Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial.

BACKGROUND: Observational studies suggest that bariatric-metabolic surgery might greatly improve non-alcoholic steatohepatitis (NASH). However, the efficacy of surgery on NASH has not yet been compared with the effects of lifestyle interventions and medical therapy in a randomised trial. METHODS: We did a multicentre, open-label, randomised trial at three major hospitals in Rome, Italy. We included participants aged 25-70 years with obesity (BMI 30-55 kg/m2), with or without type 2 diabetes, with histologically confirmed NASH. We randomly assigned (1:1:1) participants to lifestyle modification plus best medical care, Roux-en-Y gastric bypass, or sleeve gastrectomy. The primary endpoint of the study was histological resolution of NASH without worsening of fibrosis at 1-year follow-up. This study is registered at ClinicalTrials.gov, NCT03524365. FINDINGS: Between April 15, 2019, and June 21, 2021, we biopsy screened 431 participants; of these, 103 (24%) did not have histological NASH and 40 (9%) declined to participate. We randomly assigned 288 (67%) participants with biopsy-proven NASH to lifestyle modification plus best medical care (n=96 [33%]), Roux-en-Y gastric bypass (n=96 [33%]), or sleeve gastrectomy (n=96 [33%]). In the intention-to-treat analysis, the percentage of participants who met the primary endpoint was significantly higher in the Roux-en-Y gastric bypass group (54 [56%]) and sleeve gastrectomy group (55 [57%]) compared with lifestyle modification (15 [16%]; p<0·0001). The calculated probability of NASH resolution was 3·60 times greater (95% CI 2·19-5·92; p<0·0001) in the Roux-en-Y gastric bypass group and 3·67 times greater (2·23-6·02; p<0·0001) in the sleeve gastrectomy group compared with in the lifestyle modification group. In the per protocol analysis (236 [82%] participants who completed the trial), the primary endpoint was met in 54 (70%) of 77 participants in the Roux-en-Y gastric bypass group and 55 (70%) of 79 participants in the sleeve gastrectomy group, compared with 15 (19%) of 80 in the lifestyle modification group (p<0·0001). No deaths or life-threatening complications were reported in this study. Severe adverse events occurred in ten (6%) participants who had bariatric-metabolic surgery, but these participants did not require re-operations and severe adverse events were resolved with medical or endoscopic management. INTERPRETATION: Bariatric-metabolic surgery is more effective than lifestyle interventions and optimised medical therapy in the treatment of NASH. FUNDING: Fondazione Policlinico Universitario A Gemelli, Policlinico Universitario Umberto I and S Camillo Hospital, Rome, Italy.

Medium-Term Nutritional and Metabolic Outcome of Single Anastomosis Duodeno-Ileal Bypass with Sleeve Gastrectomy (SADI-S).

INTRODUCTION: Single Anastomosis Duodenal-Ileal Bypass with Sleeve Gastrectomy (SADI-S), like other hypoabsorptive procedures, could be burdened by long-term nutritional deficiencies such as malnutrition, anemia, hypocalcemia, and hyperparathyroidism. OBJECTIVES: We aimed to report our experience in terms of mid-term (2 years) bariatric, nutritional, and metabolic results in patients who underwent SADI-S both as a primary or revisional procedure. METHODS: One hundred twenty-one patients were scheduled for SADI-S as a primary or revisional procedure from July 2016 to February 2020 and completed at least 2 years of follow-up. Demographic features, bariatric, nutritional, and metabolic results were analyzed during a stepped follow-up at 3 months, 6 months, 1 year and 2 years. RESULTS: Sixty-six patients (47 female and 19 male) were included. The median preoperative BMI was 53 (48-58) kg/m2. Comorbidities were reported in 48 (72.7%) patients. At 2 years, patients had a median BMI of 27 (27-31) kg/m2 (p < 0.001) with a median %EWL of 85.3% (72.1-96.1), a TWL of 75 (49-100) kg, and a %TWL of 50.9% (40.7-56.9). The complete remission rate was 87.5% for type 2 diabetes mellitus, 83.3% for obstructive sleep apnea syndrome and 64.5% for hypertension. The main nutritional deficiencies post SADI-S were vitamin D (31.82%) and folic acid deficiencies (9.09%). CONCLUSION: SADI-S could be considered as an efficient and safe procedure with regard to nutritional status, at least in mid-term (2 years) results. It represents a promising bariatric procedure because of the excellent metabolic and bariatric outcomes with acceptable nutritional deficiency rates. Nevertheless, larger studies with longer follow-ups are necessary to draw definitive conclusions.

