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.
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.
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.
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.
Background: Increases in population waist circumference (WC) are happening at a different speed than body mass index (BMI). Assessing recent trends in WC and BMI gives us a better glimpse of how fat ...distribution has varied in and across populations and allows a better prediction of obesity associated-diseases. We investigated the changes in WC relative to BMI in five countries and assessed whether any secular changes in mean WC occurred independently of BMI. Methods: We used adult data from 1997 to 2020 from the US, England, Chile, Mexico and Peru nationally representative surveys. Sex-specific country-stratified (for the US, also race-/ethnicity) regressions were used to estimate the annual change in mean WC relative to BMI level, adjusting for age and survey year. We also tested interactions between BMI and survey year. Results: We observed increases in predicted mean WC for a given BMI level across countries except for Peru and USA-Non-Hispanic Black and USA-Mexican American populations. Overall results showed that mean WC among females increased more than males. Among females, mean WC increased more over time only at higher levels of BMI. The largest annual increase in WC was found in USA-Non-Hispanic White females (0.27cm/year, 95% CI 0.18, 0.36) with the largest reduction observed for Peru females (-0.27cm/year, 95% CI -0.46, -0.07) at BMI 35kg/m2. In contrast, males showed a more stable annual change in WC independently of BMI. Only significant increases were observed for Mexico and England males with the higher annual mean change observed for Mexico males at a BMI of 35 kg/m2 (0.14cm/year, 95% CI 0.08, 0.20). The largest reduction in WC was observed for Peru males (-0.47cm/year, 95% CI -0.76, -0.17) at that same BMI level. Conclusions: Over the last two decades, we observed across countries that secular increases in mean WC have been larger in females than males. These changes have largely occurred independently of the level of BMI. These differences bring a significant increase in disparities in abdominal obesity-associated diseases.
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.
