population and to minimize the inclusion of patients at the more severe end of the moderate spectrum, who might require escalation to systemic corticosteroids or biologics, potentially confounding the intervention effects. Exclusion criteria included patients with Crohn's disease, diabetes mellitus, heart failure, or severe renal or hepatic impairment. Pregnant or lactating individuals and those with a known allergy to metformin were also excluded. Additionally, patients were excluded if they had received systemic corticosteroids, anti-TNF agents, or cyclosporine within 8 weeks prior to the study or during the 8-week study period. Use of rectal 5-ASA or systemic corticosteroids within 4 weeks before enrollment was also not permitted. To ensure stability in baseline treatment, patients who had experienced any changes in the dosage of oral 5-ASA, 6-mercaptopurine, or azathioprine within the 12 weeks prior to study entry were excluded. Only patients on a stable dose of oral 5-ASA for at least 12 weeks before enrollment were included. Intervention Eligible patients were randomly assigned to either the Metformin group or the control group in equal numbers. Patients in the intervention group received routine treatment along with Metformin tablets (1000 mg twice daily, manufactured by Tehran Shimi Company) for two months, administered after breakfast and dinner. Patients in the control group received routine treatment plus placebo tablets (produced by the Iranian Pharmacy Laboratory) for the same duration and schedule. All participants received a stable dose of oral 5-ASA (Mesalazine, ≥ 2 g/day) for at least 12 weeks prior to the study, and, where applicable, either Azathioprine (≥ 1.5 mg/kg/day) or 6-Mercaptopurine (≥ 1 mg/kg/day) for at least 12 weeks prior to enrollment [ 16 ]. Patient compliance was monitored by counting returned tablets at each follow-up visit. Outcome The primary aim of this study was to estimate the Ulcerative Colitis Disease Activity Index (UCDAI) score at the end of two months. The UCDAI, comprising four subscales—bowel frequency, rectal bleeding, endoscopic score, and the physician's assessment of severity—was recorded individually by the investigator. The UCDAI utilizes a 12-point scoring system, where each of the four variables (stool frequency, bleeding severity, colonic mucosal appearance, and physician's overall assessment) is scored from 0 to 3. Consequently, the total index score ranges from 0 to 12, with categories defined as follows: 0–2 indicating remission, 3–6 denoting mild disease, 7–10 signifying moderate disease, and > 10 indicating severe UC [ 17 ]. The activity of UC was assessed using a comprehensive scoring system encompassing stool frequency, rectal bleeding, findings of flexible sigmoidoscopy, and the physician's global assessment. Stool frequency was scored as follows: 0 for normal, 1 for 1–2 stools more than normal, 2 for 3–4 stools more than normal, and 3 for 5 or more stools more than normal. Rectal bleeding was scored as: 0 for no blood, 1 for streaks of blood with stool less than half of the time, 2 for obvious blood with stool most of the time, and 3 for blood alone passed. Findings of flexible sigmoidoscopy were scored as: 0 for normal or inactive disease, 1 for mild disease (erythema, decreased vascular pattern, mild friability), 2 for moderate disease (marked erythema, absent vascular pattern, friability, erosions), and 3 for severe disease (spontaneous bleeding, ulceration). The physician's global assessment was scored as: 0 for normal, 1 for mild disease, 2 for moderate disease, and 3 for severe disease [ 18 ]. Safety Monitoring and Adverse Event Assessment In addition to assessing UCDAI scores, participants were monitored for potential adverse effects related to Metformin treatment throughout the study. Clinical evaluations and patient self-reports at each visit specifically assessed common side effects, including gastrointestinal symptoms (such as nausea, diarrhea, and abdominal discomfort) and signs of hypoglycemia. No formal laboratory tests for adverse events were performed due to the short duration of the study and the established safety profile of Metformin. Sample Size Determination The sample size was calculated to be 112 participants, based on an anticipated 32% difference in clinical response rates between the Metformin and placebo groups. Given the exploration nature of this pilot study, this effect size was selected to detect a potentially meaningful clinical difference that would justify conducting a larger definitive trial. The calculation was based on a two-sided significance level (type I error) of 0.05, a statistical power of 80%, and an anticipated attrition rate of 10%. Randomization and Blinding Participants were randomly allocated in a 1:1 ratio to either the Metformin or control group using block randomization (blocks of two and four), with the allocation sequence generated by a statistical consultant using random allocation software. To maintain allocation concealment, 112 opaque, sealed, and sequentially numbered envelopes (SNOSE) containing group assignments were prepared. The study coordinator (investigator responsible for enrollment and randomization) distributed the envelopes in the order of recruitment but was not involved in outcome assessment. To preserve the double-blind design, both the patients and the physician responsible for outcome evaluation were blinded to treatment assignments. The placebo tablets were matched to the Metformin tablets in size, shape, color, and packaging. Both interventions were dispensed in identical containers labeled only with participant codes. Ethical Consideration Ethical approval for this study was granted by the regional ethics committee of Sabzevar University of Medical Sciences under the code IR.MEDASB.REC.1395.80. Additionally, the study was registered with the Iranian Registry of Clinical Trials (IRCT20181006041252N20). Prior to randomization, written consent was obtained from each participant. To ensure confidentiality and anonymity, each participant was assigned a unique identification code. The study was conducted adhering to the ethical principles outlined in the 1964 Declaration of Helsinki and its subsequent revisions, or equivalent ethical standards. Statistical Analysis For continuous variables, mean and standard deviation ± SD were utilized for summarization, while categorical variables were expressed as the number and percentage. After assessing the normality of the data using the Kolmogorov–Smirnov (K–S) test, either an independent t-test or chi-squared test was employed to compare baseline data between the two groups. An ANCOVA test was then utilized to compare the mean UC activity scores between the groups, with baseline values, age, and sex included as covariates. Multiple ordinal logistic regression and linear regression techniques were employed to identify independent predictors of UCDAI levels, as well as UCDAI scores, respectively. Model development adhered to a stepwise backward selection algorithm utilizing the 10% change-in-estimate approach for confounding adjustment. Variables with a P -value < 0.2 in the univariate analysis were considered as candidates for inclusion in the multiple regression model. The outcomes were reported as adjusted odds ratios, comparing moderate