The association between previous use of anti-obesity medication and semaglutide weight loss outcomes.

AIMS: To compare weight loss outcomes between patients starting semaglutide who had previously been on another anti-obesity medication (AOM) compared to those who were AOM-naïve. MATERIALS AND METHODS: We performed a retrospective study in patients with overweight or obesity taking semaglutide for weight loss for a duration of 3 to 12 months. Our primary endpoint was assessment of percentage of total body weight loss (TBWL) in patients who started semaglutide as their first AOM (AOM-naïve) compared to those who started semaglutide and had previously taken another AOM (non-AOM-naïve). The secondary outcome was a comparison of the proportions of patients achieving ≥5%, ≥10%, ≥15% and ≥20% TBWL between the groups. Our endpoints were analysed using independent t-tests and ANOVA/ANCOVA for continuous variables and Pearson's test for categorical variables. RESULTS: This study included 305 patients. Outcomes of semaglutide treatment were superior in AOM-naïve patients (n = 231) compared to non-AOM-naïve patients (n = 74) at 3 (6.3% vs. 3.8%), 6 (10.6% vs. 6.7%), 9 (14.0% vs. 9.1%) and 12 months (14.3% vs. 10.6%; p < 0.0001 at 3, 6 and 9 months, and p = 0.01 at 12 months). A greater proportion of patients in the AOM-naïve group achieved a TBWL ≥ 15% (48% vs 21%; p = 0.02) and ≥20% (27% vs 4% p < 0.01) at 12 months. CONCLUSION: The use of semaglutide in patients with previous intake of other AOMs was associated with inferior weight loss outcomes in comparison to patients who were AOM-naïve.

Leptin-Melanocortin pathway variants and gastric emptying in patients with obesity.

BACKGROUND: Accelerated gastric emptying (GE) is a trait seen in obesity. Mutations in the hypothalamic leptin-melanocortin 4 receptor (Leptin-MC4R) pathway have been associated with obesity. We sought to investigate the association of leptin-MC4R pathway variants and GE in patients with obesity. METHODS: This is a cross-sectional study of patients with a history of severe obesity that were genotyped and completed a GE test by scintigraphy. We evaluated the percentage of GE (GE %) at 2 and 4 h between both groups using ANCOVA with weight and sex as covariates. We subdivide patients into carriers based on the location of the identified variants (i.e., upstream or downstream of the Leptin-MC4R pathway) and compared them with noncarriers using ANOVA. Results are presented as mean and standard deviation (± SD). KEY RESULTS: A total of 95 patients; nine carriers (67% females; 39.78 ± 12.33 years; BMI: 49.14 ± 12.96 kg/m2) and 86 noncarriers (87% female; 49.98 ± 13.74 years; BMI: 40.75 ± 6.29 kg/m2) were included. At 2 and 4 h, carriers had a delayed GE when compared noncarriers (p = 0.03 and p = 0.005, respectively). In carriers, when compared upstream carriers vs. downstream carriers vs. noncarriers by location there was a significant difference in GE among groups at 2 h and at 4 h (p = 0.02 and p = 0.01, respectively). CONCLUSIONS & INFERENCES: Carriers of heterozygous variants in the Leptin-MC4R pathway had a delayed GE compared to noncarriers. These findings point the important relationship between the Leptin-MC4R pathway and gastric motility.

Analysis of 1999-2017 NHANES Data: Minimal Increase and Racial Disparities in U.S. Fiber Consumption Over 18 Years.

Low dietary fiber consumption is associated with an increased risk of colorectal cancer, a leading cause of cancer-related mortality in the United States. The average daily fiber intake has declined over recent decades. Notably, Black Americans exhibit lower fiber consumption than other racial/ethnic groups, possibly influencing their elevated colorectal cancer rates. We hypothesize that there has been a significant increase in dietary fiber consumption in the United States from 1999 to 2017. The study encompassed 59,204 adult NHANES participants and observed variations in caloric intake over survey years. Although there was a slight overall increase in dietary fiber intake compared to 1999, the most substantial increment occurred among individuals classified as Hispanic (AD: +2.86 g, P < 0.001), followed by non-Hispanic Black (AD: +1.64 g, P < 0.001), and finally non-Hispanic White showed a decrease in fiber intake (AD: -0.86 g, P < 0.001). The findings suggest a modest rise in fiber consumption from 1999 to 2017, but disparities persist, particularly with non-Hispanic Black individuals consuming the least fiber. This emphasizes the need for interventions to promote fiber intake and address racial/ethnic inequalities in dietary habits.

