Search Results (86)

Spurred by the enormous therapeutic success of glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP1-RAs) against diabetes and obesity, glucagon family receptor pharmacology has garnered a tremendous amount of interest. Glucagon family receptors, e.g., the glucagon receptor itself (GCGR), the GLP-1R, and the glucose-dependent insulinotropic peptide receptor (GIPR), belong to the incretin receptor superfamily, i.e., receptors that increase blood glucose-dependent insulin secretion. All incretin receptors are class B1 G protein-coupled receptors (GPCRs), coupling to the G_s type of heterotrimeric G proteins which activates adenylyl cyclase (AC) to produce cyclic adenosine monophosphate (cAMP). Most GPCRs undergo desensitization, i.e., uncouple from G proteins and internalize, thanks to interactions with the βarrestins (arrestin-2 and -3). Since the βarrestins can also mediate their own G protein-independent signaling, any given GPCR can theoretically signal (predominantly) either via G proteins or βarrestins, i.e., be a G protein- or βarrestin-“biased” receptor, depending on the bound ligand. A plethora of experimental evidence suggests that the GLP-1R does not undergo desensitization in physiologically relevant tissues in vivo, but rather, it produces robust and prolonged cAMP signals. A particular property of constant cycling between the cell membrane and caveolae/lipid rafts of the GLP-1R may underlie its lack of desensitization. In contrast, GIPR signaling is extensively mediated by βarrestins and the GIPR undergoes significant desensitization, internalization, and downregulation, which may explain why both agonists and antagonists of the GIPR exert the same physiological effects. Here, we discuss this evidence and make a case for the GLP-1R being a phenotypically or functionally G_s-selective receptor. We also discuss the implications of this for the development of GLP-1R poly-ligands, which are increasingly pursued for the treatment of obesity and other diseases. Full article

Background: Sport plays an important role in the health promotion of people with cerebral palsy (CP). However, risk factors may impair sport performance and health in non-ambulatory athletes. Therefore, the aim of the present study was to explore body composition and bone health in a group of world-class Boccia players with CP. Methods: Five BC2-class players with CP, aged 15–42 years old, were assessed using Dual-Energy X-Ray Absorptiometry (DXA) for body composition and bone mineral density (BMD) and content (BMC). The fat mass index (kg/m²) was used to define obesity, and the BMD Z-score used to analyze bone health. A preliminary indicator of sarcopenia was considered using the appendicular lean mass index. Results: Players 1 and 3 exhibited similar body compositions (obesity class 1 and BMD Z-score are below the expected range for age). Player 5 exhibited multiple health-related risk factors. The results regarding youth players (Player 2 and Player 4) should be analyzed with caution. Conclusions: Overall, due to Boccia’s specific characteristics, players may benefit from close monitoring by multidisciplinary teams and supplementary strategies (e.g., strength training, individualized diet plans) to promote quality of life and performance. However, further research is needed to confirm the data, since these preliminary findings do not allow for broader generalizations. Full article

Background: Obesity is a growing global health concern associated with numerous comorbidities and high medication burden. This study aimed to evaluate the impact of low- and very-low-calorie diets (LCD/VLCD), combined with intensive lifestyle changes, on comorbidities and medication use in hospitalized patients with class II and III obesity. Methods: A retrospective cohort study was conducted using medical records of patients hospitalized for 3–6 months at a specialized obesity hospital in Brazil. Prescription data for antihypertensive, hypoglycemic, and lipid-lowering drugs were compared at admission, 3, and 6 months. Descriptive statistics, chi-squared tests, and t-tests were used to compare medication use and weight change over time. Results: Among 246 patients, the proportion of those using antihypertensives decreased from 74.4% at admission to 44.7% at 6 months (p < 0.02), with significant reductions also observed at 3 months (p < 0.001). Hypoglycemic prescriptions also declined at 3 months (p = 0.01), but not significantly at 6 months. Lipid-lowering medication use showed no significant changes. Average weight loss was 11% at 3 months and 21.3% at 6 months. Conclusions: Hospitalization with LCD/VLCD and lifestyle therapy was associated with a short-term reduction in medication burden, especially antihypertensives, supporting the potential of inpatient multidisciplinary strategies for severe obesity management. Full article