versus mild and remission levels, as well as moderate and mild versus remission levels, with corresponding 95% confidence intervals. Mean differences in UCDAI scores were also presented with 95% confidence intervals. Patients were assessed in accordance with Intention-to-treat (ITT) principle. Data analyses were performed using STATA (version 14, Stata Corp, College Station, Texas) at a two-sided significant level of P < 0.05. Also, sample size estimation was performed using G*power software version 3.0.10. Results Following eligibility assessments, a total of 112 subjects were randomized, and none of them withdrew from the study (Fig. 1 ). The mean age of patients was 34.52 ± 5.79 and 57 (50.1%) were male. The baseline demographic characteristics of the patients are detailed in Table 1 . Table 1 Baseline Characteristics of Study Participants; Mean ± SD and N (%). Parameters Groups P -value * Metformin Control Age, years 35.01 ± 5.76 34.03 ± 5.84 0.372 Number of previous relapses, n 2.57 ± 0.80 2.76 ± 0.91 0.230 Sex, male 26 (45.6) 31 (54.3) 0.345 Mediation 5-ASA † 48 (48.9) 50 (51.1) 0.568 5-ASA + Azathioprine 6 (42.8) 8 (57.2) * Two independent t-test or Chi-squared test, as appropriate. † 5-Aminosalisilic acid. As shown in Table 2 , the ordinal logistic regression analysis reveals that the odds of having a higher UCDAI score (moderate vs, mild and remission as well as moderate and mild vs, remission) are approximately 54% lower in the Metformin group compared to the control group (OR: 0.46; 95% CI: 0.21, 0.97; P = 0.044). Moreover, based on the multiple linear regression analysis, the mean UCDAI scores were found to be lower in the Metformin group than in the control group (β: -1.11; 95% CI: -1.86, -0.37; P = 0.004). Table 2 The Association Between UCDAI and Its Correlate Among Patients: Multiple Regression Analysis. Parameters (Reference) Subgroups Model 1 * Model 2 † UCDAI levels ‡ (remission, mild, and moderate) UCDAI scores Odd Ratio (95%CI) P -value Mean (95%CI) P -value Group (Control) Metformin 0.46 (0.21, 0.97) 0.044 -1.11 (-1.86, -0.37) 0.004 Sex (Male) Female 1.40 (0.67, 2.91) 0.366 0.29 (-.44, 1.03) 0.427 Medication (5-ASA) 5-ASA § + Azathioprine 0.61 (0.09, 3.86) 0.602 0.69 (-0.42, 1.81) 0.218 Age, years 0.95 (0.89, 1.01) 0.125 -0.03 (-0.10, 0.02) 0.245 Number of Previous Relapses, n 1.19 (0.77, 1.85) 0.428 0.29 (-0.14, 0.72) 0.188 * Multiple Ordinal Logistic Regression. † Multiple Linear Regression. ‡ Ulcerative Colitis Disease Activity Index (UCDAI) score. § 5 -Aminosalisilic acid. As shown in Table 3 , the ANCOVA test revealed that the mean scores for the physician's global assessment, colonoscopy findings, rectal bleeding, and stool frequency differed significantly between the two groups after treatment, with lower scores in the Metformin group ( P = 0.005, 0.021, 0.030, and < 0.001, respectively). Table 3 Grading of Improvement in the Assessment of Ulcerative Colitis Activity in Both Groups. Follow-up Before Treatment After Treatment P -value * Groups Metformin (Mean ± SD) Control (Mean ± SD) Metformin (Mean ± SD) Control (Mean ± SD) Physician's Global Assessment † 1.33 ± 0.76 1.78 ± 0.73 1.01 ± 0.48 1.42 ± 0.65 0.005 Colonoscopy Findings 1.30 ± 0.68 1.17 ± 0.57 0.76 ± 0.50 0.82 ± 0.60 0.021 Rectal Bleeding ‡ 1.73 ± 0.72 1.42 ± 0.65 1.01 ± 0.58 1.19 ± 0.69 0.030 Stool Frequency 1.83 ± 0.73 2.05 ± 0.55 0.92 ± 0.59 1.46 ± 0.53 < 0.001 * ANCOVA test with baseline, age, and sex as a covariate. † The physician's global assessment considered additional criteria, such as the patient's daily abdominal discomfort, overall well-being, performance status, and physical findings. ‡ This score represented the highest severity of bleeding observed during the day. No adverse events or side effects related to Metformin were reported or observed throughout the study period. All participants completed the trial without withdrawal due to medication intolerance or side effects. Commonly expected side effects of Metformin, such as gastrointestinal symptoms or hypoglycemia, were not detected, indicating good tolerability of the intervention in this patient population. Discussion This study aimed to evaluate the effectiveness of incorporating Metformin into routine treatment for the management of acute UC exacerbations. The results showed a significant decrease in UCDAI scores in the Metformin group compared to the control group. Additionally, the chance of experiencing higher UCDAI levels in the Metformin group was significantly lower than in the control group. Moreover, the mean scores for the physician's global assessment, colonoscopy findings, rectal bleeding, and stool frequency were significantly lower in the Metformin group compared to the control group after treatment. Excessive expression of inflammatory mediators plays a pivotal role in the pathogenesis of UC, and a significant long-term complication of chronic inflammation is the development of colorectal cancer [ 19 ]. Metformin, aside from its hypoglycemic properties, exhibits promising beneficial effects with several studies reporting its anti-inflammatory activity. In a combination study involving 5-ASA and metformin on the HCT-116 and Caco-2 CRC tumor cell lines, metformin demonstrated potentiation of 5-ASA's antitumor activity by reducing the gene expression of proinflammatory cytokines such as IL-1β, IL-6, COX-2, TNF-α, and their receptors [ 20 ]. In a mouse model of IBD induced by dextran sulfate sodium (DSS), the administration of metformin for 16 days attenuated disease severity and activity index scores. This effect was achieved by inhibiting the expression of p-STAT3, a key contributor to elevated levels of proinflammatory cytokines, including IL-17, and the mammalian target of rapamycin (m-TOR) in the spleen and lymph nodes [ 21 ]. Moreover, in an in vitro study simulating lipopolysaccharide (LPS)-induced IBD, metformin demonstrated the attenuation of the expression and secretion of TNF α, interleukin 1α (IL-1α), macrophage colony-stimulating factor (M CSF), T cell activation gene 3 (TCA 3), and stromal cell-derived factor 1 (SDF 1) [ 22 ]. In a recent study, the risk of IBD significantly decreased in patients with type 2 diabetes mellitus treated with metformin [ 23 ]. Metformin regulates the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), a cellular metabolic sensor, and activates its signaling pathway to exert protective effects in both the liver and intestine [ 24 ]. IBD, encompassing UC and Crohn’s disease, represents chronic inflammatory disorders of the gastrointestinal tract leading to impaired gastrointestinal structure and function. The enhanced inflammatory activation results in increased cell proliferation in the ileum and, in severe cases, neoplasia [ 25 ]. Metformin improves barrier function through AMPK activation [ 15 ]. By activating AMPK, metformin prevents nuclear factor-kappa B (NF-kappa B) [ 26 ]. Furthermore, metformin down-regulates p38 MAP kinase activation and the proinflammatory cytokine IL-6 in the epithelial and lamina propria of colic mice [ 27 ]. The intestinal epithelial barrier is compromised in ulcerative colitis due to the activation of C-Jun N-terminal kinase (JNK). In both in-vitro and in-vivo studies, metformin demonstrated protection against DSS-induced intestinal barrier dysfunction. Moreover, it