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.

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.

Low Incidence of Pulmonary Aspiration During Upper Endoscopy in Patients Prescribed a Glucagon-Like Peptide 1 Receptor Agonist.

Glucagon-like peptide 1 (GLP-1) receptor agonists have transformed the treatment of type 2 diabetes and obesity. These agents have been associated with varying degrees of delay in gastric emptying, and a significant proportion of patients experience digestive side effects.1 There have been previous case reports of gastric retention of food and pulmonary aspiration during upper gastrointestinal (GI) endoscopy in the setting of GLP-1 receptor agonist use2; however, the cumulative incidence has not been previously explored.

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.

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.

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.

Weight-centric treatment of type 2 diabetes mellitus.

Background: Chronic non-communicable diseases (CNCD) represent a major cause of morbidity and mortality. Type 2 diabetes mellitus (T2DM) is one of the most prevalent CNCD that is associated with a significant medical and economic burden. One of the main modifiable risk factors of T2DM is obesity. Many medications used for T2DM can lead to weight gain, worsening one of the root causes of this disease. Methods: In this clinical review, we study the effect of medications for T2DM on body weight. We used MEDLINE, Google scholar, PubMed, Scopus, and Embase databases to search for relevant studies between 1 January 1950 to 20 September 2022 in English language. Here, we review the most prescribed medications for T2DM and summarize their effect on patients' body weight. We will also present an expert opinion on a recommended weight-centric approach to treat T2DM. Results: Multiple T2DM medications have been associated with weight gain. Insulin, sulfonylureas, thiazolidinediones and meglitinides may increase body weight. However, biguanides (e.g., metformin), glucagon-like peptide-1 agonists (e.g., semaglutide, liraglutide, tirzepatide), sodium-glucose cotransporter 2 inhibitors, and amylin analogs (e.g., pramlintide) are associated with significant weight loss. Dipeptidyl peptidase-4 inhibitors are considered weight neutral medications. Experts in the fields of endocrinology and obesity recommend utilizing a weight-centric approach when treating T2DM. Conclusion: Considering the high prevalence and debilitating complication of T2DM, it is of utmost importance to shift from a weight gain approach (i.e., insulin, sulfonylureas) into a weight loss/neutral one (i.e., GLP-1 agonists, SGLT-2 inhibitors, metformin).

Association between anxiety and eating behaviors in patients with obesity.

Background: Given the link between eating behavior and obesity, it is critical to identify individuals who have eating behaviors which contribute to obesity etiology. This study aimed to investigate the potential relationship between symptoms of anxiety and eating behaviors in patients with obesity. Methods: This was a cross-sectional study analyzing baseline characteristics of 438 patients with obesity (BMI>30). Patients completed the Hospital Anxiety and Depression Scale (HADS) questionnaire, the Three-Factor Eating Questionnaire R21 (TFEQ-R21), and the Weight Efficacy Lifestyle Questionnaire (WEL). Pearson correlation coefficients were used to evaluate the association between questionnaires. Two-sample independent t-test were conducted to examine differences in the TFEQ-R21 and WEL between low and moderate to severe levels of symptoms of anxiety. Results: Anxiety scores (HADS-A) positively correlated with two factors of the TFEQ, emotional eating (r = 0.36) and uncontrolled eating (r = 0.27). The HADS-A score was negatively correlated with self-efficacy to resist eating in all five situational factors on the WEL (p < 0.01). Patients with symptoms of anxiety additionally showed higher mean scores for emotional eating and uncontrolled eating (p < 0.001, respectively),and lower levels of cognitive restraint (p = 0.04)) on the TFEQ-R21. Conclusion: Patients with obesity who reported having anxiety symptoms had lower self-confidence to manage their eating and more emotional eating than patients with low anxiety symptoms. Clearly more needs to be learned about symtoms of anxiety and eating behaviors.

Precision Medicine and Obesity.

Obesity is a chronic, relapsing, and multifactorial disease, with a rising prevalence and an associated high economic burden. Achieving successful and sustained weight loss outcomes with current interventions is challenging. This is due, at least in part, to the disease's heterogenous pathophysiology that is yet to be completely understood. Technological advances and greater capabilities for the extraction and storage of information have facilitated the application of precision medicine. Several precision medicine initiatives have been proposed to improve obesity outcomes. Most of these initiatives are based on -omics technologies. Although the data generated from these technologies have led to developing hypotheses that may explain the underpinnings of obesity, their applicability to the clinical practice is yet to be determined. There are other initiatives that have identified quantitative or qualitative physiologic traits that can be targeted and that could have a more immediate clinical impact. This review aims to provide a perspective of current initiatives for precision medicine for obesity.

