Lower body mass and lower adiposity are associated with differential responses to two treatment strategies for rheumatoid arthritis.

PURPOSE: To determine if body mass index (BMI) and adipokine levels identify rheumatoid arthritis (RA) patients most likely to benefit from initiation of tumour necrosis factor inhibitors (TNFi) after methotrexate inadequate response. METHODS: This is a secondary analysis of the Rheumatoid Arthritis Comparison of Active Treatments (RACAT) trial and the (TEAR) trial. Both studies compared treatment strategies starting with conventional disease-modifying anti-rheumatic drugs (DMARDs) (triple therapy) versus etanercept plus methotrexate. We compared response rates between TNFi and triple therapy among patients with different BMI. Adipokines were measured at enrolment and associations with treatment response were examined using regression, adjusting for age, sex, BMI and baseline disease activity. RESULTS: In RACAT (n=306), participants who were normal/underweight were more likely to benefit from TNFi versus triple therapy, with greater change in Disease Activity Score in 28 and greater ACR20 response (ACR 20: 64% vs 23%, p=0.001). In contrast, overweight/obese participants had similar response to TNFi versus triple therapy (p-for-interaction=0.001). Similarly, but modest patterns were observed in TEAR (n=601; ACR20: 67% vs 52%, p=0.05). In RACAT, adipokine scores consistent with lower adiposity also predicted greater response to TNFi (ACR20: 58% vs 37%, p=0.01) with better model fit compared with BMI alone. CONCLUSIONS: Lower BMI and evidence of lower adiposity based on adipokine profiles were associated with a superior response to TNFi compared with triple therapy. There was no difference between treatments among overweight/obese participants. The results support TNFi being a particularly important therapeutic among normal/underweight patients, with implications for clinical decisions and trial design.

Adherence to liraglutide among individuals with overweight and obesity: Patient characteristics and clinical measures.

AIM: To identify the sociodemographic, clinical and laboratory determinants relating to patient adherence to liraglutide treatment among individuals with overweight or obesity. METHODS: We retrospectively analysed patients with overweight or obesity who were treated with liraglutide between 2019 and 2022. Over a 6-month follow-up period, measurements of body mass index, sociodemographic characteristics, clinical and laboratory data, and prescription records for liraglutide were collected. Treatment adherence was assessed using the proportion of days covered (PDC) measure, with a PDC ≥80% indicating high adherence. RESULTS: The study population included 1890 participants (78.1% female, mean age 46 ± 12 years). At the end of the follow-up period, 84.9% of the participants exhibited low adherence to liraglutide treatment. Adherence to treatment improved with age (p = 0.04, odds ratio [OR] 1.013, confidence interval [CI] 1.001-1.025). Significant weight loss during treatment increased the likelihood of high adherence (p < 0.001, OR 1.251, CI 1.167-1.341). Individuals with a higher socioeconomic status displayed greater adherence (p = 0.023, OR 1.906, CI 1.091-3.328). Greater adherence was also seen in non-smokers (p = 0.047, OR 0.725, CI 0.528-0.996). CONCLUSIONS: Only 15.1% of study participants exhibited high adherence to treatment (PDC ≥80%) after 6 months of follow-up. Further research is needed to explore approaches to enhance adherence to liraglutide, including strategies to educate and support patients in their efforts to achieve and maintain weight loss with the use of this drug.

Impact of a pharmacist-led weight management service in a cardiology clinic.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for weight management require frequent dose titration, patient education, and insurance coverage navigation, which pharmacists are well equipped to manage. Data are lacking regarding the benefit of a pharmacist-managed service using GLP-1 RAs for weight loss in a high-risk cardiac population. OBJECTIVE: This study aimed to evaluate the impact of a pharmacist-led weight loss service within a cardiology clinic using GLP-1 RAs and lifestyle counseling in patients with overweight and obesity. PRACTICE DESCRIPTION: An outpatient cardiology clinic employs clinical pharmacists who use collaborative practice agreements to provide cardiovascular risk reduction services that did not include weight management at baseline. PRACTICE INNOVATION: This is the first description of a pharmacist-led weight management clinic using solely GLP-1 RAs in a cardiology practice. Patients were referred to the clinical pharmacist, who initiated and titrated GLP-1 RA and provided lifestyle counseling. EVALUATION METHODS: This was a single-center, prospective, pre-post analysis of adults with a body mass index of at least 30 kg/m2 or 27 kg/m2 with a weight-related comorbidity, with a preceding failed dietary effort and insurance coverage for semaglutide (Wegovy, Novo Nordisk) or liraglutide (Saxenda, Novo Nordisk) and managed by a pharmacist. The primary outcome was patients achieving ≥ 5% weight loss at 6 months, assessed via descriptive statistics. RESULTS: Between March 2022 and March 2023, 204 patients were referred by their cardiologist, and 59 patients started treatment with semaglutide (Wegovy, Novo Nordisk) or liraglutide (Saxenda, Novo Nordisk). A total of 31 patients completed 6 months of treatment at time of study completion, and all achieved ≥ 5% weight loss at 6 months, with a mean weight loss of 12.6%. Glycated hemoglobin improved by 0.6%, low-density lipoprotein by 18 mg/dL, triglycerides by 29 mg/dL, systolic blood pressure by 9 mm Hg, and diastolic blood pressure by 2 mm Hg. CONCLUSION: Pharmacist-led management of GLP-1 RA in patients with obesity or overweight led to clinically meaningful weight loss and improvements in weight-related comorbidities.

