Effect of a Low-Calorie Dietary Intervention on Liver Health and Body Weight in Adults with Metabolic-Dysfunction Associated Steatotic Liver Disease (MASLD) and Overweight/Obesity: A Systematic Review and Meta-Analysis.

INTRODUCTION: Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD) is a common cause of chronic liver disease. This review assessed the efficacy of a Low-Calorie Diet (LCD) on liver health and body weight in people living with MASLD and obesity. METHODS: The study was registered with PROSPERO (CRD42021296501), and a literature search was conducted using multiple databases. The key inclusion criteria were randomised controlled trials or cohort studies, obesity/overweight and MASLD. Two authors screened abstracts, reviewed full texts and performed data extraction and quality assessment. The primary outcome was the change in the serum ALT, and secondary outcomes included the changes in the serum AST, intrahepatic lipid content (IHL), quantified non-invasively via MRI/MRS, and body weight. RESULTS: Fifteen studies were included. The LCD reduced body weight by 9.1 kg versus the control (95%CI: -12.4, -5.8) but not serum ALT (-5.9 IU/L, -13.9, 2.0). Total Dietary Replacement (TDR) reduced IHL by -9.1% vs. the control (-15.6%, -2.6%). The Mediterranean-LCD for ≥12 months reduced ALT (-4.1 IU/L, -7.6, -0.5) and for 24 months reduced liver stiffness versus other LCDs. The Green-Mediterranean-LCD reduced IHL, independent of body weight. Limited studies assessed those of Black or Asian ethnicity, and there was heterogeneity in the methods assessing the liver fat content and fibrosis. CONCLUSIONS: In people with MASLD and obesity, an LCD intervention reduces IHL and body weight. Trials should focus on the recruitment of Black and Asian ethnicity participants.

Liraglutide 3.0 mg in the treatment of adults with obesity and prediabetes using real-world UK data: A clinical evaluation of a multi-ethnic population.

UK guidelines recommend liraglutide 3.0 mg in adults treated within specialist weight management services with BMI ≥35 kg/m2, prediabetes and high cardiovascular disease risk. We aimed to clinically evaluate liraglutide 3.0 mg in specialist weight management services. We evaluated liraglutide 3.0 mg in weight management services at Guys and St Thomas' NHS Foundation Trust. Objective body weight (BW) was measured at baseline and 4 months, allowing classification as 'responders' (≥5% BW reduction) and 'non-responders' (<5% BW reduction). One hundred and twenty-one patients were evaluated. At 4 months, 76.0% attended follow-up (82.6% responders, 17.4% non-responders); BW (-8.6 kg, 95%CI:-9.8, -7.4 kg), BMI (-3.2 kg/m2, 95%CI: -3.6, -2.8) and %-BW (-6.6%, IQR: -8.8%, -5.2%) significantly reduced. In responders, HbA1c reduced by -5.0 mmol/mol (IQR: -7.0. -4.0 mmol/mol). In responders BW continued to reduce up to 12 months (4 m: -10.2 kg, p < .0001; 6 m: -15.6 kg, p < .0001; 9 m: -16.5 kg, p < .0001; 12 m: -16.7 kg, p < .01). Those of Black African and Caribbean ethnicity experienced less BW loss than those of white ethnicity (4.12 kg, p = .017) and had a greater attrition rate. In adults with obesity and prediabetes who are treated within specialist weight management services, liraglutide 3.0 mg reduces BW and HbA1c. Those of Black African and Caribbean ethnicity experienced less BW reduction and greater attrition at 4 months. Further evaluation of the ethnic differences in response to obesity pharmacotherapy is required.

Real-world data of a digitally enabled, time-restricted eating weight management program in public sector workers living with overweight and obesity in the United Kingdom: A service evaluation of the Roczen program.

