Obesity has reached epidemic proportions globally, with its prevalence nearly tripling since 1975. It is now recognized as a chronic, relapsing disease associated with increased morbidity and mortality due to its strong relationship with several cardio-renal-metabolic conditions. This narrative review aims to explore the major obesity-related complications - namely obstructive sleep apnea syndrome (OSAS), metabolic dysfunction-associated steatotic liver disease (MASLD), dyslipidemia, and chronic kidney disease (CKD) - highlighting their pathophysiological mechanisms, clinical consequences, and current therapeutic strategies. Obesity contributes to OSAS by increasing upper airway collapsibility and to MASLD through ectopic fat accumulation, insulin resistance, and inflammatory responses. Dyslipidemia in obesity is characterized by elevated triglycerides, small dense LDL particles, and low HDL-C, driven by chronic inflammation and insulin resistance. CKD progression, particularly obesity-related glomerulopathy (ORG), is also mediated by metabolic and hemodynamic derangements, including renin-angiotensin-aldosterone system activation and glomerular hyperfiltration. Therapeutic interventions such as lifestyle modification, pharmacological therapy - including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) - and bariatric surgery have shown efficacy not only in promoting weight loss but also in improving the clinical course of these obesity-related conditions. In particular, Very Low Energy Ketogenic Therapy (VLEKT) is emerging as a promising approach in improving metabolic parameters, hepatic steatosis, and cardiovascular risk factors. A comprehensive and multidisciplinary approach to obesity is essential, focusing not only on weight loss but also on mitigating associated complications. Effective management can significantly improve patients' quality of life and reduce the long-term burden of obesity on healthcare systems.
BACKGROUND:Novel therapies targeting apolipoprotein C3 (apoC3) have recently emerged as promising treatment options for hypertriglyceridemia and have been evaluated in phase II and III randomized clinical trials. This study aimed to perform an updated meta-analysis to assess the effects of apoC3 inhibitors on triglyceride and apoC3 concentrations, as well as their impact on the risk of acute pancreatitis. METHODS:We conducted a meta-analysis of randomized, placebo-controlled trials evaluating apoC3-targeting therapies, including antisense oligonucleotides and small interfering RNA. Outcomes of interest included changes in triglyceride and apoC3 levels and the incidence of acute pancreatitis. The analysis was performed in accordance with PRISMA recommendations. RESULTS:Fourteen randomized trials comprising 3,422 participants met the inclusion criteria. Treatment with apoC3 inhibitors resulted in significant reductions in triglyceride levels compared with placebo (mean difference -58.7%; 95% CI -62.3 to -55.1; I2=93.8%). Similarly, apoC3 concentrations were markedly decreased (mean difference -75.3%; 95% CI -80.3 to -70.3; I2=94.7%). In addition, these therapies were associated with a significantly lower risk of acute pancreatitis (odds ratio 0.20; 95% CI 0.10 to 0.40; I2=0%). CONCLUSIONS:ApoC3-targeting therapies significantly reduce triglyceride and apoC3 levels in patients with hypertriglyceridemia and are associated with a reduced incidence of acute pancreatitis, supporting their potential role as an effective therapeutic strategy in this high-risk population.
BACKGROUND:Real-time continuous glucose monitoring (RT-CGM) is widely used in patients with type 1 diabetes (T1D) to improve glycemic control by reducing postprandial glucose peaks and hypoglycemic episodes. In addition, traditional biomarkers such as glycated hemoglobin (HbA1c), glycated albumin, and fructosamine provide retrospective estimates of glucose regulation over varying timeframes. This study aimed to evaluate the correlation between these biomarkers and glycemic metrics obtained from two types of RT-CGM systems: an implantable sensor (Eversense E3) and subcutaneously inserted sensors (Dexcom G6 and Guardian 4). METHODS:We analyzed data from 35 patients with T1D: 13 used the Eversense E3 system, and 22 used Dexcom G6 or Guardian 4. Mean blood glucose (MBG) and time in range (TIR) were assessed at multiple time points and correlated with HbA1c, glycated albumin, and fructosamine levels. RESULTS:In the Eversense group, no significant correlation was observed between CGM-derived metrics and any of the biomarkers. Conversely, in the Dexcom/Guardian group, MBG and TIR demonstrated significant correlations with all biomarkers, showing large effect sizes for HbA1c and fructosamine, and medium for glycated albumin. CONCLUSIONS:These findings suggest that the Dexcom G6 and Guardian 4 systems more reliably reflect established biochemical markers of mid- to long-term glucose control, while Eversense may be less consistent in this regard. This highlights the importance of sensor selection when interpreting CGM data for clinical or research applications in diabetes management.