Weight loss and cardiovascular disease risk outcomes of semaglutide: a one-year multicentered study.

BACKGROUND/OBJECTIVE: There are limited real-world studies assessing semaglutide weight loss and associated comorbidity and metabolic outcomes over periods ≥ 6 months. We aim to assess weight loss, metabolic, and cardiovascular outcomes of 12 months of semaglutide. SUBJECT/METHODS: We conducted a multicentered retrospective cohort study on semaglutide use. We included patients with a body-mass index (BMI) ≥ 27 kg/m2 who were prescribed weekly semaglutide subcutaneous injections. We excluded patients with bariatric surgeries, taking other anti-obesity medications, and with active malignancy or pregnancy. A total of 1023 patients had semaglutide prescription for obesity. INTERVENTION/METHODS: We assessed weight loss outcomes of subcutaneous semaglutide for 12 months. The primary endpoint was total body weight loss percentage (TBWL%) at 12 months. Secondary endpoints included proportion of patients achieving ≥5%, ≥10%, ≥15%, and ≥20% weight loss, and improvements in metabolic, cardiovascular, and comorbidities after 12 months of follow-up. RESULTS: We included 304 patients (73% female, 93% White, mean age 48.8 [12.4] years, BMI 40.9 [9.6] kg/m2) in the analysis. Patients achieved a TBWL of 13.4 (8.0)% at 12 months (p < 0.001 from baseline). Patients without T2DM achieved a TBWL of 16.9 (6.9)% compared to 9.9 (8.4)% in patients without T2DM at 12 months on the higher doses of semaglutide (p < 0.001 from baseline). In this cohort, 81% achieved ≥5%, 64% achieved ≥10%, 41% achieved ≥15%, and 22% achieved ≥20% TBWL at 12 months. Patients with overweight or obesity experienced significant improvements in metabolic, lipid profile, blood pressure, liver function tests, and cardiovascular disease risk outcomes. CONCLUSIONS: Semaglutide demonstrated notable improvement in obesity, metabolic, and cardiovascular disease risk outcomes in a clinical setting.

Cumulative effect of obesity phenotypes on body weight and body mass index.

BACKGROUND: Obesity originates from an imbalance between energy intake and expenditure. Changes in energy intake components (satiation, postprandial satiety, emotional eating) and energy expenditure have been linked to obesity and are referred to as obesity phenotypes. We aim to study if these obesity phenotypes have a cumulative effect on body weight and body mass index (BMI). SUBJECT/METHODS: This is a cross-sectional study of adult patients with obesity (BMI > 30 kg/m2) who completed the validated tests to measure the obesity phenotypes. A total of 464 were included in this study. INTERVENTIONS/METHODS: We defined higher calories to fullness during an ad libitum meal as abnormal satiation, accelerated time to half gastric emptying with scintigraphy as abnormal postprandial satiety, higher anxiety score on the Hospital Anxiety and Depression Scale as hedonic eating behavior, and decreased percentage of measured resting energy expenditure as abnormal energy expenditure. The primary analysis was done on the number of phenotypes ( ≤ 1 and ≥ 2) with body weight and BMI using an independent t-test. RESULTS: Our cohort included 464 patients (mean [SD] age 42.0 [10.9] years, 79% females, weight 111.2 [22.9] kg, BMI 38.9 [7.0] kg/m2). There were 294 patients who had ≤ 1 phenotype, and 170 patients with ≥ 2 phenotypes with no baseline demographical differences (i.e., age and sex). Having ≥ 2 phenotypes was associated with higher body weight (115 [25] kg vs. 109 [21] kg; p = 0.004), BMI (40 [8] kg/m2 vs. 38 [7] kg/m2; p = 0.02) and waist (118 [15] cm vs. 115 [13] cm; p = 0.04) and hip (129 [14] cm vs. 125 [13] cm; p = 0.01) circumferences compared to ≤ 1 phenotype. CONCLUSION: Obesity phenotypes are associated with an additive effect on the body weight and BMI. Patients who have multiple obesity phenotypes may require a more aggressive approach to enhance weight loss.

Weight regain after total meal replacement very low-calorie diet program with and with-out anti-obesity medications.