alleviated the severity of DSS-induced acute colitis in mice by downregulating inflammatory factors such as TNF α, IL-1α, and IL-6 in both the colon and serum. The potential mechanism underlying this effect may involve the inhibition of JNK activation via an AMPKα1-dependent signaling pathway [ 28 ]. It appears that metformin might influence multiple targets. The beneficial hypoglycemic and anti-inflammatory effects of metformin may be mediated through the activation of microbial communities (microbiota) in the intestinal tract [29; 30]. Probiotics have been reported to enhance the function of the intestinal mucosal barrier and the immune system, thereby increasing anti-inflammatory factors and inhibiting the growth of harmful bacteria in the intestine [ 31 ]. In a clinical study, diabetic patients taking metformin exhibited higher amounts of Akkermansia muciniphila, a microbiome known for mucin degradation, as well as several short-chain fatty acid-producing microbiota [ 32 ]. Akkermansia muciniphila is considered a "next-generation probiotic." [ 33 ] In another study, the anti-obesity effect of metformin on prediabetic participants was evaluated through an increase in gut microbiome [ 29 ]. Insulin-like growth factor 1 (IGF-1) is an anabolic hormone that plays a crucial role in regulating growth hormone (GH) activity, insulin metabolism, and cell proliferation, differentiation, and apoptosis. IBD is associated with reduced levels of IGF-1 [ 34 ]. However, its potential side effects limit its use for IBD patients. In a clinical trial conducted by Leo et al., a thirty-day intake of metformin significantly increased IGF-1 levels in patients with polycystic ovary syndrome [ 35 ]. Limitations and Strengths This study has several limitations. Firstly, although we did not systematically check for the frequent adverse effects of Metformin, its safety profile is considered excellent, characterized by a negligible risk of hypoglycemia, low drug interactions, and the most common adverse effects being mild gastrointestinal symptoms [ 36 ]. Side effects were monitored clinically through patient self-reports and clinical assessments, but no formal laboratory evaluation was performed due to the study’s short duration and established safety record of Metformin. Secondly, the use of a single center for data collection introduces a potential limitation that may impact on the generalizability of our results. Thirdly, the lack of follow-up beyond 8 weeks to assess disease relapse post-treatment represents another limitation. Lastly, despite these promising findings, the study did not systematically examine the effect of Metformin on each individual component of the UCDAI scale; instead, it focused on the overall score, limiting the ability to assess associations with specific UCDAI components. Conversely, this study possesses notable strengths. It represents the world’s first trial evaluating the impact of Metformin on the severity of UCDAI among patients with ulcerative colitis. This pioneering aspect contributes to the novelty and significance of the research, laying the groundwork for further investigations into Metformin’s therapeutic potential in UC management. Additionally, as a pilot study, it provides valuable preliminary evidence that supports the feasibility and safety of Metformin use in this population. Conclusions Findings indicate a notable association between Metformin use and a considerable reduction in UCDAI scores, implying a potential therapeutic advantage in controlling disease activity. Validation of these findings and a comprehensive exploration of the mechanisms underlying Metformin's impact are warranted through further research. Declarations Acknowledgments We would like to thank the Endocrinology Clinic and Clinical Research Development Center of Vasei Hospital, Sabzevar University of Medical Sciences, for their cooperation in this project. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding The author(s) received no financial support for the research, authorship, and/or publication of this article. Author's Contribution Statement: All authors have read and approved the final version of the paper. 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BMC Gastroenterol 19:83. https://doi.org/10.1186/s12876-019-1000-6 De Leo V, La Marca A, Orvieto R, Morgante G (2000) Effect of metformin on insulin-like growth factor (IGF) I and IGF-binding protein I in polycystic ovary syndrome. J Clin Endocrinol Metab 85:1598–1600. https://doi.org/10.1210/jcem.85.4.6560 Krentz AJ, Ferner RE, Bailey CJ (1994) Comparative tolerability profiles of oral antidiabetic agents. Drug Saf 11:223–241. https://doi.org/10.2165/00002018-199411040-00002 Cite Share Download PDF Status: Published Journal Publication published 10 Dec, 2025 Read the published version in Internal and Emergency Medicine → Version 1 posted Reviewers agreed at journal 22 Sep, 2025 Reviewers invited by journal 20 Sep, 2025 Editor assigned by journal 20 Sep, 2025 First submitted to journal 19 Sep, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7652190","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":518105628,"identity":"6da76778-6f94-4c05-9a87-077c9490ef71","order_by":0,"name":"Mahdi Molavi","email":"","orcid":"","institution":"MEDSAB: Sabzevar University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mahdi","middleName":"","lastName":"Molavi","suffix":""},{"id":518105629,"identity":"f1f3f898-08be-4723-9e1b-982dc11687a4","order_by":1,"name":"Bahareh Amin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYFACxgYQSgCy2Bg+gEh2UrQwzgCRzERaBNbCzAPiEdLCP+1w2wPGHXZ5/LMPH3ts82ubPB8zA+OHjzm4tUjcTmw3YDyTXCxxLi3dOLfvtmEbMwOz5MxteKy5ndgmwdjGnNhwhsdMOrfnNpANdCEvHi3yEC31ifPP8H+Ttuy5bU9QiwFEy+HEDWd42KQZfgC5hLQYgrQknjmeuPEMm5lkb8Pt5DZmxma8fpG7nf5M4uOO6sR5Z5ifSfz4c9t2fnvzwQ8f8XkfBBJgDMY2MNlAQD0K+EOK4lEwCkbBKBgpAACHoVD6p/x99QAAAABJRU5ErkJggg==","orcid":"","institution":"MEDSAB: Sabzevar University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Bahareh","middleName":"","lastName":"Amin","suffix":""},{"id":518105630,"identity":"d550b3f0-c421-4e54-8d14-3af4c613395b","order_by":2,"name":"Mohammad Sahebkar","email":"","orcid":"","institution":"University of Ottawa Faculty of Health 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08:10:46","extension":"xml","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":102415,"visible":true,"origin":"","legend":"","description":"","filename":"IAEMD25014780structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7652190/v1/1ede5425a034a941376df17c.xml"},{"id":92574158,"identity":"de123a5a-2981-44fa-b4d9-e2ad98986d98","added_by":"auto","created_at":"2025-10-01 08:10:46","extension":"html","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":113879,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7652190/v1/9db5a721dec21163ddeeb601.html"},{"id":92574149,"identity":"6c9197cf-e556-47fc-a3cc-60b2249a29e6","added_by":"auto","created_at":"2025-10-01 08:10:45","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":52043,"visible":true,"origin":"","legend":"\u003cp\u003eThe CONCORT diagram of the study.