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.

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.

The jejunum is the key factor in insulin resistance.

BACKGROUND: Biliopancreatic diversion (BPD) is more effective than Roux-en-Y gastric bypass (RYGB) on both insulin resistance and diabetes. OBJECTIVES: Because the major difference between the 2 procedures resides in the length of jejunal bypass, we investigated the role of the jejunum in insulin resistance. SETTING: University hospital in Italy. METHODS: Insulin sensitivity (IS) and secretion were measured before and 4 weeks after RYGB or BPD in 16 patients. A translational study was also conducted in 6 pigs, by isolating a jejunal loop with its vascular and nerve supply (Thiry-Vella loop [TVL]). TVL was doubly stomatized and bowel continuity restored by a side-to-side jejuno-jejunostomy. At baseline and 4 weeks postoperatively a glucose bolus was injected either in the stomach or in the TVL. Whole-body IS and jejunal heat shock proteins (HSPs) were measured. Primary porcine hepatocyte cultures were incubated with plasma or individual HSPs. RESULTS: Whole-body IS increased from 353.5 ± 26.7 to 442.0 ± 37.4 (P < .05) after RYGB and from 312.4 ± 14.9 to 441.2 ± 15.9 mL/m-2/min-1 (P < .001) after BPD. Hepatic IS was unchanged after RYGB, while it increased from .3 ± .01 to .4 ± .1 (µM/pM) - 1 (P < .01) after BPD. Total insulin secretion rate remained unchanged after RYGB but decreased (from 58.3 ± 23.6 to 33.1 ± 7.8 nmol/m-2, P < .05) after BPD. Jejunectomy in pigs enhanced IS (.3 ± .01 versus .2 ± .01 mM/pM, P < .001), while injection of glucose into TVL reduced it (.1 ± .01 versus .3 ± .01 mM/pM, P < .0001). The jejunum secreted HSPs, Hsp70, and GRP78, which impaired insulin signaling in hepatocyte cultures. CONCLUSIONS: This study shows that jejunal bypass in both humans and pigs improves IS. Injection of glucose into the TVL in pigs determines insulin resistance. In response to glucose, the jejunum secretes HSPs that impair insulin signaling.

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 WL.

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.