Efficacy and Safety of GLP-1 Receptor Agonists in Patients With Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Yuan Zhu,Dong Zhang,Xingyu Mu,Zengxiang Wu,Shangtao Chen,Yi Shi,Shuangqing Li,Jiao Xu

doi:10.3389/fendo.2021.769069

Abstract

The prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM) is increasing and there is an urgent need for new treatment strategy to prevent progression of hepatic steatosis and fibrosis. We have performed a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the treatment of hepatic steatosis and fibrosis in patients with T2DM and NAFLD. The PubMed, Web of Science, Scopus, Embase and Cochrane Central Register of Controlled Trials databases were searched for articles that met the eligibility criteria to explore the efficacy and safety of GLP-1RAs in patients with T2DM and NAFLD. We assessed pooled data using a random/fixed-effects model according to the I2 and p-values. Eight trials that included a total of 468 participants were eligible for inclusion in the review. For primary outcomes, administration of GLP-1RAs significantly decreased the content of intrahepatic adipose (IHA)[p=0.007, weight mean difference (WMD) -3.01, 95% confidence interval (CI) -4.75, -1.28], subcutaneous adipose tissue (SAT) (p<0.00001,WMD -28.53,95%CI -68.09,-26.31), and visceral adipose tissue (VAT) (p<0.0001,WMD -29.05,95%CI -42.90,-15.9). For secondary outcomes, GLP-1RAs produced a significant decrease in levels of alanine aminotransferase(ALT)(p=0.02, WMD -3.82, 95%CI -7.04, -0.60), aspartate aminotransferase (AST) (p=0.03, WMD -2.4, 95%CI -4.55,-0.25, I2 = 49%), body weight (p<0.00001,WMD -3.48,95%CI -4.58,-2.37), body mass index (p<0.00001,WMD -1.07,95%CI -1.35,-0.78), circumference waist (p=0.0002,WMD -3.87, 95%CI -5.88, -1.86) fasting blood glucose (p=0.02, WMD -0.35, 95%CI -0.06, -0.05), HbA1c (p<0.00001,WMD -0.39,95%CI -0.56,-0.22), HoMA-IR(p=0.005, WMD-1.51, 95%CI-0.87,-0.16), total cholesterol (p=0.0008, WMD -0.31, 95%CI -0.48, 0.13) and triglycerides (p=0.0008, WMD -0.27, 95%CI -0.43,-0.11) in comparison with the control regimens. The main adverse events associated with GLP-1RAs included mild-to-moderate gastrointestinal discomfort and nonsense hypoglycemia that resolved within a few weeks. GLP-1RAs were an effective treatment that improved intrahepatic visceral and subcutaneous adipose tissue, inflammatory markers, the anthropometric profiles and some metabolic indices in patients with T2DM and NAFLD, GLP-1RAs could be considered for use in these if there are no contraindications. Further studies are needed to understand the direct and indirect effects of GLP-1RAs on NAFLD and the potential mechanism via which they prevent its progression.Systematic Review Registration: PROSPERO, identifier CRD42021265806.

Highlights

The rising incidence of type 2 diabetes mellitus (T2DM) is a major concern in health care worldwide
Studies that met the following inclusion criteria were selected for review: 1) study population comprised of participants with a definitive diagnosis of T2DM and NAFLD; 2) participants aged >18 years; 3) a study period of at least 12 weeks; 4) GLP1 RAs used in the intervention group; 5) inclusion of a control group; 6) documentation of intrahepatic adipose (IHA), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) on ultrasonography/computerized tomography (CT)/Magnetic Resonance Imaging (MRI) scans and inflammatory marker levels; and7) SAT, VAT and gamma-glutamyl transpeptidase (GGT) levels included as outcomes
Our results show that, compared with placebo or other active comparators, GLP-1 RAs can significantly improve IHA, SAT, VAT, ALT, AST, body weight, body mass index (BMI), waist circumference, fasting blood glucose (FBG), percent HbA1C, HoMA- IR, TC and TG

Summary

Introduction

The rising incidence of type 2 diabetes mellitus (T2DM) is a major concern in health care worldwide. According to global epidemiological data, approximately 462 million individuals were confirmed to have T2DM in 2017 [1]. Non-alcoholic fatty liver (NAFLD) and T2DM commonly coexist in clinical practice. Epidemiological evidence suggests a strong bidirectional relationship between T2DM and NAFLD [2]. NAFLD is a strong clinical signal for insulin resistance and metabolic syndrome and is considered to be a confirmative risk factor for T2DM [4]. According to a meta-analysis of 80 trials from twenty countries [5], the global prevalence rates of NAFLD, nonalcoholic steatohepatitis (NASH), and advanced fibrosis in patients with T2DM were 55.5%, 37.3% and 17.0%, respectively. The existence of T2DM is closely associated with advanced fibrosis in cross-sectional data [6, 7], and with rapid progression of hepatic fibrosis [8, 9]. In Japan, liverrelated disease is the third leading cause of mortality (9.3%) in patients with T2DM [10]

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