Background: Hypothalamic obesity (HO) is an acquired form of severe obesity characterized by rapid and excessive weight gain resulting from insult to the hypothalamus-primarily caused by tumor ...invasion, resection, or radiotherapy-that can impair melanocortin-4 receptor (MC4R) pathway signaling. Treatment with setmelanotide, an MC4R agonist, resulted in weight and hunger reduction at 16 weeks in a Phase 2 trial of patients with HO. Here, we report changes in weightrelated parameters after 12 months of setmelanotide treatment in patients with HO who entered a long-term extension (LTE) trial. Methods: The Phase 2, multicenter, open-label study (NCT04725240) was a 16-week trial in patients aged >6 to <40 years with a clinical diagnosis of HO. Patients who demonstrated adequate safety and meaningful clinical benefit were eligible to enroll in the LTE trial (NCT03651765). Mean (standard deviation SD) percent change in body mass index (BMI) for all patients and mean (SD) change in percent of the 95th BMI percentile (%BMI95) for children (aged <18 years) from index trial baseline to Month 12 of setmelanotide treatment were assessed. Results: Of 14 patients who entered the LTE, 12 (86%) received >12 months of setmelanotide at the time of analysis. One adult who experienced nausea discontinued study drug at 7 months and 1 child who had been lost to follow-up reconsented and reentered the LTE but did not have 12-month data. At Month 12, the mean (SD) percent BMI change from baseline was -24.9% (13.0%) across all patients (n = 12) and in children (n = 11), the mean (SD) change in %BMI95 was -39.5 (19.4) percentage points. No new safety signals were identified. Conclusions: In a heterogeneous population of patients with HO secondary to treatment of hypothalamic tumors, 12 months of setmelanotide treatment was associated with sustained meaningful BMI improvement with no new safety signals.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background: The medicinal use of vinegar dates to ancient times, and empirical evidence has mounted over the past several decades supporting health benefits from vinegar ingestion, including ...reductions in blood glucose, blood pressure, and blood cholesterol. Additionally, although clinical trial data are mixed, there are several reports demonstrating reductions in body mass and fat mass with daily vinegar ingestion. This blinded, randomized controlled trial examined the impact of daily vinegar ingestion on anthropometric measures in healthy young adults recruited from a campus population. Methods: Participants (n = 28; aged 25.8 ± 7.0 years; body mass index BMI >23 kg/m2) were stratified by age, sex, and BMI and randomly assigned to the liquid VIN or pill CON groups. VIN participants diluted 2 tablespoons of red wine vinegar (750 mg acetic acid; Pompeian Inc.) in 8-12 ounces of water to drink with food at meal-time twice daily. CON participants consumed 1 vinegar pill daily (30 mg acetic acid; Walmart's Spring Valley brand). All participants provided written consent for this IRB approved trial. The study lasted 4 weeks, and anthropometric measurements were conducted in a fasted state at weeks 0 and 4. Study adherence varied slightly (90 ± 17% and 100 ± 14% for VIN and CON respectively, p = 0.084); hence, adherence was controlled for in all analyses. Results: Changes in BMI (-0.1 ± 0.5 and + 0.1 ± 0.3 kg/m2, p = 0.127) and body weight (-0.3 ± 1.4 and + 0.1 ± 1.1 kg, p = 0.158) did not differ significantly between VIN and CON groups respectively. However, both waist circumference and percent body fat were reduced significantly for VIN participants in comparison to CON participants (-0.5 ± 1.3 vs. +0.7 ± 2.4 cm p = 0.026 and -0.4 ± 0.7 vs. +0.3 ± 1.0% p = 0.045). Conclusions: Although the observed differences between groups are modest, the study was short of duration and did not apply energy restriction or exercise interventions, suggesting a possible benefit of vinegar ingestion on adiposity.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background: Obesity is common among African American and Hispanic children. Body mass index (BMI) is a more frequently reported measure of obesity than others, such as waist-to-height ratio (WHtR), ...which focuses on central obesity. We used 4 anthropometric measures to assess obesity and to characterize its relationships with children's characteristics, including age, sex, country of birth, ethnicity, and physical activity among children attending NYC Head Start. Methods: We analyzed baseline data from the Endotoxin Obesity and Asthma longitudinal study, in which mothers answered a demographic questionnaire about their child. We obtained anthropometric measurements (weight, height, skinfold thickness (SFT), and waist circumference) from children and calculated BMI, triceps and subscapular zscores, and WHtR. Results: Of 380 children, mean age 48 months, 50% were female. 25% of Mexican origin, 18% Dominican, 19% African American, 15% Puerto Rican, and 23% Other. Overall, 44% were above the 85th percentile for BMI. 75% had WHtR greater than 0.5 (obesity). Mean triceps SFT was at the 49th percentile and mean subscapular SFT at the 52nd percentile for age and sex. Children did not differ on BMI or subscapular SFTs by ethnic background. Mexican children had greater triceps z-scores (p=0.03) and WHtR (p<0.001) than others. Age was positively associated with subscapular z-score (p=0.02) and negatively associated with WHtR (p<0.001). US-born children had higher BMI z-scores than others. Conclusions: Overall, the adiposity profiles of children in the sample were poor but consistent with national data. Few factors were associated with adiposity measures, but Mexican origin was a risk factor for obesity.