Hospitalization, ICU admission, and mortality among diabetic patients with inflammatory bowel disease receiving SGLT-2 inhibitors: a retrospective cohort study from the global collaborative network

Introduction

Type 2 diabetes mellitus (T2DM) and inflammatory bowel disease (IBD) are both chronic and highly prevalent conditions influenced by environmental and genetic factors (1). The rising prevalence of both IBD and type 2 diabetes, particularly in aging populations, has increased interest in the epidemiological and biological links between these two conditions. Patients with both IBD and T2DM represent a poorly characterized group, with studies on their relationship showing mixed results (1). A large prospective cohort study of 313,008 patients in the United Kingdom (UK) found that patients with T2DM had a higher cumulative risk of IBD than the non-T2DM population (1.24% vs. 0.57%) (2). On the other hand, a large cohort study conducted in Denmark involving more than 6 million participants concluded that a higher number of diabetic individuals was found in the cohort of IBD patients compared to the general population (3). Interestingly, a study conducted by Uwagbale et al. found that patients with IBD and T2DM had a lower risk of IBD complications compared to patients with IBD alone (4). Available research suggests that IBD and diabetes mellitus (DM) share immune-mediated mechanisms and overlapping genetic risk loci. Additionally, both IBD and T2DM exhibit a disruption of the gut epithelial barrier, resulting in activation of local intestinal immune responses. Furthermore, hormonal signaling affects both glucose levels and intestinal inflammation, suggesting a potential link between IBD and DM (2). The relationship also extends to involve medications. Corticosteroids, a cornerstone first-line therapy to induce remission in IBD exacerbations, are believed to be one of the main links between IBD and T2DM. There is widely demonstrated evidence that systemic and local steroids can raise blood glucose (1).

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have emerged as effective drugs for T2DM. In addition to improving glycemic control, these agents have been shown to provide cardiovascular and renal benefits, even in patients without diabetes. Studies in mice have shown that treatment with SGLT2 inhibitors after ischemia-reperfusion injury can reduce inflammation, oxidative stress, myocardial damage, and the size of the infarct (5). It is believed that SGLT2 inhibitors exert anti-inflammatory effects by activating AMP-activated protein kinase (AMPK), thereby suppressing pro-inflammatory pathways. They also modulate NLRP3 inflammasome, TLR-4, and NF-κB signaling. Those mechanisms may be relevant for inflammatory conditions like IBD (6). However, SGLT2 inhibitors are not currently approved for the treatment of IBD. While emerging evidence suggests potential anti-inflammatory effects, most available data are derived from animal studies, and their clinical relevance in patients with established IBD is uncertain.

Consequently, real-world studies evaluating the impact of SGLT2i on patients with both T2DM and IBD remain limited. It is crucial to understand whether SGLT2i can improve clinical outcomes in this population, given the compounded risks associated with both diseases.

This study aims to evaluate the association between SGLT2i use and hospitalization rates, intensive care unit admissions, and mortality among patients with T2DM and IBD using real-world data. We present this article in accordance with the STROBE reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-2026-0131/rc).

Methods

Design and data source

This retrospective cohort study was conducted using the Global Collaborative Network within the TriNetX platform (Cambridge, MA, USA), a federated research network that provides real-time access to de-identified electronic health records (EHRs) from 173 healthcare organizations (HCOs). The study utilized structured clinical data, including diagnoses, procedures, medications, and laboratory values. Data integrity and quality assurance are ensured through automated data validation processes, and compliance with the Health Insurance Portability and Accountability Act (HIPAA) is maintained. This study was exempt from review by the Institutional Review Board of because only de-identified data were used. Informed consent was waived because only de-identified data were analyzed. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Study population

Patients were categorized into two cohorts. Cohort 1 included adult patients (aged ≥18 years) with concurrent diagnosis of T2DM and IBD (ulcerative colitis or Crohn’s disease) who were prescribed at least three dispensations of SGLT2 inhibitor (canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin), with the first SGLT2 inhibitor prescription occurring within 1 year prior to or concurrent with the IBD diagnosis. Cohort 2 included adult patients with T2DM and IBD who had never been prescribed any SGLT2 inhibitor. Patients with type 1 diabetes mellitus were excluded from both cohorts. The study population was derived from 173 HCOs within the Global Collaborative Network, and propensity score matching (PSM) was employed to balance baseline characteristics between cohorts.