BACKGROUND:Type 2 diabetes mellitus (T2DM) is frequently associated with cognitive decline in the older population. Although optimal glycemic control is known to be essential for disease management, the impact of hypoglycemic agents on cognitive function remains poorly investigated. METHODS:This retrospective study included 93 geriatric outpatients with T2DM. Hypoglycemic treatments consisted of metformin, sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors, and insulin. Patient evaluations included glycated hemoglobin (HbA1c) measurements, Standardized Mini-Mental State Examination (MMSE), and Mini Nutritional Assessment (MNA). RESULTS:After one year of treatment, patients exhibited a significant reduction in HbA1c levels (from 8.06% [±1.19] to 7.19% [±0.84], P<0.001), improvement of MMSE scores (from 25.87 [±3.09] to 27.47 [±2.9], P<0.001). Regression analysis identified GLP-1RAs as the most effective agent in improving glycemic control (P<0.001) and cognitive function (P=0.016). Treatment with GLP-1RAs was associated with a reduction in MNA scores (P<0.001), though these remained above the malnutrition threshold. CONCLUSIONS:Our findings suggest that improved glycemic control may help slow cognitive decline in older patients with T2DM. Among the drug classes examined, GLP-1RAs showed the largest reductions in HbA1c and were linked to greater MMSE score gains.
BACKGROUND:Male obesity-associated hypogonadism promotes a vicious cycle of sarcopenic obesity and increased cardiometabolic risk. Although tirzepatide is highly effective for weight loss, a subset of "late responders" has been reported, and treatment-induced lean body mass (LBM) depletion remains a significant clinical concern. This pilot study evaluated the efficacy of adding testosterone undecanoate (TRT) to tirzepatide in this specific population. METHODS:We enrolled 10 obese men (age range: 35-44 years; Body Mass Index [BMI] = 35.8±2.1 kg/m2) with functional secondary hypogonadism after ≥3 months of treatment with tirzepatide and <5% total body weight loss (late responders). Patients were then allocated to group A (tirzepatide monotherapy, N.=5) or group B (combined tirzepatide plus testosterone undecanoate 1000 mg/im, N.=5) and re-evaluated after 6 months. DXA-derived body composition, hormonal and metabolic profiles, sexual function (International Index of Erectile Function-5, IIEF-5), and physical activity levels (Global Physical Activity Questionnaire) were evaluated. RESULTS:At 6 months, group B demonstrated significantly greater body weight and fat mass reduction compared to group A (P<0.05). Notably, while group A experienced progressive LBM loss, group B achieved significant LBM recovery (66.1±3.1 kg vs. 63.4±3.0 kg in group A, P<0.01). group B showed restored testosterone levels, leading to superior improvements in insulin sensitivity (HOMA-IR: 2.9±0.6 vs. 3.8±0.7, P<0.01) and sexual health (IIEF-5: 23.2±2.1 vs. 18.0±1.5, P<0.001). Additionally, group B exhibited nearly doubled physical activity levels (P<0.001), suggesting a synergy between hormonal restoration and increased exercise motivation. CONCLUSIONS:Our preliminary findings suggest that adding TRT to tirzepatide in late tirzepatide responders who are hypogonadal may optimize weight loss quality, prevent muscle depletion, and restore sexual and metabolic health. This dual pharmacological approach represents a promising precision medicine strategy for managing complex phenotypes of male obesity-associated hypogonadism.
Survodutide represents an innovative approach to obesity management and metabolic-associated fatty liver disease (MAFLD). These conditions, often closely linked with type 2 diabetes (T2DM) and cardiovascular diseases, demand effective treatment strategies. Survodutide acts by targeting both GLP-1 and glucagon receptors. This new dual agonist offers potential transformative benefits, with early clinical trials showcasing significant weight loss and improvements in metabolic markers. Survodutide's mechanism of action includes appetite regulation, enhanced glucose metabolism, and increased energy expenditure, making it a promising option for those struggling with obesity and related health issues. This review assesses Survodutide's pharmacology, efficacy, and safety in MASH and obesity, while also outlining its broader metabolic and cardiovascular benefits. It compares Survodutide's dual-agonist mechanism and clinical performance with single-target incretin therapies to clarify its potential role in the evolving treatment landscape. While the initial results are promising, the review emphasizes the importance of continued research to fully understand Survodutide's long-term safety and effectiveness. Ongoing trials will provide critical insights into its overall impact, side effects, patient response, and cost considerations. This article highlights Survodutide's potential in the treatment of obesity and metabolic disordersand evaluates its place in therapy for seeking improved outcomes.