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7652190/v1/fb12ebff485170539f143492.png"},{"id":98245047,"identity":"62399d42-4a6f-468b-8de4-637ddfdf2c47","added_by":"auto","created_at":"2025-12-15 16:16:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":887117,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7652190/v1/deadc588-fa2f-481c-a002-d0ba3f82cb37.pdf"}],"financialInterests":"","formattedTitle":"Metformin as a Potential Adjunct in the Treatment of Mild-to-Moderate Ulcerative Colitis: A Double-Blind, Randomized, Placebo-Controlled Pilot Study.","fulltext":[{"header":"Highlights","content":"\u003cp\u003e\u0026bull; Efficacy in Disease Management: Metformin demonstrates a significant reduction in Ulcerative Colitis Disease Activity Index (UCDAI) scores compared to the control group, indicating its potential therapeutic benefit in managing disease activity.\u003c/p\u003e\u003cp\u003e\u0026bull; Promising Therapeutic Potential: As a pilot study, the findings suggest that Metformin may offer beneficial anti-inflammatory effects in mild-to-moderate ulcerative colitis, providing preliminary evidence to support further investigation through larger clinical trials.\u003c/p\u003e\u003cp\u003e\u0026bull; Safe Adjunctive Therapy: The results highlight Metformin\u0026rsquo;s safety and tolerability as an adjunct to routine treatment, suggesting its potential as a safe and effective addition in managing mild-to-moderate ulcerative colitis.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eUlcerative colitis (UC) is a chronic inflammatory disease of the intestine, with an increasing incidence over the past five decades [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This condition is characterized by symptoms such as bloody diarrhea, abdominal pain, and weight loss, which vary in severity according to disease activity [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. While severe UC is associated with high morbidity, including frequent hospitalization and surgery, patients with mild to moderate UC also experience substantial impairment in quality of life and ongoing disease management challenges [2; 3]. Pharmacological treatments for UC\u0026mdash;including Mesalazine, corticosteroids, immunosuppressants, and biological agents\u0026mdash;are effective for many patients, particularly those with mild to moderate disease; however, treatment response varies, and concerns remain regarding side effects and economic costs [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMetformin, a biguanide derivative, is widely utilized as a primary pharmacological agent in the treatment of type 2 diabetes [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Its primary mode of action involves the inhibition of hepatic glucose production and a reduction in peripheral tissue resistance to insulin, resulting in decreased circulating glucose and insulin levels [6; 7]. Beyond its hypoglycemic effects, recent research has highlighted its additional cardioprotective [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], antioxidant, and anti-inflammatory properties [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Notably, Metformin demonstrates the ability to attenuate lipopolysaccharide-induced inflammatory responses in cultured macrophages and endothelial cells, while also downregulating experimental inflammation in various organs [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Its use has been associated with a decreased risk of Parkinson's disease, and ongoing studies explore its potential anti-cancer properties [13; 14]. Furthermore, metformin has shown efficacy in mitigating lipopolysaccharide-induced inflammation in smooth muscle cells and improving intestinal epithelial barrier integrity in mice with inflammatory bowel disease (IBD) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDespite the potential benefits of Metformin, there is a significant gap in the existing literature, as there is no comparison of its effectiveness in individuals with UC. This study aims to fill this gap by assessing the therapeutic impact of adding Metformin to the current treatment regimen for individuals with mild to moderate UC.\u003c/p\u003e"},{"header":"Material and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Design\u003c/h2\u003e\u003cp\u003eThis double-blind, randomized, parallel-group clinical trial was conducted to examine the efficacy of adding Metformin on the severity of Disease Activity Index (DAI) scores in patients presenting with acute exacerbation of UC between 2017 and 2024.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003e The study participants included all patients with UC referred to the endocrinology clinic of Vasei Hospital in Sabzevar, Iran, from March 2017 to December 2024. Inclusion criteria included adults aged 18 years or older with a confirmed diagnosis of UC affecting at least the rectosigmoid region, based on colonoscopy and physical examination at study entry. Eligible participants were required to have mild to moderate recurrent UC, defined by a Disease Activity Index (DAI) score of 3 to 8, with symptom recurrence within 4 weeks prior to enrollment. Although moderate UC is often defined as a DAI score up to 10, we used a 3\u0026ndash;8 range to ensure a more homogeneous study population and to minimize the inclusion of patients at the more severe end of the moderate spectrum, who might require escalation to systemic corticosteroids or biologics, potentially confounding the intervention effects.\u003c/p\u003e\u003cp\u003eExclusion criteria included patients with Crohn's disease, diabetes mellitus, heart failure, or severe renal or hepatic impairment. Pregnant or lactating individuals and those with a known allergy to metformin were also excluded. Additionally, patients were excluded if they had received systemic corticosteroids, anti-TNF agents, or cyclosporine within 8 weeks prior to the study or during the 8-week study period. Use of rectal 5-ASA or systemic corticosteroids within 4 weeks before enrollment was also not permitted. To ensure stability in baseline treatment, patients who had experienced any changes in the dosage of oral 5-ASA, 6-mercaptopurine, or azathioprine within the 12 weeks prior to study entry were excluded. Only patients on a stable dose of oral 5-ASA for at least 12 weeks before enrollment were included.\u003c/p\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cp\u003eEligible patients were randomly assigned to either the Metformin group or the control group in equal numbers. Patients in the intervention group received routine treatment along with Metformin tablets (1000 mg twice daily, manufactured by Tehran Shimi Company) for two months, administered after breakfast and dinner. Patients in the control group received routine treatment plus placebo tablets (produced by the Iranian Pharmacy Laboratory) for the same duration and schedule. All participants received a stable dose of oral 5-ASA (Mesalazine, \u0026ge; 2 g/day) for at least 12 weeks prior to the study, and, where applicable, either Azathioprine (\u0026ge;\u0026thinsp;1.5 mg/kg/day) or 6-Mercaptopurine (\u0026ge;\u0026thinsp;1 mg/kg/day) for at least 12 weeks prior to enrollment [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Patient compliance was monitored by counting returned tablets at each follow-up visit.