Outcomes

Five outcomes were assessed. Hospitalization was defined as any inpatient encounter or observation encounter. Mortality was defined as documented patient death. ICU admission was identified using Critical Care Services procedure codes. IBD-related complications were defined as any occurrence of toxic megacolon, non-traumatic intestinal perforation, anal fistula, intestinal fistula, intestinal obstruction, or non-infective gastroenteritis and colitis. IBD-related surgical procedures were defined as partial or total colectomy or ileostomy. All outcomes were identified using standardized diagnosis, procedure, and visit codes within the TriNetX platform.

Index event and time window for the study

The index event for Cohort 1 was defined as the first occurrence of the combined IBD and T2DM criteria, with the requirement that the first SGLT2 inhibitor prescription had occurred within the preceding year. The index event for Cohort 2 was defined as the first diagnosis of Crohn’s disease or ulcerative colitis in the setting of T2DM. The time window for outcome analysis commenced one day after the index event. Patients whose index event occurred 20 or more years prior to the date of analysis were excluded. Clinical outcomes were evaluated at 1 and 5 years following the index event.

Statistical analysis

Baseline characteristics were compared using descriptive statistics, including means and standard deviations for continuous variables and proportions for categorical variables. A robust 1:1 PSM was performed to control for confounding variables. The matching algorithm balanced a comprehensive set of covariates, including demographic variables (age at index, sex, race, and ethnicity), comorbid diagnoses (hypertensive diseases, ischemic heart disease, heart failure, liver diseases including cirrhosis and hepatitis C, chronic obstructive pulmonary disease, primary sclerosing cholangitis, non-infective enteritis and colitis, other intestinal diseases, and prior IBD-related surgery), prior procedures (fecal calprotectin testing and colectomy), concomitant medications (systemic corticosteroids; biologics including infliximab, adalimumab, vedolizumab, ustekinumab, and risankizumab; JAK inhibitors including tofacitinib and upadacitinib; and S1P receptor modulators including ozanimod and etrasimod), and laboratory values (hemoglobin, body mass index, C-reactive protein, and left ventricular ejection fraction). All ICD-10 codes used and the post-match analysis are presented in Table S1 and Table 1, respectively.

Risk analysis was conducted for each outcome, calculating risk difference, risk ratio (RR), and odds ratio with 95% confidence intervals (CIs). Kaplan-Meier survival analysis was used to estimate survival probability, with log-rank tests assessing statistical significance. Cox proportional hazards models were used to compute hazard ratios (HRs) with 95% CIs. Statistical significance was defined as a two-sided P value of less than 0.05.

Outcome ascertainment relied on structured EHR data harmonized within the TriNetX platform to standard terminologies, including ICD-9/10-CM codes for diagnoses, CPT/HCPCS codes for procedures, RxNorm for medications, and LOINC codes for laboratory tests. As such, outcomes were considered absent if no corresponding diagnostic or procedural code was recorded within the observation period, as the platform does not support supplementary adjudication, manual chart review, or linkage to external registries. Missing data was therefore not imputed; rather, the absence of a recorded code was treated as non-event (7).

Results

Patient characteristics

Before matching, Cohort 1 (SGLT2 inhibitor users) included 4,086 patients and Cohort 2 (non-users) included 98,414 patients. After 1:1 PSM, each cohort consisted of 3,950 patients. Baseline characteristics were well balanced post-matching, with standardized differences below 0.1 for nearly all covariates (Table 1).

Study outcomes

Hospitalization

At 1 year, the incidence of hospitalization was significantly lower in Cohort 1 compared to Cohort 2 (34.6% vs. 39.0%). Risk analysis demonstrated a significant reduction in the risk of hospitalization with SGLT2 inhibitors (risk difference: -0.044, 95% CI: −0.066 to −0.023, P<0.001; RR: 0.886, 95% CI: 0.836–0.939; odds ratio: 0.826, 95% CI: 0.754–0.906).

This reduction persisted at 5 years (47.6% vs. 51.1%; risk difference: −0.035, 95% CI: −0.057 to −0.013, P=0.002; RR: 0.932, 95% CI: 0.891–0.975; odds ratio: 0.870, 95% CI: 0.797–0.951).

ICU admission

At 1 year, ICU admission rates were 8.1% in Cohort 1 and 9.5% in Cohort 2. Risk analysis demonstrated a significant reduction in ICU admission risk with SGLT2 inhibitors (risk difference: −0.014, 95% CI: −0.027 to −0.002, P=0.026; RR: 0.851, 95% CI: 0.738–0.981; odds ratio: 0.838, 95% CI: 0.717–0.979).

The reduction was maintained at 5 years (12.7% vs. 15.0%; risk difference: −0.023, 95% CI: −0.038 to −0.008, P=0.003; RR: 0.848, 95% CI: 0.759–0.947; odds ratio: 0.826, 95% CI: 0.727–0.939).

