Obesity is a major public health challenge. Glucagon-like peptide-1 receptor agonists (GLP1-RA) and bariatric surgery (BS) are effective weight loss interventions; however, the genetic factors influencing treatment response remain largely unexplored. Moreover, most previous studies have focused on race and ethnicity rather than genetic ancestry. Here we analyzed 10,960 individuals from 9 multiancestry biobank studies across 6 countries to assess the impact of known genetic factors on weight loss. Between 6 and 12 months, GLP1-RA users had an average weight change of -3.93% or -6.00%, depending on the outcome definition, with modest ancestry-based differences. BS patients experienced -21.17% weight change between 6 and 48 months. We found no significant associations between GLP1-RA-induced weight loss and polygenic scores for body mass index or type 2 diabetes, nor with missense variants in GLP1R. A higher body mass index polygenic score was modestly linked to lower weight loss after BS (+0.7% per s.d., P = 1.24 × 10-4), but the effect attenuated in sensitivity analyses. Our findings suggest known genetic factors have limited impact on GLP1-RA effectiveness with respect to weight change and confirm treatment efficacy across ancestry groups.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogenous clinical and histopathological entity, where multiple metabolic co-factors are intertwined with high interindividual variability. The impact and severity of each factor (including obesity and type 2 diabetes) define a systemic dysmetabolism that can lead to either advanced liver disease and its complication (including hepatocellular carcinoma and clinical events related to portal hypertension) or extrahepatic events: incident cardiovascular disease, chronic kidney disease and extrahepatic cancers. The balance between environmental factors and genetic susceptibility has unique implications in MASLD: the intermittent injury of metabolic co-factors, their fluctuation over time and their specific management, are counterbalanced by the presence of gene variants that can significantly impact the disease at multiple levels. The I148M variant in the PNPLA3 gene is the most investigated genetic susceptibility that induces a more severe steatohepatitis, enhanced fibrogenesis and can shape the incidence of long-term clinical events regardless of, or worsened by, other metabolic risk factors.

In this review, we will summarise the updated evidence on the natural history of MASLD accounting for classical metabolic risk factors, the role of PNPLA3 in clinical sub-phenotyping (e.g., 'lean MASLD'), impact on disease severity and fibrosis progression, as well as its role for prognostication, alone or in combination with non-invasive tools into polygenic risk scores.

Bariatric and metabolic surgery tourism (BMT) is becoming an increasingly popular route to treatment for patients living with obesity. Recent reports have highlighted that some patients travelling abroad for bariatric surgery have received inadequate care, fraudulent care, and, tragically, some cases have resulted in death. This study aimed to define consensus in Europe regarding safe practices concerning BMT.

IFSO-EC, EASO and ECPO initiated a task force to delineate safe practices in BMT. Two expert European panels were convened, one comprised of healthcare professionals (identified from EASO and IFSO-EC) and the other of patient representatives (identified from ECPO). The study utilized a modified Delphi consensus methodology, and 135 questions were administered. Surveys were conducted anonymously online, and consensus was defined as 70% agreement. Themes analyzed regarding BMT included regulation, pre-operative evaluation, operative care, post-operative care, advertising and online information.

One hundred and nineteen healthcare professionals and 88 patient representatives participated from 26 countries. The healthcare professional panel included 66 bariatric surgeons, 28 endocrinologists, 18 dietitians, three nurses, two psychologists, one general practitioner and one gastroenterologist. Three questionnaire rounds were conducted for the healthcare professional panel, and two were performed for the patient representative panel. Consensus recommendations were given across all themes relevant to BMT. These included evaluating and managing psychological health, sleep apnea, cardiovascular disease, liver health and dietetic assessment. The recommendations covered the requirements for regulatory standards, including surgeon accreditation and procedural volume. They also included recommendations regarding patient education, standardized operative care, online information provision, and follow-up.

Through collaboration with healthcare professionals and patients living with obesity, we provide European recommendations regarding safe practices concerning BMT. Further evaluation is required regarding outcomes following BMT. These data, alongside the Delphi consensus recommendations, will inform BMT clinical guideline development.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of end-stage liver disease and liver transplantation in the Western world, with an approximate prevalence of 30% worldwide which is continuously rising. It is characterized by intrahepatic fat deposition along with at least one cardiometabolic risk factor, such as diabetes mellitus, obesity, hypertriglyceridemia, and hypertension. MASLD consists of a spectrum of liver diseases ranging from simple liver steatosis to steatohepatitis, liver fibrosis, and cirrhosis. Recently, the European Association for the Study of the Liver (EASL), the European Association for the Study of Diabetes (EASD), and the European Association for the Study of Obesity (EASO) released the latest guidelines regarding the management of patients with MASLD. This article highlights the critical points of these guidelines and emphasizes problematic issues that need further evaluation.

