Obesity is a multidimensional condition characterized by autonomic imbalance, metabolic inflexibility, impaired physical resilience, and ectopic adiposity, pathophysiological alterations that arise long before overt cardiometabolic disease becomes clinically detectable. Despite this, current cardiometabolic risk scores continue to rely predominantly on biochemical and anthropometric variables, such as BMI, waist circumference, glucose, and lipid levels. While these markers are practical, inexpensive, and validated across large population cohorts, growing evidence shows that they offer limited incremental predictive value and fail to capture early functional and structural abnormalities. The recent literature highlights the prognostic importance of autonomic dysfunction, reduced metabolic flexibility, diminished cardiorespiratory fitness, impaired muscular strength, and ectopic fat depots including visceral and epicardial adiposity, independently of the traditional anthropometric indices. The domains remain absent from traditional algorithms such as the Metabolic Syndrome criteria, the Framingham Risk Score, and SCORE2. As a result, cardiometabolic risk is frequently underestimated in key subgroups, including young adults with obesity, individuals with high visceral adiposity but normal BMI, those with subclinical myocardial dysfunction, and metabolically unhealthy normal-weight phenotypes. This narrative review synthesizes current evidence on obesity-related cardiometabolic impairment, highlights major gaps in established risk scores, and supports the conceptual development of the C.O.R.E. (Cardio-Obesity Risk Evaluation) Indicator Model—a hypothesis-generating, non-validated multidomain framework integrating autonomic, metabolic, functional, and structural markers to enable earlier risk phenotyping in future studies.

Cardiometabolic diseases remain the leading cause of morbidity and mortality worldwide, despite major advances in pharmacological and lifestyle interventions. Exercise training is a cornerstone of prevention and treatment; however, adherence to traditional aerobic programs remains suboptimal. Isometric handgrip (IHG) training has emerged as a simple, time-efficient, and potentially effective strategy for improving cardiovascular and metabolic outcomes. This state-of-the-art review synthesizes current evidence on the physiological mechanisms underlying IHG training, including autonomic modulation, vascular function improvement, endothelial adaptation, and metabolic regulation. We summarize clinical data regarding its effects on blood pressure, arterial stiffness, endothelial function, insulin sensitivity, and inflammatory markers. Special attention is given to its applicability in specific populations, including hypertensive patients, individuals with metabolic syndrome, heart failure patients, and cancer survivors. We also discuss methodological heterogeneity across studies, safety considerations, and knowledge gaps. Finally, we outline future research directions needed to define optimal protocols and clarify long-term cardiometabolic benefits. IHG training represents a promising adjunctive strategy within cardiometabolic prevention and rehabilitation programs.

Background: Obesity has evolved from a morphometric descriptor to a chronic, relapsing, multisystem disease in which low-grade adipose-tissue inflammation, insulin resistance, endothelial dysfunction, and a prothrombotic, pro-tumorigenic milieu coexist. Venous thromboembolism (VTE) and malignancy share this substrate through a well-established bidirectional link: within twelve months of an unprovoked deep vein thrombosis (DVT), 6–15% of patients are diagnosed with occult cancer, a substantial proportion of which are already locally advanced or metastatic at detection. In this context, obesity acts as a dual amplifier of both thrombotic and oncologic risk, making the post-DVT patient with an incidentally diagnosed cancer a paradigmatic candidate for integrated management. Objective: To propose an evidence-based, unifying cardiometabolic and antithrombotic clinical framework that reconciles (i) risk-stratified screening for occult malignancy after unprovoked DVT, (ii) contemporary pharmacotherapy of obesity, and (iii) cancer-associated thrombosis (CAT) management, in the light of evidence published through 2025. Methods: Narrative synthesis based on a structured literature search (PubMed/MEDLINE, Embase, Scopus; 2000–March 2025) of current guidelines (ISTH, ASH, ESC Cardio-Oncology, EASO) and pivotal randomized evidence on GLP-1 and dual GLP-1/GIP receptor agonists (semaglutide, tirzepatide), SGLT2 inhibitors (empagliflozin, dapagliflozin), and direct oral anticoagulants (DOACs), with critical interpretation of recent meta-analytic data on oncologic signals, cardiovascular outcomes, and bleeding safety. Results: Three evidence-based pillars emerge: (1) limited screening complemented by age- and sex-specific testing in patients ≥ 50 years with unprovoked DVT, enhanced by FDG-PET/CT for high-risk phenotypes in which obesity itself degrades the sensitivity of clinical examination and conventional imaging; (2) GLP-1/GIP receptor agonist-based anti-obesity pharmacotherapy, associated in observational cohorts with a 17% relative reduction in overall cancer incidence (HR 0.83; 95% CI 0.76–0.91) and neutral-to-reassuring oncologic signals, but requiring cautious, case-by-case use in patients with active cancer because of the risk of accelerating sarcopenia and cachexia; and (3) apixaban as the preferred DOAC for cancer-associated thrombosis, with a superior efficacy-to-bleeding ratio in network meta-analyses and a reduced-dose extended strategy now validated by the API-CAT trial. Conclusions: Patients with obesity presenting with unprovoked DVT and an incidentally detected cancer embody a cardiometabolic–antithrombotic continuum. A framework integrating structured occult-cancer screening, judicious obesity pharmacotherapy, and apixaban-preferred anticoagulation—coordinated by a multidisciplinary team and illustrated here by a case-based pathway—offers the most rational, evidence-aligned approach. Prospective, dedicated trials in this specific phenotype are urgently warranted.