Background: Very low-calorie diets (VLCDs) employing total meal replacement (TMR) offer substantial short-term weight loss. Concurrently, anti-obesity medications (AOMs) have shown promise as adjunctive treatments when combined with VLCDs. Aims: This study aimed to investigate the impact of adjuvant AOMs on weight loss and weight regain within a comprehensive lifestyle program. Methods: This is a retrospective study of patients with obesity enrolled in VLCD/TMR programs,  specifically the OPTIFAST program. Results: Data from 206 patients (68% women, mean age 52.39 ± 13.05 years, BMI 41.71 ± 7.04 kg/m2) were analyzed. Of these, 139 received no AOM (AOM-), while 67 received AOMs (AOM+). Total body weight loss percentages (TWL%) at 6 and 18 months were -17.87% ± 7.02 and -12.10% ± 11.56, respectively. There was no significant difference in 6-month weight loss between the AOM groups. However, the AOM + group exhibited lower weight regain (3.29 kg ± 10.19 vs. 7.61 kg ± 11.96; p = 0.006) and weight regain percentage (WR%) (31.5% ± 68.7 vs. 52.16% ± 64.4; p = 0.04) compared with the AOM- group. Conclusion: The findings highlighted the potential of AOMs and VLCD/TMR as effective strategies for long-term weight management in individuals with obesity.

Neurohormonal response patterns to hunger, satiation, and postprandial fullness in normal weight, anorexia nervosa, and obesity.

BACKGROUND: Food intake is regulated by homeostatic and hedonic systems that interact in a complex neuro-hormonal network. Dysregulation in energy intake can lead to obesity (OB) or anorexia nervosa (AN). However, little is known about the neurohormonal response patterns to food intake in normal weight (NW), OB, and AN. MATERIAL & METHODS: During an ad libitum nutrient drink (Ensure®) test (NDT), participants underwent three pseudo-continuous arterial spin labeling (pCASL) MRI scans. The first scan was performed before starting the NDT after a > 12 h overnight fast (Hunger), the second after reaching maximal fullness (Satiation), and the third 30-min after satiation (postprandial fullness). We measured blood levels of ghrelin, cholecystokinin (CCK), glucagon-like peptide (GLP-1), and peptide YY (PYY) with every pCASL-MRI scan. Semiquantitative cerebral blood flow (CBF) maps in mL/100 gr brain/min were calculated and normalized (nCBF) with the CBF in the frontoparietal white matter. The hypothalamus (HT), nucleus accumbens [NAc] and dorsal striatum [DS] were selected as regions of interest (ROIs). RESULTS: A total of 53 participants, 7 with AN, 17 with NW (body-mass index [BMI] 18.5-24.9 kg/m2 ), and 29 with OB (BMI ≥30 kg/m2 ) completed the study. The NW group had a progressive decrease in all five ROIs during the three stages of food intake (hunger, satiation, and post-prandial fullness). In contrast, participants with OB showed a minimal change from hunger to postprandial fullness in all five ROIs. The AN group had a sustained nCBF in the HT and DS, from hunger to satiation, with a subsequent decrease in nCBF from satiation to postprandial fullness. All three groups had similar hormonal response patterns with a decrease in ghrelin, an increase in GLP-1 and PYY, and no change in CCK. CONCLUSION: Conditions of regulated (NW) and dysregulated (OB and AN) energy intake are associated with distinctive neurohormonal activity patterns in response to hunger, satiation, and postprandial fullness.

Type 2 Diabetes Remission in Patients with Heterozygous Variants in the Leptin-Melanocortin Pathway after Roux-en-Y Gastric Bypass: A Matched Case-Control Study.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) is associated with a high rate of type 2 diabetes (T2D) remission. Carriers of heterozygous variants in the leptin-melanocortin pathway (LMP) are more likely to experience weight recurrence after RYGB. Our aim was to investigate if carrier status and associated weight regain affects the rate of T2D remission after RYGB. METHODS: Carriers of LMP variants with a diagnosis of T2D prior to RYGB (N = 16) were matched to non-carriers (N = 32) based on sex, age, and BMI. We assessed for post-operative T2D remission status post-surgery on a yearly basis, for up to 15 years. Our primary endpoint was the proportion of patients achieving T2D remission at 1 year. We conducted a survival analysis for all patients that achieved remission at least at one time-point to evaluate for maintenance of T2D remission by using a log-rank test. RESULTS: Both carriers and non-carriers had similar baseline and procedural characteristics. The proopiomelanocortin gene in the LMP pathway had the most variants (n = 5, 31%). Carriers had a lower total body weight loss percentage at nadir (28.7% ± 6.9) than non-carriers (33.7% ± 8.8, p = 0.04). The proportion of patients achieving T2D remission at 1 year was 68.8% for carriers and 71.9% for non-carriers (p = 1.0). Survival curves for maintenance of first remission were similar for both groups (p = 0.73), with a median survival of 8 years for both carriers and non-carriers. CONCLUSIONS: Despite inferior weight loss outcomes at nadir, carriers had similar T2D remission rates when compared to non-carriers. Weight-independent metabolic benefits of RYGB might contribute to this observation.