Surgical weight loss (SWL) improves myocardial mechanics as measured by speckle-tracking imaging. However non-surgical versus SWL and the subsequent impact on myocardial function in overweight Asian subjects has not been evaluated. 66 patients underwent a 16-week lifestyle intervention (LSI) programme consisting of dietary interventions and exercise prescription. Echocardiography with speckle tracking was performed at baseline and post-intervention. This group was compared against a group of 12 subjects who had undergone bariatric surgery and a control group of 10 lean Asian subjects. A generalised structural equation model (gSEM) was constructed to ascertain the effect of modality of weight loss on strain parameters, adjusting for BMI. Participants attained significant weight loss after LSI (28.2 ± 2.66 kg/m2 vs. 25.8 ± 2.84 kg/m2, p = 0.001). This was associated with a non-significant trend towards improvement in strain parameters. SWL participants had significant improvement in the left ventricular global longitudinal strain (- 20.52 ± 3.34 vs. - 16.68 ± 4.15, p < 0.01) and left atrium reservoir strain (44.32 ± 14.23 vs. 34.3 ± 19.31, p = 0.02). Lean subjects had significantly higher strain parameters than overweight subjects. The gSEM model demonstrated surgical modality of weight loss as an independent predictor of improvement in strain parameters. Significant improvement in echocardiographic parameters were documented in patients who underwent bariatric surgery.

Chronic traumatic encephalopathy (CTE) has been diagnosed in 91.7% of retired United States National Football League (NFL) players at postmortem. There is no treatment or cure for CTE. Most living former NFL athletes with probable CTE suffer from obesity and its comorbidities. Our previous reviews document the improvement in cognition following metabolic/bariatric surgery (MBS) (e.g., gastric bypass, sleeve gastrectomy). These operations might reduce microglial maladaptive states, thereby attenuating neurodegeneration and CTE-like neurocognitive impairment. The study evaluated former NFL players' views on metabolic surgery in relation to reduction of obesity and CTE risk.

An online multiple-choice questionnaire (30 items, 125 response options, 10-min completion) developed in the Research Electronic Data Capture (REDCap) system was sent to 1,014 athletes screened in 2017-2022 by the Living Heart Foundation.

From 2/2022 to 7/2023, of 700 surveys opened, 72 (10.3%) of the retired players responded. Mean age was 61.6 ± 12.6 years; 45.0% had the disease of obesity with a mean BMI 35.5 ± 4.6 kg/m2. Thirty-three percent reported ≥ 2 obesity-related comorbidities; 40.3% memory-related TBI symptoms; 66.7% ≥ 1 cognitive symptom; 85.0% believed MBS was safe and effective but were unlikely to elect MBS for weight management. Yet, 57.0% of the entire cohort, and 68.8% of players with obesity were more likely to elect MBS if it could also reduce CTE risk.

Results of the study bode well for future research recruitment. Most surveyed retired NFL players with obesity believed MBS to be effective and would be more likely to undergo MBS if it also reduced CTE risk.

Nonalcoholic fatty liver disease (NAFLD) is a disease process that is gaining increasing recognition. The global prevalence of NAFLD is increasing in parallel with growing rates of risk factors for NAFLD such as hypertension, obesity, diabetes, and metabolic syndrome. NAFLD has been referred to as a risk factor for cardiovascular disease (CVD). As CVD is the leading cause of morbidity and mortality worldwide, there are constant efforts to describe and alleviate its risk factors. Although there is conflicting data supporting NAFLD as a causative or associative factor for CVD, NAFLD has been shown to be associated with structural, electrical, and atherosclerotic disease processes of the heart. Shared risk factors and pathophysiologic mechanisms between NAFLD and CVD warrant further explication. Pathologic mechanisms such as endothelial dysfunction, oxidative stress, insulin resistance, genetic underpinnings, and gut microbiota dysregulation have been described in both CVD and NAFLD. The mainstay of treatment for NAFLD is lifestyle intervention including physical exercise and hypocaloric intake in addition to bariatric surgery. Investigations into various therapeutic targets to alleviate hepatic steatosis and fibrosis by way of maintaining the balance between lipid synthesis and breakdown. A major obstacle preventing the success of many pharmacologic approaches has been the effects of these medications on CVD risk. The future of pharmacologic treatment of NAFLD is promising as effective medications with limited CVD harm are being investigated.

Metabolic bariatric surgery (MBS) not only leads to a durable weight loss but also lowers mortality, and reduces cardiovascular risks.

The current study aims to investigate the association of bariatric metabolic surgery (BMS) with admissions for acute myocardial infarction (AMI), including ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI), as well as, coronary revascularization procedures, including percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), and thrombolysis.

The National Inpatient Sample (NIS) database.

The NIS data from 2016 to 2020 were analyzed. A propensity score matching in a 1:1 ratio was performed to match patients with history of MBS with non-MBS group.

Two hundred thirty-three thousand seven hundred twenty-nine patients from the non-MBS group were matched with 233,729 patients with history of MBS. The MBS group had about 52% reduced odds of admission for AMI compared to the non-MBS group (adjusted odd ratio: .477, 95% confidence interval: .454-.502, P value <.001). In addition, the odds of STEMI and NSEMI were significantly lower in the MBS group in comparison to the non-MBS group. Also, the MBS group had significantly lower odds of CABG, PCI, and thrombolysis compared to the non-MBS group. In addition, in patients with AMI, MBS was associated with lower in-hospital mortality (adjusted odd ratio: .627, 95% confidence interval: .469-.839, P value = .004), length of hospital stays, and total charges.

History of MBS is significantly associated with reduced risk of admission for AMI including STEMI and NSTEMI, as well as the, need for coronary revascularization such as PCI and CABG.