\u003c/p\u003e\n\u003ch3\u003eOutcome\u003c/h3\u003e\n\u003cp\u003eThe primary aim of this study was to estimate the Ulcerative Colitis Disease Activity Index (UCDAI) score at the end of two months. The UCDAI, comprising four subscales\u0026mdash;bowel frequency, rectal bleeding, endoscopic score, and the physician's assessment of severity\u0026mdash;was recorded individually by the investigator. The UCDAI utilizes a 12-point scoring system, where each of the four variables (stool frequency, bleeding severity, colonic mucosal appearance, and physician's overall assessment) is scored from 0 to 3. Consequently, the total index score ranges from 0 to 12, with categories defined as follows: 0\u0026ndash;2 indicating remission, 3\u0026ndash;6 denoting mild disease, 7\u0026ndash;10 signifying moderate disease, and \u0026gt;\u0026thinsp;10 indicating severe UC [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The activity of UC was assessed using a comprehensive scoring system encompassing stool frequency, rectal bleeding, findings of flexible sigmoidoscopy, and the physician's global assessment. Stool frequency was scored as follows: 0 for normal, 1 for 1\u0026ndash;2 stools more than normal, 2 for 3\u0026ndash;4 stools more than normal, and 3 for 5 or more stools more than normal. Rectal bleeding was scored as: 0 for no blood, 1 for streaks of blood with stool less than half of the time, 2 for obvious blood with stool most of the time, and 3 for blood alone passed. Findings of flexible sigmoidoscopy were scored as: 0 for normal or inactive disease, 1 for mild disease (erythema, decreased vascular pattern, mild friability), 2 for moderate disease (marked erythema, absent vascular pattern, friability, erosions), and 3 for severe disease (spontaneous bleeding, ulceration). The physician's global assessment was scored as: 0 for normal, 1 for mild disease, 2 for moderate disease, and 3 for severe disease [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eSafety Monitoring and Adverse Event Assessment\u003c/h3\u003e\n\u003cp\u003eIn addition to assessing UCDAI scores, participants were monitored for potential adverse effects related to Metformin treatment throughout the study. Clinical evaluations and patient self-reports at each visit specifically assessed common side effects, including gastrointestinal symptoms (such as nausea, diarrhea, and abdominal discomfort) and signs of hypoglycemia. No formal laboratory tests for adverse events were performed due to the short duration of the study and the established safety profile of Metformin.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eSample Size Determination\u003c/h2\u003e\u003cp\u003eThe sample size was calculated to be 112 participants, based on an anticipated 32% difference in clinical response rates between the Metformin and placebo groups. Given the exploration nature of this pilot study, this effect size was selected to detect a potentially meaningful clinical difference that would justify conducting a larger definitive trial. The calculation was based on a two-sided significance level (type I error) of 0.05, a statistical power of 80%, and an anticipated attrition rate of 10%.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eRandomization and Blinding\u003c/h3\u003e\n\u003cp\u003eParticipants were randomly allocated in a 1:1 ratio to either the Metformin or control group using block randomization (blocks of two and four), with the allocation sequence generated by a statistical consultant using random allocation software. To maintain allocation concealment, 112 opaque, sealed, and sequentially numbered envelopes (SNOSE) containing group assignments were prepared. The study coordinator (investigator responsible for enrollment and randomization) distributed the envelopes in the order of recruitment but was not involved in outcome assessment. To preserve the double-blind design, both the patients and the physician responsible for outcome evaluation were blinded to treatment assignments. The placebo tablets were matched to the Metformin tablets in size, shape, color, and packaging. Both interventions were dispensed in identical containers labeled only with participant codes.\u003c/p\u003e\n\u003ch3\u003eEthical Consideration\u003c/h3\u003e\n\u003cp\u003eEthical approval for this study was granted by the regional ethics committee of Sabzevar University of Medical Sciences under the code IR.MEDASB.REC.1395.80. Additionally, the study was registered with the Iranian Registry of Clinical Trials (IRCT20181006041252N20). Prior to randomization, written consent was obtained from each participant. To ensure confidentiality and anonymity, each participant was assigned a unique identification code. The study was conducted adhering to the ethical principles outlined in the 1964 Declaration of Helsinki and its subsequent revisions, or equivalent ethical standards.\u003c/p\u003e\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eFor continuous variables, mean and standard deviation\u0026thinsp;\u0026plusmn;\u0026thinsp;SD were utilized for summarization, while categorical variables were expressed as the number and percentage. After assessing the normality of the data using the Kolmogorov\u0026ndash;Smirnov (K\u0026ndash;S) test, either an independent t-test or chi-squared test was employed to compare baseline data between the two groups. An ANCOVA test was then utilized to compare the mean UC activity scores between the groups, with baseline values, age, and sex included as covariates. Multiple ordinal logistic regression and linear regression techniques were employed to identify independent predictors of UCDAI levels, as well as UCDAI scores, respectively. Model development adhered to a stepwise backward selection algorithm utilizing the 10% change-in-estimate approach for confounding adjustment. Variables with a \u003cem\u003eP\u003c/em\u003e-value\u0026thinsp;\u0026lt;\u0026thinsp;0.2 in the univariate analysis were considered as candidates for inclusion in the multiple regression model. The outcomes were reported as adjusted odds ratios, comparing moderate versus mild and remission levels, as well as moderate and mild versus remission levels, with corresponding 95% confidence intervals. Mean differences in UCDAI scores were also presented with 95% confidence intervals. Patients were assessed in accordance with Intention-to-treat (ITT) principle. Data analyses were performed using STATA (version 14, Stata Corp, College Station, Texas) at a two-sided significant level of \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Also, sample size estimation was performed using G*power software version 3.0.10.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFollowing eligibility assessments, a total of 112 subjects were randomized, and none of them withdrew from the study (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The mean age of patients was 34.52\u0026thinsp;\u0026plusmn;\u0026thinsp;5.79 and 57 (50.1%) were male. The baseline demographic characteristics of the patients are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline Characteristics of Study Participants; Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD and N (%).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" morerows=\"1\" nameend=\"c2\" namest=\"c1\" rowspan=\"2\"\u003e\u003cp\u003eParameters\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003eGroups\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMetformin\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eControl\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge, years\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35.01\u0026thinsp;\u0026plusmn;\u0026thinsp;5.