This study aims to explore how cancer-related risk factors cluster among college students in Guam. Using the 2021–2022 Pacific Islands Cohort of College Students data, we conducted a latent class analysis (LCA) to organize the sample into classes based on clustering cancer risk factors, including tobacco use, binge drinking, low fruit/vegetable intake, physical inactivity, betel nut use, overweight/obesity, depression, and anxiety. Among the 577 college students surveyed, results show a high prevalence of low fruit/vegetable intake, overweight/obesity, depression, and anxiety. The LCA identified three classes, each defined by different clustering cancer risk behaviors. All classes showed high prevalence of low fruit/vegetable intake. Class 1 had the highest rates of tobacco use, betel nut use, and binge drinking. Class 2 had the highest rates of physical inactivity, depression, and anxiety. Class 3 had the lowest rates of betel nut use, overweight/obese, depression, and anxiety when compared with Classes 1 and 2. The clustering of risk behaviors highlights the need for targeted interventions and prevention strategies among Guam’s youth, aiming to address these behaviors and potentially reduce cancer risk in the region. Full article

Inflammation has been widely recognized as one of the major pathophysiological drivers of the development of atrial fibrillation (AF), which works in tandem with other risk factors of AF including obesity, diabetes, hypertension, and heart failure (HF). Our current understanding of the role of inflammation in the natural history of AF remains elusive; however, several key players, including the NLRP3 (NLR family pyrin domain containing 3) inflammasome, have been acknowledged to be heavily influential on chronic inflammation in the atrial myocardium, which leads to fibrosis and eventual degradation of its electrical function. Nevertheless, our current methods of pharmacological modalities with reported immunomodulatory properties, including well-established classes of drugs e.g., drugs targeting the renin–angiotensin–aldosterone system (RAAS), statins, and vitamin D, have proven effective in reducing the overall risk of developing AF, the onset of postoperative atrial fibrillation (POAF), and reducing overall mortality among patients with AF. This might bring hope for further progress in developing new treatment modalities targeting cellular checkpoints of the NLRP3 inflammasome pathway, or revisiting other well-known anti-inflammatory drugs e.g., colchicine, vitamin C, nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticosteroids, and antimalarial drugs. In our review, we aim to find relevant upstream anti-inflammatory treatment methods for the management of AF and present the most current real-world evidence of their clinical utility. Full article

Pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (PH-HFpEF) represents a frequent form of PH related to left ventricular dysfunction. The pathophysiology of PH-HFpEF is intricate, and varied and includes vascular, cardiac, and pulmonary factors that contribute synergistically to developing this clinical syndrome. Improved knowledge of the pathophysiology of PH-HFpEF has paved the way for the use of new drugs such as angiotensin receptor neprilysin inhibitors (ARNIs), non-steroidal mineral corticoid receptor antagonist (nsMRA), sodium-glucose cotransporter inhibitors (SGLT2is), levosimendan, and glucagon-like peptide 1 (GLP-1) agonists. ARNIs are a widely used drug for the treatment of PH associated with heart failure with reduced ejection fraction. They have also recently been used in PH-HFpEF patients with hemodynamic benefits that need to be confirmed in future research. Finerenone is an innovative non-steroidal mineralocorticoid receptor antagonist that exhibits notable cardioprotective and renoprotective properties in individuals suffering from chronic diabetic kidney disease. It also enhances outcomes for patients with heart failure, whether they have mildly reduced or preserved ejection fraction. Moreover, in experimental studies, finerenone has been found to lower pulmonary artery pressure, reduce muscularization, and decrease the wall thickness of pulmonary arteries. SGLT2i have revolutionized the treatment of patients with heart failure irrespective of left ventricular ejection fraction, and their treatment is also associated with an improvement in the hemodynamics profile in patients with PH-HFpEF. Levosimendan is a widely used inodilator in the treatment of acute and advanced heart failure. In addition, its use in patients with PH-HFpEF (supported by the positive effects on pulmonary hemodynamics that levosimendan exerts) has recently demonstrated hemodynamic benefit in a small phase 2 study that paved the way for phase 3 studies and the creation of an oral formulation of levosimendan. Finally, GLP1 agonists are a class of drugs that, in preliminary evidence, have shown a positive effect on cardiac hemodynamics, mainly by facilitating left ventricular unloading. These effects, along with the reduction in insulin resistance and weight loss, likely lead to beneficial outcomes for PH-HFpEF patients, especially those with obesity as a comorbidity. Full article