The beneficial impacts of metabolic surgery (MS) on patients with heart failure (HF) are incompletely characterized. We aimed to describe the cardiac and metabolic effects of MS in patients with HF and hypothesized that patients with HF would experience both improved metabolic and HF profiles using glycemic control and diuretic dependency as surrogate markers. In this single-center, university-affiliated academic study in the United States, a review of 2,342 hospital records of patients who underwent MS (2017 to 2023) identified 63 patients with a medical history of HF. Preoperative characteristics, 30-day outcomes, and up to 2-year biometric and metabolic outcomes, medication usage, and emergency department utilization were collected. At 24 months, mean body mass index change was -16 kg/m2 (p <0.001) that corresponded to a mean percentage total body weight loss of 29% (p <0.001). Weight loss was accompanied by significant reductions in hemoglobin A1c (p <0.001) and a 65% decrease in diuretic use at 24 months after surgery (p <0.001). Similarly, emergency visits for cardiac conditions (p = 0.06) and intravenous diuresis (p = 0.07) trended favorably at 1 year after surgery compared with 1 year before surgery but were not statistically significant. In conclusion, in patients with HF who were carefully selected, MS appears to provide significant reduction in oral diuretic dependency, and metabolic improvements with trends toward lower rates of emergency department utilization.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes (T2D) or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as FIB-4) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification - including weight loss, dietary changes, physical exercise and discouraging alcohol consumption - as well as optimal management of comorbidities - including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for T2D or obesity, if indicated - is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.

and design: Considering the clinical link between non-alcoholic fatty liver disease (NAFLD) and atherosclerosis (AS), we performed bioinformatics analysis to uncover their pathogenic interrelationship.

Data from the U.S. National Health and Nutritional Examination Survey (NHANES) 1999-2018 were included. Among 4851 participants in NHANES, NAFLD was significantly associated with atherosclerotic cardiovascular disease risk (ASCVD risk) (OR = 2.32, 95%CI: 2.04-2.65, P < 0.0001). We conducted WGCNA analysis for NAFLD (GSE130970) and AS (GSE28829) and identified three modules positively related to NAFLD severity and two modules accelerating atherosclerosis plaque progression. 198 key-modules genes were obtained via overlapping these modules. Next, we mined the disease-controlled differentially expressed genes (DEGs) from NAFLD (GSE89632) and AS (GSE100927), respectively. The final common risk genes (ACP5, TP53I3, RPS6KA1, TYMS, TREM2, CA12, and IFI27) were defined by intersecting the upregulated DEGs with 198 genes and validated in new datasets (GSE48452 and GSE43292). Importantly, they showed good diagnostic ability for NAFLD and AS. Immune infiltration analysis showed both illnesses have dysregulated immunity. Analysis of single-cell sequencing datasets NAFLD (GSE179886) and AS (GSE159677) uncovered different abnormal expressions of seven common genes in different immune cells while highlighting metabolic disturbances including upregulation of fatty acid biosynthesis, downregulation of fatty acid degradation and elongation.

We found 7 shared hub genes with good diagnostic ability and depicted the landscapes of immune and metabolism involved in NAFLD and AS. Our results provided a comprehensive association between them and may contribute to developing potential intervention strategies for targeting both disorders based on these risk factors.

Obesity is a global epidemic associated with an increased risk of severe health conditions such as type 2 diabetes, cardiovascular diseases, and certain cancers. Bariatric surgery has become a pivotal treatment for severe obesity, offering significant improvements in weight loss and comorbidity resolution. This comprehensive review aims to assess the long-term effectiveness and outcomes of various bariatric surgical procedures, highlighting current evidence and emerging trends in the field. We extensively reviewed the literature, including randomized controlled trials, cohort studies, and meta-analyses, to evaluate long-term weight loss, resolution of obesity-related comorbidities, quality of life (QoL), and complications associated with different bariatric procedures. Bariatric surgery has demonstrated substantial and sustained weight loss over the long term, with varying degrees of effectiveness among different procedures. Gastric bypass and sleeve gastrectomy are associated with significant improvements in comorbidities such as type 2 diabetes and hypertension. QoL outcomes are generally positive, improving physical health, mental well-being, and social functioning. However, long-term complications, including nutritional deficiencies and the need for reoperations, remain challenges. Emerging trends such as minimally invasive techniques and nonsurgical interventions show promise in enhancing patient outcomes. Bariatric surgery remains a highly effective intervention for managing severe obesity and its related health issues. While long-term outcomes are generally favorable, continued advancements in surgical techniques and postoperative care are crucial for optimizing results and minimizing complications. Future research should focus on personalized approaches to patient management and the development of novel treatment modalities to further improve outcomes in the long term.

Metabolic and bariatric surgery (MBS) is the most effective and durable treatment for obesity. We aimed to compare the trajectories of antihypertensive medication (AHM) use among obese individuals treated and not treated with MBS.

Adults with a body mass index of ≥35 kg/m2 were identified in the Merative Database (US employer-based claims database). Individuals treated with versus without MBS were matched 1:1 using baseline demographic and clinical characteristics as well as AHM utilization. Monthly AHM use was examined in the 3 years after the index date using generalized estimating equations. Subanalyses investigated rates of AHM discontinuation, AHM initiation, and apparent treatment-resistant hypertension.

