Rethinking weight loss treatments as cardiovascular medicine in obesity, a comprehensive review.

The global escalation of obesity has made it a worldwide health concern, notably as a leading risk factor for cardiovascular disease (CVD). Extensive evidence corroborates its association with a range of cardiac complications, including coronary artery disease, heart failure, and heightened vulnerability to sudden cardiac events. Additionally, obesity contributes to the emergence of other cardiovascular risk factors including dyslipidaemia, type 2 diabetes, hypertension, and sleep disorders, further amplifying the predisposition to CVD. To adequately address CVD in patients with obesity, it is crucial to first understand the pathophysiology underlying this link. We herein explore these intricate mechanisms, including adipose tissue dysfunction, chronic inflammation, immune system dysregulation, and alterations in the gut microbiome.Recent guidelines from the European Society of Cardiology underscore the pivotal role of diagnosing and treating obesity to prevent CVD. However, the intricate relationship between obesity and CVD poses significant challenges in clinical practice: the presence of obesity can impede accurate CVD diagnosis while optimizing the effectiveness of pharmacological treatments or cardiac procedures requires meticulous adjustment, and it is crucial that cardiologists acknowledge the implications of excessive weight while striving to enhance outcomes for the vulnerable population affected by obesity. We, therefore, sought to overcome controversial aspects in the clinical management of heart disease in patients with overweight/obesity and present evidence on cardiometabolic outcomes associated with currently available weight management interventions, with the objective of equipping clinicians with an evidence-based approach to recognize and address CVD risks associated with obesity.

Immune checkpoint modulators in early clinical development for the treatment of type 1 diabetes.

INTRODUCTION: Despite the improvements of insulin therapy, people with type 1 diabetes (T1D) still suffer from a decreased quality of life and life expectancy. The search toward a cure for T1D is therefore still a scorching open field of research. AREAS COVERED: Tackling the immune checkpoint signaling pathways has gained importance in the field of cancer immunotherapy. The same pathways can be targeted in autoimmunity with an opposite principle: to dampen the exaggerated immune response. In this review, we report a comprehensive excursus on the cellular and molecular mechanisms that lead to loss of immunological tolerance, and recent evidence on the role of immune checkpoint molecules in the development of T1D and their potential application for the mitigation of autoimmune diabetes. EXPERT OPINION: Contrasting results about the efficacy of immune checkpoint modulators for T1D have been published, with very few molecules from preclinical studies eligible for use in humans. The heterogeneous and complex pathophysiology of T1D may explain the conflicting evidence. Designing clinical trials that acknowledge the pathophysiological and clinical complexity of T1D and that forecast the need of simultaneously tackling different disease pathways will be crucial to enhance the benefits which may be gained by such compounds.

Usefulness of Color Doppler Ultrasonography in the Risk Stratification of Thyroid Nodules.

INTRODUCTION: Thyroid ultrasound (US) is crucial for clinical decision in the management of thyroid nodules. In this cross-sectional study, we aimed to test if the evaluation of thyroid nodules' vascularization could improve the risk stratification ability of the American College of Radiology (ACR) TI-RADS classification system. METHODS: A total of 873 thyroid nodules undergoing fine-needle aspiration were classified according to ACR TI-RADS US classification. Three types of vascularization were identified: type 0, no vascular signals; type 1, peripheral vascular signals; type 2, peripheral and intralesional vascular signals. Cytology specimens were evaluated conforming to the Italian Reporting System for Thyroid Cytology, and TIR3b, TIR4, and TIR5 were defined as high risk for malignancy. Odds ratios (ORs) with 95% confidence intervals (CI) and the areas under the receiver operating characteristic curves (ROC-AUC) for high-risk cytology categories were calculated. RESULTS: The 3 vascular patterns were differently distributed within the cytology categories: 52.4% of TIR1c, 15.9% of TIR2, 5.9% of TIR3a, 6.7% of TIR3b, 12.5% of TIR4, and 28.9% of TIR5 nodules had no vascular signals (p < 0.001). Nodule vascularity alone was not associated with a higher risk of malignant cytology (OR [95% CI] 0.75 [0.43-1.32], p = 0.32), without differences between peripheral (OR [95% CI] 0.65 [0.35-1.20]) and intranodular (OR [95% CI] 0.88 [0.48-1.62]) vascularization (p = 0.22). The ROC-AUC (95% CI) for the diagnosis of malignant cytology was similar when considering TI-RADS classification alone (0.736 [0.684-0.786]) and when considering TI-RADS classification plus the presence/absence of vascular signals (0.736 [0.683-0.789], p value for differences between the ROC-AUCs: 0.91). Among TR1, TR2, and TR3 TI-RADS classes, no nodules without vascular signals showed a malignant cytology, allowing the identification of nodules with benign cytology with 100% specificity within these US classes. CONCLUSIONS: Color Doppler study of thyroid nodules does not improve the risk stratification ability of the ACR TI-RADS US classification system.