Background: Atrial fibrillation (AF) is prevalent among obese patients, and cryoballoon ablation (CBA) is an effective strategy for the rhythm control of AF. The impact of body mass index (BMI) on the clinical outcomes of CBA for AF is not fully explored. Methods: 85 consecutive patients with paroxysmal AF were enrolled and were categorized into three groups as per their BMI: normal weight (BMI 18.5–25 kg/m²), overweight (BMI 25–30 kg/m²), and obese patients (BMI > 30 kg/m²). The primary study endpoint was a late (12 month) recurrence of AF. Early recurrence of AF, symptom improvement, and procedural outcomes were some key secondary outcomes. Results: 20 patients had normal weight, 35 were overweight, and 30 were obese. Obese patients featured a higher prevalence of diabetes mellitus, heavier exposure to smoking, and worse baseline symptoms (as assessed through EHRA class at admission and 12 months before CBA) compared to overweight and normal weight patients. Both late and early (<3 months) AF recurrence rates were comparable across the three groups. Of note, obese patients showed greater improvement in their symptoms post-CBA, defined as improvement by at least one EHRA class, compared to normal weight patients; this might be explained by improved diastolic function. Total procedure time and dose area product were significantly increased in obese patients. The multivariate logistic regression analysis indicated that early AF recurrence and the duration of hypertension are independent predictors of late AF recurrence. Conclusion: CBA is effective in overweight and obese patients with paroxysmal AF. Procedure time and radiation exposure are increased in obese patients undergoing CBA. Full article

Introduction: Studies have compared the group-averages of liver stiffness measures (LSMs) from multiple rib spaces by vibration-controlled transient elastography (VCTE) to stage liver fibrosis. No previous study has assessed within-individual liver stiffness variation from two rib spaces in individuals with metabolic-dysfunction associated steatotic liver disease (MASLD). Methods: We evaluated within-individual LSM variation according to body weight classification and its clinical implication. From October 2019 to March 2024, VCTE was performed on MASLD patients or those at high risk, in accordance with FibroScan guidelines. The LSMs were categorized into stages: <5 kPa (stage 0), 5–7.99 kPa (stage 1), 8–9.99 kPa (stage 2), 10–13.99 kPa (stage 3), and 14+ kPa (stage 4). Measurements with 10 values and IQR/median ≤ 0.30 were included, using SPSS V25.0 for analysis. Results: Among 1107 subjects (age 54.4 ± 13.9 years, 56.9% female), 7.7% were normal weight, 20.7% overweight, 28.9% class 1 obesity, 21.3% class 2 obesity, and 21.2% class 3 obesity. Significant within-individual variation was noted: 67% (0–2 kPa) variation, 23.4% (2.1–6 kPa), and 10% (≥6.1 kPa). Class 3 obese individuals had the maximum variation. Comparing the group-average of LSM at each ICS site showed that 95% of individuals were within one fibrosis stage. Conclusions: While LSM group-averages at different rib sites provides reliable fibrosis staging, significant within-individual variability exists especially in class 3 obesity. This should be considered when serial LSM assessments are used to assess medical therapeutic efficacy. Full article

