GLP1 Agonists and Dietary Fiber May Reduce VTE Risk and Improve GVHD Outcomes

Glucagon-like peptide 1 receptor agonists (GLP1 RA), initially approved by the FDA for the treatment of type 2 diabetes mellitus (T2DM), have shown benefits beyond glycemic control with well-documented cardiovascular and weight loss advantages, but data have remained limited in the evaluation of atherosclerotic disease, explained Cho Han Chiang, MD, at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California. However, experimental research has demonstrated that GLP1-RAs may attenuate thromboxane-induced platelet activation; additionally, obesity is an established risk factor for venous thromboembolism (VTE). In light of this, Chiang explained that her team hypothesized a potential for GLP1 RAs to reduce venous thromboembolism (VTE) risk and potentially lower the severity of graft-versus-host disease (GVHD).^1,2

“The starting point of this project is several publications from the Vanden Brink Lab that find a relationship between the microbiome composition and overall survival after [allogeneic hematopoietic cell transplantation (allo-HCT)]. This includes the fact that patients with higher diversity in their microbiome have better overall survival, as well as patients that have higher relative abundance of butyrate producers and patients that have lower abundance of the opportunistic pathogen Enterococcus,” said Chiang, a clinical fellow in medicine at Mount Auburn Hospital in Cambridge, Massachusetts.¹

Chiang noted that there is also a significant body of work that shows that fiber increases microbial growth and the production of shortchange fatty acids, especially butyrate and acetate. Fiber is also correlated with better epithelial hemostasis and is able to reduce the opportunistic pathogens of the Gram-positive Enterococcaceae family, which includes Enterococcus, as well as the inflammation of effector Th1 cells.^1,2

“My hypothesis was: Can we use dietary fiber interventions to improve microbiome diversity, reduce opportunistic pathogens, increase butyrate producers, and hopefully ameliorate GVHD severity,” Chiang said during the ASH presentation.¹

A depiction of deep vein thrombosis. Image Credit: © milkyway - stock.adobe.com

Chiang and her colleagues conducted a retrospective, propensity score-matched multicenter database analysis to explore this hypothesis using the TriNetX Analytics Network, which includes de-identified electronic health records of more than 250 million patients from over 120 health care institutions globally. Researchers compared patients with T2DM treated with GLP1 RAs to those receiving dipeptidyl peptidase-4 (DPP-4) inhibitors, both of which target the incretin system for glycemic control. Excluding patients on anticoagulants, those with prior VTE, or atrial fibrillation, the study propensity-matched patients (1:1) on GLP1 RAs with those on DPP-4 inhibitors based on predetermined clinical variables, including age, sex, race, BMI, hemoglobin A1c, use of other anti-diabetic agents including metformin and insulin, and underlying comorbidities based on the components of the Charleston Comorbidity index. Additionally, a subgroup analysis was performed that was stratified by the presence of obesity, which was defined as having a BMI of 30 kg/m² or greater. The primary outcome was incidence rate per 1000-patient years of all VTE at 1-year after first initiation of GLP1 RAs or DPP-4 inhibitors, and the secondary outcomes were pulmonary embolism and deep venous thrombosis individually.^1,2

“We had a rich dataset that combined clinical correlates with nutritional intake as well as taxonomical analysis,” Chiang said. “I think it's important to highlight a detail of this dataset, [as] we tracked more than 35,000 meals with daily tracking of 173 patients. We corrected every single meal for proportions in dry grams of nutrition, as well as paired this information with stool samples taken every 2 days.”¹

During analysis of these data, Chiang noted that the first step was to separate fiber intake from the rest of the nutritional groups and to further dissect fiber in the most common fiber types to be able to establish 2 cohorts: a high fiber intake cohort and a low fiber intake cohort.¹