Obesity is a multidimensional condition characterized by autonomic imbalance, reduced metabolic inflexibility, impaired physical resilience, and ectopic adiposity, pathophysiological alterations that arise long before overt cardiometabolic disease becomes clinically detectable. Despite this, current cardiometabolic risk scores continue to rely predominantly on biochemical and anthropometric variables, such as BMI, waist circumference, glucose, and lipid levels. While these markers are practical, inexpensive, and validated across large population cohorts, growing evidence shows that they offer limited incremental predictive value and fail to capture early functional and structural abnormalities. Recent literature highlights the prognostic importance of autonomic dysfunction, reduced metabolic flexibility, diminished cardiorespiratory fitness, impaired muscular strength, and ectopic fat depots including visceral and epicardial adiposity, independently of the traditional anthropometric indices. The domains remain absent from traditional algorithms such as the Metabolic Syndrome criteria, the Framingham Risk Score, and SCORE2. As a result, cardiometabolic risk is frequently underestimated in key subgroups, including young adults with obesity, individuals with high visceral adiposity but normal BMI, those with subclinical myocardial dysfunction, and metabolically unhealthy normal-weight phenotypes. This narrative review synthesizes current evidence on the multidimensional nature of obesity-related cardiometabolic impairment, identifies major gaps in established risk scores, and supports the conceptual development of the C.O.R.E. (Cardio-Obesity Risk Evaluation) Indicator Model, a proposed multidomain framework integrating autonomic, metabolic, functional, and structural markers to enable earlier and more accurate cardiometabolic risk stratification.

Background: Glucagon-like peptide-1 receptor agonists and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP-1) receptor agonists have substantially improved the management of obesity and cardiometabolic disease, providing significant benefits on weight reduction, glycemic control, and cardiovascular outcomes. Despite these advances, gastrointestinal (GI) adverse events remain a major cause of dose reduction, treatment interruption, and poor long-term adherence. Increasing evidence suggests that interactions between incretin-based therapies and the intestinal microenvironment may contribute to GI tolerability and influence treatment persistence. Methods: We conducted a narrative review of the literature examining the relationship between incretin-based therapies, gut microbiota, intestinal barrier function, and microbial metabolites. Evidence from randomized clinical trials, observational studies, systematic reviews, and mechanistic investigations was evaluated to explore potential gut-directed supportive strategies during incretin-based treatment. Results: Preclinical and mechanistic evidence suggests possible bidirectional interactions between incretin pharmacology and the intestinal microenvironment, whereas direct human evidence remains limited and inconsistent. Alterations in gastrointestinal motility induced by GLP-1 receptor agonists could theoretically influence microbial composition and fermentation dynamics, although human studies have not consistently demonstrated significant microbiota changes. Based on these observations, we propose the Incretin–Microbiota Tolerance Axis (IMTA) as a conceptual framework linking gut homeostasis, GI tolerability, and treatment adherence. Among potential supportive interventions, partially hydrolyzed guar gum (PHGG) may promote SCFA-producing microbiota and improve bowel function, whereas simethicone may provide symptomatic relief of gas-related discomfort during dose escalation. SCFA-supportive nutritional approaches may further contribute to maintenance of intestinal homeostasis. Conclusions: Optimization of the intestinal microenvironment may represent a complementary strategy to improve GI tolerability and support long-term adherence during incretin-based therapy. Although the IMTA framework is supported by biological plausibility and emerging evidence, prospective clinical studies are required to determine whether microbiota-targeted interventions improve treatment persistence and cardiometabolic outcomes in patients receiving GLP-1 receptor agonists or dual GIP/GLP-1 receptor agonists.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent worldwide and represents the hepatic manifestation of a systemic cardiometabolic-inflammatory syndrome rather than an isolated organ disease. In parallel, anticancer therapies carry a well-recognised burden of cancer therapy-related cardiovascular toxicity (CTR-CVT). Evidence suggests that the metabolic-inflammatory cascade driving steatosis → steatohepatitis → fibrosis may also contribute to endothelial dysfunction, myocardial remodelling and cardiomyocyte vulnerability to chemotherapy-induced oxidative stress. This narrative review proposes a unifying conceptual framework in which MASLD may act as a potential amplifier of cardiotoxicity in oncology patients and examines whether lifestyle and dietary interventions could mitigate this cumulative risk. Methods: A structured literature search of PubMed, Scopus and Web of Science was performed, prioritising systematic reviews, meta-analyses, randomised controlled trials, large cohort studies and recent international guidelines on MASLD, cardio-oncology and nutritional interventions. Results: Four converging molecular axes were identified as plausible links between MASLD and cardiomyocyte susceptibility to anticancer therapy: mitochondrial dysfunction with reactive oxygen species overproduction, NLRP3 inflammasome activation and metaflammation, endothelial nitric oxide impairment, and pro-fibrotic TGF-β/hepatic stellate cell signalling. Mediterranean-style dietary patterns, selected micronutrients and emerging metabolic therapies modulate the same network and may offer translational opportunities. Conclusions: Reframing MASLD as a potentially modifiable amplifier of CTR-CVT supports the integration of hepatic phenotyping into baseline cardio-oncology risk stratification and the use of personalised nutrition as a precision tool acting on shared mitochondrial, inflammatory, endothelial and fibrotic pathways. Multidisciplinary framework and prospective interventional studies, adopting composite hepato-cardio-oncological endpoints, are warranted.