Background:

In asymptomatic indolent non-Hodgkin lymphomas (iNHL) including follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), Waldenstrom's macroglobulinemia (WM), common practice includes “active surveillance” until patient meets specified criteria for starting therapy. There are no widely accepted models that accurately predict the risk of requiring treatment in asymptomatic patients with iNHL. Both diabetes and obesity are pro-inflammatory comorbidities that are associated with development and poor survival outcomes in NHL through various proposed mechanisms. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are approved for type 2 diabetes and obesity and have shown reduction in cardiovascular risk. In patients with monoclonal gammopathy of undetermined significance (MGUS), GLP-1RAs have been shown to reduce the risk of progression to multiple myeloma. This study is aimed to assess the association of GLP-1RA use in the progression of asymptomatic iNHL to symptomatic disease states requiring treatment and risk of transformation.

Methods:

A retrospective database review was performed using the TriNetX Research Network, a federated network of HIPPA compliant de-identified data from multiple organizations from the Global Collaborative Network. All patients with either FL, MCL, MZL, or WM that did not receive treatment including radiation or systemic therapy in the first year of diagnosis were included. FL IIIb and those that died prior to one year were excluded. Outcomes for patients receiving GLP-1RAs six months before or any time after diagnosis and before initiation of an oncologic treatment were compared to those without exposure to GLP-1RAs after cohort balancing. The primary outcome was initiation of treatment at any time. Secondary outcomes included time to first treatment, overall survival (OS), and cardiovascular events. Sensitivity analysis included FL patients alone with same criteria and outcomes with the addition of transformation to diffuse large B-cell lymphoma (DLBCL). Data was analyzed using Kaplan-Meier method as well as odds ratio with 95% confidence interval.

Results:

A total of 68,638 patients were diagnosed with iNHL and met selection criteria. Of these patients, 1239 received a GLP-1RA prior to initiation of any treatment. The cohorts were balanced for age, gender, race, and comorbidities of heart failure, obstructive sleep apnea, BMI, A1c, LDH, and hemoglobin and after matching, each cohort had 1218 patients. The mean age was 65 years. Caucasians made up the majority of each cohort. Most patients had a BMI between 30-40 and had diabetes. Mean hemoglobin was 13. Mean LDH was 202u/L in GLP-1RA cohort and 205u/L in the non-GLP-1RA cohort.

In the GLP-1RA cohort, 210 (17.3%) required treatment compared to 247(20.3%) [OR 0.822, CI 0.67-1.008]. The median time to first treatment was not reached in GLP-1RA group and 14 years in non-GLP-1RA [p=0.0066]. The median OS was not reached in either cohort and was not significantly different[p<0.0964]. The GLP-1RA group had a lower risk of acute cardiac events including myocardial infarction or cardiac arrest (4.9% vs 7.3%, OR 0.649, CI 0.458-0.921). There was also a lower risk of heart failure with 10.6% risk in GLP-1RA cohort vs 15.2% [OR0.658, CI 0.507-0.855].

In a sensitivity analysis evaluating only those with stage I-IIIA FL receiving GLP-1RA compared to those without (both n=790), comparable but significant results were seen with fewer patients requiring treatment, 17.2% vs 21.3% [OR 0.768, CI 0.597-0.987]. Median OS was not met in either group. There was also a reduction in those who progressed to DLBCL with a risk of 4.5% in GLP-1RA cohort versus 8.3% [OR 0.514, CI 0.331-0.798].

Conclusions:

In this study, the use of GLP-1RAs was associated with a trend in reduction in need for treatment in untreated patients with iNHL that are undergoing active surveillance. This difference in treatment indication and transformation is apparent in the sensitivity analysis with FL alone, signifying a stronger relationship in this population. To our knowledge, our study is the first to report on these novel findings in iNHL. The mechanisms in which GLP-1RA's reduce the need for treatment in iNHL remain unclear. Future prospective studies are warranted to further assess this relationship as the use of GLP-1RA may reduce the risk of chemotherapeutic toxicity and healthcare cost associated with treatment for asymptomatic iNHL.

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2025
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