Diagnostic Accuracy of Dehydroepiandrosterone Sulfate and Corticotropin in Autonomous Cortisol Secretion.

Autonomous cortisol secretion (ACS) affects up to 50% of patients with adrenal adenomas. Despite the limited evidence, clinical guidelines recommend measurement of serum concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and corticotropin (ACTH) to aid in the diagnosis of ACS. Our objective was to determine the accuracy of serum concentrations of DHEA-S and ACTH in diagnosing ACS. We conducted a retrospective single center study of adults with adrenal adenoma evaluated between 2000-2020. Main outcome measure was diagnostic accuracy of DHEA-S and ACTH. ACS was defined as post-dexamethasone cortisol >1.8 mcg/dL. Of 468 patients, ACS was diagnosed in 256 (55%) patients with a median post-DST cortisol of 3.45 mcg/dL (range, 1.9-32.7). Patients with ACS demonstrated lower serum concentrations of DHEA-S (35 vs. 87.3 mcg/dL, p < 0.0001) and ACTH (8.3 vs. 16 pg/mL, p < 0.0001) compared to patients with non-functioning adrenal tumors (NFAT). Serum DHEA-S concentration <40 mcg/dL diagnosed ACS with 84% specificity and 81% PPV, while serum ACTH concentration <10 pg/mL diagnosed ACS with 75% specificity and 78% PPV. The combination of serum concentrations of DHEA-S <40 mcg/dL and ACTH <10 pg/mL diagnosed ACS with the highest accuracy with 92% specificity and 87% PPV. Serum concentrations of DHEA-S and ACTH provide additional value in diagnosing ACS.

Drivers of the Decision to Biopsy and Follow-Up of Small Suspicious Thyroid Nodules.

OBJECTIVE: In 2015, the updated American Thyroid Association (ATA) guidelines recommended observation for suspicious subcentimeter thyroid nodules, based on their indolent course. We aimed to evaluate the frequency of biopsy in suspicious thyroid nodules since the introduction of these guidelines, including factors contributing to clinical decision-making in a tertiary care center. METHODS: We conducted a retrospective study of patients in the Mayo Clinic, Rochester, Minnesota, with new, subcentimeter suspicious thyroid nodules (by report or by sonographic features) between March, 2015, and November, 2017, not previously biopsied. RESULTS: We identified 141 nodules in 129 patients: mean age 58.1±14.1 years, 74% female, 87% Caucasian. The frequency of biopsy in suspicious thyroid nodules was 39%. Ultrasound features that were the strongest predictors for biopsy on multivariate analysis included: nodule volume (odds ratio [OR] 37.3 [7.5-188.7]), radiology recommendation for biopsy (OR 2.6 [1.8-3.9]) and radiology report of the nodule as "suspicious" (OR 2.1 [1.4-3.2]). Patient's age and degree of comorbidities did not change the likelihood for biopsy, nor did it vary by clinician type or how the nodule was initially found (incidentally or not incidentally). Among 86 nodules that were not biopsied, 41% had no specific follow-up recommendations. CONCLUSION: One third of suspicious thyroid nodules underwent biopsy since the release of updated ATA guidelines. Factors driving thyroid biopsy seem to be associated with nodule characteristics but not with patient factors including age and comorbidities. Further studies and development of decision aides may be helpful in providing individualized approaches for suspicious thyroid nodules. ABBREVIATIONS: ATA = American Thyroid Association; OR = odds ratio.

TRANSIENT OSTEOPOROSIS: CLINICAL SPECTRUM IN ADULTS AND ASSOCIATED RISK FACTORS.

Objective: We aimed to describe the natural history of the rare clinical syndrome of transient osteoporosis (TO) and ascertain potential risk factors. Methods: Retrospective cohort study of adults with TO at Mayo Clinic, Rochester, Minnesota, over 15 years. Adults with acute-onset joint pain worsened by weight bearing and bone marrow edema on magnetic resonance imaging were included; exclusion criteria were trauma, tumors, rheumatic diseases, avascular necrosis, infection, and hyperesthesia. Results: Thirty-three patients with TO were identified: 20 males, median age at diagnosis 47 years, and median body mass index 28 kg/m2. Median time to diagnosis was 2 months, and time to symptom resolution was 4 months. All cases involved the lower extremity, with the majority affecting the hip. Most patients (79%) had at least one possible identified risk factor. The most frequent risk factor was low bone mineral density (BMD) in 13 patients (39% of cohort). Of the 16 patients with BMD measure, 8 had low BMD at a site other than TO. The next most frequent risk factors were sudden limb overuse and more than one episode of TO, observed in 30%, followed by a disorder of bone and mineral metabolism in 27%. Conclusion: TO affects middle-age men more than women, primarily involves weight-bearing joints, and usually resolves with conservative management. Its etiology remains unclear; however, the common presence of risk factors, abnormalities in bone and mineral laboratories, and decrease in BMD suggest that systemic factors may be important in its development. Abbreviations: AVN = avascular necrosis; BMD = bone mineral density; DXA = dual-energy X-ray absorptiometry; MRI = magnetic resonance imaging; TO = transient osteoporosis.