Menopause brings a series of endocrine changes that significantly increase the risk of developing metabolic syndrome (MetS), a condition characterized by central obesity, dyslipidemia, hypertension, and insulin resistance. In this context, the gut microbiota has gained relevance as a key modulating factor in the pathophysiology of MetS in postmenopausal women. The decline in estrogen levels affects microbial diversity and composition, promoting a dysbiotic environment marked by the loss of beneficial bacteria, such as Akkermansia muciniphila and Bifidobacterium spp., and an increase in proinflammatory, lipopolysaccharide (LPS)-producing microorganisms, such as Proteobacteria and Escherichia coli. This imbalance leads to increased intestinal permeability and endotoxin translocation, triggering systemic low-grade inflammation associated with various MetS components. Clinical studies have identified correlations between specific microbial taxa, metabolites such as imidazole propionate and phenylacetylglutamine, and clinical markers of metabolic dysfunction. In this scenario, dietary intervention emerges as an effective therapeutic tool. Dietary patterns like the Mediterranean diet - rich in polyphenols, fiber, and monounsaturated fats - have shown beneficial effects on gut microbiota modulation, enhancing short-chain fatty acid production, reducing inflammation, and improving metabolic homeostasis. Likewise, the DASH diet and plant-based dietary patterns have demonstrated potential in the prevention and management of MetS in postmenopausal women. In conclusion, the interaction between gut microbiota, metabolism, and postmenopausal hormonal changes represents a critical axis in the development of MetS. Personalized dietary approaches aimed at restoring eubiosis may offer an effective strategy to improve metabolic health in this vulnerable population.
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the destruction of insulin-producing β-cells in the pancreatic islets, resulting in complete insulin deficiency. The pathogenesis of T1D is multifactorial and includes genetic predisposition and environmental triggers. Recent research has highlighted the role of microRNAs (miRNAs) in regulating immune responses and β-cell function, making them promising biomarkers and therapeutic targets. Our research included published articles focused on MiRNAs are small, non-coding RNA molecules that modulate gene expression post-transcriptionally, influencing processes such as cell proliferation, differentiation and apoptosis. Data was gathered from different sources including different databases. This review examines the biogenesis and function of miRNAs, their involvement in T1D pathogenesis, and their potential role as therapeutic targets. Also addressing the challenges and future directions for miRNA-based therapies. In T1D, miRNAs have been shown to regulate immune-mediated β-cell destruction and inflammatory responses, contributing to disease progression. miR-21, miR-146a, and miR-155 play important roles in modulating immune pathways that influence β-cell survival. Due to their potential for early diagnosis and therapeutic modulation, miRNAs are being explored as non-invasive biomarkers detectable in blood and urine and targets for therapeutic interventions. However, challenges related to the specificity of the miRNA targeting, stability, and delivery systems must be addressed to realize their clinical potential. Nanoparticle-based delivery systems promise to overcome these challenges by increasing the precision of miRNA targeting and improving their stability.
BACKGROUND:Prenatal exposure to dioxin, a known endocrine disruptor, after the Seveso accident of 1976 has been associated with thyroid dysfunction, metabolic syndrome and semen quality reduction. Experimental exposure to dioxin in utero produced epigenetic endocrine modifications associated with reduction of semen quality, while in men epigenetic effects are not known. Our objective was to study, by a case control approach, the long-term epigenetic effects of prenatal dioxin exposure in 38 men whose mothers had been exposed to high doses of dioxin, serum median 52.0 ppt at exposure, and therefore who were exposed in utero, median 24.7 ppt at pregnancy, vs. 41 unexposed men. METHODS:Bisulfite-converted DNA was hybridized onto illumina Infinium Methylation EPIC BeadChip and methylation differences were studied at both individual probe (DMPs) and gene region (DMRs) levels. RESULTS:We identified hypomethylation of the SPAG1 gene region and a slightly hypermethylated region containing genes of the HOXA family associated with thyroid and skeletal development. An elevated level of epigenetic drift was noted in the exposed group potentially contributing to disease risk. Epigenetic age acceleration did not show significant association with in-utero dioxin exposure. Additionally, we found heightened neutrophils and diminished natural killer cells in blood of dioxin exposed men. CONCLUSIONS:These observations are the first in the literature and align with the long-term semen quality reduction and alteration of thyroid homeostasic mechanisms reported in children exposed in utero to dioxin in Seveso. The actual dioxin background serum levels, 1.0-2.0 ppt, are much lower than those associated to these effects.
