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

10-Year follow-up after laparoscopic sleeve gastrectomy. Outcomes in a monocentric series

BACKGROUND: Sleeve gastrectomy (SG) has grown into the most popular bariatric operation. Nevertheless, a scarcity of long-term outcomes are available. OBJECTIVES: This study aims at evaluating the long-term percent weight loss (%WL), excess weight loss (%EWL), weight regain (WR), and co-morbidity resolution rates in a single-center cohort undergoing SG as a primary procedure, with a minimum 10-year follow-up. SETTING: University hospital, Italy. METHODS: One hundred eighty-two morbidly obese patients with body mass index (BMI) 46.6 ± 7.3 kg/m2 underwent SG. Obesity-related co-morbidities (type 2 diabetes, hypertension, sleep apnea, gastroesophageal reflux disease) were investigated. Predictors of dichotomous dependent-variable diabetes remission were computed using a binomial logistic regression. RESULTS: Patient retention rate was 77%. Mean %WL was 30.9, %EWL was 52.5%, and WR (≥25% maximum WL) occurred in 10.4%. Baseline BMI significantly (P = .001) and linearly predicted %EWL (10 yr %EWL = 18.951 + initial BMI × .74); the super-obese subgroup generated substantially greater WL compared with those with BMI <50 kg/m2 (%EWL 48.0 ± 18.5 versus 61.5 ± 23.2; P < .001). Type 2 diabetes remission occurred in 64.7%; 42.9% patients developed de novo gastroesophageal reflux disease symptoms postoperatively (P < .0001). CONCLUSIONS: SG generates sustained WL and co-morbidity resolution up to 10 years postoperatively. Although a notable portion of patients experience WR, mean %WL persists to exceed 30%, translating in adequate WL also in the long term. Additionally, WR does not seem to impact negatively on co-morbidity resolution. SG represents a safe and effective bariatric operation, which easily grants the possibility to proceed to revisional bariatric surgery in patients with WR or failure to W

Metabolic surgery and depression

The incidence of obesity is rising worldwide and so are its comorbidities: type-2 diabetes mellitus (T2DM), dyslipidaemia, hypertension, cardiovascular disease, sleep apnoea, and depression. Bariatric/metabolic surgery has established itself over the past several years as an effective treatment not only for morbid obesity but also for its associated morbidities. The effects of bariatric/metabolic surgery on depression are controversial, with some studies showing improvement and others demonstrating a worsening. However, a major drawback of these studies is that they do not compare patients with the same baseline psychiatric disorders. In fact, mild to severe depressive symptoms are observed in most candidates for bariatric/metabolic surgery. Preoperative evaluation of the patient’s mental state would enable identification of the appropriate interventions, enhancing long-term compliance and weight maintenance. It could also leverage psychological support in case the patient’s disorder relapses postoperatively. Preoperative evaluation should detect potential psychological contraindications to surgery, such as severe eating disorders

Lipidomic changes in skeletal muscle in patients after biliopancreatic diversion

The mechanisms behind the fast improvements of insulin sensitivity and release of the diabetic metabolic state after bariatric surgery are still not completely understood. To further elucidate the effects on the individual cellular level, we applied mass spectrometry to investigate the changes in the lipidomic profile of skeletal muscle cells before and after biliopancreatic diversion in six patients. We found a decrease in lipid storage species, mainly triacylglycerides (e. g., TAG 52:2 from 19.84 to 13.26 mol%; p=0.028), and an increase in structural and signaling lipids, including phosphatidylcholines [PC 36:2 (18:1/18:1) from 0.12 to 0.65 mol%; p=0.046], phosphatidylinositols (PI 36:2 from 0.008 to 0.039 mol%; p=0.046), and cardiolipins (CL 72:8 from 0.16 to 1.22 mol%; p=0.043). The proportional increase in structural lipids was directly and the decrease in TAGs was inversely correlated to improved post-operative insulin sensitivity, measured by euglycemic hyperinsulinemic clamp. Thus, short-term recovery of insulin sensitivity after biliopancreatic diversion may, beside gut hormonal adaptation, mechanical factors, shifts in the gut microbiome, and changes in bile acid and phospholipid metabolism, additionally be attributed to a metabolic recovery of skeletal muscle cells, reflected by normalization of the cellular lipidomic profile. Further studies are needed to investigate whether improved insulin sensitivity of skeletal muscle might be directly associated with the degradation of ectopic triglycerides, thereby reducing the reservoir of lipotoxic intermediates, which might interfere with insulin signaling and hamper mitochondrial metabolism

