Obesity contributes to atherosclerotic cardiovascular disease development through interconnected pathways involving hypertension, dyslipidemia, insulin resistance, and chronic inflammation [16]. Epidemiological and pathophysiological studies, including Mendelian randomization analyses, support a causal association between adiposity and cardiovascular disease [17]. Notably, extensive cohort data suggest that obesity is more strongly linked to heart failure than to atherosclerotic cardiovascular events [18]. A US-based cohort study further demonstrated a significant association between BMI and increased cardiovascular risk, particularly heart failure, across all obesity classifications [19].

Differentiating between clinical and preclinical obesity provides explicit criteria for early intervention, facilitating differentiation between healthy and diseased states, and enabling personalized intervention strategies based on individual health risk profiles [2]. This distinction allows clinicians to identify individuals at subclinical risk who may benefit substantially from timely lifestyle modifications. Individuals with preclinical obesity have preserved organ function, making targeted lifestyle interventions particularly beneficial in preventing progression to clinical disease. Additionally, this stratification aids the strategic allocation of healthcare resources, directing more intensive interventions toward individuals identified as having a higher cardiovascular risk [20].

The relationship between obesity and cardiovascular disease is intricate, and BMI alone is insufficient for accurately evaluating cardiovascular risk at an individual level [21]. Incorporating cardiovascular abnormalities—such as hypertension, heart failure, and atrial fibrillation—into clinical obesity diagnostic criteria allows for more precise identification of individuals already at heightened cardiovascular risk [2]. Obesity contributes to heart failure through mechanisms including hemodynamic overload, metabolic dysfunction, inflammation, and mechanical effects [22]. These mechanisms are particularly significant in heart failure with preserved ejection fraction (HFpEF), where obesity plays a specific pathophysiological role [22]. For example, data from the Framingham Heart Study revealed that a 1-unit increase in BMI elevates heart failure risk by 5% in men and 7% in women [23]. A retrospective US cohort study reported that over 80% of HFpEF patients were overweight or obese, highlighting the strong association between adiposity and HFpEF [24]. Epicardial fat also contributes to cardiovascular pathology through both physical proximity and proinflammatory signaling, as cytokines produced by epicardial adipose tissue negatively impact myocardial function and induce structural remodeling, particularly relevant in HFpEF [25].

Therapeutic interventions targeting obesity, particularly with glucagon-like peptide-1 (GLP-1) receptor agonists, have shown promising cardiovascular benefits. Clinical trials such as STEP-HFpEF (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity) showed that weight reduction with semaglutide significantly improved symptoms and quality of life in patients with HFpEF and obesity [26]. Additional studies confirmed that caloric restriction and exercise training similarly enhance cardiovascular fitness in this patient population [27]. Beyond HFpEF, several large-scale cardiovascular outcome trials have validated significant cardiovascular advantages associated with GLP-1 receptor agonists. The PIONEER 6 (Peptide Innovation for Early Diabetes Treatment 6) trial with oral semaglutide [28] and the SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects With Type 2 Diabetes) trial with injectable semaglutide [29] established cardiovascular safety, with trends toward reduction in major adverse cardiovascular events (MACE). More recent landmark research in the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial demonstrated that semaglutide significantly reduced the risk of MACE by 20% in patients with established cardiovascular disease and overweight or obesity without diabetes [30]. Similarly, the REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes) trial using dulaglutide reported a 12% reduction in MACE among a broad participant group, many of whom lacked established cardiovascular disease [31]. These cardiovascular benefits likely result from multiple mechanisms, including reduced adiposity, improved endothelial function, anti-inflammatory effects, and direct cardiovascular actions [32]. Collectively, this accumulating evidence underscores that addressing clinical obesity pharmacologically, particularly with GLP-1 receptor agonists, can offer substantial cardiovascular protection, representing a paradigm shift in cardiovascular risk reduction strategies in obese patients.

From a treatment perspective, clearly distinguishing between clinical and preclinical obesity helps inform and tailor management goals. Clinical obesity requires active intervention aimed at reversing organ dysfunction and enhancing clinical outcomes, whereas preclinical obesity necessitates preventive strategies to halt or slow disease progression [2]. This clear differentiation enables more efficient resource allocation and targeted interventions for cardiovascular disease prevention.

Managing clinical obesity effectively, especially when cardiovascular manifestations are involved, typically necessitates a multidisciplinary approach incorporating primary care physicians, cardiologists, endocrinologists, dietitians, exercise specialists, and behavioral health professionals. Such a team-based model addresses both physiological and behavioral aspects of obesity, facilitating comprehensive treatment of the multifaceted mechanisms through which obesity influences cardiovascular health.

Traditionally, obesity treatments have predominantly used weight loss as the primary indicator of success. However, the new paradigm emphasizes improvement in organ function and remission of clinical obesity as essential treatment goals [2]. This shift directly prioritizes enhancing cardiovascular health rather than focusing exclusively on weight reduction. Remission of clinical obesity is defined as partial or complete resolution of tissue or organ dysfunction abnormalities evident in clinical and laboratory evaluations. Given that treatment responses may differ based on the specific systems affected (e.g., cardiovascular, metabolic, musculoskeletal), individualized treatment plans are crucial for effectively addressing each patient's unique health profile [2].