Association of Bariatric Surgery With Major Adverse Liver and Cardiovascular Outcomes in Patients With Biopsy-Proven Nonalcoholic Steatohepatitis

Abstract

Importance: No therapy has been shown to reduce the risk of serious adverse outcomes in patients with nonalcoholic steatohepatitis (NASH).

Objective: To investigate the long-term relationship between bariatric surgery and incident major adverse liver outcomes and major adverse cardiovascular events (MACE) in patients with obesity and biopsy-proven fibrotic NASH without cirrhosis.

Design, setting, and participants: In the SPLENDOR (Surgical Procedures and Long-term Effectiveness in NASH Disease and Obesity Risk) study, of 25 828 liver biopsies performed at a US health system between 2004 and 2016, 1158 adult patients with obesity were identified who fulfilled enrollment criteria, including confirmed histological diagnosis of NASH and presence of liver fibrosis (histological stages 1-3). Baseline clinical characteristics, histological disease activity, and fibrosis stage of patients who underwent simultaneous liver biopsy at the time of bariatric surgery were balanced with a nonsurgical control group using overlap weighting methods. Follow-up ended in March 2021.

Exposures: Bariatric surgery (Roux-en-Y gastric bypass, sleeve gastrectomy) vs nonsurgical care.

Main outcomes and measures: The primary outcomes were the incidence of major adverse liver outcomes (progression to clinical or histological cirrhosis, development of hepatocellular carcinoma, liver transplantation, or liver-related mortality) and MACE (a composite of coronary artery events, cerebrovascular events, heart failure, or cardiovascular death), estimated using the Firth penalized method in a multivariable-adjusted Cox regression analysis framework.

Results: A total of 1158 patients (740 [63.9%] women; median age, 49.8 years [IQR, 40.9-57.9 years], median body mass index, 44.1 [IQR, 39.4-51.4]), including 650 patients who underwent bariatric surgery and 508 patients in the nonsurgical control group, with a median follow-up of 7 years (IQR, 4-10 years) were analyzed. Distribution of baseline covariates, including histological severity of liver injury, was well-balanced after overlap weighting. At the end of the study period in the unweighted data set, 5 patients in the bariatric surgery group and 40 patients in the nonsurgical control group experienced major adverse liver outcomes, and 39 patients in the bariatric surgery group and 60 patients in the nonsurgical group experienced MACE. Among the patients analyzed with overlap weighting methods, the cumulative incidence of major adverse liver outcomes at 10 years was 2.3% (95% CI, 0%-4.6%) in the bariatric surgery group and 9.6% (95% CI, 6.1%-12.9%) in the nonsurgical group (adjusted absolute risk difference, 12.4% [95% CI, 5.7%-19.7%]; adjusted hazard ratio, 0.12 [95% CI, 0.02-0.63]; P = .01). The cumulative incidence of MACE at 10 years was 8.5% (95% CI, 5.5%-11.4%) in the bariatric surgery group and 15.7% (95% CI, 11.3%-19.8%) in the nonsurgical group (adjusted absolute risk difference, 13.9% [95% CI, 5.9%-21.9%]; adjusted hazard ratio, 0.30 [95% CI, 0.12-0.72]; P = .007). Within the first year after bariatric surgery, 4 patients (0.6%) died from surgical complications, including gastrointestinal leak (n = 2) and respiratory failure (n = 2).

Conclusions and relevance: Among patients with NASH and obesity, bariatric surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident major adverse liver outcomes and MACE.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Aminian reported receiving research support and speaking honoraria from Medtronic. Dr Brethauer reported being a consultant for GI Windows and receiving speaking honoraria from Medtronic. Dr Dasarathy reported being supported by research grants from the National Institutes of Health. Dr Alkhouri reported being on an advisory board or review panel for Echosens, Fibronostics, Gilead, Intercept, Perspectum, Pfizer, and Zydus; receiving research support from 89Bio, Akero, Bristol-Myers Squibb, Genentech, Gilead, Intercept, Madrigal, NGM Bio, Novo Nordisk, Pfizer, Viking, and Zydus; and being a speaker for AbbVie, Alexion Echosens, Gilead, and Intercept. Dr Schauer reported being a consultant for GI Dynamics, Keyron, Persona, and Mediflix; receiving research support from Ethicon, Medtronic, and Pacira; receiving honoraria from Ethicon, Medtronic, BD Surgical, and Gore; and having an ownership interest in SE Healthcare LLC. Dr Nissen reported receiving research support from Medtronic and Ethicon. No other disclosures were reported.