Prenatal exposure to Per- and polyfluoroalkyl substances and adiposity measures of children at 4 and 6 years: A prospective birth cohort in China.

There is growing evidence that prenatal exposure to Per- and polyfluoroalkyl substances (PFAS) was associated with childhood obesity, but evidence on multiple adiposity measures including arm circumference (AC), and waist circumference (WC) among Chinese children is limited. We investigated the associations of prenatal exposure to PFAS with adiposity measures of children at 4 and 6 years of age in the Shanghai-Minhang Birth Cohort Study. A total of 573 mother-child pairs with maternal PFAS concentrations and at least one measurement of adiposity measures of children were included in the present study. Eleven PFAS were assessed in maternal fasting blood samples. Information on children's weight, height, AC, and WC was collected at follow-ups. Weight for age Z score (WAZ), body mass index for age Z score (BMIz), and children overweight were calculated based on the World Health Organization Child Growth Standards. Multivariate linear regression, Poisson regression with robust error variance, and Bayesian Kernel Machine Regression (BKMR) models were used to examine the associations of prenatal exposure to PFAS with children's adiposity measures. Eight PFAS with detection rates above 85 % were included in the analyses. In the multivariate linear regression models, maternal PFNA concentrations were associated with a greater AC (ß = 0.29, 95 % Confidence Interval (CI): 0.04-0.55) in 4-year-old children and with an increase in WAZ (ß = 0.26, 95 % CI: 0.06-0.46), BMIz (ß = 0.31, 95 % CI: 0.09-0.53), AC (ß = 0.49, 95 % CI: 0.08-0.90), and WC (ß = 1.47, 95 % CI: 0.41-2.52) in 6-year-old children. We also observed the associations of maternal concentrations of PFOS, PFNA, PFUdA, and PFTrDA with the increased risk of children overweight in 6-year-old children. BKMR models further supported the findings from multivariate linear regression and Poisson regression models, and identified PFNA as the most important contributor. Moreover, the associations described above were generally more pronounced in girls. In conclusion, prenatal exposure to PFAS was associated with an increased risk of children's adiposity with a sex-specific manner, and PFNA contributed most to the associations after controlling for the effect of co-exposure to other PFAS compounds, especially among girls at 6 years of age.

Urinary antibiotic levels and risk of overweight/obesity in preschool children: A biomonitoring-based study from eastern China.

There is limited evidence linking antibiotic exposure, particularly from contaminated food or drinking water, to childhood obesity. The study aimed to investigate the association between urinary antibiotic levels and overweight/obesity in preschool children. In the case-control study, 121 overweight/obese preschoolers and 242 controls (aged 3-6 years) from eastern China were enrolled in 2022 based on age, sex, and study site matching. Overweight/obesity was determined using body mass index (BMI) and weight for height (WFH) criteria derived from national data. A total of 50 antibiotics from 8 categories were analyzed using ultra-performance liquid chromatography and tandem mass spectrometry (UPLC-MS/MS). We identified major dietary patterns using principal component analysis (PCA) and examined the associations of antibiotic exposure with childhood overweight/obesity using multivariate logistic regression. Twenty-four individual antibiotics were detected in more than 10 % of the samples, and overall detection rates were up to 100 %. Overweight/obese children had a higher exposure to veterinary antibiotics (VAs) than normal weight children. PCA analysis showed that children who were overweight/obese had higher scores of "Aquatic products preferred dietary pattern" and "Cereals preferred dietary pattern" compared to children with normal weight. Multivariate logistic regression analyses indicated that exposure to elevated levels of deoxytetracycline (OR: 1.72; 95 %CI: 1.00-2.93) and quinolones (OR: 1.63; 95 %CI: 1.04-2.57) was significantly related to an increased risk of BMI-based overweight/obesity. Quinolones exposure was also significantly associated with WFH-based overweight/obesity, primarily in boys. After adjustment for all covariates, higher exposure to ofloxacin (of the quinolones) was significantly related to overweight/obesity in girls. Exposure to certain antibiotics, especially quinolones, may increase the risk of overweight/obesity in preschoolers. More prospective, well-designed studies are needed to clarify these findings.

Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta-analysis including the 2-year STEP 5 trial.

AIM: To explore the safety and efficacy of subcutaneous semaglutide 2.4 mg, administered once a week in non-diabetic overweight or obese individuals. METHODS: A thorough search was performed of various databases including PubMed, Embase, the Cochrane Library, Web of Science, clinicaltrials.gov, CNKI and Wanfang from their inception up to April 11, 2023. Our aim was to identify randomized controlled trials (RCTs) that compared the efficacy of semaglutide administered once weekly with placebo in overweight or obese adults. Through a review of the literature, data were extracted from relevant studies and assessed for quality, and a meta-analysis was conducted using RevMan 5.4.1 software. RESULTS: Six RCTs comprising 3962 overweight or obese individuals were identified. The findings indicated that, in comparison to the placebo group, semaglutide caused a significant and sustainable reduction in the percentage of body weight (BW; mean difference [MD]: -11.80% [95% confidence interval {CI} -12.93, -10.68]; P < 0.00001) as well as a decrease in absolute BW (MD: -12.2 kg [95% CI -13.3, -11.1]; P < 0.00001), body mass index (MD: -4.5 kg/m2 [95% CI -4.9, -4.1]; P < 0.00001) and waist circumference (MD:-9.4 cm [95% CI -10.1, -8.8]; P < 0.00001). Moreover, it achieved a higher proportion of patients who experienced weight loss exceeding 5%, 10%, 15% and 20%. Furthermore, semaglutide showed significant efficacy in controlling blood pressure, blood sugar levels, C-reactive protein levels, and lipid profiles. In terms of safety, the most common adverse effects following semaglutide treatment were gastrointestinal adverse reactions (risk ratio: 1.49 [95% CI 1.38, 1.60]; P < 0.00001), which were generally mild to moderate in severity and temporary. CONCLUSION: In overweight or obese non-diabetic individuals, semaglutide had a remarkable and sustained weight loss effect that was well tolerated and safe.

Safety and efficacy of weight-based ganciclovir dosing strategies in overweight/obese patients.

BACKGROUND: The management of cytomegalovirus (CMV) is particularly challenging as both CMV and its usual first-line treatment, ganciclovir, are associated with neutropenia. Ganciclovir dosing is weight-based, most commonly utilizing total body weight (TBW). The subsequent high doses of ganciclovir in overweight/obese patients may increase the risk of toxicity. Utilizing adjusted body weight (AdjBW) dosing may help mitigate this risk. Therefore, the objective of this study was to evaluate the difference in toxicity and efficacy between TBW and AdjBW ganciclovir dosing strategies in overweight/obese patients. METHODS: This retrospective study conducted safety and efficacy analyses of ganciclovir courses (≥72 h) used as CMV treatment. The primary safety outcome was the incidence of neutropenia (absolute neutrophil count <1000 cells/µL), and the primary efficacy outcome was a 2-log decrease in CMV polymerase chain reaction within 4 weeks following ganciclovir initiation. In both analyses, courses were excluded in which ganciclovir was dosed outside of specified renal dosing parameters for >20% of the course. RESULTS: Among the 253 courses in the safety cohort, there was no difference in the incidence of neutropenia (17.4% vs. 13.5%, p = .50) in AdjBW compared to TBW dosing. In the 62 courses evaluating efficacy, there was no statistical difference between AdjBW and TBW dosing (60.0% vs. 45.2%, p = .28). No subgroups were identified in which AdjBW dosing was advantageous. CONCLUSION: Utilization of AdjBW ganciclovir dosing did not result in decreased neutropenia or treatment efficacy as compared to TBW dosing. Further studies with larger patient populations would be beneficial to confirm these findings.

Growth Parameters in Adolescents With Idiopathic Nephrotic Syndrome Diagnosed at the Age of 1-6 Years.

OBJECTIVE: To determine the prevalence of impaired growth parameters (height and BMI z scores) among adolescents aged 10-19 years, with onset of idiopathic nephrotic syndrome between the age of 1 and 6 years. METHODS: A cross-sectional study was conducted among adolescents aged 10-19 years with onset of idiopathic nephrotic syndrome between the age of 1-6 years, and under regular follow-up at our center. The data were retrieved for a 10-year period (2012-2022). The current weight, height and body mass index (BMI) were recorded and interpreted as per world Health Organization (WHO) growth standards. RESULTS: 116 adolescents [60 Frequently relapsing nephrotic syndrome (FRNS)/Steroid dependent nephrotic syndrome (SDNS), and 56 Steroid resistant nephrotic syndrome (SRNS)] patients were enrolled with median (IQR) age of 133 (120,168) months and age at disease onset of 48 (26,68) months. The proportion of children with overweight (BMI for age >1z and cushingoid features), obesity (BMI for age >2z), stunting (height for age (HFA) <2z), and severe stunting (HFA <3z) were 29 (25%), 3 (2.6%), 31 (26.7%), and 7 (6%), respectively. The median (IQR) cumulative steroid dose for FRNS/SDNS and SRNS group was 19986.96 (14597.1, 26181.96) mg/m2 and 14385 (10758.82, 21355.95) mg/m2, respectively (P=0.003). CONCLUSION: The proportion of short stature and overweight was high among adolescents with nephrotic syndrome, emphasizing the need for measures to reduce steroid use and other measures to support growth.