Introduction: The health of the United Kingdom workforce is key; approximately 186 million days are lost to sickness each year. Obesity and type 2 diabetes (T2D) remain major global health challenges. The aim of this retrospective service evaluation was to assess the impact of a digitally enabled, time-restricted eating (TRE) intervention (Roczen Program, Reset Health Ltd) on weight and other health-related outcomes. Methods: This service evaluation was conducted in people living with overweight/obesity, with 89% referred from public sector employers. Participants were placed on a TRE, low-carbohydrate, moderate protein plan delivered by clinicians and mentors with regular follow up, dietary guidance, goal setting, feedback, and social support. Results: A total of 660 members enrolled and retention was 41% at 12 months. The majority were female (73.2%), 58.9% were of White ethnicity, with a mean (SD) age of 47.5 years (10.1), and a body mass index of 35.0 kg/m2 (5.7). Data were available for 82 members at 12-month. At 12-month, members mean actual and percentage weight loss was -9.0 kg (7.0; p < 0.001) and -9.2% (6.7, p < 0.001) respectively and waist circumference reduced by -10.3 cm (10.7 p < 0.001), with 45.1% of members achieving ≥10% weight loss. Glycated hemoglobin was significantly improved at 6 months in people living with T2D (-11 mmol/mol [5.7] p = 0.012). Binge eating score significantly reduced (-4.4 [7.0] p = 0.006), despite cognitive restraint increasing (0.37 [0.6] p = 0.006). Conclusion: Our service evaluation showed that the Roczen program led to clinically meaningful improvements in body weight, health-related outcomes and eating behaviors that were sustained at 12-month.

Laparoscopic adjustable gastric banding with liraglutide in adults with obesity and type 2 diabetes (GLIDE): a pilot randomised placebo controlled trial.

INTRODUCTION: Obesity drives type 2 diabetes (T2DM) development. Laparoscopic adjustable gastric banding (LAGB) has lower weight reduction than other bariatric procedures. Liraglutide, a GLP-1 receptor agonist, improves weight and glycaemic control in patients with T2DM. This study aimed to determine the efficacy and safety of liraglutide 1.8 mg in participants undergoing LAGB. METHODS: GLIDE, a pilot randomised, double-blind, placebo-controlled trial, evaluated LAGB with either liraglutide 1.8 mg or placebo in participants with T2DM and obesity. Participants were randomised (1:1) to 6-months therapy post-LAGB, with further 6 months off-treatment follow-up. The primary outcome was change in HbA1c from randomisation to the end of treatment, secondary outcomes included body weight change. A sample size of 58 (29 per group) had 80% power to detect a 0.6% difference in HbA1c between groups. RESULTS: Twenty-seven participants were randomised to liraglutide (n = 13) or placebo (n = 14). Multivariate analysis showed no difference between placebo and liraglutide arms in HbA1c at 6 months (HbA1c:0.2 mmol/mol, -11.3, 11.6, p = 0.98) however, at 12 months HbA1c was significantly higher in the liraglutide arm (HbA1c:10.9 mmol/mol, 1.1, 20.6, p = 0.032). There was no difference between arms in weight at 6 months (BW:2.0 kg, -4.2, 8.1, p = 0.50), however, at 12 months weight was significantly higher in the liraglutide arm (BW:8.2 kg, 1.6, 14.9, p = 0.02). There were no significant differences in adverse events between groups. CONCLUSIONS: Our pilot data suggest no additional improvement in glycaemic control or BW with LAGB and liraglutide therapy. However, this trial was significantly underpowered to detect a significant change in the primary or secondary outcomes. Further trials are needed to investigate whether GLP-1 agonists, and particularly with more effective weekly agents (i.e. semaglutide or tirzepatide), are of benefit following metabolic surgery. CLINICAL TRIAL REGISTRATION: EudraCT number 2015-005402-11.

Mendelian randomisation reveals Sodium-glucose Cotransporter-1 inhibition's potential in reducing Non-Alcoholic Fatty Liver Disease risk.

Non-alcoholic fatty liver disease (NAFLD) has no approved pharmacological treatments. Sodium-glucose cotransporter (SGLT)-1 is a glucose transporter that mediates small intestinal glucose absorption. We evaluated the impact of genetically proxied SGLT-1 inhibition (SGLT-1i) on serum liver transaminases and NAFLD risk. We used a missense variant, rs17683430, in the SLC5A1 gene (encoding SGLT1) associated with HbA1c in a genome-wide association study (n = 344 182) to proxy SGLT-1i. Outcome genetic data comprised 1483 NAFLD cases and 17 781 controls. Genetically proxied SGLT-1i was associated with reduced NAFLD risk (OR 0.36; 95%CI 0.15, 0.87; P = .023) per 1 mmol/mol HbA1c reduction, and with reductions in liver enzymes (alanine transaminase, aspartate transaminase, gamma-glutamyl transferase). Genetically proxied HbA1c, not specifically via SGLT-1i, was not associated with NAFLD risk. Colocalisation did not demonstrate genetic confounding. Overall, genetically proxied SGLT-1i is associated with improved liver health, this may be underpinned by SGLT-1-specific mechanisms. Clinical trials should evaluate the impact of SGLT-1/2 inhibitors on the prevention and treatment of NAFLD.