Figures

Figure 1.. Identification of Eligible Patients and Development of Cohorts in the Study

Diagnoses and procedure codes appear in eTables 1-5 in Supplement 2. BMI indicates body mass index (calculated as weight in kilograms divided by height in meters squared); NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis. aHistory of excessive alcohol use or any medical conditions related to alcohol use disorder, organ transplantation, dialysis, HIV infection, severe heart failure (ejection fraction <20%), and received total parenteral nutrition prior to liver biopsy. bGastric banding, gastric plication, or biliopancreatic diversion. cAccording to criteria from the Nonalcoholic Steatohepatitis Clinical Research Network, which awards at least 1 point for each of the following to establish a diagnosis: steatosis, hepatocellular ballooning, and lobular inflammation. dSelection criteria resulted in a total of 650 patients who underwent bariatric surgery and 508 patients in the nonsurgical control group with biopsy-proven fibrotic (fibrosis stages 1, 2, or 3) NASH without cirrhosis and BMI of 30 or greater for primary comparison using overlap weighting. The date of bariatric surgery and liver biopsy was considered as the index date for patients in the bariatric surgery group. The date of first liver biopsy on which all selection criteria were met served as the index date for patients in the nonsurgical control group.

Figure 2.. Cumulative Incidence Estimates (Kaplan-Meier) for 2 Composite End Points in the Overlap-Weighted Analysis

HR indicates hazard ratio. The date of bariatric surgery and liver biopsy was considered as the index date for patients in the bariatric surgery group. The date of first liver biopsy on which all selection criteria were met served as the index date for patients in the nonsurgical control group. aComposite end point that was defined as the first occurrence of progression to clinical or histological cirrhosis, development of hepatocellular carcinoma, liver transplantation, or liver-related mortality after the index date. The median observation time was 84.6 months (IQR, 37.1-118.5 months) in the bariatric surgery group and 85.3 months (IQR, 48.5-127.4 months) in the nonsurgical control group. bComposite end point that was defined as the first occurrence of coronary artery events, cerebrovascular events, heart failure, or cardiovascular mortality after the index date. The median observation time was 81.6 months (IQR, 34.9-116.0 months) in the bariatric surgery group and 80.6 months (IQR, 46.2-126.1 months) in the nonsurgical control group.

Figure 3.. Trend Curves of Mean Change in Body Weight and Hemoglobin A1c Level Over 10 Years of Follow-up in the Overlap-Weighted Analysis

Data are illustrated as smoothed mean trends from baseline to follow-up. The shaded areas indicate 95% CIs. The mean between-group differences at 10 years from baseline were estimated from a flexible regression model with a 4-knot restricted cubic spline for time × treatment interaction because the time from index date interacted with the treatment group. The date of bariatric surgery and liver biopsy was considered as the index date for patients in the bariatric surgery group. The date of first liver biopsy on which all selection criteria were met served as the index date for patients in the nonsurgical control group. The sample sizes at different time points appear in eTable 7 in Supplement 2. aThe median observation time was 74.9 months (IQR, 27.6-110.2 months) in the bariatric surgery group and 77.3 months (IQR, 38.4-123.1 months) in the nonsurgical control group. bThe median observation time was 41.2 months (IQR, 7.1-85.3 months) in the bariatric surgery group and 81.9 months (IQR, 43.7-120.0 months) in the nonsurgical control group. The shorter observation time in the bariatric surgery group is likely due to less need for regular testing in patients with improved diabetes after surgery.