DOACs use in extreme body-weighted patients: results from the prospective START-register.

BACKGROUND: Direct oral anticoagulants (DOACs) are widely used for the treatment of venous thromboembolism (VTE) and for stroke prevention in atrial fibrillation (AF). However, evidence in obese and underweight patients is limited. We assessed the safety and effectiveness of DOACs and vitamin K antagonists (VKAs) in patients ≥ 120 kg or ≤ 50 kg enrolled in an observational prospective cohort study, the START-Register. METHODS: Adult patients started on anticoagulant therapy were followed up for a median of 1.5 years (IQR 0.6-2.8). Primary efficacy outcome was the occurrence of VTE recurrence, stroke and systemic embolism. Primary safety outcome was major bleeding (MB). RESULTS: 10,080 AF and VTE patients were enrolled between March 2011 and June 2021, 295 patients weighted ≤ 50 kg and 82 patients ≥ 120 kg. Obese patients were significantly younger than underweight patients. Rates of thrombotic events were low and similar between DOACs and VKAs in underweight patients (1 event on DOACs therapy [0.9% 95% CI 0.11-5.39] and 2 on VKAs [1.1% 95% CI 0.01-47.68]) and in overweight patients (0 events on DOACs, 1 on VKAs [1.6%, 95% CI 0.11-5.79]. Two MB events occurred on DOACs (1.9%, 95% CI 0.38-6.00) and 3 on VKAs (1.6%, 95% CI 0.04-22.06) in the underweight group; 1 MB on DOACs (5.3% 95% CI 0.33-16.68) and 2 on VKAs (3.3%, 95% CI 0.02-130.77) in the overweight group. CONCLUSIONS: DOACs seem to be effective and safe also for the treatment of patients with extreme body weights, both underweight and overweight. Further prospective studies are needed to support these findings.

Elevated Body Mass Index Is Associated with Improved Overall Survival in Castration-Resistant Prostate Cancer Patients Undergoing Prostate-Specific Membrane Antigen-Directed Radioligand Therapy.

In patients with prostate cancer scheduled for systemic treatment, being overweight is linked to prolonged overall survival (OS), whereas sarcopenia is associated with shorter OS. We investigated fat-related and body composition parameters in patients undergoing prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) to assess their predictive value for OS. Methods: Body mass index (BMI, in kg/m2) and CT-derived body composition parameters (total, subcutaneous, visceral fat area, and psoas muscle area at the L3-L4 level) were determined for 171 patients scheduled for PSMA-directed RLT. After normalization for stature, the psoas muscle index was used to define sarcopenia. Outcome analysis was performed using Kaplan-Meier curves and Cox regression including fat-related and other clinical parameters (Gleason score, C-reactive protein [CRP], lactate dehydrogenase [LDH], hemoglobin, and prostate-specific antigen levels). The Harrell C-index was used for goodness-of-fit analysis. Results: Sixty-five patients (38%) had sarcopenia, and 98 patients (57.3%) had increased BMI. Relative to the 8-mo OS in normal-weight men (BMI < 25), overweight men (25 ≥ BMI > 30) and obese men (BMI ≥ 30) achieved a longer OS of 14 mo (hazard ratio [HR], 0.63; 95% CI, 0.40-0.99; P = 0.03) and 13 mo (HR, 0.47; 95% CI, 0.29-0.77; P = 0.004), respectively. Sarcopenia showed no impact on OS (11 vs. 12 mo; HR, 1.4; 95% CI, 0.91-2.1; P = 0.09). Most of the body composition parameters were tightly linked to OS on univariable analyses, with the highest C-index for BMI. In multivariable analysis, a higher BMI (HR, 0.91; 95% CI, 0.86-0.97; P = 0.006), lower CRP (HR, 1.09; 95% CI, 1.03-1.14; P < 0.001), lower LDH (HR, 1.08; 95% CI, 1.03-1.14; P < 0.001), and longer interval between initial diagnosis and RLT (HR, 0.95; 95% CI, 0.91-0.99; P = 0.02) were significant predictors of OS. Conclusion: Increased fat reserves assessed by BMI, CRP, LDH, and interval between initial diagnosis and RLT, but not CT-derived body composition parameters, were relevant predictors for OS. As BMI can be altered, future research should investigate whether a high-calorie diet before or during PSMA RLT may improve OS.