Childhood, adolescent, and adulthood adiposity are associated with risk of PCOS: a Mendelian randomization study with meta-analysis.

STUDY QUESTION: What is the influence of body composition during childhood, adolescence, and adulthood, as well as metabolic parameters, on incident polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Excess body fat, even during childhood/adolescence, and metabolic parameters, suggestive of hyperinsulinaemia/insulin resistance, significantly impact the risk of PCOS in a linear fashion. WHAT IS KNOWN ALREADY: Observational and Mendelian randomization (MR) data have demonstrated an association between adulthood overweight/obesity and development of PCOS. However, the contribution of body composition in childhood/adolescence to incident PCOS is unclear, as is the influence of childhood overweight/obesity. STUDY DESIGN, SIZE, DURATION: We conducted a systematic review and meta-analysis and integrated our results with a previously published systematic review. Two blinded investigators screened abstracts published between November 2010 and May 2021. Furthermore, we incorporated summary statistics from genome-wide association study (GWAS) data in subjects of European ancestry. Adult overweight was defined as BMI ≥ 25 kg/m2 and obesity as BMI ≥ 30 kg/m2; in Asian subjects, overweight was defined as BMI ≥ 23 kg/m2 and obesity as BMI ≥ 25 kg/m2. PARTICIPANTS/MATERIALS, SETTING, METHODS: We utilized meta-analysis and MR together to allow synthesis of genetic and observational data. For the systematic review, the search revealed 71 studies, of which 63 were included in meta-analysis by calculating odds ratios (ORs) using the random-effects model. Furthermore, we conducted a two-sample MR study of GWAS data to determine the impact of childhood and adult body size (defined categorically by BMI and childhood body size proportions), abnormal body composition and metabolic parameters (higher fasting serum insulin or lower sex hormone-binding globulin (SHBG) concentration) on the odds of incident PCOS via the inverse-variance weighted method. MAIN RESULTS AND THE ROLE OF CHANCE: Significant associations were shown between body composition and PCOS incidence. From the systematic review/meta-analysis, women with overweight (OR 3.80, 2.87-5.03), obesity (OR 4.99, 3.74-6.67), and central obesity (OR 2.93, 2.08-4.12) had increased odds of PCOS. For adolescents with overweight and/or obesity, the PCOS odds were greater than for adults. From MR, for every standard deviation increase in BMI (4.8 kg/m2), the odds of PCOS increased by 2.76 (2.27-3.35). Childhood body size had an independent effect on PCOS odds after adjusting for adult body size (OR: 2.56, 1.57-4.20). Genetically determined body fat percentage (OR 3.05, 2.24-4.15), whole body fat mass (OR 2.53, 2.04-3.14), fasting serum insulin (OR 6.98, 2.02-24.13), and SHBG concentration (OR 0.74, 0.64-0.87) were all significantly associated with PCOS in a linear relation. LIMITATIONS, REASONS FOR CAUTION: The meta-analysis included studies which were cross-sectional and retrospective, limiting our ability to determine causality. MR was limited by interrogating subjects only of European ancestry and including cases classified by either self-diagnosis or diagnostic criteria. WIDER IMPLICATIONS OF THE FINDINGS: Our study demonstrates for the first time a critical role of the impact of excess childhood/adolescent adiposity on the pathophysiology of adult PCOS. Our results, driven by genetically determined childhood/adolescent body composition, higher BMI, hyperinsulinaemia, and lower SHBG, clearly favour obesity driving the metabolic, but not reproductive, PCOS phenotype. Overall, effective weight maintenance, even from the early years, is likely to reduce the risk of this reproductive endocrine disorder. STUDY FUNDING/COMPETING INTEREST(S): S.S.Z. was funded by a National Institute for Health and Care Research (NIHR) Academic Clinical Lectureship. U.A. is chair of the NIHR Steering Committee Trial-CASSANDRA-DN. No other authors declare any sources of funding or relevant conflicts of interest. The authors declare that the research was conducted in the absence of any commercial or financial relations that could be construed as a potential conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Clinical evaluation of patients living with obesity.