Association of bone biomarkers with advanced atherosclerotic disease in people with overweight/obesity.

BACKGROUND: A growing body of evidence suggests a potential link between bone metabolism and cardiovascular disease. Aim of this study was to investigate the relationship between levels of circulating bone turnover biomarkers and advanced atherosclerosis. METHODS: Klotho (KL), sclerostin (SOST), osteopontin (OPN) and osteoprotegerin (OPG) were measured in patients undergoing elective coronary angiography and carotid Doppler ultrasound. The primary outcome was the difference in bone biomarkers levels between participants with and without advanced atherosclerosis, defined as the presence of a critical coronary (≥70%) and/or carotid (≥50%) stenosis. RESULTS: A total of 80 subjects (32.5% females) with a mean age of 68 ± 10 years were included. Advanced atherosclerosis was detected in 55 (68.8%) patients. Subjects with advanced atherosclerosis showed higher serum levels of OPG (p = 0.0015) and SOST (p = 0.017) and similar levels of KL (p = 0.62) and OPN (p = 0.06) compared to patients without. After adjustment for age and sex, only elevated levels of OPG remained significantly associated with advanced atherosclerosis (p = 0.011). CONCLUSIONS: Higher serum levels of OPG are independently associated with advanced atherosclerosis confirming a common bond between bone metabolism and vascular disease. Further investigations on the role of selected bone biomarkers in the pathogenesis of cardiovascular disease are needed.

Use of DPP4 inhibitors in Italy does not correlate with diabetes prevalence among COVID-19 deaths.

In a nationwide study of 3818 charts from patients with fatal COVID-19, we found that geographical differences in Dipeptidyl peptidase 4 (DPP4) inhibitors use did not correlate with diabetes prevalence among COVID-19 deaths, thus not supporting the hypothesis of a clinically relevant involvement of DPP4 inhibition in COVID-19 development and progression.

Risk of cardiac autonomic neuropathy in latent autoimmune diabetes in adults is similar to type 1 diabetes and lower compared to type 2 diabetes: A cross-sectional study.

AIMS: Microvascular complications' risk differs between people with latent autoimmune diabetes in adults (LADA) and people with type 2 diabetes. We aimed to investigate whether the prevalence of cardiac autonomic neuropathy, a life-threatening complication of diabetes, also varies depending on diabetes type. METHODS: In this cross-sectional study, 43 adults with LADA, 80 with type 1 diabetes and 61 with type 2 diabetes were screened for cardiac autonomic neuropathy with recommended tests. Logistic regression models were used to test differences between diabetes types adjusting for confounders. RESULTS: Cardiac autonomic neuropathy was diagnosed in 17 (40%) participants with LADA, 21 (26%) participants with type 1 diabetes and 39 (64%) participants with type 2 diabetes (p < 0.001). The odds ratio (OR) for cardiac autonomic neuropathy in type 1 diabetes and in type 2 diabetes compared to LADA were 0.54 (95% CI: 0.25-1.20, p-value: 0.13) and 2.71 (95% CI: 1.21-6.06, p-value 0.015) respectively. Smoking (adj OR 3.09, 95% CI: 1.40-6.82, p-value: 0.005), HDL cholesterol (adj OR 0.29, 95% CI: 0.09-0.93, p-value: 0.037) and hypertension (adj OR 2.11, 95% CI: 1.05-4.24, p-value: 0.037) were independent modifiable risk factors for cardiac autonomic neuropathy. Differences among diabetes types did not change after correction for confounders. CONCLUSIONS: This is the first study offering a comparative evaluation of cardiac autonomic neuropathy among LADA, type 1 and type 2 diabetes, showing a lower risk of cardiac autonomic neuropathy in LADA compared to type 2 diabetes and similar compared to type 1 diabetes. This disparity was not due to differences in age, metabolic control or cardiovascular risk factors.

Lifestyle Management of Diabetes: Implications for the Bone-Vascular Axis.