Relationship Between Pretreatment Body Composition and Clinical Outcomes in Patients With Metastatic Renal Cell Carcinoma Receiving First-Line Ipilimumab Plus Nivolumab.

INTRODUCTION: Biomarkers are needed to identify patients with metastatic renal cell carcinoma (mRCC) most likely to benefit from immune checkpoint inhibitors. We examined associations between radiographically assessed body composition (BC) variables and body mass index (BMI) with clinical outcomes for patients with mRCC receiving first-line ipilimumab + nivolumab (ipi/nivo). PATIENTS AND METHODS: We retrospectively reviewed all patients with mRCC treated with first-line ipi/nivo at one institution before June 1, 2021 with an analyzable baseline computed tomography (CT) scan. BC variables (skeletal muscle index [SMI], subcutaneous adipose tissue index [SATI], and visceral adipose tissue index [VATI]) were measured using baseline CT scans. Relationships between BC variables and clinical outcomes were examined using Cox proportional hazard regression models. RESULTS: Ninety-nine patients were analyzed (74% male, 64% overweight/obese, 75% low SMI). Controlling for age, IMDC risk, and sex (for BMI analyses), high vs. low SMI (HR=2.433, CI: 1.397-4.238, P=.0017), high vs. low SATI (HR=1.641, CI: 1.023-2.632, P=.0398), and obese BMI (≥ 30 kg/m2) vs. normal/overweight BMI (<30 kg/m2) (HR=1.859, CI: 1.156-2.989, P=.0105) were significantly associated with progression-free survival (PFS). Median overall survival (OS) for low SMI patients was higher (42.74 months, CI: 26.84, NR) than median OS for high SMI patients (27.01 months, CI: 15.28, NR) (adjusted HR=1.728, CI: 0.909-3.285, P=.0952). No BC variables were significantly associated with OS or objective response rate. CONCLUSIONS: Low SMI and low SATI were associated with significantly better PFS for patients with mRCC receiving first-line ipi/nivo. Radiographic BC variables may be useful prognostic biomarkers in this setting.

Associations of Gestational Perfluoroalkyl Substances Exposure with Early Childhood BMI z-Scores and Risk of Overweight/Obesity: Results from the ECHO Cohorts.

BACKGROUND: Gestational per- and polyfluoroalkyl substances (PFAS) exposure may be associated with adiposity and increased risk of obesity among children and adolescents. However, results from epidemiological studies evaluating these associations are inconsistent. OBJECTIVES: We estimated the associations of pregnancy PFAS concentrations with child body mass index (BMI) z-scores and risk of overweight/obesity in eight U.S. cohorts. METHODS: We used data from 1,391 mother-child pairs who enrolled in eight Environmental influences on Child Health Outcomes (ECHO) cohorts (enrolled: 1999-2019). We quantified concentrations of seven PFAS in maternal plasma or serum in pregnancy. We measured child weight and height between the ages of 2 and 5 y and calculated age- and sex-specific BMI z-scores; 19.6% children had more than one BMI measurement. We estimated covariate-adjusted associations of individual PFAS and their mixture with child BMI z-scores and risk of overweight/obesity using linear mixed models, modified Poisson regression models, and Bayesian approaches for mixtures. We explored whether child sex modified these associations. RESULTS: We observed a pattern of subtle positive associations of PFAS concentrations in pregnancy with BMI z-scores and risk of overweight/obesity. For instance, each doubling in perfluorohexane sulfonic acid concentrations was associated with higher BMI z-scores (ß=0.07; 95% CI: 0.01, 0.12). Each doubling in perfluroundecanoic acid [relative risk (RR)=1.10; 95% CI: 1.04, 1.16] and N-methyl perfluorooctane sulfonamido acetic acid (RR=1.06; 95% CI: 1.00, 1.12) was associated with increased risk of overweight/obesity, with some evidence of a monotonic dose-response relation. We observed weaker and more imprecise associations of the PFAS mixture with BMI or risk of overweight/obesity. Associations did not differ by child sex. DISCUSSION: In eight U.S.-based prospective cohorts, gestational exposure to higher levels of PFAS were associated with slightly higher childhood BMI z-score and risk of overweight or obesity. Future studies should examine associations of gestational exposure to PFAS with adiposity and related cardiometabolic consequences in older children. https://doi.org/10.1289/EHP11545.

Safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of the novel long-acting glucagon analogue HM15136 in overweight and obese patients with co-morbidities.