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e34.03\u0026thinsp;\u0026plusmn;\u0026thinsp;5.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.372\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNumber of previous relapses, n\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.57\u0026thinsp;\u0026plusmn;\u0026thinsp;0.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.230\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSex, male\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26 (45.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e31 (54.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.345\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eMediation\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e5-ASA\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e48 (48.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e50 (51.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e0.568\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e5-ASA\u0026thinsp;+\u0026thinsp;Azathioprine\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (42.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8 (57.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e*\u003c/sup\u003eTwo independent t-test or Chi-squared test, as appropriate.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e 5-Aminosalisilic acid.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, the ordinal logistic regression analysis reveals that the odds of having a higher UCDAI score (moderate vs, mild and remission as well as moderate and mild vs, remission) are approximately 54% lower in the Metformin group compared to the control group (OR: 0.46; 95% CI: 0.21, 0.97; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.044). Moreover, based on the multiple linear regression analysis, the mean UCDAI scores were found to be lower in the Metformin group than in the control group (β: -1.11; 95% CI: -1.86, -0.37; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe Association Between UCDAI and Its Correlate Among Patients: Multiple Regression Analysis.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eParameters\u003c/p\u003e\u003cp\u003e(Reference)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eSubgroups\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003eModel 1\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u003cp\u003eModel 2\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003eUCDAI levels \u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e\u003cp\u003e(remission, mild, and moderate)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u003cp\u003eUCDAI scores\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOdd Ratio (95%CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMean (95%CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGroup\u003c/p\u003e\u003cp\u003e(Control)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eMetformin\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.46 (0.21, 0.97)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.044\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-1.11 (-1.86, -0.37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003cp\u003e(Male)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eFemale\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.40 (0.67, 2.91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.366\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.29 (-.44, 1.03)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.427\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedication\u003c/p\u003e\u003cp\u003e(5-ASA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003e5-ASA\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026sect;\u003c/b\u003e\u003c/sup\u003e \u003cb\u003e+ Azathioprine\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.61 (0.09, 3.86)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.602\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.69 (-0.42, 1.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.218\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eAge, years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.95 (0.89, 1.01)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.03 (-0.10, 0.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.245\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eNumber of Previous Relapses, n\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.19 (0.77, 1.85)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.428\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.29 (-0.14, 0.72)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.188\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e*\u003c/sup\u003e Multiple Ordinal Logistic Regression.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e Multiple Linear Regression.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u0026Dagger;\u003c/sup\u003e Ulcerative Colitis Disease Activity Index (UCDAI) score.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u0026sect;\u0026nbsp;5\u003c/sup\u003e-Aminosalisilic acid.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, the ANCOVA test revealed that the mean scores for the physician's global assessment, colonoscopy findings, rectal bleeding, and stool frequency differed significantly between the two groups after treatment, with lower scores in the Metformin group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005, 0.021, 0.030, and \u0026lt;\u0026thinsp;0.001, respectively).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eGrading of Improvement in the Assessment of Ulcerative Colitis Activity in Both Groups.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFollow-up\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eBefore Treatment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eAfter Treatment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGroups\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMetformin\u003c/p\u003e\u003cp\u003e(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eControl\u003c/p\u003e\u003cp\u003e(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMetformin\u003c/p\u003e\u003cp\u003e(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eControl\u003c/p\u003e\u003cp\u003e(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePhysician's Global Assessment\u003c/b\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.78\u0026thinsp;\u0026plusmn;\u0026thinsp;0.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eColonoscopy Findings\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.82\u0026thinsp;\u0026plusmn;\u0026thinsp;0.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.021\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRectal Bleeding\u003c/b\u003e\u003csup\u003e\u003cb\u003e\u0026Dagger;\u003c/b\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.19\u0026thinsp;\u0026plusmn;\u0026thinsp;0.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.030\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eStool Frequency\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.83\u0026thinsp;\u0026plusmn;\u0026thinsp;0.