The primary cohort included 43 206 adults who underwent MBS matched with 43 206 who did not. Compared with no MBS, those treated with MBS had sustained, markedly lower rates of AHM use (31% versus 15% at 12 months; 32% versus 17% at 36 months). Among patients on AHM at baseline, 42% of patients treated with MBS versus 7% treated medically discontinued AHM use (P<0.01). The risk of apparent treatment-resistant hypertension was 3.41× higher (95% CI, 2.91-4.01; P<0.01) 2 years after the index date in patients who did not undergo MBS. Among those without hypertension treated with MBS versus no MBS, 7% versus 21% required AHM at 2 years.

MBS is associated with lower rates of AHM use, higher rates of AHM discontinuation, and lower rates of AHM initiation among patients not taking AHM. These findings suggest that MBS is both an effective treatment and a preventative measure for hypertension.

There is a strong association between metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity which are both important risk factors for cardiovascular diseases (CVDs). The current study aimed to assess the association of MBS with different CVDs in patients with MASLD.

The National Inpatient Sample (NIS) database from 2016 to 2020 were analyzed by using ICD-10 codes. A propensity score matching in a 1:1 ratio was done to match the MBS and non-MBS groups.

After weighted analysis, 1,124,155 and 68,215 patients were included in non-MBS and MBS groups, respectively. MBS was associated with significantly lower risk of hospitalization for coronary artery disease (OR 0.633 (0.569-0.703), p value < 0.001), acute myocardial infarction (OR 0.606 (0.523-0.701), p value < 0.001), percutaneous coronary intervention (OR 0.578 (0.489-0.682), p value < 0.001), and thrombolysis (OR 0.765 (0.589-0.993), p value = 0.044) compared to the non-MBS group in patients with MASLD. Furthermore, MBS was associated with 52% reduced risk of hospitalization for hemorrhagic stroke in patients with MASLD (OR 0.481, 95% CI 0.337-0.686, p value < 0.001). However, ischemic stroke was not significant between the two groups (OR 1.108 (0.905-1.356), p value = 0.322). In addition, MBS was associated with 63% and 60% reduced risk of hospitalization for heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) in patients with MASLD (OR 0.373, 95% CI 0.300-0.465 and OR 0.405, 95% CI 0.325-0.504, p value < 0.001 for both), respectively.

The current study showed that MBS is significantly associated with a reduced risk of hospitalization for CVD in patients with MASLD.

Some research have indicated that Bariatric and metabolic surgery (BMS) can reduce the risk of cardiovascular disease (CVD) among individuals with obesity. However, there are few reports available that focuses on assessing effect of BMS on the risk of CVD in Chinese population using multiple models.

This research aims to assess the function of BMS on the risk of CVD in Chinese patients with obesity using multiple CVD risk models.

We performed a retrospective analysis of the basic data and glycolipid metabolism data preoperatively and postoperatively from patients with obesity at our hospital. Subgroup analysis was carried out according to different surgical procedures. Then, the function of BMS on the risk of CVD in the Chinese population was assessed using four models, including: China-PAR risk model, Framingham risk score (FRS), World Health Organization (WHO) risk model, and Globorisk model.

We enrolled 64 patients, 24 (37.5%) of whom underwent laparoscopic sleeve gastrectomy (LSG) while 40 (62.5%) underwent Roux-en-Y gastric bypass (RYGB). The 10-year CVD risk for patients calculated using the China-PAR risk model decreased from 6.3% preoperatively to 2.0% at 1 year postoperatively and was statistically significantly different. Similarly, the 10-year CVD risk of patients calculated using the FRS, WHO, Global risk model decreased significantly at 1 year postoperatively compared to preoperatively. When the FRS risk model was used to calculate the patients' 30-year postoperative CVD risk, there was a significant decrease at 1 year after surgery compared to the preoperative period. When employing various models to evaluate the 10-year CVD risk for LSG and RYGB, no statistically significant difference was found in the 1-year postoperative RRR between the procedures.

The CVD risk after BMS was significantly reduced compared to preoperatively. In terms of improving cardiovascular risk, SG and RYGB appear to be equally effective.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes (T2D) or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as FIB-4) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification - including weight loss, dietary changes, physical exercise and discouraging alcohol consumption - as well as optimal management of comorbidities - including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for T2D or obesity, if indicated - is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.

Glycoursodeoxycholic acid (GUDCA) has been acknowledged for its ability to regulate lipid homeostasis and provide benefits for various metabolic disorders. However, the impact of GUDCA on arterial thrombotic events remains unexplored. The objective of this study is to examine the effects of GUDCA on thrombogenesis and elucidate its underlying mechanisms.

Plasma samples from patients with arterial thrombotic events and diet-induced obese mice were collected to determine the GUDCA concentrations using mass spectrometry. Multiple in vivo murine thrombosis models and in vitro platelet functional assays were conducted to comprehensively evaluate the antithrombotic effects of GUDCA. Moreover, lipidomic analysis was performed to identify the alterations of intraplatelet lipid components following GUDCA treatment.

Plasma GUDCA level was significantly decreased in patients with arterial thrombotic events and negatively correlated with thrombotic propensity in diet-induced obese mice. GUDCA exhibited prominent suppressing effects on platelet reactivity as evidenced by the attenuation of platelet activation, secretion, aggregation, spreading, and retraction (P<0.05). In vivo, GUDCA administration robustly alleviated thrombogenesis (P<0.05) without affecting hemostasis. Mechanistically, GUDCA inhibited DGK (diacylglycerol kinase) activity, leading to the downregulation of the phosphatidic acid-mediated signaling pathway. Conversely, phosphatidic acid supplementation was sufficient to abolish the antithrombotic effects of GUDCA. More importantly, long-term oral administration of GUDCA normalized the enhanced DGK activity, thereby remarkably alleviating the platelet hyperreactivity as well as the heightened thrombotic tendency in diet-induced obese mice (P<0.05).