AIM: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of the novel long-acting glucagon analogue HM15136 in overweight/obese patients with co-morbidities, with and without type 2 diabetes (T2D). MATERIALS AND METHODS: This was a phase 1, double-blind, randomized, placebo-controlled, two-part trial with a 12-week treatment period of once-weekly subcutaneous HM15136 (0.02/0.04/0.06 mg/kg). Part 1 included patients with dyslipidaemia and/or hypertension and no T2D. Part 2 included patients with dyslipidaemia and/or hypertension plus T2D. RESULTS: In part 1, 23/27 (85.2%) patients receiving HM15136 and all patients receiving placebo (9/9 [100%]) experienced a treatment-emergent adverse event (TEAE). Five of 27 (18.5%) patients receiving HM15136 developed anti-HM15136 antibodies. Dose-dependent increases in mean HM15136 serum concentration and fasting plasma glucose (FPG) were observed, as were dose-dependent weight reductions of 0.5%/2.3%/2.6% at doses of 0.02/0.04/0.06 mg/kg, respectively. In part 2, 8/12 (66.7%) patients receiving HM15136 and all patients receiving placebo (4/4 [100.0%]) reported a TEAE. Two (16.7%) patients developed anti-HM15136 antibodies. Dose-dependent increases in mean HM15136 serum concentration were observed. FPG of more than 200 mg/dL was reported in 4/9 (44.4%) and 2/3 (66.7%) patients receiving 0.02 and 0.06 mg/kg, respectively. The 0.06 mg/kg dose was not tolerated in part 2 because of hyperglycaemia. Patients receiving 0.02 mg/kg showed a 0.9% weight reduction. No serious TEAEs leading to discontinuation were reported in either study part. CONCLUSIONS: This study of HM15136 provides a preliminary safety and tolerability profile with initial insights into its efficacy profile.

Effects of metformin on glycaemic variability in combination with insulin in overweight/obese patients with type 1 diabetes.

BACKGROUND: The prevalence of overweight and obesity in type 1 diabetes mellitus (T1DM) individuals is increasing. Overweight people with T1DM may be insulin resistant. Glycaemic variability (GV) is an emerging measure of glycaemic control. The aim of this study is to investigate whether metformin, in adjunct to insulin, would have any favourable effect on GV. METHODS: This was a multi-centre, open-label randomised crossover study. Twenty-four overweight/obese T1DM patients aged ⩾18 years old with HbA1c ⩾ 7.0% (53 mmol/mol) were recruited and randomised into two study arms. For first 6-week, one arm remained on standard of care (SOC), the other arm received metformin, adjunctive to SOC. After 2-week washout, patients crossed over and continued for another 6 weeks. Glycaemic variability, other glycaemic parameters and metabolic profile were monitored. RESULTS: There were significant reduction in metformin group for GV: mean (0.18 ± 1.73 vs -0.95 ± 1.24, p = 0.014), %CV (-15.84 (18.92) vs -19.08 (24.53), p = 0.044), glycemic risk assessment of diabetes equation (-0.69 (3.83) vs -1.61 (3.61), p = 0.047), continuous overlapping net glycaemic action (0.25 ± 1.62 vs -0.85 ± 1.22, p = 0.013), J-index (-0.75 (21.91) vs -7.11 (13.86), p = 0.034), time in range (1.13 ± 14.12% vs 10.83 ± 15.47%, p = 0.032); changes of systolic blood pressure (2.78 ± 11.19 mmHg vs -4.30 ± 9.81 mmHg, p = 0.027) and total daily dose (TDD) insulin (0.0 (3.33) units vs -2.17 (11.45) units, p = 0.012). Hypoglycaemic episodes were not significant in between groups. CONCLUSION: Metformin showed favourable effect on GV in overweight/obese T1DM patients and reduction in systolic blood pressure, TDD insulin, fasting venous glucose and fructosamine.

Gut microbiome profiles may be related to atypical antipsychotic associated overweight in Asian children with psychiatric disorder: a preliminary study.

Objective: Atypical antipsychotics (APs) modify the gut microbiome, and weight gain in response to AP could be mediated by the gut microbiome. Thus, the present study aimed to explore the changes in the gut bacterial microbiome in AP-exposed children with obesity. Methods: To rule out the confounder of AP indication, the gut bacterial microbiome was compared between healthy controls (Con) and AP-exposed individuals with overweight (APO) or normal weight (APN). Fifty-seven AP-treated outpatients (21 APO and 36 APN) and 25 Con were included in this cross-sectional microbiota study. Results: AP users, regardless of body mass index, exhibited decreased microbial richness and diversity and a distinct metagenomic composition compared to the Con. Although no differences in the microbiota structure were observed between APO and APN groups, the APO group was characterised by a higher abundance of Megamonas and Lachnospira. Additionally, the differences in the microbial functions were observed between APO and APN groups. Conclusions: The gut bacterial microbiota of APO children revealed taxonomic and functional differences compared to Con and APN. Further studies are needed to verify these findings and to explore the temporal and causal relationships between these variables.