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.92\u0026thinsp;\u0026plusmn;\u0026thinsp;0.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e*\u003c/sup\u003e ANCOVA test with baseline, age, and sex as a covariate.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u0026dagger;\u003c/sup\u003e The physician's global assessment considered additional criteria, such as the patient's daily abdominal discomfort, overall well-being, performance status, and physical findings.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003e\u0026Dagger;\u003c/sup\u003e This score represented the highest severity of bleeding observed during the day.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eNo adverse events or side effects related to Metformin were reported or observed throughout the study period. All participants completed the trial without withdrawal due to medication intolerance or side effects. Commonly expected side effects of Metformin, such as gastrointestinal symptoms or hypoglycemia, were not detected, indicating good tolerability of the intervention in this patient population.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study aimed to evaluate the effectiveness of incorporating Metformin into routine treatment for the management of acute UC exacerbations. The results showed a significant decrease in UCDAI scores in the Metformin group compared to the control group. Additionally, the chance of experiencing higher UCDAI levels in the Metformin group was significantly lower than in the control group. Moreover, the mean scores for the physician's global assessment, colonoscopy findings, rectal bleeding, and stool frequency were significantly lower in the Metformin group compared to the control group after treatment.\u003c/p\u003e\u003cp\u003eExcessive expression of inflammatory mediators plays a pivotal role in the pathogenesis of UC, and a significant long-term complication of chronic inflammation is the development of colorectal cancer [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Metformin, aside from its hypoglycemic properties, exhibits promising beneficial effects with several studies reporting its anti-inflammatory activity. In a combination study involving 5-ASA and metformin on the HCT-116 and Caco-2 CRC tumor cell lines, metformin demonstrated potentiation of 5-ASA's antitumor activity by reducing the gene expression of proinflammatory cytokines such as IL-1β, IL-6, COX-2, TNF-α, and their receptors [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn a mouse model of IBD induced by dextran sulfate sodium (DSS), the administration of metformin for 16 days attenuated disease severity and activity index scores. This effect was achieved by inhibiting the expression of p-STAT3, a key contributor to elevated levels of proinflammatory cytokines, including IL-17, and the mammalian target of rapamycin (m-TOR) in the spleen and lymph nodes [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Moreover, in an in vitro study simulating lipopolysaccharide (LPS)-induced IBD, metformin demonstrated the attenuation of the expression and secretion of TNF α, interleukin 1α (IL-1α), macrophage colony-stimulating factor (M CSF), T cell activation gene 3 (TCA 3), and stromal cell-derived factor 1 (SDF 1) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn a recent study, the risk of IBD significantly decreased in patients with type 2 diabetes mellitus treated with metformin [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Metformin regulates the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), a cellular metabolic sensor, and activates its signaling pathway to exert protective effects in both the liver and intestine [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. IBD, encompassing UC and Crohn\u0026rsquo;s disease, represents chronic inflammatory disorders of the gastrointestinal tract leading to impaired gastrointestinal structure and function. The enhanced inflammatory activation results in increased cell proliferation in the ileum and, in severe cases, neoplasia [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Metformin improves barrier function through AMPK activation [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. By activating AMPK, metformin prevents nuclear factor-kappa B (NF-kappa B) [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Furthermore, metformin down-regulates p38 MAP kinase activation and the proinflammatory cytokine IL-6 in the epithelial and lamina propria of colic mice [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe intestinal epithelial barrier is compromised in ulcerative colitis due to the activation of C-Jun N-terminal kinase (JNK). In both in-vitro and in-vivo studies, metformin demonstrated protection against DSS-induced intestinal barrier dysfunction. Moreover, it alleviated the severity of DSS-induced acute colitis in mice by downregulating inflammatory factors such as TNF α, IL-1α, and IL-6 in both the colon and serum. The potential mechanism underlying this effect may involve the inhibition of JNK activation via an AMPKα1-dependent signaling pathway [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIt appears that metformin might influence multiple targets. The beneficial hypoglycemic and anti-inflammatory effects of metformin may be mediated through the activation of microbial communities (microbiota) in the intestinal tract [29; 30]. Probiotics have been reported to enhance the function of the intestinal mucosal barrier and the immune system, thereby increasing anti-inflammatory factors and inhibiting the growth of harmful bacteria in the intestine [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In a clinical study, diabetic patients taking metformin exhibited higher amounts of Akkermansia muciniphila, a microbiome known for mucin degradation, as well as several short-chain fatty acid-producing microbiota [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. \u003cem\u003eAkkermansia muciniphila\u003c/em\u003e is considered a \"next-generation probiotic.\" [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] In another study, the anti-obesity effect of metformin on prediabetic participants was evaluated through an increase in gut microbiome [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Insulin-like growth factor 1 (IGF-1) is an anabolic hormone that plays a crucial role in regulating growth hormone (GH) activity, insulin metabolism, and cell proliferation, differentiation, and apoptosis. IBD is associated with reduced levels of IGF-1 [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. However, its potential side effects limit its use for IBD patients. In a clinical trial conducted by Leo et al., a thirty-day intake of metformin significantly increased IGF-1 levels in patients with polycystic ovary syndrome [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eLimitations and Strengths\u003c/h2\u003e\u003cp\u003eThis study has several limitations. Firstly, although we did not systematically check for the frequent adverse effects of Metformin, its safety profile is considered excellent, characterized by a negligible risk of hypoglycemia, low drug interactions, and the most common adverse effects being mild gastrointestinal symptoms [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Side effects were