Obesity: A Review of Pathophysiology and Classification.

Obesity is a chronic, multifactorial, and morbid disease. In the United States, 69% of adults are overweight or have obesity, and the global prevalence of obesity is increasing. Obesity is influenced by genetic, neurologic, metabolic, enteric, and behavioral processes. It remains a key modifiable risk factor for many comorbid diseases, including cardiovascular disease, diabetes mellitus, and cancer. Whereas there are recent and significant advances in obesity therapy, including diets, lifestyle modifications, pharmacotherapies, endoscopic procedures, and bariatric surgeries, there is an immense need for a better understanding of the heterogeneity in the pathophysiologic process of obesity and outcomes. Here we review salient pathophysiologic mechanisms underlying the development and morbidity of obesity as well as pathophysiologically based classification systems that inform current obesity management and may inform improved and individualized management in the future.

Phenotype tailored lifestyle intervention on weight loss and cardiometabolic risk factors in adults with obesity: a single-centre, non-randomised, proof-of-concept study.

Background: Lifestyle interventions for weight loss are currently not individualised to underlying pathophysiology and behavioral traits in obesity. We aim to compare the outcome of a standard lifestyle intervention (SLI) to phenotype-tailored lifestyle interventions (PLI) on weight loss, cardiometabolic risk factors and physiologic variables contributing to obesity. Methods: This 12-week, single-centre non-randomised proof-of-concept clinical trial including men and women aged 18-65 years with a body mass index (BMI) greater than 30 without history of any bariatric procedure, and current use of any medication known to affect weight. Participants lived anywhere in the United States, and underwent in-person testing in Rochester, MN at a teaching hospital. All participants completed in-person phenotype testing at baseline and after 12 weeks. Participants were assigned to their intervention based on their period of enrollment. In the first phase, participants were assigned to SLI with a low-calorie diet (LCD), moderate physical activity, and weekly behavioral therapy sessions. In the second phase, other participants were assigned to PLI according to phenotype: abnormal satiation (time-restricted volumetric LCD); abnormal postprandial satiety (LCD with pre-meal protein supplementation); emotional eating (LCD with intensive behavioral therapy); and abnormal resting energy expenditure (LCD with post-workout protein supplementation and high-intensity interval training). The primary outcome was total body weight loss in kg at 12 weeks using multiple imputation for missing data. Linear models estimated the association of study group allocation and study endpoints adjusting for age, sex, and baseline weight. This study was registered with ClinicalTrials.gov, NCT04073394. Findings: Between July 2020 and August 2021, 211 participants were screened, and 165 were assigned to one of the two treatments in the two phases: 81 SLI (mean [SD] age 42.9 [12] years; 79% women; BMI 38.0 [6.0]) and 84 PLI (age 44.8 [12.2] years; 83% women; BMI 38.7 [6.9]); 146 completed the 12-week programs. The weight loss was -7.4 kg (95%CI, -8.8, -6.0) with PLI vs. -4.3 kg (95%CI, -5.8, -2.7) with SLI (difference, -3.1 kg [95%CI, -5.1 to -1.1]; P = 0.004). No adverse events were reported in any group. Interpretation: Phenotype-tailored lifestyle interventions may result in significant weight loss, but a randomised controlled trial is required to confirm causality. Funding: Mayo Clinic; NIH (K23-DK114460).

Association Between Food Intake and Gastrointestinal Symptoms in Patients With Obesity.