Impact of body mass index on the severity of bexarotene-associated hypertriglyceridemia: A post hoc analysis of an open-labeled clinical study of combined bexarotene and phototherapy in Japanese patients with cutaneous T-cell lymphoma.

Bexarotene is an effective oral drug for the treatment of cutaneous T-cell lymphoma, but careful management is required due to its various side effects. In particular, hypertriglyceridemia often requires a reduction or even suspension of bexarotene therapy. The risk factors of bexarotene-associated severe hypertriglyceridemia are not clear. Here, we conducted a post hoc analysis of the data from our previous clinical trial, which confirmed the efficacy and safety of combined bexarotene and phototherapy, to evaluate the effect of body mass index on bexarotene-associated hypertriglyceridemia. Twenty-five subjects were divided into two subgroups: normal and underweight (body mass index [BMI] <25 kg/m2 group) and overweight and obese (BMI ≥25 kg/m2 group) patients. The overall incidence of hypertriglyceridemia was 81.3% (13/16) in the BMI <25 kg/m2 group and 88.9% (8/9) in the BMI ≥25 kg/m2 group. The incidence of grade ≥3 hypertriglyceridemia (≥500 mg/dL) was 7.7% (1/13) in the BMI <25 kg/m2 group and 7/8 (87.5%) in the BMI ≥25 kg/m2 group (P < 0.001). Consequently, dose reduction in the BMI ≥25 kg/m2 group was larger than that in the BMI <25 kg/m2 group. The bexarotene-induced change in the serum triglyceride concentration was significantly increased in cutaneous T-cell lymphoma patients with a higher body mass index (ρ = 0.508, P = 0.009). The area under the curve was 0.886 (95% confidence interval 0.748-1.000, P = 0.002). With a body mass index cut-off of 24.85 kg/m2 , the sensitivity and specificity for identifying grade ≥3 hypertriglyceridemia were 0.875 and 0.882, respectively. The present findings suggest that BMI ≥25 kg/m2 is a risk factor for bexarotene-associated severe hypertriglyceridemia, therefore overweight and obese patients treated with bexarotene should receive lipid-lowering drugs prophylactically. Further studies for optimizing the initial bexarotene dose in such patients are required.

Impact of body mass on P2Y12-inhibitor de-escalation in acute coronary syndromes-a substudy of the TROPICAL-ACS trial.

AIMS: Clinical guidelines recommend de-escalation antiplatelet strategies to reduce bleeding risk in acute coronary syndrome (ACS) patients, albeit with a weak recommendation. This substudy of the TROPICAL-ACS trial aimed to determine the impact of body mass on the efficacy of a platelet function testing-guided de-escalation regimen in ACS patients after percutaneous coronary intervention. METHODS AND RESULTS: Patients were randomized to prasugrel (control group) or a platelet function testing-guided regimen with clopidogrel or prasugrel defined after 1-week clopidogrel. The primary endpoint was the net clinical benefit [cardiovascular death, myocardial infarction, stroke, or Bleeding Academic Research Consortium (BARC) 2-5 bleeding] for 12 months. Overweight was defined as a body mass index >25 kg/m2.Patients without overweight showed a significant net clinical benefit from the de-escalation strategy, while in overweight cases de-escalation was comparable to prasugrel treatment [hazard ratio (HR): 0.52; 95% confidence interval (CI): 0.31-0.88; P = 0.013 and HR: 0.95; 95% CI: 0.69-1.31, P = 0.717, P-non-inferiority = 0.03, respectively, P-interaction = 0.053]. The benefit of de-escalation in terms of the risk of bleeding or of the ischaemic events did not reach statistical significance. Bleeding events with de-escalation were less frequent in non-overweight patients but comparable in overweight patients (HR: 0.55; 95% CI: 0.30-1.03; P = 0.057 and HR: 0.95; 95% CI: 0.64-1.41, respectively, P-interaction = 0.147). Non-overweight patients had lower ischaemic event rates with de-escalation, while overweight cases had slightly less (HR: 0.47; 95% CI: 0.18-1.25; P = 0.128 and HR: 0.89; 95% CI: 0.53-1.50, respectively, P-interaction = 0.261). CONCLUSION: The strategy of guided dual antiplatelet therapy de-escalation was associated with a significant net clinical benefit in non-overweight patients, while the two strategies were equivalent in overweight patients.

The association of body mass index with safety and effectiveness of first-line carboplatin-based chemotherapy in patients with metastatic non-small cell lung cancer.