Background and Objectives: Heart failure (HF) is one of the most common initial presentations of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM). There are different cardiac biomarkers related to the pathophysiological mechanisms of HF in T2DM. The current research aims to identify additional biomarkers that could improve the diagnosis and prognosis of HFpEF, which is currently assessed using NT pro-BNP levels. NT pro-BNP is a valuable tool for diagnosing heart failure but may not always correlate with clinical symptom severity or can present normal levels in certain cases, such as obesity. Biomarkers like FGF-21 and galectin-3 could provide greater insight into heart failure severity, especially in diabetic patients. The main objective of the current study is to assess the performance of NT-proBNP, FGF21, Galectin-3 and Copeptin to discriminate between advanced and mild HF. Materials and Methods: A total of 117 patients were enrolled in this study and divided into two groups: 67 patients in NYHA functional class I-II (mild HF) and 50 patients in NYHA III-IV (advanced HF). NT-pro BNP, FGF21, Galectin 3 and Copeptin serum levels were determined with the ELISA method. Receiver operating characteristic (ROC) analysis and binomial logistic regression analysis were used to measure the ability of the studied biomarkers to distinguish between advanced and mild HF patients. Results: In patients with T2DM with advanced HF, serum FGF21 level was significantly positively correlated with eGFR (ρ = 0.35, p = 0.0125) and triglycerides (ρ = 0.28, p = 0.0465) and significantly negatively correlated with serum levels of HDL cholesterol (ρ = −0.29, p = 0.0386) and with RV-RA gradient (ρ = −0.30, p = 0.0358). In patients with mild HF, serum FGF21 level was significantly negatively correlated with NT-proBNP levels (ρ = −0.37, p = 0.0022), E/e’ ratio (ρ = −0.29, p = 0.0182), TR velocity (ρ = −0.24, p = 0.0470) and RV-RA gradient (ρ = −0.24, p = 0.0472). FGF21 (AUC = 0.70, 95% CI: 0.60−0.79) and NT-proBNP (AUC = 0.73, 95% CI: 0.63–0.82) demonstrated significant predictive value to discriminate T2DM patients with advanced HF from those with mild HF. Elevated values for FGF21 (≥377.50 ng/mL) or NTproBNP (≥2379 pg/mL) were significantly associated with increased odds of advanced HF after adjusting for demographic and clinical covariates. Conclusions: NTpro-BNP and FGF21 have a similar ability to discriminate T2DM patients with advanced HF from those with mild HF. Univariable and multivariable logistic models showed that, FGF21 and NTproBNP were independent predictors for advanced HF in patients with preserved and mildly reduced ejection fraction and T2DM. Full article

Objective: To assess the complementary role of the Body Mass Index (BMI) and Edmonton Obesity Staging System (EOSS) in predicting all-cause and cause-specific mortality in people living with overweight and obesity (PLwOW/O). Methods: A longitudinal analysis of prospectively collected data from the 1999–2018 cycles of the National Health and Nutrition Examination Survey (NHANES) was conducted. The association between BMI, EOSS, and mortality was evaluated through Cox regression models, adjusted for confounders. Results: The analysis included 36,529 subjects; 5329 deaths occurred over a median follow-up of 9.1 years (range: 0–20.8). An increased mortality risk was observed for obesity class II and III (HR = 1.21, 95% CI 1.08–1.36, p = 0.001 and HR = 1.58, 95% CI 1.39–1.80, p < 0.001; compared to overweight), and for EOSS stage 2 and 3 (HR = 1.36, 95% CI 1.16–1.58, p < 0.001 and HR = 2.66, 95% CI 2.26–3.14, p < 0.001; compared to stage 0/1). The prognostic role of BMI was more pronounced in younger patients, males, and non-Black individuals, while that of EOSS was stronger in women. Both BMI and EOSS independently predicted cardiovascular- and diabetes-related mortality. EOSS stage 3 was the only predictor of death from malignancy or renal causes. Conclusions: BMI and EOSS independently predict all-cause and cause-specific mortality in PLwOW/O. Their integrated use seems advisable to best define the obesity-related mortality risk. Full article