BACKGROUND AND AIMS: Hunger, satiation, postprandial satiety, and hedonic eating constitute key food intake parameters. We aim to study whether these symptoms are associated with gastrointestinal symptoms (GIS) in patients with obesity. METHODS: This is a cross-sectional study of patients with obesity. Patients completed the following validated biomarkers and questionnaires: hunger was measured via visual analog scale (100 mm) following a standard meal, satiation was measured via ad libitum meal (calories to fullness; kcal), postprandial satiety was measured via gastric emptying scintigraphy (T1/2; mins), and hedonic eating was measured via the Hospital Anxiety and Depression Scale questionnaire. Participants completed the abridged Bowel Disease Questionnaire to evaluate their GIS. We calculated the odds ratios (ORs) adjusted for sex, weight, and age between food intake parameters <25th or >75th percentile observed in a prior cohort of 450 participants with obesity and GIS. RESULTS: A total of 274 participants (41 ± 10 [SD] years, 75% females, body mass index 39 ± 8 kg/m2) were included in the analysis. Increased hunger was associated with a lower prevalence of lumpy stools (OR = 0.18, P = .02). Satiation was associated with abdominal pain/discomfort (relieved by defecation [OR = 2.4, P = .02] or associated with change in stool consistency [OR = 2.92, P < .01]), loose/watery stools (OR = 2.09, P = .02), and bloating (OR = 2.49, P < .01). Abnormal postprandial satiety was associated with bloating (OR = 2.26, P < .01) and loose/watery stools (OR = 1.84, P = .04). Hedonic eating was associated with abdominal pain/discomfort with stool frequency change (OR = 2.4, P = .02), >3 bowel movements per day (OR = 1.93, P = .048), bloating (OR = 2.49, P = .01), abdominal pain after meals >1 per month (OR = 4.24, P < .01), and nausea >1 per week (OR = 4.51, P < .01). CONCLUSION: Alterations in hunger, satiation, postprandial satiety, and hedonic eating are associated with GIS in patients with obesity.

Cardiovascular Risk and Diseases in Patients With and Without Leptin-Melanocortin Pathway Variants.

OBJECTIVE: To study differences in cardiovascular risk factors and diseases between patients with and without genetic variants in the leptin-melanocortin pathway. METHODS: A cross-sectional study of patients with a history of severe obesity genotyped in June 2019 as participants of the Mayo Clinic Biobank was conducted in March 2022 to assess differences in cardiovascular risk and diseases between carriers of a heterozygous variant in the leptin-melanocortin pathway and noncarriers. Cardiovascular risk factors included hypertension, diabetes, dyslipidemia, and smoking. Cardiovascular disease includes coronary artery disease, peripheral artery disease, and cerebrovascular accidents. Patients with a history of bariatric surgery were excluded. We used logistic regression models to estimate the odds ratio and 95% CI, adjusting for age, body mass index (BMI), and sex. RESULTS: Among a total of 168 carriers (8%; 121 [72%] female; mean [SD] age, 65.1 [14.9] years; BMI, 44.0 [7.4] kg/m2) and 2039 noncarriers (92%; 1446 [71%] female; mean [SD] age, 64.9 [14.4] years; BMI, 42.9 [6.6] kg/m2), carriers had higher prevalence odds of hypertension (odds ratio, 3.26; 95% CI, 2.31 to 4.61; P<.001) and reported higher number of cardiovascular risk factors compared with noncarriers (2.4 [1.1] vs 2.0 [1.1]; P<.001). There were no significant differences in the adjusted odds associated with diabetes, dyslipidemia, smoking, or cardiovascular disease. CONCLUSION: Despite having similar body weight and BMI, carriers of heterozygous variants in the leptin-melanocortin pathway had higher rates of hypertension than noncarriers. These findings point to an association between hypertension and leptin-melanocortin pathway variants.

Sex as an independent variable in the measurement of satiation: a retrospective cohort study.

BACKGROUND: Satiation is a key component of food intake regulation as it brings an eating episode to an end. The effect of sex on satiation measurement has not been characterized. OBJECTIVE: To assess the effects of biological variables on satiation. DESIGN: Retrospective cohort study. We included 959 participants (mean age 39 [SD 12] years; 70.7% female, and BMI 33 kg/m2 [8]) who had measurements of satiation with a nutrient-drink test to assess volume to fullness (VTF) and maximum tolerated volume (MTV), and/or an ad libitum meal test to assess calories consumed to fullness (CTF). We performed univariate and multiple regression analyses to estimate the contribution of sex to VTF, MTV, and CTF, compared to other biological variables, such as age, weight, height, BMI, waist-to-hip circumference (W/H), and lean mass percentage (LM%), that are known to affect these parameters. RESULTS: Females had higher BMI, W/H, and LM%. VTF, MTV, and CTF were lower in females: 704 [323] vs. 783 [328] mL, p = 0.001; 1226 [384] vs. 1419 [410] mL, p < 0.001; and 871 [291] vs. 1086 [326] kcal, p < 0.001; respectively. Sex was a strong and independent predictor of VTF, MTF and CTF: parameter estimate [PE] = -80.8, p = 0.006; PE = -124.2, p = 0.0007; and PE = -110, p = 0.001; respectively. CONCLUSIONS: Sex has a strong effect on satiation measured by VTF, MTV, and CTF, even after adjusting for other biological factors known to affect these parameters. Females seem to integrate intra-meal inhibition signals to consume fewer calories unrelated to body size or composition. CLINICAL TRIAL REGISTRATION: None.