“When we analyzed the taxonomical composition in these 2 cohorts, we first established that the high fiber intake cohort had a higher abundance of Blautia, which is a butyrate producer that has been associated with better outcomes in GVHD, as well as a reduction of Enterococcus, which also contributes to overall survival,” Chiang said. “We were very happy to see that, in fact, the overall survival positively correlated with high fiber intake, and this was seen with an analysis through 24 months.”¹

The findings revealed that patients on GLP1 RAs exhibited an 18% lower risk of VTE compared to patients on DPP-4s (HR, 0.82). Sub-analyses showed consistent reductions in pulmonary embolism (HR, 0.78) and deep vein thrombosis (HR, 0.85) rates. Notably, the benefits extended across subgroups, irrespective of obesity status.^1,2

Dietary Fiber and Microbiome Health in GVHD Outcomes

Chiang noted that her team further explored this cohort by focusing on GVHD outcomes. For this purpose, they focused on patients who did not develop GVHD vs patients that developed lower gastrointestinal (GI) GVHD, which is where fiber fermentation takes place.¹

“When we analyzed the shortchange fatty acids, we see that the high fiber intake cohort had higher concentrations of butyrate acetate, and this was also true for non-GVHD patients when compared to patients with lower GI GVHD. We also evaluated how fiber was associated with GVHD cumulative incidence, and we see here that high fiber diet actually had a significantly lower accumulative incidence of GVHD, and this was also true for the [patients with] lower GI GVHD,” Chiang said.¹

Chiang and her team also explored the mechanistic action of fiber in the context of GVHD, and for this investigation, they shifted to using preclinical mice models, with cellulose as the fiber source.¹

“When we compare average fiber diet of 12% cellulose with the control group, which is 6% and complete absence of fiber, we can see here that a rich fiber diet of 12% cellulose results in better overall survival. When we explore the microbiome composition of these mice, we see that, in fact, cellulose concentration results in a unique microbiome composition that results in higher abundance of butyrate producers, as well as lower levels of Enterococcus,” Chiang said.¹

Chiang and her team then performed a single cell analysis to understand the mechanisms of fiber at the cellular level. They started with epithelial cells and enterocytes, which manage nutritional uptake, and they observed that 12% fiber actually increased genes associated with epithelial homeostasis.^1,2

“We validated these results by demonstrating that 12% fiber decreases gut barrier damage, as well as the correlation with higher butyrate,” Chiang said. “Lastly, we explored single cell in CD4 effector cells, which are the main drivers of the GVHD phenotype in mouse models. We saw that 12% actually reduces a lot of the activation markers as well as the inflammatory markers, and when we did flow cytometry analysis to validate these results, we see that in the 12% group, we have higher ratio of T regulatory cells.”¹

Converging Insights

The findings from this research underscore the transformative potential of targeting systemic and localized mechanisms to improve patient outcomes. While GLP1 RAs vascular benefits open avenues for mitigating thrombotic risks, dietary fiber’s role in shaping microbiome health highlights a novel approach to managing complications in patients following allo-HCT.^1,2

“After studying [patients undergoing] allo-HCT as well as GVHD preclinical models, we demonstrated that fiber consumption is possibly correlated with increased overall survival and decreased accumulative incidence,” Chiang said. “In our GVHD mouse models, we demonstrated that 12% cellulose, which is a rich fiber concentration, increased GVHD survival, as well as reduced gene expression of inflammatory markers of effector cells.”¹

REFERENCES

1. Chiang CH. Food for Thought: How Diet and Lifestyle Affects Hematologic Care. Presented at: 66th ASH Annual Meeting and Exposition; San Diego, California; December 7-10, 2024.

2. Chiang CH, Osataphan S, Chang YC, et al. 701 Glucagon-like Peptide 1 Receptor Agonists Reduce the Risk of Venous Thromboembolism in Patients with Diabetes Irrespective of Obesity: A Propensity Score-Matched Multicenter Database Analysis. American Society of Hematology. 2024. Accessed December 7, 2024. https://ash.confex.com/ash/2024/webprogram/Paper206409.html