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Bariatric Surgery vs Lifestyle Interventions and Best Medical Care in Patients With NASH
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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.
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.
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.
Bariatric-metabolic surgery is more effective than lifestyle interventions and optimised medical therapy in the treatment of NASH.
Fondazione Policlinico Universitario A Gemelli, Policlinico Universitario Umberto I and S Camillo Hospital, Rome, Italy.
Disclosure statements are available on the authors' profiles:
Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trialLancet 2023 Apr 20;[EPub Ahead of Print], O Verrastro, S Panunzi, L Castagneto-Gissey, A De Gaetano, E Lembo, E Capristo, C Guidone, G Angelini, F Pennestrì, L Sessa, FM Vecchio, L Riccardi, MA Zocco, I Boskoski, JR Casella-Mariolo, P Marini, M Pompili, G Casella, E Fiori, F Rubino, SR Bornstein, M Raffaelli, G Mingrone
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The cardiometabolic benefits of bariatric surgery are well established;1 however, its effects on underlying nonalcoholic steatohepatitis are not well established in rigorously controlled trials. The BRAVES study prospectively compared lifestyle modifications as the best medical therapy to Roux-en-Y gastric bypass (RGB) and sleeve gastrectomy (SG) in an open-label randomized trial conduced in three centres in Italy.2 The primary endpoint of NASH resolution without worsening of fibrosis was met in 16% of medical management versus 56% and 57% of those undergoing RGB or SG respectively. Fibrosis regression by one stage or more was noted in 23%, 37%, and 39% in medical care, RGB, and SG, respectively. These data provide high quality evidence of the benefits of bariatric surgery on NASH and provide a rationale for considering this as a treatment option for NASH.
There are, however, several caveats that must be considered in evaluating this important work. First, over 80% of patients recruited had stages 0 to 2 fibrosis which is associated with a rather low risk of liver events within a median duration of 4 to 5 years.3 Fibrosis has emerged as the most important predictor of clinical outcomes in those with NASH,4 and only a small number of patients with bridging fibrosis were included. The small number of patients in this subgroup and the improvement in fibrosis after 52 weeks in all treatment arms create some uncertainty around the potential benefit of this procedure with respect to this clinically highly relevant endpoint. Also, medical therapy for obesity has evolved considerably in the last 5 years, and GLP-1 anchored therapeutics could be argued as the best medical care. Importantly, the NASH resolution results with bariatric surgery are similar to those reported with semaglutide.5
In summary, this is a landmark study providing strong evidence of improvement in histological markers of disease activity of NASH. While highly promising, additional data are needed around the liver benefits in populations most at risk, ie, those with stage 3 and potentially compensated stage 4 patients, where a strong antifibrotic benefit is needed. Regardless of this, for those with NASH and lower stages of fibrosis as well as conventional criteria for bariatric surgery, these data provide evidence for histological benefit for NASH.
NASH is a progressive liver disease which can lead to cirrhosis, liver cancer, and liver failure. Losing >10% body weight can improve liver histology in patients with NASH, but achieving and sustaining significant weight loss is difficult without either pharmacological agents (eg, semaglutide) or bariatric surgery. Several studies to date have provided evidence supporting bariatric surgery in patients with NASH. In a recent retrospective study, investigators from Cleveland Clinic have shown that bariatric surgery improves survival in patients with NASH. The recently published BRAVES trial compared bariatric surgery (either Roux-en-Y or sleeve gastrectomy) to lifestyle management in a randomized controlled trial. Compared to lifestyle management, bariatric surgery led to a 2.6-fold higher likelihood of NASH resolution. Additionally, compared with lifestyle management, bariatric surgery led to greater improvement in liver fibrosis. Collectively, it is reasonable to summarize that bariatric surgery is very effective in improving steatohepatitis and fibrosis in patients with NASH. GLP-1 agonists (eg, semaglutide) and dual GLP-1/GIP agonists (eg, tirzapetide) show great promise for weight loss and are rapidly growing in popularity. Endoscopic bariatric procedures also show promise in promoting weight loss and improving liver histology in NAFLD/NASH. It is unclear how pharmacotherapy and endobariatrics stack up against bariatric surgery in patients with NASH.
In summary, several effective options are rapidly emerging to promote weight loss and improve liver histology in patients with NASH, but relative advantages of one approach over another are not clear. Currently, it is best to make therapeutic decisions for the patient on an individual basis, depending on local expertise and the patient’s preference.