BACKGROUND:Amiodarone is a source of iodine excess that may persist in the body for long time after its withdrawal. The aim of the present analysis was to evaluate the magnitude and long-term time course of 24-h urinary iodine (UI) excretion in patients on antiarrhythmic therapy with amiodarone. METHODS:24-h UI excretion and thyroid function were evaluated in 67 patients on amiodarone therapy. All patients were clinically and biochemically euthyroid before starting treatment and were followed-up by 6-month measurements of 24-h UI excretion and plasma thyroid hormones levels. RESULTS:Upon amiodarone withdrawal, normal range of UI was achieved after a mean time of 15.2±7.7 months. Since amiodarone initiation, 20 patients developed thyroid dysfunction. No differences were observed in terms of treatment length or median UI levels between patients remaining euthyroid and those developing thyroid dysfunction: median UI in the euthyroid group was 8094 µg/24 h (Interquartile Range [IQR]: 4082-10766) vs. 10851 µg/24 h (IQR: 8529-12804) in the thyroid dysfunction group at 6 months (P=0.176) and 8651 µg/24 h (IQR: 6924-11574) vs. 8551 µg/24 h (IQR: 4916-13580) at one year from amiodarone initiation (P=0.886). The occurrence of thyroid dysfunction was equally distributed among patients taking amiodarone for more than one year versus those under treatment for less than one year. CONCLUSIONS:These results confirm the long-lasting total-body iodine stores and consequent excretion in patients after amiodarone withdrawal. These long-lasting iodine stores might be taken into special account in patients necessitating therapy with radioactive iodine and for long-term monitoring of thyroid function after amiodarone discontinuation.
Insulin resistance (IR) is a condition where insulin-targeted tissues (muscle, liver, and adipose tissue) fail to normally respond to insulin action, leading to impaired insulin signaling and hyperglycemia. It is common in individuals with obesity and diagnosed with type 2 diabetes mellitus (T2DM), with the most prevalent disorders being polycystic ovarian syndrome and coronary artery disease. IR is also associated with cardiovascular risk factors such as hypertension and dyslipidemia. Current methods for detecting and measuring insulin sensitivity include the oral glucose tolerance test, insulin tolerance test, hyperinsulinemic-euglycemic clamp. Therapies for treating and preventing IR includes physical activity, diet modifications, and medications like Glucagon-like peptide-1 receptor agonists, gliclazide and metformin. This review aims at deciphering the molecular mechanisms and factors contributing to IR, potential clinical practices for measuring IR, medications for treating T2DM and the physical activity and dietary measures for controlling IR.
Currently, worldwide millions of individuals, athletes, and non-athletes, of different ages and probably of all social genders (cisgender males and females, male to female (MtF) and female to male (FtM) transgenders, etc.), are current or former androgenic anabolic steroids (AAS) abusers. AAS abuse is associated with seriously increased short- and long-term risks for general, reproductive and sexual health. Indeed, to improve the knowledge and health of the population at risk of AAS misuse and standardize the current clinical practice concerning the health risks of such abuse, it is essential to also prevent, detect, diagnose, and treat all reproductive and sexual sequelae of non-therapeutic AAS assumption. The main AAS-related pathways and factors influencing reproduction and sexuality in humans, the possible reproductive and sexual signs and symptoms associated with AAS abuse and to AAS withdrawal, and the major concerns in the diagnosis and management of such clinical conditions are reported. The scientific literature has mainly evaluated male AAS abusers, but, we tried to describe/hypothesize all the possible reproductive and sexual side effects and concerns of AAS abuse also in other genders.
BACKGROUND:Papillary thyroid carcinoma (PTC) has classically been considered a sporadic carcinoma. However, a subgroup with familial clustering has been observed, which appears to present a poorer prognosis than the sporadic form. The aim of this study is to analyze the recurrence rates and prognostic factors for familial PTC (FPTC) treated with curative intent. METHODS:Multicenter national study, endorsed by the Spanish Association of Surgeons. Study population: patients with FPTC (families who have at least 2 first-degree relatives with a confirmed PTC) who meet cure criteria after the treatment. Study endpoints: recurrence rate and risk factors for recurrence. Statistical analysis: Cox regression analysis and survival analysis. RESULTS:The study included 252 cases with a mean follow-up of 90±68,9 months, recurrence in 26.9% (N.=68) and a disease-free survival of 183,46±7,8 months. In the multivariate analysis, the independent factors for the risk of recurrence were: 1) the number of patients with FPTC in the family (OR 1.165); 2) the multifocality (OR 2.525); 3) the vascular invasion (OR 2.770); and 4) TNM staging system (OR 5.128). In the reanalysis that included the American Thyroid Association (ATA) risk of recurrence, this variable was highly predictive of recurrence (OR 12.048). CONCLUSIONS:FPTC presents a high recurrence rate, which is related to the number of cases of FPTC in the family, the presence of multifocality and vascular invasion, the TNM staging system and the ATA recurrence risk assessment.