Prevalence and predictors of non-alcoholic steatohepatitis in subjects with morbid obesity and with or without type 2 diabetes.

AIM: To investigate the prevalence of biopsy-proven non-alcoholic steatohepatitis (NASH) in a cohort of patients with morbid obesity and with or without type 2 diabetes (T2D) and to find non-invasive predictors of NASH severity. METHODS: We evaluated a cohort of 412 subjects (age 19-67 years, body mass index-BMI: 44.98 kg/m2), who underwent fine-needle liver biopsy during bariatric surgery. Thirty-six percent of the subjects were affected by T2D. Liver biopsies were classified according to the Kleiner's NAFLD Activity Score (NAS). NAFLD Fibrosis Score (NFS), AST/ALT ratio, AST to Platelet ratio (APRI), fibrosis-4 score (FIB4) were calculated. A neural network analysis (NNA) was run to predict NASH severity. RESULTS: The prevalence of biopsy-proven NASH was 63% and 78% in subjects with obesity and without or with T2D, respectively. T2D doubled the risk of NASH [OR 2.079 (95% IC=1.31-3.29)]. The prevalence of NAFL increased with the increase of BMI, while there was an inverse correlation between BMI and NASH (r=-0.145 p=0.003). Only mild liver fibrosis was observed. HOMA-IR was positively associated with hepatocyte ballooning (r=0.208, p<0.0001) and fibrosis (r=0.159, p=0.008). The NNA highlighted a specificity of 77.3% using HDL-cholesterol, BMI, and HOMA-IR as main determinants of NASH. CONCLUSIONS: Our data show a higher prevalence of NASH in patients with morbid obesity than reported in the literature and the pivotal role of T2D among the risk factors for NASH development. However, the inverse correlation observed between BMI and biopsy-proven NASH suggests that over a certain threshold adiposity can be somewhat protective against liver damage. Our model predicts NASH presence with high specificity, thus helping identifying subjects who should promptly undergo liver biopsy.

Advice of General Practitioner, of Surgeon, of Endocrinologist, and Self-determination: the Italian Road to Bariatric Surgery.

PURPOSE: Bariatric surgery (BS) is considered the most efficient treatment for severe obesity. International guidelines recommend multidisciplinary approach to BS (general practitioners, endocrinologists, surgeons, psychologists, or psychiatrists), and access to BS should be the final part of a protocol of treatment of obesity. However, there are indications that general practitioners (GPs) are not fully aware of the possible benefits of BS, that specialty physicians are reluctant to refer their patients to surgeons, and that patients with obesity choose self-management of their own obesity, including internet-based choices. There are no data on the pathways chosen by physicians and patients to undergo BS in the real world in Italy. METHODS: An exploratory exam was performed for 6 months in three pilot regions (Lombardy, Lazio, Campania) in twenty-three tertiary centers for the treatment of morbid obesity, to describe the real pathways to BS in Italy. RESULTS: Charts of 2686 patients (788 men and 1895 women, 75.5% in the age range 30-59 years) were evaluated by physicians and surgeons of the participating centers. A chronic condition of obesity was evident for the majority of patients, as indicated by duration of obesity, by presence of several associated medical problems, and by frequency of previous dietary attempts to weight loss. The vast majority (75.8%) patients were self-presenting or referred by bariatric surgeons, 24.2% patients referred by GPs and other specialists. Self-presenting patients were younger, more educated, more professional, and more mobile than patients referred by other physicians. Patients above the age of 40 years or with a duration of obesity greater than 10 years had a higher prevalence of all associated medical problems. CONCLUSIONS: The majority of patients referred to a tertiary center for the treatment of morbid obesity have a valid indication for BS. Most patients self-refer to the centers, with a minority referred by a GP or by specialists. Self-presenting patients are younger, more educated, more professional, and more mobile than patients referred by other physicians. Older patients and with a longer duration of obesity are probably representative of the conservative approach to BS, often regarded as the last resort in an endless story.

