From Adipose Tissue Dysfunction to Venous Thromboembolism

Background/Objectives: Obesity is a major modifiable risk factor for venous thromboembolism (VTE), driven by adipose tissue dysfunction, chronic inflammation, endothelial dysfunction, hypercoagulability, impaired fibrinolysis, immunothrombosis, and venous stasis. Modern incretin-based therapies induce substantial weight loss and improve multiple cardiometabolic abnormalities that may influence thrombotic risk. To critically evaluate the biological rationale and clinical evidence supporting a potential role of incretin-based therapies in modifying VTE risk, while distinguishing mechanistic plausibility from proven clinical benefit and weight-loss-mediated effects from direct pharmacological actions. Methods: Narrative review of MEDLINE/PubMed and EMBASE (2000–2026), with critical appraisal of mechanistic studies, randomized trials, pharmacoepidemiological evidence, and current clinical recommendations. Results: Experimental and translational studies provide biological plausibility for potential antithrombotic effects of incretin-based therapies through modulation of inflammation, endothelial function, platelet activation, and coagulation pathways; however, these biomarkers are not validated surrogate endpoints for VTE. An expanding body of contemporary observational evidence, including active-comparator studies and target-trial emulations, has generally reported lower rates of VTE, pulmonary embolism, and/or deep vein thrombosis among patients receiving incretin-based therapies, although effect estimates vary according to population, comparator, and clinical setting. In contrast, recent meta-analyses of randomized trials have not demonstrated a significant reduction in overall VTE and have yielded partly conflicting findings for pulmonary embolism and deep vein thrombosis. Major cardiovascular outcome trials were not specifically designed or powered to assess VTE. Current evidence suggests that sustained weight loss is the most plausible mediator of any potential long-term reduction in VTE risk, whereas a clinically relevant weight-independent antithrombotic effect remains unproven. Conclusions: Incretin-based therapies have a compelling biological rationale and a growing observational signal for potential VTE risk reduction, but current evidence is insufficient to establish a causal protective effect. Any potential long-term benefit appears most plausibly related to sustained weight loss and reversal of obesity-associated prothrombotic abnormalities, while a clinically relevant weight-independent antithrombotic effect remains unproven. Accordingly, these therapies should continue to be prescribed according to established metabolic indications, and any reduction in VTE risk should be regarded as a potential but unconfirmed additional benefit. Dedicated randomized trials with prespecified and adjudicated VTE outcomes are required before VTE prevention can be considered a therapeutic indication.