Simulation of gastric bypass effects on glucose metabolism and non-alcoholic fatty liver disease with the Sleeveballoon device

BACKGROUND Gastric bypass surgery is a very effective treatment of obesity and type 2 diabetes. However, very few eligible patients are offered surgery. Some patients also prefer less invasive approaches. We aimed to study the effects of the Sleeveballoon - a new device combining an intragastric balloon with a connecting sleeve, which covers the duodenal and proximal jejunal mucosa - on insulin sensitivity, glycemic control, body weight and body fat distribution. METHODS We compared the effects of Sleeveballoon, Roux-en-Y Gastric-Bypass (RYGB) and sham-operation in 30 high-fat diet (HFD) fed Wistar rats. Whole body and hepatic insulin sensitivity and insulin signaling were studied. Transthoracic echocardiography was performed using a Vevo 2100 system (FUJIFILM VisualSonics Inc., Canada). Gastric emptying was measured using gastrografin. FINDINGS Hepatic (P = .023) and whole-body (P = .011) insulin sensitivity improved in the Sleeveballoon and RYGB groups compared with sham-operated rats. Body weight reduced in both Sleeveballoon and RYGB groups in comparison to the sham-operated group (503.1 ± 8.9 vs. 614.4 ± 20.6 g, P = .006 and 490.0 ± 17.7 vs. 614.4 ± 20.6 g, P = .006, respectively). Ectopic fat deposition was drastically reduced while glycogen content was increased in both liver and skeletal muscle. Gastric emptying (T) was longer (157.7 ± 29.2 min, P = .007) in the Sleeveballoon than in sham-operated rats (97.1 ± 26.3 min), but shorter in RYGB (3.5 ± 1.1 min, P < .0001). Cardiac function was better in Sleeveballoon and RYGB versus sham-operated rats. INTERPRETATION The Sleeveballoon reduces peripheral and hepatic insulin resistance, glycaemia, body weight and ectopic fat deposition to a similar level as RYGB, although the contribution of gastric emptying to blood glucose reduction is different

Duodenal-jejunal bypass improves nonalcoholic fatty liver disease independently of weight loss in rodents with diet-induced obesity

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver-related mortality. NAFLD is associated with obesity, hepatic fat accumulation, and insulin resistance, all of which contribute to its pathophysiology. Weight-loss is the main therapy for NAFLD, and metabolic surgery is the most effective treatment for morbid obesity and its metabolic comorbidities. Although has been reported that Roux-en-Y gastric bypass can reverse NAFLD, it is unclear whether such effects result from reduced weight, from a lower calorie-intake, or from the direct influence of surgery on mechanisms contributing to NAFLD. We aimed to investigate whether gastrointestinal (GI) bypass surgery could induce direct effects on hepatic fat accumulation and insulin resistance, independently of weight reduction. Twenty Wistar rats on a high-fat diet underwent duodenal-jejunal-bypass (DJB) or sham operation and were pair fed (PF) for 15 wk after surgery to obtain a matched weight. Outcome measures include ectopic fat deposition, expression of genes and proteins involved in fat metabolism, insulin-signaling, and gluconeogenesis in liver and muscle. Despite no differences in body weight and calorie intake, DJB showed lower ectopic fat accumulation, improved peripheral and hepatic insulin sensitivity, and enhanced lipid droplet degradation. In both tissues, DJB increased insulin signaling, whereas hepatic key enzymes involved in gluconeogenesis and de novo lipogenesis were decreased. These findings suggest that DJB can reverse, independently of weight loss, ectopic fat deposition and insulin resistance, two features of NAFLD that share a mutual pathway, in which perilipin-2 (PLIN2) seems to be the main player, supporting further investigation into strategies that target the gut to treat metabolic liver diseases.NEW & NOTEWORTHY Our findings suggest that duodenal-jejunal bypass can reverse, independently of weight loss, ectopic fat deposition and insulin resistance, two features of nonalcoholic fatty liver disease that share a mutual pathway, in which perilipin-2 seems to be the main player. Our study supports further investigation into the role of proximal small intestine exclusion in the pathophysiology of nonalcoholic fatty liver disease to uncover less invasive treatments that mimic the effects of metabolic surgery and aims to prevent and treat metabolic liver disease

Correction: 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 efcient 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 fnal part of a protocol of treatment of obesity. However, there are indications that general practitioners (GPs) are not fully aware of the possible benefts 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 twentythree 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 patient