Circulating irisin levels in functional hypothalamic amenorrhea: a new bone damage index? A pilot study.

PURPOSE: Patients with functional hypothalamic amenorrhea (FHA) could commonly have bone damage, often preceded by metabolic alterations due to a relative energy deficit state. To date, there are no markers capable of predicting osteopenia before it is manifested on DXA. Irisin is a myokine that promotes the differentiation of osteoblastic cells and appears to be inversely correlated with the incidence of bone fragility and fractures in postmenopausal women. The aim of this study was to measure irisin levels in FHA patients and to correlate it with bone density parameters. METHODS: Thirty-two patients with FHA and 19 matched controls underwent the same clinical and laboratory evaluation. RESULTS: Irisin and body mass index (BMI) were significantly lower in the case group than in healthy controls (2.03 ± 0.12 vs. 2.42 ± 0.09 p < 0.05 and 19.43 ± 2.26 vs. 22.72 ± 0.67 p < 0.05, respectively). Additionally, total body mass density (BMD g/cm2) was significantly lower in the case group than in the healthy controls (1.09 ± 0.08 vs. 1.14 ± 0.05, p < 0.05), without signs of osteopenia. CONCLUSIONS: The FHA group showed lower irisin levels associated with significantly reduced BMD parameters that did not reach the severity of osteopenia. Therefore, we could speculate that irisin could predict DXA results in assessing modifications of body composition parameters. Future research is warranted to study these parameters in a larger population to confirm our results, so that irisin could be used as a predictor and screening method for bone deprivation. Furthermore, irisin is strictly related to energy metabolism and could be an indirect marker of nutritional status in FHA patients, identifying earlier states of energy deficit.

Effects of weight loss medications on mortality and cardiovascular events: A systematic review of randomized controlled trials in adults with overweight and obesity.

AIMS: Adults affected by obesity are at higher risk of premature mortality. Medications can help to lose weight and to maintain weight loss. Aim of this meta-analysis was to assess whether anti-obesity medications affect all-cause mortality, mortality due to cardiovascular events, cardiovascular risk factors and body weight. DATA SYNTHESIS: A Medline search was performed to identify randomized controlled trials (RCTs) of anti-obesity medications in adults with overweight or obesity reporting data on all-cause mortality, cardiovascular mortality or non-fatal cardiovascular events, with a follow-up of at least 6 months. We identified 28 RCTs with 50,106 participants. The median follow-up was 52 weeks. Evidence did not show superiority of anti-obesity medications over placebo in reducing all-cause mortality (risk ratio 1.03, 95%Confidence Interval [CI] 0.87 to 1.21) or cardiovascular mortality (risk ratio 0.92, 95%CI 0.72 to 1.18). All-cause mortality rate was positively associated with weight loss (ß = 0.0007; p = 0.045); hence, for each kg of body weight lost there was a 0.07% decrease of all-cause mortality. The pharmacological treatment reduced total-cholesterol (7.15 mg/dl; 95%CI 1.46-12.85), LDL-cholesterol (5.06 mg/dl; 95%CI 1.12-9.00), and triglycerides levels (9.88 mg/dl; 95%CI 5.02-14.75), while it increased HDL-cholesterol (1.37 mg/dl; 95%CI 0.17-2.57). Systolic blood pressure decreased (0.90 mmHg; 95%CI 0.15-1.64). CONCLUSIONS: Although we were unable to demonstrate a superiority of anti-obesity medications over placebo on mortality, metaregression showed that even a small weight reduction tends to reduce all-cause mortality in obesity. Our data support public health measures to reduce the obesity burden by including the use of anti-obesity medications. REGISTRATION NUMBER (PROSPERO): CRD42020210329.

Comparative efficacy of different weight loss treatments on knee osteoarthritis: A network meta-analysis.

