GLP‑1 receptor agonists and clonal hematopoiesis: Early human signals of anti‑inflammatory clone mitigation and lower MDS‑to‑AML progression Free

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have become a near-ubiquitous consumer phenomenon for weight loss, frequently eclipsing their intended indications in diabetes and cardioprotection. Accumulating data indicates that GLP-1 signaling may exert anti-inflammatory effects and immune modulation: GLP-1R activation in monocytes/macrophages and neutrophils may dampen NF-κB activity, limit NLRP3 inflammasome priming, and lower oxidative stress; in T-cells, it may reduce Th1/Th17 skew and favor regulatory pathways. Pro-inflammatory cytokines TNF-α, IL-6, and IL-1β are suppressed in GLP-1R–expressing immune cells, while anti-inflammatory IL-10 is increased, helping restore immune balance.¹ These pervasive effects on inflammation prompted our hypothesis that GLP-1RAs could alter hematopoietic selection and mitigate clonal expansion in CHIP/CCUS and, potentially, MDS. To date, no drugs with favorable enough toxicity profiles are available for prevention of myeloid progression.

We predicted that, in CHIP/CCUS and related myeloid disorders, GLP-1–mediated immunomodulation reduces the competitive fitness of mutant clones and mitigates clonal burden. From a registry of 199 CHIP/CCUS cases, we identified a longitudinal subset who initiated a GLP-1RAs after molecular diagnosis and had serial NGS on continuous therapy. Among them, 3 cases were illustrative showing stability or declining clonal burden. In a CHIP case, baseline JAK2 (1.1%) and CALR (5.9%) turned undetectable at 9mo following GLP-1RA initiation and remained absent at 18mo. In another case with CCUS, DNMT3A and LUC7L2 decreased by 1.4-fold and 2-fold, respectively, over 20 months. In an MDS case, BCORL1 and SRSF2 decreased by 5x and 1.7x, respectively, over six months.

Finally, we also noted a paroxysmal nocturnal hemoglobinuria (PNH) patient, who, under our observation, initiated GLP-1RA therapy for their diabetes. GLP-1RA was associated with decline of PNH granulocyte burden from baseline (27%) to 1-year (14%), 2-years (7%) and 3-years (6%) with no changes in complement inhibition therapy during this time.

These clinical observations prompted us to conduct a meta-analytic analysis utilizing TriNetX database. There were 147,556 patients with MDS in which 2,392 were started on GLP-1RA therapy after their MDS diagnosis. We performed 1:1 greedy propensity matching by MDS morphologic subtypes, balancing for reported chromosomal abnormalities, variants, and MDS treatment. MDS transformation to AML was used as a surrogate for clonal evolution. In patients with lower risk MDS, there was significantly decreased progression to AML across all subtypes; notably, in MDS-RS (n=178 per arm), AML progression rates were 5.6% with GLP-1RA vs. 18.0% without (OR .272, 95% CI [0.129–0.571]; p=.0003). However, in high-risk MDS there was no difference in progression rates; in MDS EB-2 (n=56 per arm), rates were 50.0% with GLP-1RA vs 46.4% without (OR 1.154, 95% CI [0.550–2.423]; p = .7053). To correlate these finding to GLP-1RA therapy, we also compared for patients on metformin to rule-out diabetes control as improving clonal burden. There were 9,182 patients with MDS who were started on metformin. There were no changes in progression across low risk and high risk subtypes; in MDS-RS (n=496 per arm), AML progression rates were 13.3% with metformin versus 12.7% without (OR 1.05, 95% CI [0.729-1.527]; p=.78). Similarly, in MDS EB-2 (n=687 per arm), AML progression rates were 50% with metformin versus 45% without (OR 1.23, 95% CI [0.99, 1.52]; p=.06).

Our preliminary meta-analyses and clinical observations indicate that further systematic studies of GLP-1RAs in CHIP/CCUS and low-risk MDS may be warranted. The known activity profile of GLP-1RA suggests that its multifactorial anti-inflammatory effects may mitigate clonal evolution in these pre-malignant diseases. We are currently conducting a prospective clinical study analyzing GLP-1RAs effects in in 150 CHIP individuals at our institution.

We thank TriNetX and all participants for their contribution, without whom this research would not have been possible. References

• Alharbi SH. Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications. Ther Adv Endocrinol Metab. 2024 Jan 27;15:20420188231222367. doi: 10.1177/20420188231222367. PMID: 38288136; PMCID: PMC10823863.