PURPOSE OF REVIEW: To describe the main pathways involved in the interplay between bone and cardiovascular disease and to highlight the possible impact of physical activity and medical nutrition therapy on the bone-vascular axis. RECENT FINDINGS: Diabetes increases the risk of both cardiovascular disease and bone fragility fractures, sharing common pathogenic pathways, including OPG/RANK/RANKL, the FGF23/Klotho axis, calciotropic hormones, and circulating osteogenic cells. This may offer new therapeutic targets for future treatment strategies. As lifestyle intervention is the cornerstone of diabetes treatment, there is potential for an impact on the bone-vascular axis. Evidence published suggests the bone-vascular axis encompasses key pathways for cardiovascular disease. This, along with studies showing physical activity plays a crucial role in the prevention of both bone fragility and cardiovascular disease, suggests that lifestyle intervention incorporating exercise and diet may be helpful in managing skeletal health decline in diabetes. Studies investigating the controversial role of high-fiber diet and dietary vitamin D/calcium on bone and cardiovascular health suggest an overall benefit, but further investigations are needed in this regard.

Exogenous Insulin Infusion Can Decrease Atherosclerosis in Diabetic Rodents by Improving Lipids, Inflammation, and Endothelial Function.

OBJECTIVE: The objective of this study is to evaluate whether exogenously induced hyperinsulinemia may increase the development of atherosclerosis. APPROACH AND RESULTS: Hyperinsulinemia, induced by exogenous insulin implantation in high-fat fed (60% fat HFD) apolipoprotein E-deficient mice (ApoE-/-) mice, exhibited insulin resistance, hyperglycemia, and hyperinsulinemia. Atherosclerosis was measured by the accumulation of fat, macrophage, and extracellular matrix in the aorta. After 8 weeks on HFD, ApoE-/- mice were subcutaneously implanted with control (sham) or insulin pellet, and phlorizin, a sodium glucose cotransporters inhibitor (1/2)inhibitor, for additional 8 weeks. Intraperitoneal glucose tolerance test showed that plasma glucose levels were lower and insulin and IGF-1 (insulin-like growth factor-1) levels were 5.3- and 3.3-fold higher, respectively, in insulin-implanted compared with sham-treated ApoE-/- mice. Plasma triglyceride, cholesterol, and lipoprotein levels were decreased in mice with insulin implant, in parallel with increased lipoprotein lipase activities. Atherosclerotic plaque by en face and complexity staining showed significant reductions of fat deposits and expressions of vascular adhesion molecule-1, tumor necrosis factor-α, interleukin 6, and macrophages in arterial wall while exhibiting increased activation of pAKT and endothelial nitric oxide synthase (P<0.05) comparing insulin-implanted versus sham HFD ApoE-/- mice. No differences were observed in atherosclerotic plaques between phlorizin-treated and sham HFD ApoE-/- mice, except phlorizin significantly lowered plasma glucose and glycated hemoglobin levels while increased glucosuria. Endothelial function was improved only by insulin treatment through endothelial nitric oxide synthase/nitric oxide activations and reduced proinflammatory (M1) and increased anti-inflammatory (M2) macrophages, which were inhibited by endothelial nitric oxide synthase inhibitor. CONCLUSIONS: Exogenous insulin decreased atherosclerosis by lowering inflammatory cytokines, macrophages, and plasma lipids in HFD-induced hyperlipidemia, insulin resistant and mildly diabetic ApoE-/- mice.

Severe hypophosphatemic osteomalacia secondary to fanconi syndrome due to adefovir: a case report.

OBJECTIVE: Generalized proximal, type 2, renal tubular acidosis, also known as Fanconi syndrome, is a generalized dysfunction of the proximal renal tubule characterized by impaired reabsorption and increased urinary loss of phosphate and other solutes, such as uric acid, glucose, amino acids, and bicarbonate. Chronic hypophosphatemia is the second most common cause of osteomalacia after vitamin D deficiency in adult patients and can have a heterogeneous presentation, ranging from mild symptoms such as muscle weakness and skeletal pain to more severe presentation, such as disabling myopathy, severe bone and joint pain, difficulty walking, and even bone fractures. METHODS: This report describes a case of severe hypophosphatemic osteomalacia with multiple fragility fractures induced by adefovir, which was worsened and confounded by a previous treatment with zoledronic acid and required prolonged intravenous potassium phosphate administration. RESULTS: We highlight the limited diagnostic value of dual X-ray absorptiometry and bone scintigraphy in this challenging diagnosis. Bone metabolism should always be assessed in patients treated with adefovir for early detection of osteomalacia due to Fanconi syndrome. CONCLUSION: Although rare, this condition may be life-threatening and mimic other bone metabolic disorders that are treated with drugs that may further impair phosphate balance.