The lifetime risk of developing symptomatic knee osteoarthritis is 60% in subjects with obesity. It is unclear which is the best weight loss interventions leading to a meaningful improvement of osteoarthritis symptoms and clinical conditions in subjects with obesity. Our network meta-analysis compares different weight loss interventions on the improvement of osteoarthritis symptoms and clinical conditions in subjects affected by obesity. PubMed, Embase, and Cochrane databases were systematically searched for eligible studies until November 2020. Thirty eligible studies comprising 4651 adults (74.6% women) were included. The most effective interventions reducing pain were bariatric surgery, low-calorie diet and exercise, and intensive weight loss and exercise (-62.7 [95% CrI: -74.6, -50.6]; -34.4 [95% CrI: -48.1, -19.5]; -27.1 [95% CrI: -40.4, -13.6] respectively). For every 1% weight loss Western Ontario and McMaster Universities Osteoarthritis (WOMAC) pain, function, and stiffness scores decreased by about 2% points. In conclusion, our meta-analysis shows that a substantial weight loss is necessary to reduce significantly knee pain and joint stiffness and to improve physical function: 25% weight reduction from baseline is necessary to obtain a 50% reduction of each subscale of the WOMAC score. However, performing physical exercise is essential to preserve the lean body mass and to avoid sarcopenia. Our results apply to a large spectrum of body mass index (BMI), from overweight to severe obesity.

Metabolic surgery versus conventional medical therapy in patients with type 2 diabetes: 10-year follow-up of an open-label, single-centre, randomised controlled trial.

BACKGROUND: No data from randomised controlled trials of metabolic surgery for diabetes are available beyond 5 years of follow-up. We aimed to assess 10-year follow-up after surgery compared with medical therapy for the treatment of type 2 diabetes. METHODS: We did a 10-year follow-up study of an open-label, single-centre (tertiary hospital in Rome, Italy), randomised controlled trial, in which patients with type 2 diabetes (baseline duration >5 years; glycated haemoglobin [HbA1c] >7·0%, and body-mass index ≥35 kg/m2) were randomly assigned (1:1:1) to medical therapy, Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion (BPD) by a computerised system. The primary endpoint of the study was diabetes remission at 2 years (HbA1c <6·5% and fasting glycaemia <5·55 mmol/L without ongoing medication for at least 1 year). In the 10-year analysis, durability of diabetes remission was analysed by intention to treat (ITT). This study is registered with ClinicalTrials.gov, NCT00888836. FINDINGS: Between April 30, 2009, and Oct 31, 2011, of 72 patients assessed for eligibility, 60 were included. The 10-year follow-up rate was 95·0% (57 of 60). Of all patients who were surgically treated, 15 (37·5%) maintained diabetes remission throughout the 10-year period. Specifically, 10-year remission rates in the ITT population were 5·5% for medical therapy (95% CI 1·0-25·7; one participant went into remission after crossover to surgery), 50·0% for BPD (29·9-70·1), and 25·0% for RYGB (11·2-46·9; p=0·0082). 20 (58·8%) of 34 participants who were observed to be in remission at 2 years had a relapse of hyperglycaemia during the follow-up period (BPD 52·6% [95% CI 31·7-72·7]; RYGB 66·7% [41·7-84·8]). All individuals with relapse, however, maintained adequate glycaemic control at 10 years (mean HbA1c 6·7% [SD 0·2]). Participants in the RYGB and BPD groups had fewer diabetes-related complications than those in the medical therapy group (relative risk 0·07 [95% CI 0·01-0·48] for both comparisons). Serious adverse events occurred more frequently among participants in the BPD group (odds ratio [OR] for BPD vs medical therapy 2·7 [95% CI 1·3-5·6]; OR for RYGB vs medical therapy 0·7 [0·3-1·9]). INTERPRETATION: Metabolic surgery is more effective than conventional medical therapy in the long-term control of type 2 diabetes. Clinicians and policy makers should ensure that metabolic surgery is appropriately considered in the management of patients with obesity and type 2 diabetes. FUNDING: Fondazione Policlinico Universitario Agostino Gemelli IRCCS.

Metabolite Changes After Metabolic Surgery - Associations to Parameters Reflecting Glucose Homeostasis and Lipid Levels.

