Caterina Conte

Obesity stigma remains a pervasive yet insufficiently recognized social and clinical problem that can compromise healthcare engagement and health outcomes. Over the past decade, substantial efforts have promoted person‐first language, respectful representation, and recognition of obesity as a chronic, biologically regulated disease. However, the advent of highly effective obesity pharmacotherapy has made treatment an increasingly prominent target of obesity stigma: People are now blamed not only for having obesity but also for treating it. Although the immediate focus of judgment has evolved, the underlying willpower‐based model persists: Weight loss is often considered legitimate only when achieved through unaided personal effort. Emerging evidence indicates that users of obesity medications may be evaluated less favorably than individuals losing weight through lifestyle intervention, while metabolic–bariatric surgery has long been associated with the “easy way out” narrative. Treatment‐related stigma may also be present among people living with obesity. It could discourage treatment‐seeking and disclosure, influence clinical decision‐making, undermine long‐term treatment persistence, and reinforce therapeutic inertia and inequalities in care. Addressing treatment stigma does not require indiscriminate medicalization but rather individualized, evidence‐based treatment free from moral judgment. Obesity destigmatization must therefore extend beyond recognition of the disease to acceptance of its treatment.

Vitamin D deficiency and insulin resistance frequently coexist, and a growing body of evidence links low vitamin D status to obesity, prediabetes, type 2 diabetes, metabolic syndrome, metabolic dysfunction-associated fatty liver disease, polyendocrine metabolic ovarian syndrome, and cardiovascular risk. Yet causality, mechanisms, and the clinical benefit of supplementation remain debated. This Special Issue brings together eleven original research articles, reviews, and a systematic review exploring the relationship between vitamin D and insulin resistance across diverse populations, including children, pregnant women, and adults with obesity. Contributions examine biological mechanisms linking vitamin D to glucose metabolism and adipose tissue, report on associations observed in clinical cohorts from several countries and critically assess the evidence for vitamin D supplementation as a strategy to improve insulin sensitivity and prevent type 2 diabetes. By gathering this work in one place, the Special Issue offers researchers and clinicians a current, integrated view of an actively evolving field and highlights open questions for future study, particularly the design of supplementation trials capable of establishing causal effects.

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.

The distribution of adipose tissue is a key determinant of obesity‐related disease risk. When the capacity of subcutaneous adipose tissue to safely store energy is exceeded, lipid overflow into visceral depots occurs, increasing free fatty acid flux, promoting insulin resistance, and triggering chronic low‐grade inflammation. More than 80 years ago, the physician Jean Vague recognized the association between android (central) obesity and cardiometabolic disease; subsequent advances from imaging technologies have expanded this framework to include ectopic fat accumulation within non‐adipose organs. Ectopic fat deposition in the liver, pancreas, heart, kidneys, skeletal muscle, and upper airway contributes to organ‐specific dysfunction through mechanisms including lipotoxicity, adipokine dysregulation, oxidative stress, and local inflammatory signaling. This review summarizes the evidence linking visceral and ectopic fat to metabolic dysfunction–associated steatotic liver disease and steatohepatitis, type 2 diabetes, cardiovascular and renal disease, sarcopenic obesity, and obstructive sleep apnea. Importantly, visceral and ectopic fat depots are modifiable. Lifestyle‐induced energy deficit, incretin‐based pharmacotherapy, and metabolic bariatric surgery reduce visceral and ectopic fat and improve glycemic control, liver fat content, cardiovascular risk factors, physical function, and sleep‐disordered breathing. Incorporating ectopic fat characterization into clinical practice may enhance risk stratification and support more personalized management of obesity phenotypes.

Background/Objectives: Clinically meaningful weight loss reduces fat mass but is commonly accompanied by loss of fat-free mass (FFM). Ketogenic diets are of interest because ketone bodies have plausible anabolic and anti-catabolic actions. This narrative review examined whether these mechanisms translate into preservation of lean compartments or skeletal muscle during weight loss in clinical studies. Methods: MEDLINE was searched via PubMed from database inception to 14 August 2026 using terms related to ketogenic exposure, body composition, muscle metabolism, and weight loss. Evidence was synthesised according to dietary context, energy and protein intake, population, exercise exposure, measurement modality, and timing relative to carbohydrate restriction or reintroduction. Results: Acute human studies demonstrate biological effects of ketone bodies on muscle protein turnover and signalling, but these findings do not establish long-term tissue preservation during ketogenic weight-loss diets. Supervised very-low-energy ketogenic diets generally produce weight loss composed predominantly of fat mass; however, comparative meta-analyses report small yet larger reductions in FFM or lean body mass than non-ketogenic regimens. Because most studies used hydration-sensitive compartment methods rather than direct anatomical imaging of skeletal muscle, the contributions of glycogen, water, and non-muscle lean tissues remain uncertain. Energy deficit, protein intake, resistance exercise, baseline adiposity, age, metabolic health, and training status may modify the observed response. Conclusions: Current evidence is insufficient to determine whether ketosis itself has either a protective or harmful effect on contractile skeletal muscle during weight loss. Ketogenic diets may be effective short-term options for selected adults with obesity, particularly within supervised protocols, but adequate protein, resistance exercise, and monitoring of strength and physical function remain the best-supported muscle-preserving strategies.