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background: Alström syndrome is characterized by multiorgan dysfunction and obesity associated with impaired primary cilia function that may disrupt melanocortin-4 receptor (MC4R) pathway signaling. ...We evaluated the impact of ≥6 months of the MC4R agonist setmelanotide in patients with Alström syndrome. Methods: Patients with Alström syndrome aged ≥6 years were enrolled in Phase 2 and 3 trials of setmelanotide (NCT03013543, NCT03746522). Changes in weight, hunger, and quality of life (QOL) were evaluated. Clinical benefit was defined as meaningful improvement (ie, ≥5% body weight and/or body mass index BMI reduction for adults or ≥0.2 decrease in BMI Z score and/or ≥5-percentage point decrease in the percentage of the 95th percentile for BMI for pediatric patients, ≥25% decrease in hunger score, and/or increase in IWQOL-Lite score of >7.7 or increase in PedsQL score of >4.4). Adverse events (AEs) were assessed. Results: Eight patients received >6 months of treatment (range, 9.7-18.2 months). No patients aged >18 years achieved >5% body weight loss/BMI reduction; however, 1 of 2 adults (50%) had >25% decrease in hunger score. Five of 6 (83.3%) and 3 of 6 patients (50%) aged <18 years achieved >0.2- and >0.3-point decrease in BMI Z score, respectively. Three of 4 patients (75%) aged >12 to <18 years achieved >25% hunger score decrease. Two of 8 patients (25%) had improved QOL. Overall, 7 of 8 patients (87.5%) had improvement in >1 measure. Tolerability of setmelanotide was consistent with that in other rare MC4R disease populations. The most common AE was skin hyperpigmentation (10 of 12 patients 83.3%). Three patients discontinued treatment because of AEs; 1 AE (facial edema) was related to setmelanotide. Conclusions: Most patients with Alström syndrome had positive response regarding clinical benefit of setmelanotide across weight, hunger, and QOL. Further research into the full extent of clinical benefit and specific characteristics of responders is needed.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background: Limited data exist regarding the association of degree of intentional weight reduction and incident obesity-related complications. Methods: Optum's Market Clarity database (2007-2020) was ...used to identify individuals >18 years of age with overweight/obesity, defined by body mass index (BMI), who intentionally reduced and maintained their weight (surgery, procedure, medication, lifestyle) from their highest BMI (index date) 6 months prior to and including the intervention start (pre-index period) over 3 years (weight reduction period). Follow-up continued until the earliest of end of clinical activity, death, pregnancy, or 29FEB2020. Individuals were classified by the age change BMI during the weight reduction period: 0%-<5%, 5%-<10%, 10%-<15%, 15%-<20%, 20%-<30%, and >30%. Kaplan-Meier analysis was used to estimate time to first diagnosis of type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) in follow-up among individuals with no diagnosis during the pre-index or weight reduction periods. Results: Of 145,944 eligible individuals, the mean age was 50.3 (SD 13.4) years, 71% were female, 15% were African American, and mean index BMI was 39.2 (SD 9.3). The largest and smallest BMI change cohorts were 0%-<5% (38.2%) and >30% (6.7%), respectively. Three years after the weight reduction period (6 years post index), T2D and ASCVD incidence was estimated at 6.0% and 5.7%, respectively, though incidence differed by degree of BMI reduction, p<0.001 for both (T2D diagnosis: 0%-<5%: 7.3%, 5%-<10%: 6.7%, 10%-<15%: 5.1%, 15%-<20%: 4.0%, 20%-<30%: 3.3%, and >30%: 3.2%; ASCVD diagnosis: 0%-<5%: 5.9%, 5%-<10%: 6.3%, 10%-<15%: 6.2%, 15%-<20%: 5.5%, 20%-<30%: 4.6%, and >30%: 3.7%). Conclusions: T2D and ASCVD incidence at six years post index were inversely associated with the degree of intentional weight reduction. For T2D, incidence decreased monotonically. For ASCVD, the association was not linear.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background: In the past 30 years, obesity prevalence has doubled among adults in the U.S. and disproportionately affected ancestral minorities. The prevalence of severe obesity in the U.S. in 2013 ...was nearly twice as high in women (9.9%) as men (5.5%) and highest in minority groups, particularly Hispanic/Latinos (H/L). Environmental and genetic contributions to severe obesity are widely acknowledged, yet few studies have estimated the heritability of adult severe obesity. Methods: We assembled the largest multi-ancestral genome-wide association study (GWAS) of severe obesity phenotypes in 120,676 participants (62% female; 65% WHITE, 15% Black, 14% H/L, 3% East Asian). We estimated the heritability of three traits: age and sex stratified defined severe obesity 95th percentile body mass index (BMI) vs. 5-50th percentile BMI controls; class 3 obesity (BMI>40) vs. BMI<25 controls; and class 4 obesity (BMI>50) vs. BMI<25 controls. Further, we calculated the genetic correlation (rg) between each trait with BMI. We conducted analyses for the whole sample, and stratified by sex and self-reported ancestry, via linkage disequilibrium score regression. Results: The SNP-based heritability for 95th percentile BMI, class 3 obesity, and class 4 obesity is 0.13 (SE=0.01), 0.27 (0.01), and 0.29 (0.02), respectively. All three traits displayed rgs above 0.90 with BMI. Men had a significantly higher heritability than women for class 4 sity (0.05) vs. 0.31 (0.02). Heritability also differed by self-reported ancestry, with values of 0.17 (0.01), 0.37 (0.02), 0.52 (0.04) in WHITE participants, 0.11 (0.02), 0.22 (0.04), 0.08 (0.05) in BLACK participants, and 0.13 (0.03), 0.27 (0.05), 0.11 (0.08) in H/L, for 95th percentile BMI, class 3 obesity, and class 4 obesity, respectively. Conclusions: Results suggest distinct patterns of heritability by sex and ancestry. Although only limited evidence exists for sex- and ancestral-specific BMI loci, our study supports sex- and ancestral-specific GWAS for severe obesity traits.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