Aims: To test the hypothesis that adipose tissue gene expression patterns would be affected by metabolic surgery and we aimed to identify genes and metabolic pathways as well as metabolites correlating with metabolic changes following metabolic surgery. Materials and Methods: This observational study was conducted at the Obesity Unit at the Catholic University Hospital of the Sacred Heart in Rome, Italy. Fifteen patients, of which six patients underwent Roux-en-Y gastric bypass and nine patients underwent biliopancreatic diversion, were included. The participants underwent an oral glucose tolerance test and a hyperinsulinemic euglycemic clamp. Small polar metabolites were analyzed with a two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC-TOFMS). Gene expression analysis of genes related to metabolism of amino acids and fatty acids were analyzed in subcutaneous adipose tissue. All procedures were performed at study start and at follow-up (after 185.3 ± 72.9 days). Results: Twelve metabolites were significantly changed after metabolic surgery. Six metabolites were identified as 3-indoleacetic acid, 2-hydroxybutyric acid, valine, glutamic acid, 4-hydroxybenzeneacetic acid and alpha-tocopherol. The branched chain amino acids displayed a significant decrease together with a decrease in BCAT1 adipose tissue mRNA levels. Changes in the identified metabolites were associated to changes in lipid, insulin and glucose levels. Conclusions: Our study has identified metabolites and metabolic pathways that are altered by metabolic surgery and may be used as biomarkers for metabolic improvement.

Pioglitazone and bariatric surgery are the most effective treatments for non-alcoholic steatohepatitis: A hierarchical network meta-analysis.

AIMS: To compare different treatments for non-alcoholic steatohepatitis (NASH) and to determine an effectiveness hierarchy. MATERIALS AND METHODS: We conducted a systematic review and Bayesian network meta-analysis including randomized controlled trials or prospective trials with at least 6 months' follow-up and histologically proven NASH in adult participants. Monte Carlo simulations were performed, each generating 10 000 data points, and results are reported as medians and 95% credibility intervals (CrIs). A meta-regression was conducted to find the effects of body mass index (BMI) decrement or reduction of homeostatic model assessment of insulin resistance (HOMA-IR) index on non-alcoholic fatty liver disease activity score (NAS) change. RESULTS: The review identified 48 eligible trials comprising 2356 adults (55.6% men). Data were pooled using a random-effects model. The most effective treatments in terms of NAS reduction per semester were pioglitazone and Roux-en-Y gastric bypass (RYGB; -1.50 [95% CrI -2.08, -1.00] for pioglitazione and -1.00 [95% CrI -1.70, -0.32] for RYGB). Pioglitazone was also the best therapy for steatosis and lobular inflammation reduction. RYGB was the best treatment for hepatocellular ballooning reduction, whereas antioxidants appeared to be best for fibrosis improvement. For each 1% decrement in BMI, NAS was reduced by 1.3% (ß = 1.28%, P = 0.01). Conversely, a 1% reduction of HOMA-IR index reduced NAS by 0.3% (ß = 0.31%, P < 0.001). Treatments that were regarded as promising, such as elafibranor, simtuzumab, selonsertib, cenicriviroc, obeticholic acid and liraglutide, did not reduce either NAS or liver fibrosis significantly. CONCLUSIONS: Pioglitazione and RYGB are the most effective therapies for NASH. Antioxidants may be effective in reducing liver fibrosis. Weight loss and improvement of hepatic insulin resistance are promising approaches in the treatment of NASH.

Insulin sensitivity depends on the route of glucose administration.