To examine the role of pharmacologic obesity treatment in people with type 2 diabetes (T2D), with a focus on efficacy, safety, and clinical positioning in the context of T2D-specific metabolic and therapeutic challenges. Contemporary incretin receptor agonists enable clinically meaningful weight loss in people with T2D while improving glycemic control and cardio-renal, hepatic, and functional outcomes, including improvements in physical performance and symptoms in heart failure with preserved ejection fraction (HFpEF). However, weight loss is consistently attenuated compared with obesity without diabetes, reflecting reduced metabolic flexibility (impaired ability to appropriately adjust fuel utilization), background therapies, and social determinants of health rather than treatment failure. Obesity pharmacotherapy should be considered a disease-modifying component of T2D care. Treatment success should be defined by improvements in adiposity-related complications, organ protection, and patient-centered outcomes, not by fixed weight-loss thresholds. A complication-focused, individualized approach is essential to optimize long-term benefit in T2D.

The coexistence of type 2 diabetes (T2D), metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiovascular disease (CVD) defines a clinical profile that is frequently observed in clinical practice. In addition to being highly prevalent, patients with this triad of diseases experience accelerated vascular aging and poor prognosis. Insulin resistance remains the common symptom; however, the systemic impact of this extends far beyond glucose handling, shaping inflammation, oxidative stress, and endothelial dysfunction. In this review, we highlight how these intertwined conditions challenge current diagnostic frameworks and therapeutic approaches. Moreover, we discuss under-recognized aspects, such as the contribution of gut-derived metabolites and adipose dysfunction, which often remain neglected in routine care despite strong mechanistic evidence. We also summarize the potential of noninvasive tools, biomarkers, and cardioprotective agents, such as sodium–glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and tirzepatide. While promising, these agents still face gaps in translation to everyday hepatology and cardiology clinics. Our message is that prevention and care should not be compartmentalized. Instead, an integrated, patient-centered approach, with early screening and multidisciplinary management, is needed to address this complex interplay. Moreover, recognizing the shared pathways of T2D, MASLD, and CVD may help clinicians anticipate potential complications and design more effective and sustainable strategies for long-term outcomes.

BACKGROUND Achieving optimal glycemic control is a cornerstone of cardiovascular risk reduction in type 2 diabetes (T2D). However, the extent to which multifactorial interventions influence this relationship remains uncertain. AIM To evaluate the association between glycated hemoglobin (HbA1c) target achievement and long-term cardiovascular outcomes in patients receiving standard of care (SoC) or multifactorial intensive therapy (MT). METHODS This post-hoc analysis of the nephropathy in diabetes type 2 cluster-randomized trial included 323 patients with T2D, albuminuria, and retinopathy (SoC: n = 139; MT: n = 184), who underwent a 4-year intervention phase. Outcomes were major adverse cardiovascular events (MACE) and all-cause mortality. Associations with HbA1c target achievement (≤ 7% vs > 7%) were assessed using Kaplan-Meier curves and shared frailty Cox regression models. RESULTS During a median follow-up of 12.1 years, 190 MACEs and 139 deaths occurred. Achievement of the HbA1c target was not associated with reduced mortality in either group. However, a significant reduction in MACEs was observed only among SoC patients achieving HbA1c ≤ 7% (P = 0.031), whereas no benefit was seen in the MT group (P = 0.645). In multivariable Cox regression models adjusted for cluster effect, in the MT group age [hazard ratio (HR) = 1.07, P < 0.001] and female sex (HR = 0.38, P < 0.001) were independent predictors of MACE, while in the SoC group only age (HR = 1.04, P = 0.009). For all-cause mortality, age (HR = 1.11, P < 0.001) and blood pressure control (HR = 0.55, P = 0.041) were significant predictors in the MT group, whereas age (HR = 1.06, P = 0.002) was independently associated with increased mortality in the SoC group. CONCLUSION In high-risk patients with T2D receiving standard care, achieving an HbA1c ≤ 7% was associated with fewer cardiovascular events only under standard care, but not with reduced mortality. This association was not observed in patients managed with a multifactorial strategy. These findings suggest that the prognostic value of glycemic control depends on the broader treatment context and highlight the central role of comprehensive risk factor management in microvascular-complicated T2D.