Obesity is a significant public health concern which is implicated in cardiometabolic disease, mechanical complications and psychiatric sequelae. BMI is currently used for diagnosis; however, it has limited sensitivity for adiposity in certain circumstances. This has led to the development of risk stratification tools like the Edmonton Staging criteria and the Kings Obesity Staging Criteria: these facilitate and guide comprehensive obesity-related complication assessment. Healthcare professionals working within obesity clinics should adopt evidence-based communication strategies, including shared decision-making, motivational interviewing, and realistic goal setting. It is also vital to avoid weight-stigmatising terminology in all aspects of care, as this can negatively impact patients. Primary care plays an essential part in obesity care and should work to promptly identify cases, initiate treatment and forward on to specialist services where appropriate. Clinical evaluation of the patient living with obesity should take a holistic approach and involve input from bariatric physicians, dietitians, psychologists, and bariatric surgeons, wider members of the multi-disciplinary team should be involved where needed. Clinicians should take a detailed history, examination and order laboratory tests to investigate for complications. Overall, with appropriate evaluation, these assessments can guide patient management and facilitate long-term improvement in health.

The Impact of the COVID-19 Pandemic on Mobility Trends and the Associated Rise in Population-Level Physical Inactivity: Insights From International Mobile Phone and National Survey Data.

Introduction: The COVID-19 pandemic has reduced physical activity (PA) levels. This is important as physical inactivity is linked to poor COVID-19 outcomes. This study aimed to assess the impact of COVID-19 pandemic restrictions on greenspace and residence mobility, walking levels and in turn how these translated to trends in (UK) PA levels. Methods: Google Mobility Reports, the Oxford COVID-19 Government Response Tracker and Apple Mobility geospatial datasets were interrogated for international data. Residence mobility represents home mobility, greenspace mobility includes parks, walking direction requests is proportion of walking directions; stringency index measures lockdown intensity. The Sports England Active Lives Survey dataset was assessed for complementary changes in English PA levels. Results: Using mobility data of 10 countries we observed that during lockdown there were reductions in greenspace mobility and walking directions alongside increased residence mobility; more pronounced changes were seen in countries with higher stringency indices. From a UK perspective, complementary English PA survey data demonstrated the impact of these mobility changes on the proportion and demographic characteristics of PA levels. The most vulnerable in society, the elderly (ages 75+) and Black and Asian minority ethnicity (BAME) individuals were more likely to become physically inactive. Conclusions: The COVID-19 pandemic reduced greenspace mobility and walking direction requests globally. Complementary assessment of English PA levels demonstrated a greater proportion of the population became inactive. Demographics (75+ and BAME) prone to worse COVID-19 outcomes became disproportionately inactive. UK Urban planning should prioritize greenspace development. This could improve city walkability and PA levels.

Exercise in Obesity-the Role of Technology in Health Services: Can This Approach Work?

PURPOSE OF REVIEW: Physical activity (PA) is an important strategy to prevent and treat obesity. Electronic health (eHealth) interventions, such as wearable activity monitors and smartphone apps, may promote adherence to regular PA and successful weight loss. This review highlights the evidence for eHealth interventions in promoting PA and reducing weight. RECENT FINDINGS: Wearables can increase PA and are associated with moderate weight loss in middle/older-aged individuals, with less convincing effects long-term (> 1 year) and in younger people. Data for interventions such as mobile phone applications, SMS, and exergaming are less robust. Investigations of all eHealth interventions are often limited by complex, multi-modality study designs, involving concomitant dietary modification, making the independent contribution of each eHealth intervention on body weight challenging to assess. eHealth interventions may promote PA, thereby contributing to weight loss/weight maintenance; however, further evaluation is required for this approach to be adopted into routine clinical practice.

Low Screening Rates Despite a High Prevalence of Significant Liver Fibrosis in People with Diabetes from Primary and Secondary Care.