AIMS/HYPOTHESIS: The small intestine plays an important role in hepatic and whole-body insulin sensitivity, as shown by bariatric surgery. Our goal was to study whether routes and dose of glucose administration have an acute impact on insulin sensitivity. The primary endpoint of this proof-of-concept study was the difference in insulin-mediated metabolic clearance rate (MCR/I) of glucose between the oral and intravenous routes of glucose administration. Secondary endpoints were differences in insulin effect on proteolysis, ketogenesis, lipolysis and glucagon levels. METHODS: In this parallel cohort study, we administered multiple oral glucose loads to 23 participants (aged between 18 and 65 years) with morbid obesity and with normal or impaired glucose tolerance or type 2 diabetes. In a different session, we administered isoglycaemic intravenous glucose infusions (IGIVI) to match the plasma glucose levels observed during the oral challenges. Glucose rate of appearance (Ra) and disappearance (Rd) and endogenous glucose production (EGP) were calculated by infusing [6,6-2H2]glucose with or without oral [U-13C6]glucose. Plasma small polar metabolites were measured by gas chromatography and time-of-flight mass spectrometry. Lipids were measured by ultra-HPLC and quadrupole mass spectrometry. Glucagon-like peptide-1, insulin, C-peptide and glucagon were also measured. Participants, caregivers, people doing measurements or examinations, and people assessing the outcomes were unblinded to group assignment. RESULTS: Glucose MCR/I was significantly higher during IGIVI than during oral glucose administration, independently of glycaemic status (12 ± 6 for IGIVI vs 7.4 ± 3 ml min-1 kg-1 per nmol/l for oral, p< 0.001 from paired t test). Insulin secretion was higher during oral administration than during IGIVI (p< 0.001). The disposition index was significantly lower during the oral procedure: 4260 ± 1820 vs 5000 ± 2360 (ml min-1 kg-1 (nmol/l)-1 pmol/min; p = 0.005). Insulin clearance was significantly higher when glucose was infused rather than ingested (2.53 ± 0.82 vs 2.16 ± 0.49 l/min in intravenous and oral procedure, respectively, p = 0.006). The efficacy of insulin in inhibiting lipolysis and proteolysis was decreased after oral glucose loads. A heat map diagram showed a different pattern for the metabolites between the two routes of glucose administration. CONCLUSIONS/INTERPRETATION: Our study shows that insulin sensitivity depends on the route of glucose administration, the oral route leading to increased insulin secretion and compensatory insulin resistance compared with the intravenous route. The efficacy of insulin in blocking lipolysis and protein breakdown is lower after oral glucose loads vs the intravenous route. Our findings suggest that, while the glucose-mediated incretin release is followed by an increase in insulin release, the effect of the released insulin is limited by an increase in insulin resistance. TRIAL REGISTRATION: ClinicalTrials.gov NCT03223129. Graphical abstract.

A new sensitive and accurate model to predict moderate to severe obstructive sleep apnea in patients with obesity.

Obstructive sleep apnea (OSA) has a high prevalence in patients with obesity. Only patients with clinical symptoms of OSA are admitted to polysomnography; however, many patients with OSA are asymptomatic. We aimed to create and validate a population-based risk score that predicts the severity of OSA in patients with obesity.We here report the cross-sectional analysis at baseline of an ongoing study investigating the long-term effect of bariatric surgery on OSA. One-hundred sixty-one patients of the Obesity Center of the Catholic University Hospital in Rome, Italy were included in the study. The patients underwent overnight cardiorespiratory monitoring, blood chemistry analyses, hepatic ultrasound, and anthropometric measurements. The patients were divided into 2 groups according OSA severity assessed by the apnea-hypopnea index (AHI): AHI < 15 = no or mild and AHI ≥ 15 moderate to severe OSA. A statistical prediction model was created and validated. C statistics was used to evaluate the discrimination performance of the model.The prevalence of OSA was 96.3% with 74.5% of the subjects having moderate/severe OSA. Sex, body mass index, diabetes, and age were included in the final prediction model that had excellent discrimination ability (C statistics equals to 83%). An OSA risk chart score for clinical use was created.Patients with severe obesity are at a very high risk for moderate or severe OSA in particular if they are men, older, more obese, and/or with type 2 diabetes. The OSA risk chart can be useful for general practitioners and patients as well as for bariatric surgeons to select patients with high risk of moderate to severe OSA for further polysomnography.

Effect of single anastomosis duodenal-ileal bypass with sleeve gastrectomy on glucose tolerance test: comparison with other bariatric procedures.