Weight Loss Outcomes Associated With Semaglutide Treatment for Patients With Overweight or Obesity.

Importance: No retrospective cohort study has assessed the effectiveness of semaglutide at doses used in randomized clinical trials to treat obesity (ie, 1.7 and 2.4 mg). Objective: To study weight loss outcomes associated with semaglutide treatment at doses used in randomized clinical trials for patients with overweight or obesity. Design, Setting, and Participants: This cohort study, conducted at a referral center for weight management, retrospectively collected data on the use of semaglutide for adults with overweight or obesity between January 1, 2021, and March 15, 2022, with a follow-up of up to 6 months. A total of 408 patients with a body mass index (BMI) of 27 or more were prescribed weekly semaglutide subcutaneous injections for 3 months or more. Patients with a history of bariatric procedures, taking other antiobesity medications, and with an active malignant neoplasm were excluded. Exposures: Weekly 1.7-mg or 2.4-mg semaglutide subcutaneous injections for 3 to 6 months. Main Outcomes and Measures: The primary end point was the percentage of weight loss. Secondary end points were the proportion of patients achieving weight loss of 5% or more, 10% or more, 15% or more, and 20% or more after 3 and 6 months and the percentage of weight loss for patients with or without type 2 diabetes after 3 and 6 months. Results: The study included 175 patients (132 women [75.4%]; mean [SD] age, 49.3 [12.5] years; mean [SD] BMI, 41.3 [9.1]) in the analysis at 3 months and 102 patients at 6 months. The mean (SD) weight loss after 3 months was 6.7 (4.4) kg, equivalent to a mean (SD) weight loss of 5.9% (3.7%) (P < .001), and the mean (SD) weight loss after 6 months was 12.3 (6.6) kg, equivalent to a mean (SD) weight loss of 10.9% (5.8%) (P < .001 from baseline). Of the 102 patients who were followed up at 6 months, 89 (87.3%) achieved weight loss of 5% or more, 56 (54.9%) achieved weight loss of 10% or more, 24 (23.5%) achieved weight loss of 15% or more, and 8 (7.8%) achieved weight loss of 20% or more. Patients with type 2 diabetes had a lower mean (SD) percentage weight loss at 3 and 6 months compared with those without type 2 diabetes: 3.9% (3.1%) vs 6.3% (3.7%) at 3 months (P = .001) and 7.2% (6.3%) vs 11.8% (5.3%) at 6 months (P = .005). Conclusions and Relevance: The results of this cohort study suggest that weekly 1.7-mg and 2.4-mg doses of semaglutide were associated with weight loss similar to that seen in randomized clinical trials. Studies with longer periods of follow-up are needed to evaluate prolonged weight loss outcomes.

Association between CYP metabolizer phenotypes and selective serotonin reuptake inhibitors induced weight gain: a retrospective cohort study.