Diabetes is a driver of non-alcoholic fatty liver disease (NAFLD) and fibrosis. We determine current practices in examining liver fibrosis in people with diabetes and record prevalence levels in primary and secondary care. We extracted HbA1c results ≥48 mmol/mol to identify people with diabetes, then examined the proportion who had AST, ALT, and platelets results, facilitating calculation of non-invasive fibrosis tests (NIT), or an enhanced liver fibrosis score. Fibrosis markers were requested in only 1.49% (390/26,090), of which 29.7% (n = 106) had evidence of significant fibrosis via NIT. All patients at risk of fibrosis had undergone transient elastography (TE), biopsy or imaging. TE and biopsy data showed that 80.6% of people with raised fibrosis markers had confirmed significant fibrosis. We also show that fibrosis levels as detected by NIT are marginally lower in patients treated with newer glucose lowering agents (sodium-glucose transporter protein 2 inhibitors, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists). In conclusion by utilising a large consecutively recruited dataset we demonstrate that liver fibrosis is infrequently screened for in patients with diabetes despite high prevalence rates of advanced fibrosis. This highlights the need for cost-effectiveness analyses to support the incorporation of widespread screening into national guidelines and the requirement for healthcare practitioners to incorporate NAFLD screening into routine diabetes care.

Thromboprophylaxis in congenital nephrotic syndrome: 15-year experience from a national cohort.

INTRODUCTION: Congenital nephrotic syndrome (CNS) is an ultra-rare disease associated with a pro-thrombotic state and venous thromboembolisms (VTE). There is very limited evidence evaluating thromboprophylaxis in patients with CNS. This study aimed to determine the doses and duration of treatment required to achieve adequate thromboprophylaxis in patients with CNS. METHODS: From 2005 to 2018 children in Scotland with a confirmed genetic or histological diagnosis of CNS were included if commenced on thromboprophylaxis. The primary study endpoint was stable drug monitoring. Secondary outcomes included VTE or significant haemorrhage. RESULTS: Eight patients were included; all initially were commenced on low-molecular weight heparin (enoxaparin). Four patients maintained therapeutic anti-Factor Xa levels (time 3-26 weeks, dose 3.2-5.07 mg/kg/day), and one patient developed a thrombosis (Anti-Factor Xa: 0.27 IU/ml). Four patients were subsequently treated with warfarin. Two patients maintained therapeutic INRs (time 6-11 weeks, dose 0.22-0.25 mg/kg/day), and one patient had two bleeding events (Bleed 1: INR 6, Bleed 2: INR 5.5). CONCLUSIONS: Achieving thromboprophylaxis in CNS is challenging. Similar numbers of patients achieved stable anticoagulation on warfarin and enoxaparin. Enoxaparin dosing was nearly double the recommended starting doses for secondary thromboprophylaxis. Bleeding events were all associated with supra-therapeutic anticoagulation.

Validation of semi-automated flow-mediated dilation measurement in healthy volunteers.

BACKGROUND: Flow-mediated dilation (FMD) is a non-invasive imaging modality used to measure endothelial function but has significant intra- and inter-observer variability. The use of semi-automated FMD devices could overcome this limitation. We assessed the reproducibility of same-day semi-automated FMD measurements by investigators who received basic training on the correct use of the device. METHODS: Forty-three healthy volunteers had two brachial artery FMD measurements performed 20 minutes apart using the UNEX EF 38G device, and automated outputs were produced. Images were also manually analysed using edge-detection software. The reproducibility of repeat FMD measurements within individuals was compared for automated and manual readings, and the correlation between analytical techniques was calculated. RESULTS: Twenty-five percent of scans were of non-diagnostic quality (n = 32). Automated analyses demonstrated sub-optimal reproducibility and measurement variability [intraclass correlation coefficient (ICCC) = 0.334, coefficient of variation (CV) = 45.87%]. In contrast, manually analysed scans had excellent reproducibility and low measurement variance (ICCC = 0.815, CV = 11.40%). FMD values obtained from automated and manual analysis correlated poorly (r = 0.164), whereas resting (r = 0.955) and maximal brachial artery diameters demonstrated excellent correlation (r = 0.867). CONCLUSION: Manually evaluated serial UNEX EF readings have good reproducibility and therefore, the optimal FMD workflow involves manual analyses prior to independent automated interrogation. The high non-diagnostic scan rate is most likely the result of insufficient training and indicates that semi-automatic devices such as UNEX EF should be used by experienced investigators to achieve optimal results.