INTRODUCTION: Carboplatin is an anticancer drug used for treatment of various types of cancer including non-small cell lung cancer (NSCLC). Dosing is based on estimated glomerular filtration rate (GFR) using the Cockcroft-Gault formula. In overweight patients, the GFR is more likely overestimated, resulting in a potentially overdose of carboplatin affecting treatment response. This study investigated the association of body mass index (BMI) on overall survival (OS) and progression-free survival (PFS) in stage-IV NSCLC patients treated with first-line carboplatin-based chemotherapy. Secondary safety endpoints were thrombocytopenia and toxicity-related hospitalizations. MATERIALS AND METHODS: This was a retrospective multicenter cohort study. Patients were categorized according to BMI<25.0 kg/m2 (normal weight and reference), 25.0-29.9 kg/m2 (overweight) or ≥30.0 kg/m2 (obese). For survival analyses adjusted hazard ratios [aHR] were calculated using multivariate Cox regression analysis. Secondary outcomes were analyzed using multivariate logistic regression providing adjusted odd ratios [aOR]. RESULTS: Overweight patients (n=174) had a significantly better OS (aHR=0.72, 95%-CI:0.59-0.89) and PFS (aHR=0.74, 95%-CI:0.61-0.90) compared to normal weight patients (n=268). OS nor PFS were different in obese (n=51) compared to normal weight patients. However, obesity was associated with significantly higher incidences of thrombocytopenia grade ≥3 (aOR=3.47, 95%-CI:1.75-6.90). CONCLUSION: This study shows a significantly longer survival for overweight compared to normal weight patients. Obese patients have an increased risk for grade ≥3 thrombocytopenia without a difference in survival following carboplatin-based chemotherapy. The implications for clinical practice are to use the Cockcroft-Gault formula with caution in patients with BMI≥30.0 kg/m2, and to verify calculated dosing of carboplatin for appropriateness.

Associations of phthalates with prostate cancer among the US population.

Human exposure to harmful phthalates has raised global health concerns. According to cellular and molecular investigations, phthalates and their metabolites can promote prostate cancer (PCa). Despite being a prevalent cancer afflicting the global male population, the epidemiological association between phthalates and prostate cancer remains understudied. This work aims to investigate whether phthalate metabolites are related to prostate cancer. Moreover, we sought to understand whether their elevated concentrations are associated with increased serum concentrations of prostate-specific antigen (PSA), among non-prostate cancer interviewees. According to National Health and Nutrition Examination Survey (NHANES) data from 2003 to 2010, we screened eligible men aged 20 years or older. Then, crude and multivariate regression models were constructed to assess the relationship. The phthalates significantly related to PCa were analyzed based on variables associated with PCa status and PSA. The molar sum ∑di-2-ethylhexyl phthalate (∑DEHP) was simultaneously associated with increased risk of PCa and increasing PSA concentrations. Among PCa-related phthalates, high molecular weight phthalate metabolites included mono-benzyl phthalate (MBzP) and three metabolites of DEHP. In summary, phthalates are potentially associated with prostate tumorigenesis in the US population. However, additional in-depth prospective studies in different ethnic groups are required to validate the causality between both.

Association between body mass index and long-term clinical outcomes in patients with non-valvular atrial fibrillation taking oral anticoagulants.

BACKGROUND AND AIMS: The association between body mass index (BMI) and clinical outcomes of patients with non-valvular atrial fibrillation (NVAF) taking oral anticoagulants (OACs) are controversial, and we thus analyzed the large registry data to elucidate them. METHODS AND RESULTS: We conducted a historical cohort study at 71 centers in Japan and included outpatients with NVAF taking vitamin K antagonists (VKAs). Physicians in charge could change VKAs to direct OACs based on their judgement during follow-up period. We categorized patients into four BMI groups (kg/m2): underweight (BMI < 18.5), normal weight (18.5 ≤ BMI < 25), overweight (25 ≤ BMI < 30), and obese (30 ≤ BMI). The effects of each BMI group relative to the normal weight group on clinical outcomes consisting of all-cause death, ischemic events, and bleeding events were estimated using Cox proportional hazard models adjusting for potential confounders. We also constructed restricted cubic spline regression model adjusted by multivariable Cox proportional hazard models. We included 6927 patients consisting of an underweight (n = 386), normal weight (n = 3785), overweight (n = 2174), and obese (n = 582) groups. The median follow-up period was 3.9 years. In the underweight group, the adjusted hazard ratios (HRs) for all-cause death and ischemic events were 1.75 (1.30-2.34) and 1.61 (1.04-2.50). The HR for all-cause death was 0.63 (0.49-0.82) in the overweight group. Restricted cubic spline regression models confirmed that lower BMI showed significantly higher risks for all-cause death and ischemic events. CONCLUSION: Among NVAF patients taking OACs, underweight patients had higher risks of all-cause death and ischemic events than other patients. Overweight patients had lower risk of all-cause death.