BACKGROUND: No data have been reported regarding the risk of hyperinsulinemic response and reactive hypoglycemia after single anastomosis duodenal-ileal bypass with sleeve gastrectomy (SADI-S). Furthermore, comparative studies with other bariatric procedures are lacking. OBJECTIVES: To compare response to oral glucose tolerance test (OGTT) in patients who underwent SADI-S, Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and biliopancreatic diversion (BPD). SETTING: Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Università Cattolica del Sacro Cuore, Rome. METHODS: Consenting, nondiabetic patients matched for age, sex, and preoperative body mass index, who underwent SADI-S, RYGB, SG, and BPD, were recruited. A 75 g OGTT was performed pre and postoperatively. Plasma insulin and glucose (pGlu-mg/dL) were measured at baseline, and at +30, +60, +90, +120, +150, and +180 minutes. Severe hypoglycemia was defined as pGlu concentration <55 mg/dL. RESULTS: Thirty-five patients were recruited: 9 SADI-S, 11 RYGB, 7 SG, and 8 BPD. Comparing preoperative and postoperative responses to OGTT, all procedures improved the glycemic control with better early results after SADI-S and BPD compared with RYGB and SG. No patients showed severe hypoglycemia. Significantly more patients who underwent RYGB and SG showed asymptomatic pGlu <70 mg/dL during OGTT compared with SADI-S and BPD (63.6% and 57.1% vs 22.2% and 12.5%, respectively, P < .05). CONCLUSIONS: Similar to BPD, SADI-S seems to be associated to insulin sensitivity and glucose homeostasis improvement, together with a reduced risk of hyperinsulinemia and, consequently, to hypoglycemia, often associated with RYGB and SG.

Obesity is associated with impaired responsiveness to once-daily low-dose aspirin and in vivo platelet activation.

BACKGROUND: The prevalence and degree of obesity is rising worldwide, increases cardiovascular risk, modifies body composition and organ function, and potentially affects the pharmacokinetics and/or pharmacodynamics of drugs. OBJECTIVES: To investigate the pharmacodynamics of once-daily low-dose aspirin in healthy obese subjects, and to assess whether body weight (BW) and body mass index (BMI) affect the pharmacology of aspirin. PATIENTS/METHODS: Otherwise healthy, obese (BMI > 30 kg/m2 ) subjects were studied before and after 3-4 weeks of 100-mg once-daily aspirin intake. Aspirin pharmacodynamics were assessed according to serum thromboxane (TX) B2 levels measured at 4 hours, 24 hours (i.e., posologic interval) and 48 hours after the last witnessed intake; age-matched and sex-matched non-obese controls were included. A previously calibrated pharmacokinetic/pharmacodynamic in silico model of aspirin was used to fit serum TXB2 data from obese subjects. At baseline, the major urinary TXA2 and prostacyclin metabolites, urinary isoprostane and plasma inflammatory biomarkers were measured. RESULTS: In 16 obese subjects (aged 47 ± 11 years; BMI of 39.4 ± 5.1 kg/m2 ), residual serum TXB2 values between 4 and 48 hours after aspirin intake were increased 3- to 5-fold as compared with controls. At 24 hours, the residual serum TXB2 level was log-linearly associated with body size over a wide range of BMI and BW values, without any apparent threshold. The in silico model predicted that reduced aspirin bioavailability would be inversely related to body size and rescued by 200 mg of aspirin once daily or 85 mg twice daily. Baseline urinary TXA2 metabolite, isoprostane and plasma C-reactive protein levels were significantly increased in obese subjects. CONCLUSIONS: Obesity is associated with impaired aspirin responsiveness, largely because of body size. Impaired inhibition of platelet activation by conventional low-dose aspirin may affect antithrombotic efficacy.