Our study implicated that GUDCA reduces platelet hyperreactivity and improves thrombotic propensity by inhibiting DGKs activity, which is a potentially effective prophylactic approach and promising therapeutic agent for arterial thrombotic events.

Metabolic and bariatric surgery (MBS) is the most effective and durable treatment for obesity; however, access to MBS is not equitable.

To determine the rate of MBS among eligible adults with obesity by demographics, health characteristics, and geography to better define populations that would benefit from resources to reduce barriers to access for this treatment.

Adults with obesity were identified in the US employer-based retrospective claims database (Merative™).

Rates of MBS were examined across demographics (age, sex, region, year, health plan type) health characteristics (obesity-related comorbidities, healthcare costs, inpatient admissions), and by state. Given differences in coverage requirements, rates are examined for 2 populations: Class 2 (BMI 35-39.9 kg/m2) and Class 3 (BMI 40+ kg/m2) obesity.

Of the 777,565 eligible adults, 49,371 (6.4%) had MBS; 3.2% of those with Class 2 and 8.3% of those with Class 3 obesity had MBS. MBS rates varied substantially by demographic and health characteristics, ranging from 1% to 14%, and from 2% to 41% among those with Class 2 and Class 3 obesity, respectively. Geographically, rates ranged from 0% (Hawaii) to 7.4% (New Mexico) for those with Class 2 Obesity and from 4.2% (Hawaii) to 15.3% (Mississippi) among those with Class 3 Obesity.

Use of MBS among eligible adults with obesity varies substantially across characteristics, indicating inequity in access to this treatment. To ensure greater access to the most effective treatment for obesity, policies should be implemented to reduce or eliminate barriers to care.

Obesity refers to the excessive accumulation of fat caused by a long-term imbalance between energy intake (EI) and energy expenditure (EE). Over recent years, obesity has become a major public health challenge. Caffeine is a natural product that has been demonstrated to exert anti-obesity effects; however, the mechanisms responsible for the effect of caffeine on weight loss have yet to be fully elucidated. Most obesity-related deaths are due to cardiovascular disease. Recent research has demonstrated that caffeine can reduce the risk of death from cardiovascular disease; thus, it can be hypothesized that caffeine may represent a new therapeutic agent for weight loss. In this review, we synthesize data arising from clinical and animal studies over the last decade and discuss the potential mechanisms by which caffeine may induce weight loss, focusing particularly on increasing energy consumption, suppressing appetite, altering lipid metabolism, and influencing the gut microbiota. Finally, we summarize the major challenges associated with caffeine and anti-obesity research and highlight possible directions for future research and development.

We examined the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) initiation on long-term Adverse Liver Outcomes (ALO) in patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) cirrhosis and type 2 diabetes using real-world data from the MarketScan database.

We conducted a retrospective cohort study of patients with MASLD cirrhosis and type 2 diabetes between 2012 and 2020. Cox proportional hazard models examine the association between GLP-1RAs initiation, modelled as time-dependent, and the risk of ALO, a composite endpoint defined by the first occurrence of hepatic decompensation(s), portal hypertension, hepatocellular carcinoma (HCC) or liver transplantation (LT). We used Overlap Propensity Score Weighting (OPSW) to account for confounding. The study included 459 GLP-1RAs and 4837 non-GLP-1RAs patients.

The non-GLP-1RAs patients presented with 1411 (29%) ALO over 7431.7 person years, while GLP-1RAs patients had 32 (7%) ALO over 586.6 person years - risk rate difference 13.5 (95% CI: 11.4-15.7) per 100 person-years. The OPSW-adjusted risk of ALO was reduced by 36% (hazard ratio [HR]: 0.64; 95% CI: 0.54-0.76) in patients with vs. without GLP-1RAs initiation. GLP-1RAs initiation was associated with significant reductions in the adjusted risk of hepatic decompensation (HR: 0.74; 95% CI: 0.61-0.88), portal hypertension (HR: 0.73; 95% CI: 0.60-0.88), HCC (HR: 0.37; 95% CI: 0.20-0.63) and LT (HR: 0.24; 95% CI: 0.12-0.43).

The use of GLP-1RAs was associated with significant risk reductions in long-term adverse liver outcomes, including hepatic decompensation, portal hypertension, HCC and LT, in MASLD cirrhosis patients with type 2 diabetes.

Although postoperative adjuvant transarterial chemoembolization (PA-TACE) improves survival outcomes in a subset of patients with resected hepatocellular carcinoma (HCC), the lack of reliable biomarkers for patient selection remains a significant challenge. The present study aimed to evaluate whether computed tomography imaging can provide more value for predicting benefits from PA-TACE and to establish a new scheme for guiding PA-TACE benefits.

In this retrospective study, patients with HCC who had undergone preoperative contrast-enhanced computed tomography and curative hepatectomy were evaluated. Inverse probability of treatment weight was performed to balance the difference of baseline characteristics. Cox models were used to test the interaction among PA-TACE, imaging features, and pathological indicators. An HCC imaging and pathological classification (HIPC) scheme incorporating these imaging and pathological indicators was established.