Overall mortality

At 1 year, the mortality rate was significantly lower in Cohort 1 compared to Cohort 2 (5.4% vs. 10.2%). Risk analysis showed a substantial reduction in mortality with SGLT2 inhibitors (risk difference: −0.049, 95% CI: −0.060 to −0.037, P<0.001; RR: 0.525, 95% CI: 0.447–0.616; odds ratio: 0.498, 95% CI: 0.419–0.591). Kaplan-Meier survival analysis demonstrated significantly higher survival probability in Cohort 1 (94.27%) compared to Cohort 2 (88.76%) (Figure 1). The difference was significant on log-rank testing (P<0.001), and the hazard ratio for mortality was 0.490 (95% CI: 0.415–0.579, P<0.001).

Figure 1 Forest plot of clinical outcomes comparing diabetic patients with inflammatory bowel disease on SGLT2 inhibitors (Cohort 1) versus non-users (Cohort 2), after propensity score matching (n=3,950 per cohort). Outcomes are presented at 1 year (blue) and 5 years (orange) of follow-up. Squares represent ORs, and horizontal lines indicate 95% CIs. Odds ratios less than 1.0 favor SGLT2 inhibitor use. For all-cause mortality, hazard ratios derived from Kaplan-Meier survival analysis are shown. CI, confidence interval; IBD, inflammatory bowel disease; ICU, intensive care unit; OR, odds ratio; SGLT2, sodium-glucose co-transporter-2.

At 5 years, the survival advantage widened. Mortality remained markedly lower in Cohort 1 compared to Cohort 2 (9.7% vs. 17.8%; risk difference: −0.081, 95% CI: −0.096 to −0.066, P<0.001; RR: 0.545, 95% CI: 0.486–0.613; odds ratio: 0.497, 95% CI: 0.435–0.567). Kaplan-Meier survival probability was higher in Cohort 1 (85.01%) than in Cohort 2 (74.95%), the difference remained significant on log-rank testing (P<0.001), and the hazard ratio for mortality was 0.532 (95% CI: 0.469–0.602, P<0.001).

IBD complications

At 1 year, the rate of IBD-related complications was lower in Cohort 1 compared to Cohort 2 (18.9% vs. 21.5%). Risk analysis demonstrated a statistically significant reduction in IBD complications with SGLT2 inhibitors (risk difference: −0.026, 95% CI: −0.044 to −0.008, P=0.004; RR: 0.879, 95% CI: 0.805–0.959; odds ratio: 0.850, 95% CI: 0.762–0.949).

At 5 years, the absolute difference narrowed and was no longer statistically significant on risk analysis (28.9% vs. 30.3%; risk difference: −0.014, 95% CI: −0.034 to 0.006, P=0.175; RR: 0.954, 95% CI: 0.891–1.021; odds ratio: 0.935, 95% CI: 0.849–1.030), although time-to-event analysis remained significant (log-rank P=0.02; hazard ratio: 0.907, 95% CI: 0.837–0.984).

Surgical procedures

At 1 year, the rate of IBD-related surgical interventions was lower in Cohort 1 compared to Cohort 2 (0.6% vs. 1.1%). Risk analysis revealed a statistically significant reduction in surgical procedures with SGLT2 inhibitors (risk difference: −0.005, 95% CI: −0.009 to −0.001, P=0.02; RR: 0.548, 95% CI: 0.330–0.909; odds ratio: 0.545, 95% CI: 0.327–0.908).

At 5 years, surgical rates remained numerically lower in Cohort 1, but the difference was no longer statistically significant (1.0% vs. 1.4%; risk difference: −0.004, 95% CI: −0.008 to 0.001, P=0.15; RR: 0.741, 95% CI: 0.493–1.112; odds ratio: 0.738, 95% CI: 0.489–1.114).

Discussion

This retrospective cohort study used the TriNetX Global Collaborative Network to compare clinical outcomes between diabetic patients with IBD who received SGLT2 inhibitors and those who did not, after rigorous 1:1 PSM. SGLT2 inhibitor use was associated with significantly lower rates of hospitalization, ICU admission, and all-cause mortality at both 1 and 5 years. Benefits with respect to IBD-related complications and surgical procedures were primarily observed during the first year of follow-up.

Emerging literature suggests that IBD and T2DM share an overlapping pathophysiology, including increased cytokine activity and alterations in gut microbiota (8-10). A large Taiwanese cohort study demonstrated reduced IBD incidence with SGLT2 inhibitors, this association was consistent across sensitivity analyses and applied to both ulcerative colitis and Crohn’s disease subtypes (11).