BACKGROUND:Treatment of type 2 diabetes mellitus (T2DM) relies on diverse glucose-lowering medications, championing sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists as viable options to address concurrent cardiovascular risk. An oral formulation of semaglutide (Rybelsus®, Novo Nordisk) has been recently introduced to clinical use for managing T2DM. Accordingly, there is a paucity of practice evidence while building experience on its combination with SGLT2i. METHODS:In this observational, single-arm, retrospective study, data collected from 142 T2DM patients (66% males, 68% older than 60 years, 85% overweight/obese) treated with oral semaglutide in combination with SGLT2i were analyzed. RESULTS:After 6.8±2.6 months of treatment, both glycosylated hemoglobin (HbA1c) and fasting plasma glucose levels significantly improved: 39.6% of patients achieved HbA1cDCCT ≤7% (HbA1cIFCC ≤53.0 mmol/mol) and 18.8% experienced both a decrease of HbA1c ≥1% and a weight loss ≥5%. In addition, body weight, body mass index, waist circumference, triglycerides, and total cholesterol levels were significantly reduced. Regarding safety, 94.7% of reported adverse events were non-serious gastrointestinal symptoms and 1 patient experienced hypoglycemia. CONCLUSIONS:The herein presented real-world data suggest that oral semaglutide can be regarded as safe and effective, when used as add-on medication for uncontrolled T2DM on background SGLT2i.
BACKGROUND:Serum uric acid (UA), the end product of purine metabolism, has been implicated in metabolic and cardiovascular diseases. While obesity, particularly visceral fat accumulation, is related with hyperuricemia, limited studies have explored the association between serum UA levels and the visceral-to-subcutaneous fat ratio as a novel marker of cardiometabolic risk. This study investigates the relationship between serum UA levels and abdominal fat distribution, focusing on the visceral-to-subcutaneous fat ratio in Korean men. METHODS:This retrospective, cross-sectional study analyzed 5114 male participants who underwent serum UA measurement and abdominopelvic computed tomography (CT) as part of health examinations from 2014 to 2019. Visceral and subcutaneous fat areas were quantified using CT imaging, and the visceral-to-subcutaneous fat ratio was calculated. Participants were stratified into quartiles based on serum UA levels. Univariate and multivariate analyses were performed to assess the association between serum UA levels and abdominal fat area and visceral fat/subcutaneous fat ratio were evaluated using univariate and multivariate analyses. RESULTS:Higher serum UA levels were significantly associated with increased visceral fat area, subcutaneous fat area, and visceral-to-subcutaneous fat ratio in both univariate and multivariate analyses. Participants in the highest UA quartile demonstrated the greatest visceral fat accumulation and the highest visceral-to-subcutaneous fat ratios. Multivariate analyses revealed that the association between serum UA and the visceral-to-subcutaneous fat ratio remained significant after adjusting for covariates. CONCLUSIONS:This study demonstrated a positive correlation between serum UA levels and both visceral fat area and subcutaneous fat areas in Korean men. Furthermore, higher serum UA levels were positively correlated with the visceral-to-subcutaneous fat ratio, offering insights into its potential contribution to elevated cardiometabolic and cardiovascular risk.
Premature ovarian insufficiency (POI) is a critical condition affecting young women before the median age of menopause and consisting of spontaneous oligo-amenorrhea for at least four months associated with follicle stimulating hormone (FSH) levels ≥25 UI/L detected before 40 years of age. Several causes like genetic abnormalities, autoimmune diseases, drugs and/or pelvic surgery may favor this condition that is associated with a deeper clinical impact on women's health compared to physiological menopause. Specifically, cardiovascular and musculoskeletal systems as well as brain could be especially affected by the early loss of ovarian hormones. Therefore, appropriate treatment is necessary to adequately narrow the biological gap with the average age of menopause. Hormone replacement therapy (HRT) is the treatment of choice, regardless of the presence of neurovegetative symptoms. Transdermal high dosage of natural estradiol is generally preferred to guarantee the preservation of cardio-metabolic and bone health. When contraception is required, oral estroprogestins (EPs) maybe considered. A referral to reproductive experts for fertility preservation techniques should be considered case by case.
