Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are becoming more popular in managing type 2 diabetes mellitus (T2DM). Concerns linger over potential links to malignancies like pancreatic and thyroid cancers, requiring more research to clarify their safety profiles. Additionally, evidence suggests GLP-1 RAs may lower colorectal and pancreatic cancer risk, especially in obese and overweight individuals, indicating a protective effect beyond weight loss. Current studies leave a gap in comprehensively understanding cancer risks associated with GLP-1 RAs, which prompts further research to enhance our understanding of their overall safety. Methods: We queried the US Collaborative Network (63 health care organizations) of the TriNetX research database. Patients with T2DM were identified and divided into two cohorts: patients on GLP-1 RAs and patients not on GLP-1 RAs. We excluded tobacco use and alcohol use disorders, obese patients with a body mass index (BMI) of >25 kg/m², and those with a family history of gastrointestinal malignancy, infectious mononucleosis, chronic gastritis, pernicious anemia, helicobacter pylori infection, or gastroesophageal reflux disease (GERD). We used a 1:1 propensity score matching (PSM) model using patients’ baseline characteristics, medications, labs, and genetics. We compared the rate of gastric cancer and esophageal cancer at the seven-year mark. Results: A total of 2,748,431 patients with T2DM were identified. Of those, 6% (n = 167,077) were on a GLP-1 RA and 94% (n = 2,581,354) were not on a GLP-1 RA. After PSM, both cohorts included 146,277 patients. Patients with T2DM who were on a GLP-1 RA, compared to those who were not, had a statistically significant lower risk of both gastric cancer (0.05% vs. 0.13%, p < 0.0001) and esophageal cancer (0.04% vs. 0.13%, p < 0.0001) at the seven-year mark. Conclusion: The use of GLP-1 RAs in patients with T2DM does not significantly increase the risk of gastric or esophageal cancer. This finding supports the continued use of GLP-1 analogues as a therapeutic option in managing T2DM, considering their well-established benefits and low risk of complications. Based on the study results, these medications may even have a protective effect against these malignancies.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease (CLD) globally and is closely linked to metabolic risk factors and systemic inflammation. Emerging evidence suggests that vitamin D deficiency may influence MASLD severity and outcomes, though limited real-world data often assess long-term clinical outcomes in MASLD patients stratified by vitamin D status. Methods: We conducted a retrospective cohort study using the TriNetX US Collaborative Network (2006–2025). Adult patients with MASLD were stratified into two cohorts based on serum 25-hydroxyvitamin D levels: normal (≥30 ng/mL) and deficient (<20 ng/mL). Patients with other CLD, malignancy, decompensated cirrhosis, and relevant confounding conditions were excluded. Primary outcomes included all-cause mortality, hospital readmissions, and ICU admissions at 1-year and 5-year follow-up. Results: After propensity score matching, 6959 patients were included in each cohort. Compared with patients with normal vitamin D levels, those with vitamin D deficiency had significantly higher rates of hospital readmissions, ICU admissions, and all-cause mortality at both 1-year and 5-year follow-up. A 1 year, readmissions occurred in 10% vs. 6%, ICU admissions 2.6% vs. 1.2%, and mortality 1.5% vs. 0.5% of patients (p = 0.01). Similar findings were observed at 5 years, with higher rates of readmissions 15% vs. 10%, ICU admissions 4.4% vs. 2.4% and mortality 3.2% vs. 1.3% in the vitamin D-deficient cohort (p = 0.01). Conclusions: Vitamin D deficiency was associated with significantly increased mortality, hospital readmissions, and ICU admissions among patients with MASLD. Our findings suggest that vitamin D status may represent a valuable prognostic indicator in this population. Although the observational nature of this study precluded establishing causality, our results support the consideration of routine assessment of vitamin D levels in patients with MASLD. Further prospective and mechanistic studies are needed to determine whether vitamin D supplementation can improve outcomes in this population.