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) play an important role in the treatment of type 2 diabetes (T2D) and obesity. The relationship between efficacy and dosing regimen has been studied extensively for this class of molecules. However, a comprehensive analysis of the translation of in vitro data to in vivo efficacious exposure is still lacking. Methods: We collected clinical pharmacokinetics for five approved GLP-1RAs to enable the simulation of exposure profiles and compared published clinical efficacy endpoints (HbA1c and body weight) with in-house in vitro potency values generated in different cell-based assays. Additionally, we investigated the correlation with target coverage, expressed as a ratio between the steady state drug exposure and unbound potency, body weight, or HbA1c reduction in patients with T2D. Results: We found that the best correlation with in vivo efficacy was seen for in vitro potency data generated in cellular assays performed in the absence of any serum albumin or using ovalbumin. Residual variability was larger using in vitro potency data generated in endogenous cell lines or in the presence of human serum albumin. For the human receptor assay with no albumin, exposures above 100-fold in vitro EC50 resulted in >1.5% point HbA1c reduction, while a 5% BW reduction was related to approximately 3× higher exposures. A similar relationship was seen in the ovalbumin assay. Conclusions: Overall, the relationship established for in vitro potency and in vivo efficacy will help to increase confidence in human dose prediction and trial design for new GLP-1RAs in the discovery and early clinical phases. Full article

Background: Liraglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP1RA), is a well-established anti-diabetic drug, has also been approved for the treatment of obesity at a dose of 3 mg. There are a limited number of studies in the literature that have looked at changes in metabolite levels before and after liraglutide treatment in patients with obesity. To this end, in the present study we aimed to explore the changes in the plasma metabolomic profile, using liquid chromatography-high resolution mass spectrometry (LC-HRMS) in patients with obesity. Methods: A single-center prospective study was undertaken to evaluate the effectiveness of 3 mg liraglutide therapy in twenty-three patients (M/F: 8/15) with obesity, mean BMI 40.81 ± 5.04 kg/m², and mean age of 36 ± 10.9 years, in two groups: at baseline (pre-treatment) and after 12 weeks of treatment (post-treatment). An untargeted metabolomic profiling was conducted in plasma from the pre-treatment and post-treatment groups using LC-HRMS, along with bioinformatics analysis using ingenuity pathway analysis (IPA). Results: The metabolomics analysis revealed a significant (FDR p-value ≤ 0.05, FC 1.5) dysregulation of 161 endogenous metabolites (97 upregulated and 64 downregulated) with distinct separation between the two groups. Among the significantly dysregulated metabolites, the majority of them were identified as belonging to the class of oxidized lipids (oxylipins) that includes arachidonic acid and its derivatives, phosphorglycerophosphates, N-acylated amino acids, steroid hormones, and bile acids. The biomarker analysis conducted using MetaboAnalyst showed PGP (a21:0/PG/F1alpha), an oxidized lipid, as the first metabolite among the list of the top 15 biomarkers, followed by cysteine and estrone. The IPA analysis showed that the dysregulated metabolites impacted the pathway related to cell signaling, free radical scavenging, and molecular transport, and were focused around the dysregulation of NF-κB, ERK, MAPK, PKc, VEGF, insulin, and pro-inflammatory cytokine signaling pathways. Conclusions: The findings suggest that liraglutide treatment reduces inflammation and modulates lipid metabolism and oxidative stress. Our study contributes to a better understanding of the drug’s multifaceted impact on overall metabolism in patients with obesity. Full article

Objectives. The health consequences of adolescent obesity are understudied in young adult Israeli Arabs. We aimed to evaluate the association of weight categories during adolescence with hypertension (HTN), diabetes mellitus type 2 (DM2), and the composite endpoint of ischemic stroke (IS), myocardial infarction (MI), and heart failure (HF) in young adult Israeli Arabs on a nationwide level. Methods. A retrospective cohort study of 53,726 Arab adolescents born from 1988–1992 was conducted. The cohort was followed, beginning with BMI measurements at ages 17–19 years, until whichever came first among the diagnosis of outcome disease, death, discontinuation of health insurance, or age of 30 years. Results. The incidence (95% CI) of HTN, DM2, and the composite endpoint of IS, MI, and HF was 138.2 (129.1–147.9), 136.7 (127.6–146.3), and 27.3 (23.3–31.7) cases per 10⁵ person-years, respectively. The risk for DM and HTN increased gradually, starting from the ‘overweight’ category, and reaching fully adjusted HRs (95% CI) of 2.80 (1.82–4.30), and 1.97 (1.31–2.96), respectively, in the ‘class 3 obesity’ category. The Hazard ratio (HR) for the composite endpoint, its incidence and components, was highest in the ‘overweight’ category (aHR of 1.64 (1.08–2.50)). Conclusions. The findings emphasize the long-term health consequences of adolescent obesity in early adulthood and, hence, the need for interventions aimed at reducing the rate of adolescent overweight and obesity. The finding of a very high rate of DM2 incidence in early adulthood, even among adolescents without obesity, necessitates an integrated public health approach to all risk factors to prevent DM2 in this population. Full article

