A groundbreaking subanalysis of the LoDoCo2 trial unveiled compelling evidence that daily administration of low-dose colchicine may decelerate the expansion of clonal hematopoiesis (CH), a common acquired gene mutation in the blood of elderly individuals. These mutations materially elevate the risk of hematologic malignancies as well as cardiovascular disease, making the findings significant for both oncology and cardiology. The study, published in the prestigious Journal of the American College of Cardiology (JACC) and presented at ESC Congress 2025, sheds light on novel mechanisms underpinning age-related cardiovascular risk and introduces promising therapeutic opportunities.
Clonal hematopoiesis refers to the somatic mutations in hematopoietic stem cells that lead to the expansion of mutated clones within peripheral blood. This phenomenon, often silent, has been linked to a drastically increased probability of developing leukemia and other blood cancers. Moreover, evidence accumulated over recent years indicates a robust association between CH and adverse cardiovascular outcomes, including coronary artery disease, heart failure, and arrhythmias. The most frequently mutated driver genes implicated in CH, namely DNMT3A, TET2, and ASXL1, represent approximately 80% of cases and reflect the mutational landscape influenced by aging hematopoiesis.
Importantly, epidemiological studies have demonstrated that the prevalence of clonal hematopoiesis rises exponentially with age; over 10% of people aged 70 years and older harbor one or more of these mutations. Given this high prevalence and the significant health risks linked with CH, researchers have prioritized understanding factors that modulate clonal expansion. The current study focuses on addressing whether colchicine, a historically well-established anti-inflammatory drug primarily used to treat gout, could influence the growth dynamics of CH clones.
The LoDoCo2 trial, originally designed to test colchicine’s efficacy in reducing cardiovascular events in patients with chronic coronary disease, revealed a substantial 31% relative risk reduction in cardiovascular incidents with a daily 0.5 mg dose of colchicine. Building on these findings, the current subanalysis interrogated longitudinal blood samples from trial participants to assess the drug’s potential impact on the clonal architecture of hematopoietic mutations over time. Specifically, four sequential blood draws were performed: baseline, 30 days post-randomization, one year, and at the conclusion of the study.
Using next-generation sequencing technology, researchers quantified the burden and allelic fraction of key CH mutations across these time points. Additionally, inflammation biomarkers in the blood, which have been implicated in both clonal expansion and atherogenesis, were assayed during the initial three time points. The study’s advanced genomic and biomarker profiling provided a multidimensional perspective on how anti-inflammatory therapy intersects with genetic and cellular alterations in aging blood.
The results revealed that individuals receiving colchicine exhibited a markedly reduced rate of clonal expansion compared to placebo recipients. While placebo-treated participants showed a significant 14.9% increase annually in overall CH clone size, those on colchicine experienced a non-significant rise of merely 6.3% per year. Notably, this growth attenuation was especially pronounced for TET2-mutated clones. The TET2 clone size increased by only 9.1% annually among the colchicine group, contrasting sharply with a 29.6% increase in the placebo group, suggesting a specific vulnerability of TET2-mutated hematopoietic cells to anti-inflammatory mechanisms.
Michael Honigberg, MD, MPP, FACC, the study’s senior author and a cardiologist at Massachusetts General Hospital, emphasized the clinical relevance of these findings. Larger CH clones have consistently correlated with higher risks of cardiovascular disease and malignancy, with TET2 mutations linked particularly closely to increased cardiovascular risk. This study not only elucidates colchicine’s multifaceted benefits in reducing cardiovascular events but also raises the possibility that the drug may interrupt the pathogenetic expansion of deleterious clonal blood populations.
In a complementary investigation also published in JACC and unveiled at ESC Congress 2025, researchers examined the relationship between CH and cardiovascular disease risk specifically in an elderly female cohort. The Women’s Health Initiative Long Life Study enrolled over 6,600 women, with a median age of 80, to probe whether the impact of clonal hematopoiesis wanes in advanced age as some prior research suggested. Contradicting earlier assumptions, this study found that several CH subtypes, including TET2, ASXL1, and JAK2 mutations, were indeed associated with increased incident cardiovascular disease in these older women.
This finding confirms that clonal hematopoiesis remains a critical contributor to cardiovascular health and disease progression well into late adulthood. Such insights underscore the enduring need to consider CH when evaluating cardiovascular risk profiles among the elderly, a demographic population growing rapidly worldwide. The mechanistic links between inflammation, aging hematopoiesis, and vascular pathology are increasingly recognized as fertile ground for therapeutic intervention.
Editorial leadership from Harlan Krumholz, MD, FACC, Editor-in-Chief of JACC and Harold H. Hines Jr Professor of Medicine at Yale University, contextualized the broader implications of these studies. Clonal hematopoiesis serves as a pivotal intersection connecting aging biology, cardiovascular disease, and cancer pathophysiology. Advances in understanding how inflammation and somatic genetic alterations coalesce to shape disease trajectories open novel pathways for precision prevention and treatment strategies that target both genetic drivers and inflammatory mediators.
The cumulative evidence spotlights colchicine as a cost-effective, well-tolerated pharmacological tool with potential to modify underlying disease mechanisms beyond symptomatic relief or secondary prevention. Its ability to attenuate inflammatory signaling pathways, notably those involving the NLRP3 inflammasome and interleukin-1 β, combined with the demonstrated suppression of CH clone expansion, positions colchicine at the forefront of next-generation cardio-oncology paradigms.
As our population ages and the burden of cardiovascular disease and hematologic malignancies escalates, identifying interventions that mitigate foundational biological causes takes on paramount importance. The synergy of genomic medicine, longitudinal biomarker monitoring, and repurposed anti-inflammatory agents heralds a transformative era in individualized cardiovascular and cancer risk management.
Further research aimed at delineating the molecular crosstalk between mutated hematopoietic clones and the vascular microenvironment will be critical in optimizing treatment algorithms. Trials designed to verify colchicine’s effects on CH populations across diverse demographics, as well as exploring combination therapies targeting multiple pathogenic axes, are eagerly anticipated. The integration of these discoveries into clinical practice offers the promise of dramatically altering the course of age-associated chronic diseases.
In summary, the groundbreaking research presented at ESC Congress 2025 and published in JACC reveals colchicine’s unprecedented role in modulating clonal hematopoiesis, particularly mutations in TET2, which are intimately tied to cardiovascular disease and malignancy risk. These findings highlight innovative pathways to combat the intertwined epidemics of aging, inflammation, blood cancer, and heart disease, providing hope for novel preventative and therapeutic strategies that address the root causes of morbidity and mortality in elderly populations.
Subject of Research: Effects of low-dose colchicine on clonal hematopoiesis and cardiovascular disease risk in elderly populations
Article Title: Low-Dose Colchicine Attenuates Clonal Hematopoiesis Expansion and Reduces Cardiovascular Risk: Insights from the LoDoCo2 Trial Subanalysis
News Publication Date: Not explicitly stated, presented at ESC Congress 2025
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Keywords: Clonal hematopoiesis, colchicine, cardiovascular disease, TET2 mutation, DNMT3A, ASXL1, inflammation, aging, hematologic malignancies, LoDoCo2 trial, anti-inflammatory therapy, cardiovascular risk reduction