Increased Rates of Meal Absorption Do Not Explain Elevated 1-Hour Glucose in Subjects With Normal Glucose Tolerance.

Context: In subjects with normal fasting glucose (NFG) and normal glucose tolerance (NGT), glucose concentrations >155 mg/dL 1 hour after 75 g of oral glucose predict increased risk of progression to diabetes. Recently, it has been suggested that the mechanism underlying this abnormality is increased gut absorption of glucose. Objective: We sought to determine the rate of systemic appearance of meal-derived glucose in subjects classified by their 1-hour glucose after a 75-g oral glucose challenge. Design: This was a cross-sectional study. Participating subjects underwent a 75-g oral glucose challenge and a labeled mixed meal test. Setting: An inpatient clinical research unit at an academic medical center. Participants: Thirty-six subjects with NFG/NGT participated in this study. Interventions: Subjects underwent an oral glucose tolerance test. Subsequently, they underwent a labeled mixed meal to measure fasting and postprandial glucose metabolism. Main Outcome Measures: We examined ß-cell function and the rate of meal appearance (Meal Ra) in NFG/NGT subjects. Subsequently, we examined the relationship of peak postchallenge glucose with Meal Ra and indices of ß-cell function. Results: Peak glucose concentrations correlated inversely with ß-cell function. No relationship of Meal Ra with peak postchallenge glucose concentrations was observed. Conclusion: In subjects with NFG/NGT, elevated 1-hour peak postchallenge glucose concentrations reflect impaired ß-cell function rather than increased systemic meal appearance.

Extensive clinical experience: Hypothalamic-pituitary-adrenal axis recovery after adrenalectomy for corticotropin-independent cortisol excess.

OBJECTIVE: To identify predictors of hypothalamic-pituitary-adrenal (HPA) axis recovery interval and severity of glucocorticoid withdrawal symptoms (GWS) in patients undergoing adrenalectomy for corticotropin-independent cortisol excess. DESIGN: This is a retrospective study of patients with mild autonomous cortisol excess (MACE), moderate and severe Cushing syndrome (CS) who developed adrenal insufficiency after unilateral adrenalectomy between 1998 and 2017. RESULTS: Adrenalectomy was performed in 81 patients (79% women, median age 52 years [IQR 42-62]). HPA axis recovery occurred at a median of 4.3 months (IQR 1.6-11.4) after adrenalectomy (severe CS vs moderate CS vs MACE: median 11.4 vs 2.8 vs 2.1 months, P < 0.01). Main predictors of HPA axis recovery interval included: preoperative serum cortisol concentration after 1-mg overnight dexamethasone suppression test >10 µg/dL or >276 nmol/L (9.7 vs 1.3 months if cortisol ≤10 µg/dL or ≤276 nmol/L, P < 0.01); body mass index (for every 3 kg/m2 decrease, glucocorticoid taper increased by 1 month, P < 0.05); age <45 (11.4 vs 2.3 months if ≥45 years, P < 0.05); duration of symptoms prior to diagnosis >1 year (11.4 vs 2.8 months if ≤1 year); moon facies (11.4 vs 2.2 months if no rounding of the face); and myopathy (13.1 vs 2.7 months if no myopathy, P < 0.05). Patients with severe CS had a higher incidence of GWS compared to patients with MACE (66.7% vs 40.0%, P < 0.05) with a median of 1 and 0 events/patient, respectively. CONCLUSIONS: The HPA axis recovery interval was the longest for patients with severe CS. Surprisingly, patients with moderate CS recovered their HPA axis as quickly as those with MACE. Glucocorticoid withdrawal symptoms were observed in all groups, with more events in patients with severe CS. This study emphasizes the need to counsel patients on expectations for HPA axis recovery and address intervention for GWS based on individual preoperative parameters.