monitored clinically through patient self-reports and clinical assessments, but no formal laboratory evaluation was performed due to the study\u0026rsquo;s short duration and established safety record of Metformin. Secondly, the use of a single center for data collection introduces a potential limitation that may impact on the generalizability of our results. Thirdly, the lack of follow-up beyond 8 weeks to assess disease relapse post-treatment represents another limitation. Lastly, despite these promising findings, the study did not systematically examine the effect of Metformin on each individual component of the UCDAI scale; instead, it focused on the overall score, limiting the ability to assess associations with specific UCDAI components. Conversely, this study possesses notable strengths. It represents the world\u0026rsquo;s first trial evaluating the impact of Metformin on the severity of UCDAI among patients with ulcerative colitis. This pioneering aspect contributes to the novelty and significance of the research, laying the groundwork for further investigations into Metformin\u0026rsquo;s therapeutic potential in UC management. Additionally, as a pilot study, it provides valuable preliminary evidence that supports the feasibility and safety of Metformin use in this population.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eFindings indicate a notable association between Metformin use and a considerable reduction in UCDAI scores, implying a potential therapeutic advantage in controlling disease activity. Validation of these findings and a comprehensive exploration of the mechanisms underlying Metformin's impact are warranted through further research.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the Endocrinology Clinic and Clinical Research Development Center of Vasei Hospital, Sabzevar University of Medical Sciences, for their cooperation in this project.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Conflicting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) received no financial support for the research, authorship, and/or publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026apos;s Contribution Statement:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the final version of the paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Design:\u003c/strong\u003e MM, BA, MS\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Collection and Analysis:\u003c/strong\u003e MM, BA, MS\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eManuscript Writing:\u003c/strong\u003e MM, BA, MS\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAgrees to be accountable for all aspects of work:\u003c/strong\u003e MM, BA, MS\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBurisch J, Munkholm P (2013) Inflammatory bowel disease epidemiology. 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Drug Saf 11:223\u0026ndash;241. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.2165/00002018-199411040-00002\u003c/span\u003e\u003cspan address=\"10.2165/00002018-199411040-00002\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"internal-and-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"iaem","sideBox":"Learn more about [Internal and Emergency Medicine](http://link.springer.com/journal/11739)","snPcode":"11739","submissionUrl":"https://www.editorialmanager.com/iaem/default.aspx","title":"Internal and Emergency Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Ulcerative colitis, Metformin, Ulcerative Colitis Disease Activity Index","lastPublishedDoi":"10.21203/rs.3.rs-7652190/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7652190/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eManaging relapsing ulcerative colitis (UC) remains a clinical challenge despite therapeutic advances. Metformin, primarily an antidiabetic agent with demonstrated anti-inflammatory properties, has been proposed as an adjunctive treatment for UC. This double-blind, randomized, placebo-controlled pilot trial evaluated the effectiveness of adjunctive Metformin in reducing disease activity among patients experiencing acute UC exacerbations. A total of 112 patients with UC were enrolled at Sabzevar, Iran, between 2017 and 2024. The mean age of participants was 34.52\u0026thinsp;\u0026plusmn;\u0026thinsp;5.79 years, and 57 patients (50.1%) were male. Patients were randomly assigned to receive either 1000 mg Metformin tablets twice daily (after breakfast and dinner) in addition to routine treatment or placebo tablets with routine treatment for two months. The primary outcome was the change in UC Disease Activity Index (UCDAI) scores after the follow-up period. Ordinal logistic regression demonstrated that the odds of having a higher UCDAI score were approximately 54% lower in the Metformin group compared with the control group (OR: 0.46; 95% CI: 0.21\u0026ndash;0.97; P\u0026thinsp;=\u0026thinsp;0.044). Multiple linear regression further confirmed significantly lower mean UCDAI scores in the Metformin group (β = \u0026minus;1.11; 95% CI: \u0026minus;1.86 to \u0026minus;\u0026thinsp;0.37; P\u0026thinsp;=\u0026thinsp;0.004). These findings suggest that adjunctive Metformin is associated with meaningful reductions in disease activity scores, supporting its potential therapeutic role in managing acute exacerbations of UC. While the results are promising, larger-scale clinical trials are needed to validate these outcomes and investigate the underlying mechanisms by which Metformin may exert its anti-inflammatory effects in UC management.\u003c/p\u003e","manuscriptTitle":"Metformin as a Potential Adjunct in the Treatment of Mild-to-Moderate Ulcerative Colitis: A Double-Blind, Randomized, Placebo-Controlled Pilot Study.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-01 08:10:41","doi":"10.21203/rs.3.rs-7652190/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-09-22T05:49:42+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-20T18:30:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-20T10:36:23+00:00","index":"","fulltext":""},{"type":"submitted","content":"Internal and Emergency Medicine","date":"2025-09-19T15:50:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"internal-and-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"iaem","sideBox":"Learn more about [Internal and Emergency Medicine](http://link.springer.com/journal/11739)","snPcode":"11739","submissionUrl":"https://www.editorialmanager.com/iaem/default.aspx","title":"Internal and Emergency Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d73f10ca-b079-4cad-a961-ef3f785cce0e","owner":[],"postedDate":"October 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-15T16:11:41+00:00","versionOfRecord":{"articleIdentity":"rs-7652190","link":"https://doi.org/10.1007/s11739-025-04222-9","journal":{"identity":"internal-and-emergency-medicine","isVorOnly":false,"title":"Internal and Emergency Medicine"},"publishedOn":"2025-12-10 15:58:37","publishedOnDateReadable":"December 10th, 2025"},"versionCreatedAt":"2025-10-01 08:10:41","video":"","vorDoi":"10.1007/s11739-025-04222-9","vorDoiUrl":"https://doi.org/10.1007/s11739-025-04222-9","workflowStages":[]},"version":"v1","identity":"rs-7652190","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7652190","identity":"rs-7652190","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}