BACKGROUND: Prescription medications such as selective serotonin reuptake inhibitors (SSRIs), commonly used to treat depression, are associated with weight gain. The role of pharmacogenomics in predicting SSRI-induced weight gain is unclear. METHODS: In this retrospective cohort study from participants in the Mayo Clinic RIGHT study who were prescribed citalopram, paroxetine, sertraline, or fluoxetine, our aim was to evaluate the association of metabolizer phenotype and total body weight after 6 months of SSRIs initiation. We evaluated the metabolizer phenotypes (poor/intermediate, normal, and rapid/ultra-rapid) of the cytochromes P450 enzymes genes: CYP2C9, CYP2C19, and CYP2D6 known to influence the metabolism of SSRI medications: CYP2C19 for citalopram, CYP2D6 for paroxetine, CYP2D6 and CYP2C19 for sertraline, and CYP2D6 and CYP2C9 fluoxetine. In addition, we assessed the association of metabolizer phenotype and total body weight change at six months following SSRI prescription using parametric analysis of covariance adjusted for baseline body weight and multivariate regression models. RESULTS: CYP2C19 poor/intermediate metabolizers prescribed citalopram gained significantly more weight than normal or rapid/ultra-rapid metabolizers at 6 months (TBWG %: 2.6 [95% CI 1.3-4.1] vs. 0.4 [95% CI -0.5 - 1.3] vs. -0.1 [-95% CI -1.5-1.1]; p = 0.001). No significant differences in weight outcomes at six months of treatment with paroxetine, sertraline, or fluoxetine were observed by metabolizer status. CONCLUSIONS: Weight gain observed with citalopram may be mediated by CYP2C19 metabolizer status.

Effect of caloric intake and macronutrient composition on intestinal cholesterol absorption and bile acids in patients with obesity.

Obesity is associated with alterations in cholesterol and bile acid (BA) metabolism. However, the interaction among dietary intake, cholesterol absorption, and BA metabolism in patients with obesity remains unclear. We conducted a 4-wk nutritional intervention nonrandomized clinical trial with three different sequential diets for a week in the following order: regular diet (RD); high calorie, high-fat diet (HCHF), washout period on RD; and low-calorie, low-fat diet (LCLF). We provided participants with meal replacements during HCHF and LCLF diets. A total of 16 participants completed the study [n = 8 normal weight (NW); n = 8 with obesity (OB)]. Overall, there was a significant increase in intestinal cholesterol uptake when changing from RD to HCHF and a reduction in intestinal cholesterol uptake from HCHF to LCLF. When analyzing by BMI groups, these findings were similar in patients with NW (RD to HCHF: P < 0.007; HCHF to LCLF: P = 0.02); however, in patients with obesity, the change in intestinal cholesterol uptake was only observed when changing from RD to HCHF (P = 0.006). There was no correlation between cholesterol absorption and fecal bile acids or other markers of BA metabolism in all patients or the subgroups. Dietary caloric content had a significant effect on cholesterol absorption, however, this effect is blunted in patients with obesity. These data are consistent with the impaired effect of a low-fat diet on cholesterol absorption in obesity.NEW & NOTEWORTHY We show how switching from a regular diet to an HCHF increases cholesterol absorption in patients with normal weight and obesity. The decrease in cholesterol absorption from an HCHF to an LCLF, on the other hand, was only seen in normal-weight controls, underlining the importance of body weight in this regulation. In addition, changes in caloric and fat content had an immediate and direct effect on hepatic bile acid production.

Effects of Heterozygous Variants in the Leptin-Melanocortin Pathway on Roux-en-Y Gastric Bypass Outcomes: a 15-Year Case-Control Study.

INTRODUCTION: Heterozygous variants in the leptin-melanocortin pathway are associated with obesity. However, their effect on the long-term outcomes after Roux-en-Y gastric bypass (RYGB) is still unknown. METHODS: In this matched case-control study, 701 participants from the Mayo Clinic Biobank with a history of RYGB were genotyped. Sixty-three patients had a heterozygous variant in the leptin-melanocortin pathway. After excluding patients with potential confounders, carriers were randomly matched (on sex, age, body mass index [BMI], and years since surgery) with two non-carrier controls. The electronic medical record of carriers and matched non-carriers was reviewed for up to 15 years after RYGB. RESULTS: A total of 50 carriers and 100 matched non-carriers with a history of RYGB were included in the study. Seven different genes (LEPR, PCSK1, POMC, SH2B1, SRC1, MC4R, and SIM1) in the leptin-melanocortin pathway were identified. At the time of surgery, the mean age was 50.8 ± 10.6 years, BMI 45.6 ± 7.3 kg/m2, and 79% women. There were no differences in postoperative years of follow-up, Roux limb length, or gastric pouch size between groups. Fifteen years after RYGB, the percentage of total body weight loss (%TBWL) in carriers was - 16.6 ± 10.7 compared with - 28.7 ± 12.9 in non-carriers (diff = 12.1%; 95% CI, 4.8 to 19.3) and the percentage of weight regain after maximum weight loss was 52.7 ± 29.7 in carriers compared with 29.8 ± 20.7 in non-carriers (diff = 22.9%; 95% CI, 5.3 to 40.5). The nadir %TBWL was lower - 32.1 ± 8.1 in carriers compared with - 36.8 ± 10.4 in non-carriers (diff = 4.8%; 95% CI 1.8 to 7.8). CONCLUSIONS: Carriers of a heterozygous variant in the leptin-melanocortin pathway have a progressive and significant weight regain in the mid- and long-term after RYGB. Genotyping patients experiencing significant weight regain after RYGB could help implement multidisciplinary and individualized weight loss interventions to improve weight maintenance after surgery.