Alexithymia affects patients with hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that impairs patients' quality of life. Various psychiatric or psychological conditions have been associated with HS, however, no data are available on alexithymia, a psychological construct characterized by the inability to express, describe, and recognize feelings. OBJECTIVES: To assess the presence of alexithymia in HS patients. MATERIALS & METHODS: Demographic and clinical data from patients with HS were collected. Alexithymia was assessed using the Toronto Alexithymia Scale (TAS)-20 questionnaire to define non-alexithymic subjects (scoring 20-50), borderline (possible) alexithymia subjects (scoring 51-60), and alexithymic subjects (scoring ≥61). The alexithymic personality trait is identified based on TAS-20 score ≥51. RESULTS: This multicentre study included 86 HS patients, 100 obese individuals, and 85 healthy control subjects. The mean TAS-20 score was significantly higher in the HS patient cohort (55.37 ±13.42) than in the control group (40.96±10.47) (p<0.001). Compared to the healthy and obese control groups, the prevalence of alexithymic personality trait in HS patients was 61.6% versus 21.95% and 32%, respectively (p<0.001). Of the HS patients, 37.2% were classified as alexithymic and 24.4% as borderline alexithymia. CONCLUSIONS: This is the first study in which an association between HS and alexithymia has been reported, expanding the spectrum of psychological disorders associated with HS.

Cognitive Function in Individuals with Normal Weight Obesity: Results from the Third National Health and Nutrition Examination Survey (NHANES III).

BACKGROUND/OBJECTIVE: Normal weight obesity (NWO) is associated with increased risk of metabolic syndrome, cardiovascular- and all-cause mortality. However, no data have been reported on the relationship between adiposity and cognitive performance in NWO. We therefore studied the association between cognitive function and body fat percentage (BF%) in NWO, using a representative sample of the United States population. METHODS: A cross-sectional study was performed using the nationwide 1988 to 1994 data set from the Third National Health and Nutrition Examination Survey. Cognitive function was measured by three validated cognitive tests: simple reaction time test (SRTT), symbol digit substitution test (SDST), and serial digit learning test (SDLT). The association between BF% and cognitive performance was evaluated in 2,039 adults aged 20-59 years and with a body mass index ranging from 18.5 to 24.9 kg/m2. Linear regression modeling was used to adjust for potential confounders. RESULTS: Increased BF% was significantly associated with poorer performance on SDLT in the entire study sample (coefficient [95% CI]: 0.15 [0.01, 0.29]) and with poorer performance on SDST in the age group 20-29 years (coefficient [95% CI]: 0.30 [0.10, 0.49]). Increased BF% did not significantly predict poorer performance on SRTT. CONCLUSION: Higher BF% is significantly associated with poorer cognitive function in a nationally representative sample of US adults with NWO. The identification of possible complications associated with increased adipose tissue underlines the need to measure body fat content in NWO individuals, whose metabolic and cognitive dysfunction could go undetected for years due to their young age and normal body weight.

Incidence of Hypoglycemia After Gastric Bypass vs Sleeve Gastrectomy: A Randomized Trial.

Context: We compared the incidence of hypoglycemia after Roux-en-Y gastric bypass (RYGB) vs sleeve gastrectomy (SG). Design, Setting, and Main Outcome Measures: Randomized, open-label trial conducted at the outpatient obesity clinic in a university hospital in Rome, Italy. The primary aim was the incidence of reactive hypoglycemia (<3.1 mmol/L after 75-g oral glucose load) at 1 year after surgery. Secondary aims were hypoglycemia under everyday life conditions, insulin sensitivity, insulin secretion, and lipid profile. Results: Of 175 eligible patients, 120 were randomized 1:1 to RYGB or SG; 117 (93%) completed the 12-month follow-up. Reactive hypoglycemia was detected in 14% and 29% of SG and RYGB patients (P = 0.079), respectively, with the effect of treatment in multivariate analysis significant at P = 0.018. Daily hypoglycemic episodes during continuous glucose monitoring did not differ between groups (P = 0.75). Four of 59 RYGB subjects (6.8%) had 1 to 3 hospitalizations for symptomatic hypoglycemia vs 0 in SG. The static ß-cell glucose sensitivity index increased after both treatments (P < 0.001), but the dynamic ß-cell glucose sensitivity index increased significantly in SG (P = 0.008) and decreased in RYGB (P = 0.004 for time × treatment interaction). Whole-body insulin sensitivity increased about 10-fold in both groups. Conclusions: We show that reactive hypoglycemia is no less common after SG and is not a safer option than RYGB, but RYGB is associated with more severe hypoglycemic episodes. This is likely due to the lack of improvement of ß-cell sensitivity to changes in circulating glucose after RYGB, which determines an inappropriately high insulin secretion.