This study included 1488 patients [median age, 52 years (IQR, 45-61 years); 1309 male]. Microvascular invasion (MVI) positive, and diameter >5 cm tumors achieved a higher recurrence-free survival (RFS), and overall survival (OS) benefit, respectively, from PA-TACE than MVI negative, and diameter ≤5 cm tumors. Patients with internal arteries (IA) positive benefited more than those with IA-negative in terms of RFS ( P =0.016) and OS ( P =0.018). PA-TACE achieved significant RFS and OS improvements in HIPC3 (IA present and diameter >5 cm, or two or three tumors) patients but not in HIPC1 (diameter ≤5 cm, MVI negative) and HIPC2 (other single tumor) patients. Our scheme may decrease the number of patients receiving PA-TACE by ~36.5% compared to the previous suggestion.

IA can provide more value for predicting the benefit of PA-TACE treatment. The proposed HIPC scheme can be used to stratify patients with and without survival benefits from PA-TACE.

Previous studies have examined the effects of metabolic syndrome (MetS) rather than its severity on race and ethnic disparities in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). We used the MetS severity score, a validated sex-race-ethnicity-specific severity measure, to examine the effects of race/ethnicity on the association between MetS severity and MASLD.

This study included 10,605 adult participants from the Third National Health and Nutrition Examination Survey. The MASLD diagnosis was based on ultrasound findings in patients without excessive alcohol intake or other liver diseases. MetS severity Z-scores were calculated and stratified into four categories low (1st-50th), moderate (>50th-75th), high (>75th-90th), and very high (>90th+)]. Multivariable adjusted logistic regression models with complex survey methods were used to test the effect of MetS severity on MASLD.

The age-adjusted MASLD prevalence was 17.4%, 25.7%, 42.5, and 54.9% in adults with mild, moderate, high, and very high MetS severities, respectively (P-trend <0.001). MetS severity was significantly higher in patients with MASLD than in those without [mean percentile 60th vs. 44th, P<0.001]. Among patients with MASLD, Mexican-American and Black non-Hispanic females had significantly higher age-adjusted MetS severity (68th and 61st, respectively) than White non-Hispanic females 54th, while Black non-Hispanic males had significantly lower MetS severity (56th) than White non-Hispanic males (70th) (P-Interaction = 0.02). Adults with high and very high MetS severity had 2.27 (95% CI:1.70 to 3.03) and 3.12 (95% CI:2.20 to 4.42), respectively, higher adjusted odds of MASLD than those with mild MetS severity.

Racial/ethnic disparities in MetS severity play a pivotal role in the risk of MASLD. Our findings highlight the potential clinical utility of the MetS severity score in identifying at-risk individuals, which will help guide targeted prevention and tailoring management strategies to mitigate the MASLD burden.

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) pose a significant threat to human health and cause a tremendous socioeconomic burden. Currently, the molecular mechanisms of NAFLD and NASH remain incompletely understood, and no effective pharmacotherapies have been approved. In the past five years, significant advances have been achieved in our understanding of the pathomechanisms and potential pharmacotherapies of NAFLD and NASH. Research advances include the investigation of the effects of the fibroblast growth factor 21 (FGF21) analog pegozafermin and the thyroid hormone receptor-β (THRβ) agonist resmetriom on hepatic fat content, NASH resolution and/or fibrosis regression. Future directions of NAFLD and NASH research (including combination therapy, organoids and humanized mouse models) are also discussed in this state-of-the-art review.

Non-alcoholic fatty liver disease (NAFLD) has increasing worldwide prevalence, fuelled by rising obesity rates, and weight reduction is the mainstay of its management. We sought to study the effect of bariatric surgery, the most effective long-term treatment for obesity and associated metabolic disorders, on liver function in people with obesity.

We performed a retrospective longitudinal cohort study of 511 patients who had undergone bariatric surgery (71 sleeve gastrectomy and 440 gastric bypass) over 60 months of follow-up. Patients were stratified into groups based on their baseline alanine aminotransferase (ALT) into Group A (ALT < 40 U/L) and Group B (ALT > 40 U/L). Postoperative follow-up weight loss, liver function tests, HbA1c, blood pressure and lipid profiles were collected.

Bariatric surgery resulted in nadir total weight loss of 33.1% by 24 months (p < 0.001) with no significant difference between groups. In people with raised baseline ALT (Group B), ALT and gamma glutamyl transferase (GGT) levels decreased significantly by 4 months postoperatively (p < 0.001) and sustained over 60 months of follow-up. There was also significant and sustained reduction in HbA1c, blood pressure, total cholesterol, and non-HDL cholesterol overall with no differences between groups.

Bariatric surgery results in significant weight loss, improves liver function tests and metabolic outcomes in people with obesity. Bariatric surgery could be a therapeutic consideration for patients with NAFLD associated with severe obesity who have otherwise been unresponsive to conservative management.

As the rate of obesity increases, so does the incidence of obesity-related comorbidities. Metabolic and bariatric surgery (MBS) is the most effective treatment for obesity, yet this treatment is severely underused. MBS can improve, resolve, and prevent the development of obesity-related comorbidities; this improvement in health also results in lower healthcare costs. The studies that have examined these outcomes are often limited by small sample sizes, reliance on outdated data, inconsistent definitions of outcomes, and the use of simulated data. Using recent real-world data, we will identify characteristics of individuals who qualify for MBS but have not had MBS and address the gaps in knowledge around the impact of MBS on health outcomes and healthcare costs.