Besides adequate glycemic control, SGLT2i have shown to decrease the hyperfiltration and the continuous systemic inflammatory nature that occurs in diabetic patients (12,13).

The anti-inflammatory effect was demonstrated in animal model studies, where SGLT-2 inhibition was associated with reduced inflammatory responses and decreased production of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 and interleukin-6. Furthermore, SGLT-2 inhibitors suppressed the expression of additional inflammatory mediators such as prostaglandin E2, cyclooxygenase-2 and nitric oxide synthase in these studies, providing additional evidence of their anti-inflammatory effect (14).

Given these properties, SGLT-2 inhibitors have gained attention as a possible treatment option in IBD management (15,16), which may also explain the observed effect of decreased mortality.

Murine studies reveal that some SGLT-2 inhibitors, such as dapagliflozin, mitigate colitis severity in a dose-dependent manner, likely by attenuating colonic apoptosis and reducing oxidative stress (17). Moreover, A recent meta-analysis and case reports have demonstrated that off-label use of SGLT-2 inhibitors in pediatric patients with Glycogen Storage Disease Type Ib (GSD Ib) who develop Crohn’s-like IBD is associated with higher remission rates (18,19). In documented cases, patients experienced rapid improvement in both systemic and gastrointestinal symptoms within the first week of therapy. Improvement was also evidenced by the normalization of the Crohn’s Disease Activity Index (CDAI) within one month, with successful weaning from enteral nutrition over the next few months. Histological evaluation at 5.5 months revealed mucosal healing, and normalization of hemoglobin levels and fecal calprotectin levels at 7.5 months (20). These findings align with the results of our study of decreased incidence of early IBD-related complications, including irreversible surgeries. Nevertheless, any potential benefits of SGLT2 inhibitors should be weighed against their known risks, including dehydration, genitourinary infections, and euglycemic ketoacidosis.

IBD already imposes a major financial burden on the healthcare system, with aggregate annual hospitalization costs rising by $9.1 billion between 2010 and 2020, while IBD patients face significantly higher ICU admission rates than the general population, with 32% 1-year mortality following critical care admission (21,22). Given this trajectory, the association between SGLT2 inhibitor use and lower hospitalization and ICU utilization may carry substantial economic value, particularly as these medications are increasingly available as low-cost generics.

This study benefits from several methodological strengths. The TriNetX Global Collaborative Network, encompassing 173 HCOs, provides a large, diverse sample, enhancing generalizability. The 1:1 PSM balanced a comprehensive covariate set, including demographics, comorbidities, heart failure diagnosis with balancing on the level of the ejection fraction, IBD-specific medications, including steroids and biological agents, and laboratory values, minimizing confounding. Inclusion of all four SGLT2 inhibitors strengthens class-level conclusions, while the selection of five clinically meaningful outcomes directly reflects real-world disease burden.

However, this matching approach reduced the size of the comparison cohort, representing a trade-off between sample size and improved balance of baseline characteristics, and does not eliminate all sources of confounding. Residual confounding and channeling bias may persist because factors influencing SGLT2 inhibitor prescribing, such as clinician preference, frailty, dehydration risk, recurrent genitourinary infections, and concern for ketoacidosis, are not consistently captured in TriNetX. As a retrospective observational study using EHR-derived data, causal inference cannot be established, and the findings may not be generalizable to IBD patients without comorbid T2DM. The absence of validated disease activity indices, endoscopic data, and verified medication adherence further limits the interpretability of outcomes.

Conclusions

In this large, propensity score-matched real-world cohort, SGLT2 inhibitor use among diabetic patients with IBD was associated with significantly lower hospitalization, ICU admission, and all-cause mortality at both 1 and 5 years. IBD-related complications and surgical procedures were significantly lower at 1 year, although the 5-year differences were no longer statistically significant on risk analysis. These findings suggest that SGLT2 inhibitors may confer clinically meaningful benefits beyond glycemic control in this high-risk population; however, further prospective studies with endoscopic and histologic endpoints are warranted to confirm these observations and establish the role of SGLT2 inhibitors in the management of IBD.

Acknowledgments

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-2026-0131/rc

Data Sharing Statement: Available at https://atm.amegroups.com/article/view/10.21037/atm-2026-0131/dss

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-2026-0131/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-2026-0131/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study utilized de-identified data from a federated research database (TriNetX) and is compliant with HIPAA and was exempt from the Institutional Review Board of approval. Informed consent was waived because only de-identified data were analyzed.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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