Meta-Analysis
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 7, 2023; 29(37): 5327-5338
Published online Oct 7, 2023. doi: 10.3748/wjg.v29.i37.5327
Efficacy and safety of semaglutide in non-alcoholic fatty liver disease
Kai Zhu, Rohan Kakkar, Daljeet Chahal, Eric M Yoshida, Trana Hussaini
Kai Zhu, Rohan Kakkar, Internal Medicine, University of British Columbia, Vancouver V5Z 1M9, BC, Canada
Daljeet Chahal, Eric M Yoshida, Department of Gastroenterology, University of British Columbia, Vancouver V5Z 1M9, BC, Canada
Daljeet Chahal, Eric M Yoshida, Trana Hussaini, BC Liver Transplant Program, Vancouver General Hospital, Vancouver V5Z 1M9, BC, Canada
Trana Hussaini, Pharmaceutical Sciences, University of British Columbia, Vancouver V5Z 1M9, BC, Canada
Author contributions: Zhu K contributed to conception and design, analysis and interpretation of data, drafting the article, and final approval; Rohan K contributed to acquisition of data, analysis and interpretation of data, drafting the article; Chahal D contributed to revising the article and final approval; Yoshida E contributed to conception and design, revising the article, and final approval; Hussaini T contributed to conception and design, revising the article, and final approval.
Conflict-of-interest statement: Zhu K, Kakkar R and Chahal D have no conflicts of interests to declare; Yoshida EM is an investigator of clinical trials sponsored by Gilead Sciences, Pfizer, Genfit, Intercept, Celgene, Allergan, and Madrigal; Yoshida EM has received research funding from Paladin Labs Inc; Hussaini T has received research funding from Transplant Research Foundation of BC, and Paladin Labs Inc.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Trana Hussaini, BPharm, MHSc, PharmD, Associate Professor, Pharmacist, BC Liver Transplant Program, Vancouver General Hospital, 899 West 12th Avenue, Vancouver V5Z 1M9, BC, Canada. trana.hussaini@vch.ca
Received: June 28, 2023
Peer-review started: June 28, 2023
First decision: August 15, 2023
Revised: August 23, 2023
Accepted: September 12, 2023
Article in press: September 12, 2023
Published online: October 7, 2023
Processing time: 89 Days and 3.7 Hours
ARTICLE HIGHLIGHTS
Research background

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease. The prevalence and disease burden of NAFLD are projected to exponentially increase resulting in significant healthcare expenditures and lower health-related quality of life. To date, there are no approved pharmacotherapies for NAFLD or non-alcoholic steatohepatitis (NASH).

Research motivation

Several randomized clinical trials have demonstrated the beneficial effects of semaglutide in patients with NAFLD. Prior systematic review with meta-analysis assessing the impact of semaglutide did not report histological outcomes and were not focused on a NAFLD specific population.

Research objectives

This study aimed to review the efficacy and safety of semaglutide, focusing on patients with NAFLD, in order to more specifically reflect the NAFLD population and expand the current understanding of semaglutide in NAFLD.

Research methods

MEDLINE, CENTRAL, EMBASE, and grey literature sources were searched from inception to May 1, 2023, to identify eligible randomized controlled trials (RCTs) using a predefined search strategy. Predetermined outcomes were extracted, and quality assessment was performed using the Cochrane risk-of-bias 2 tool and GRADE framework. Meta-analysis was performed using random effects model expressing continuous outcomes as mean differences (MD) or standardized MDs (SMD), and dichotomous outcomes as odds ratios (OR) with 95% confidence intervals (CI). Statistical heterogeneity was assessed using the Cochran’s Q test and I2statistic.

Research results

A total of three RCTs involving 458 patients were included. Semaglutide increased the likelihood of NASH resolution (OR: 3.18, 95%CI: 1.70, 5.95; P < 0.001), improvement in steatosis (OR: 2.83, 95%CI: 1.19, 6.71; P = 0.03), lobular inflammation (OR: 1.81, 95%CI: 1.11, 2.96; P = 0.02), and hepatocellular ballooning (OR: 2.92, 95%CI: 1.83, 4.65; P < 0.001), but not fibrosis stage (OR: 0.71, 95%CI: 0.15, 3.41; P = 0.67). Radiologically, semaglutide reduced liver stiffness (SMD: -0.48, 95%CI: -0.86, -0.11; P = 0.01) and steatosis (MD: -4.96%, 95%CI: -9.92, 0.01; P = 0.05). It also reduced ALT (MD: -14.06 U/L, 95%CI: -22.06, -6.07; P < 0.001) and AST (MD: -11.44 U/L, 95%CI: -17.23, -5.65; P < 0.001).

Semaglutide led to improved cardiometabolic outcomes, including decreased HgA1c (MD: -0.77%, 95%CI: -1.18, -0.37; P < 0.001) and weight loss (MD: -6.53 kg, 95%CI: -11.21, -1.85; P = 0.006), but increased the occurrence of GI-related side effects (OR: 3.72, 95%CI: 1.68, 8.23; P = 0.001). Overall risk of serious adverse events was similar compared to placebo (OR: 1.40, 95%CI: 0.75, 2.62; P < 0.29).

Research conclusions

Semaglutide demonstrated significant histologic improvements, with a higher likelihood of NASH resolution and improved NAS components, but it did not significantly improve fibrosis stage compared to placebo. Furthermore, semaglutide resulted in radiologic improvements in liver stiffness and steatosis, liver enzymes, as well as cardiometabolic effects on body weight and HgA1c, while maintaining a well-tolerated safety profile.

Research perspectives

Additional RCTs with larger sample sizes and longer durations are required to characterize the effects of semaglutide on fibrosis regression and its role in the different phases of NAFLD.