Using a large US employer-based retrospective claims database (Merative), we will identify all obese adults (21+) who have had a primary MBS from 2016 to 2021 and compare their characteristics and outcomes with obese adults who did not have an MBS from 2016 to 2021. Baseline demographics, health outcomes, and costs will be examined in the year before the index date, remission and new-onset comorbidities, and healthcare costs will be examined at 1 and 3 years after the index date.

As this was an observational study of deidentified patients in the Merative database, Institutional Review Board approval and consent were exempt (in accordance with the Health Insurance Portability and Accountability Act Privacy Rule). An IRB exemption was approved by the wcg IRB (#13931684). Knowledge dissemination will include presenting results at national and international conferences, sharing findings with specialty societies, and publishing results in peer-reviewed journals. All data management and analytic code will be made available publicly to enable others to leverage our methods to verify and extend our findings.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasingly common liver disease worldwide. MAFLD is diagnosed based on the presence of steatosis on images, histological findings, or serum marker levels as well as the presence of at least one of the three metabolic features: overweight/obesity, type 2 diabetes mellitus, and metabolic risk factors. MAFLD is not only a liver disease but also a factor contributing to or related to cardiovascular diseases (CVD), which is the major etiology responsible for morbidity and mortality in patients with MAFLD. Hence, understanding the association between MAFLD and CVD, surveillance and risk stratification of MAFLD in patients with CVD, and assessment of the current status of MAFLD management are urgent requirements for both hepatologists and cardiologists. This Taiwan position statement reviews the literature and provides suggestions regarding the epidemiology, etiology, risk factors, risk stratification, nonpharmacological interventions, and potential drug treatments of MAFLD, focusing on its association with CVD.

Several drugs on the market are substrates for P-glycoprotein (P-gp), an efflux transporter highly expressed in barrier tissues such as the intestine. Body weight, weight loss, and a Roux-en-Y gastric bypass (RYGB) may influence P-gp expression and activity, leading to variability in the drug response. The objective of this study was therefore to investigate digoxin pharmacokinetics as a measure of the P-gp phenotype in patients with obesity before and after weight loss induced by an RYGB or a strict diet and in normal weight individuals.

This study included patients with severe obesity preparing for an RYGB (n = 40) or diet-induced weight loss (n = 40) and mainly normal weight individuals scheduled for a cholecystectomy (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day) followed by an additional 6 weeks of <800 kcal/day induced by an RYGB (performed at week 3) or a very-low-energy diet. Follow-up time was 2 years, with four digoxin pharmacokinetic investigations at weeks 0, 3, and 9, and year 2. Hepatic and jejunal P-gp levels were determined in biopsies obtained from the patients undergoing surgery.

The RYGB group and the diet group had a comparable weight loss in the first 9 weeks (13 ± 2.3% and 11 ± 3.6%, respectively). During this period, we observed a minor increase (16%) in the digoxin area under the concentration-time curve from zero to infinity in both groups: RYGB: 2.7 µg h/L [95% confidence interval (CI) 0.67, 4.7], diet: 2.5 µg h/L [95% CI 0.49, 4.4]. In the RYGB group, we also observed that the time to reach maximum concentration decreased after surgery: from 1.0 ± 0.33 hours at week 3 to 0.77 ± 0.08 hours at week 9 (-0.26 hours [95% CI -0.47, -0.05]), corresponding to a 25% reduction. Area under the concentration-time curve from zero to infinity did not change long term (week 0 to year 2) in either the RYGB (1.1 µg h/L [-0.94, 3.2]) or the diet group (0.94 µg h/L [-1.2, 3.0]), despite a considerable difference in weight loss from baseline (RYGB: 30 ± 7%, diet: 3 ± 6%). At baseline, the area under the concentration-time curve from zero to infinity was -5.5 µg h/L [95% CI -8.5, -2.5] (-26%) lower in patients with obesity (RYGB plus diet) than in normal weight individuals scheduled for a cholecystectomy. Further, patients undergoing an RYGB had a 0.05 fmol/µg [95% CI 0.00, 0.10] (29%) higher hepatic P-gp level than the normal weight individuals.

Changes in digoxin pharmacokinetics following weight loss induced by a pre-operative low-energy diet and an RYGB or a strict diet (a low-energy diet plus a very-low-energy diet) were minor and unlikely to be clinically relevant. The lower systemic exposure of digoxin in patients with obesity suggests that these patients may have increased biliary excretion of digoxin possibly owing to a higher expression of P-gp in the liver.

MASLD prevalence is growing towards the leading cause of end-stage liver disease. Up to today, the most effective treatment is weight loss. Weight loss interventions are moving from lifestyle changes to bariatric surgery or endoscopy, and, more recently, to a new wave of anti-obesity drugs that can compete with bariatric surgery. Liver-targeted therapy is a necessity for those patients who already present liver fibrosis. The field is moving fast, and in the near future, we will testify to a disruptive change in MASLD treatment, similar to the paradigm-shift that occurred for hepatitis C almost one decade ago with direct antiviral agents.