Metabolic syndrome prevalence is between 24 and 27% and poses a significant risk for the development of atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes (T2D), or other comorbidities. Currently, no drugs are approved for metabolic syndrome treatment itself, so the risk factors are treated with therapies approved for cardiac and metabolic conditions. These are approved drugs for dyslipidemia treatment such as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, cornerstone antihypertensive drugs, or novel class glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RA) for T2D and overweight or obesity treatment. We have also evaluated new pharmacological interventions in clinical development that have reached Phase 2 and/or Phase 3 randomized clinical trials (RCTs) for the management of the risk factors of metabolic syndrome. In the pipeline are glucose-dependent insulinotropic polypeptide (GIP), GLP-1, glucagon receptor (GCGR), amylin agonists, and a combination of the latter for T2D and overweight or obesity treatment. Non-entero-pancreatic hormone-based therapies such as ketohexokinase (KHK) inhibitor, growth differentiation factor 15 (GDF15) agonists, monoclonal antibodies (mAbs) as activin type II receptors (ActRII) inhibitors, and a combination of anti-α-myostatin (GFD8) and anti-Activin-A (Act-A) mAbs have also reached Phase 2 or 3 RCTs in the same indications. Rilparencel (Renal Autologous Cell Therapy) is being evaluated in patients with T2D and chronic kidney disease (CKD) in a Phase 3 trial. For dyslipidemia treatment, novel PCSK9 inhibitors (oral and subcutaneous) and cholesteryl ester transfer protein (CETP) inhibitors are in the final stages of clinical development. There is also a surge of a new generation of an antisense oligonucleotide (ASO) and small interfering RNA (siRNA)-targeting lipoprotein(a) [Lp(a)] synthesis pathway that could possibly contribute to a further step forward in the treatment of dyslipidemia. For resistant and uncontrolled hypertension, aldosterone synthase inhibitors and siRNAs targeting angiotensinogen (AGT) messenger RNA (mRNA) are promising new therapeutic options. It would be interesting if a few drugs in clinical development for metabolic syndrome such as 6-bromotryptophan (6-BT), vericiguat, and INV-202 as a peripherally-acting CB1 receptor (CB1r) blocker would succeed in finally gaining the first drug approval for metabolic syndrome itself. Full article

Background: Obesity is one of the most neglected public health problems affecting both developed and developing countries. The most clinically severe obesity (Class 3 obesity) has both clinical and service delivery implications on dental services. However, associations between Class 3 obesity and oral health are minimally explored in the literature and thus poorly understood. Aims: This scoping review aimed to explore the existing evidence on Class 3 obesity and oral health. Methods: A literature search was performed via Medline, Scopus, Google scholar and Embase research databases. Results: A total of 375 papers were sourced from the database search. Twenty seven full-text papers were included in the final literature review. Results revealed findings from both quantitative and qualitative studies. Papers included results pertaining to associations with dental disease, oral health and associated behaviours, oral health-related quality of life and the barriers experienced by adults with Class 3 obesity in accessing dental services. Conclusions: While mixed findings were identified, this scoping review reports associations between Class 3 obesity and poor oral health across various domains including clinical parameters and oral health related quality of life. The literature has also highlighted important barriers to dental care in those with the most severe Class 3 obesity. Based upon our findings, we have summarised current oral health management implications and directions for future research. Full article