Evaluation and Management of Patients Referred for Post-Bariatric Surgery Hypoglycemia at a Tertiary Care Center.

PURPOSE: Following bariatric surgery, patients can develop non-specific symptoms self-described as hypoglycemia. However, confirming hypoglycemia can be technically challenging, and therefore, these individuals are frequently treated empirically. This study aimed to describe what diagnostic evaluation and therapeutic interventions patients referred for post-bariatric surgery hypoglycemia undergo. METHODS: Retrospective observational cohort study of patients with a history of bariatric surgery was evaluated for post-bariatric surgery hypoglycemia in a tertiary referral center from 2008 to 2017. We collected demographic and bariatric surgery information, clinical presentation of symptoms referred to as hypoglycemia, laboratory and imaging studies performed to evaluate these symptoms, and symptom management and outcomes. RESULTS: A total of 60/2450 (2.4%) patients who underwent bariatric surgery were evaluated in the Department of Endocrinology for hypoglycemia-related symptoms. The majority were middle-aged women without type 2 diabetes who had undergone Roux-en-Y gastric bypass. Thirty-nine patients (65%) completed a biochemical assessment for hypoglycemia episodes. Six (10%) had confirmed hypoglycemia by Whipple's triad, and four (6.7%) met the criteria for post-bariatric surgery hypoglycemia based on clinical and biochemical criteria. All patients were recommended dietary modification as the initial line of treatment, and this intervention resulted in most patients reporting at least some improvement in their symptoms. Eight patients (13%) were prescribed pharmacotherapy, and two patients required additional interventions for symptom control. CONCLUSIONS: In our experience, evaluation for hypoglycemia-related symptoms after bariatric surgery was rare. Hypoglycemia was confirmed in the minority of patients. Even without establishing a diagnosis of hypoglycemia, dietary changes were a helpful strategy for symptom management for most patients.

A comparison between weight loss outcomes with anti-obesity medications before and during Covid-19 pandemic at a tertiary weight management center.

Background: /Objectives: Obesity is a risk factor for COVID-19 infection severity and mortality. Anti-obesity medications (AOM) are effective for weight loss. However, weight loss outcomes with AOM during the COVID-19 pandemic are yet to be described. Subjects: /Methods: Between January 1, 2016, and June 30, 2021, a total of 966 patients were prescribed long-term FDA-approved AOMs at the Mayo Clinic. From these patients, 711 patients did not meet inclusion criteria. A total of 255 patients were included. Interventions/methods: We performed a retrospective systematic review of electronic medical records and included patients who started a long-term FDA-approved AOM. We excluded patients with history of bariatric procedure, AOM prescription with lorcaserin, orlistat, semaglutide (approved for weight loss after the pandemic), or phentermine (short-term AOM), those taking ≥2 AOMs, <3 months of prescribed AOM, and/or pregnancy. Analysis was divided by 1)preCOVID-19: those who started an AOM before COVID-19 restrictions, 2)COVID-19: those who started an AOM during first quarter of 2020 after the establishment of COVID-19 restrictions. Our primary endpoint was the total body weight loss percentage (%TBWL) at 3, 6, and 12 months after AOM initiation. Results: There was a statistical difference in TBWL% between the preCOVID-19 and COVID-19 group: 5.3 ± 3.5% vs 4 ± 3.0% (95% CI -2.4 to -0.2; p = 0.02) and 9.7 ± 7.2% vs 6.2 ± 4.7% (95% CI -5.7 to -1.3; p = 0.002) at 3 and 12 months, respectively. At 6 months, the TBWL% was 7.1 for the preCOVID-19 group compared to 6.2% for the COVID-19 (95% CI -2.5 to 0.7; p = 0.25). Conclusion: With the possible exception of liraglutide, this study shows that weight loss outcomes to AOMs were inferior when prescribed during the routine clinical practice throughout COVID-19 pandemic, compared to the outcomes observed prior to the COVID-19 pandemic.