Fatty liver disease in the absence of excessive alcohol consumption is an increasingly common condition with a global prevalence of ~ 25-30% and is also associated with cardiovascular disease (CVD). Since systemic metabolic dysfunction underlies its pathogenesis, the term metabolic (dysfunction)-associated fatty liver disease (MAFLD) has been proposed for this condition. MAFLD is closely intertwined with obesity, type 2 diabetes mellitus and atherogenic dyslipidemia, which are established cardiovascular risk factors. Unlike CVD, which has received attention in the literature on fatty liver disease, the CVD risk associated with MAFLD is often underestimated, especially among Cardiologists.

A multidisciplinary panel of fifty-two international experts comprising Hepatologists, Endocrinologists, Diabetologists, Cardiologists and Family Physicians from six continents (Asia, Europe, North America, South America, Africa and Oceania) participated in a formal Delphi survey and developed consensus statements on the association between MAFLD and the risk of CVD. Statements were developed on different aspects of CVD risk, ranging from epidemiology to mechanisms, screening, and management.

The expert panel identified important clinical associations between MAFLD and the risk of CVD that could serve to increase awareness of the adverse metabolic and cardiovascular outcomes of MAFLD. Finally, the expert panel also suggests potential areas for future research.

Heart failure with reduced ejection fraction (HFrEF) and nonalcoholic fatty liver disease (NAFLD) are two common comorbidities that share similar pathophysiological mechanisms. There is a growing interest in the potential of targeted therapies to improve outcomes in patients with coexisting HFrEF and NAFLD. This manuscript reviews current and potential therapies for patients with coexisting HFrEF and NAFLD. Pharmacological therapies, including angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, mineralocorticoids receptor antagonist, and sodium-glucose cotransporter-2 inhibitors, have been shown to reduce fibrosis and fat deposits in the liver. However, there are currently no data showing the beneficial effects of sacubitril/valsartan, ivabradine, hydralazine, isosorbide nitrates, digoxin, or beta blockers on NAFLD in patients with HFrEF. This study highlights the importance of considering HFrEF and NAFLD when developing treatment plans for patients with these comorbidities. Further research is needed in patients with coexisting HFrEF and NAFLD, with an emphasis on novel therapies and the importance of a multidisciplinary approach for managing these complex comorbidities.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to increase to over half of the adult population by 2040 globally. Since the final diagnosis of NAFLD is made by a liver biopsy, several non-invasive approaches have been developed and validated to define NAFLD and evaluate NAFLD-associated diseases. Presently, NAFLD has been identified as an important and independent risk factor for developing several extrahepatic diseases, including atherosclerosis, cardiovascular disease (CVD), diabetes, and dementia. This review discusses current findings of up-to-date literature regarding the effects of NAFLD on the risk of atherosclerosis and CVD in Asia along with potential underlying biological mechanisms and therapeutic approaches to lower the NAFLD-related CVD risk. We further focus on the difference between NAFLD and metabolic dysfunction-associated fatty liver disease (MAFLD) on the risk of CVD and its implication by comparing the risk of NAFLD and MAFLD.

Observational studies suggest that bariatric-metabolic surgery might greatly improve non-alcoholic steatohepatitis (NASH). However, the efficacy of surgery on NASH has not yet been compared with the effects of lifestyle interventions and medical therapy in a randomised trial.

We did a multicentre, open-label, randomised trial at three major hospitals in Rome, Italy. We included participants aged 25-70 years with obesity (BMI 30-55 kg/m2), with or without type 2 diabetes, with histologically confirmed NASH. We randomly assigned (1:1:1) participants to lifestyle modification plus best medical care, Roux-en-Y gastric bypass, or sleeve gastrectomy. The primary endpoint of the study was histological resolution of NASH without worsening of fibrosis at 1-year follow-up. This study is registered at ClinicalTrials.gov, NCT03524365.

Between April 15, 2019, and June 21, 2021, we biopsy screened 431 participants; of these, 103 (24%) did not have histological NASH and 40 (9%) declined to participate. We randomly assigned 288 (67%) participants with biopsy-proven NASH to lifestyle modification plus best medical care (n=96 [33%]), Roux-en-Y gastric bypass (n=96 [33%]), or sleeve gastrectomy (n=96 [33%]). In the intention-to-treat analysis, the percentage of participants who met the primary endpoint was significantly higher in the Roux-en-Y gastric bypass group (54 [56%]) and sleeve gastrectomy group (55 [57%]) compared with lifestyle modification (15 [16%]; p<0·0001). The calculated probability of NASH resolution was 3·60 times greater (95% CI 2·19-5·92; p<0·0001) in the Roux-en-Y gastric bypass group and 3·67 times greater (2·23-6·02; p<0·0001) in the sleeve gastrectomy group compared with in the lifestyle modification group. In the per protocol analysis (236 [82%] participants who completed the trial), the primary endpoint was met in 54 (70%) of 77 participants in the Roux-en-Y gastric bypass group and 55 (70%) of 79 participants in the sleeve gastrectomy group, compared with 15 (19%) of 80 in the lifestyle modification group (p<0·0001). No deaths or life-threatening complications were reported in this study. Severe adverse events occurred in ten (6%) participants who had bariatric-metabolic surgery, but these participants did not require re-operations and severe adverse events were resolved with medical or endoscopic management.

Bariatric-metabolic surgery is more effective than lifestyle interventions and optimised medical therapy in the treatment of NASH.

Fondazione Policlinico Universitario A Gemelli, Policlinico Universitario Umberto I and S Camillo Hospital, Rome, Italy.