GLP-1 RAs and SGLT-2 Inhibitors for Insulin Resistance in Nonalcoholic Fatty Liver Disease: Systematic Review and Network Meta-Analysis

Abstract

ObjectiveGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduce glycaemia and weight and improve insulin resistance (IR) via different mechanisms. We aim to evaluate and compare the ability of GLP-1 RAs and SGLT-2 inhibitors to ameliorate the IR of nonalcoholic fatty liver disease (NAFLD) patients.Data SynthesisThree electronic databases (Medline, Embase, PubMed) were searched from inception until March 2021. We selected randomized controlled trials comparing GLP-1 RAs and SGLT-2 inhibitors with control in adult NAFLD patients with or without T2DM. Network meta-analyses were performed using fixed and random effect models, and the mean difference (MD) with corresponding 95% confidence intervals (CI) were determined. The within-study risk of bias was assessed with the Cochrane collaborative risk assessment tool RoB.Results25 studies with 1595 patients were included in this network meta-analysis. Among them, there were 448 patients, in 6 studies, who were not comorbid with T2DM. Following a mean treatment duration of 28.86 weeks, compared with the control group, GLP-1 RAs decreased the HOMA-IR (MD [95%CI]; -1.573[-2.523 to -0.495]), visceral fat (-0.637[-0.992 to -0.284]), weight (-2.394[-4.625 to -0.164]), fasting blood sugar (-0.662[-1.377 to -0.021]) and triglyceride (- 0.610[-1.056 to -0.188]). On the basis of existing studies, SGLT-2 inhibitors showed no statistically significant improvement in the above indicators. Compared with SGLT-2 inhibitors, GLP-1 RAs decreased visceral fat (-0.560[-0.961 to -0.131]) and triglyceride (-0.607[-1.095 to -0.117]) significantly.ConclusionsGLP-1 RAs effectively improve IR in NAFLD, whereas SGLT-2 inhibitors show no apparent effect.Systematic Review RegistrationPROSPERO https://www.crd.york.ac.uk/PROSPERO/, CRD42021251704

To Do One and To Get More: Part II. Diabetes and metabolic dysfunction-associated fatty liver diseases

“…The other SGLT-2 inhibitors, such as ipragliflozin, 114,124 luseogliflozin, 125,126 and tofogliflozin, 114 also showed the benefits on reduction of metabolic syndrome for DM patients, supporting the potential role in treatment for MAFLD.…”

“…One study also claimed that dapagliflozin is the most effective SGLT-2 inhibitor for reducing GGT level compared with other SGLT-2 inhibitors. 114 The other SGLT-2 inhibitors, such as ipragliflozin, 114,124 luseogliflozin, 125,126 and tofogliflozin, 114 also showed the benefits on reduction of metabolic syndrome for DM patients, supporting the potential role in treatment for MAFLD.…”

“…Yan et al 126 (25 studies, 1595 subjects) found that GLP-1R agonists decreased the HOMA-IR (MD: −1.57), visceral fat (MD: −0.64), body weight (MD: −2.39), fasting blood sugar (MD: −0.66), and TG (MD: −0.610) during the mean treatment duration of 29 weeks. Additionally, compared with SGLT-2 inhibitors, GLP-1R agonists significantly decreased visceral fat (MD: −0.56) and TG (MD: −0.61).…”

“…In theory, this class medication is linked to the suppression of dysfunctional endoplasmic reticulum stress response, sparing hepatocytes from damage by FFA; the blockage of the process of macroautophagy to injury hepatocytes, and inhibition of FGF 21 production to avoid obesity-related liver injury. 71 Yan et al 126 (25 studies, 1595 subjects) found that GLP-1R agonists decreased the HOMA-IR (MD: −1.57), visceral fat (MD: −0.64), body weight (MD: −2.39), fasting blood sugar (MD: −0.66), and TG (MD: −0.610) during the mean treatment duration of 29 weeks. Additionally, compared with SGLT-2 inhibitors, GLP-1R agonists significantly decreased visceral fat (MD: −0.56) and TG (MD: −0.61).…”

“…The third class is GLP-1R agonist, 71,73,74,79,114,119,126 the effect of this class may provide a protective role in the ceased progression of MAFLD (Table 2), and it is reported that GLP-1R may have much stronger benefit on the reduction of IR in MAFLD compared with other ADA. 126 Zafar et al 71 (10 studies, 5 studies, 4 studies, 2 studies) also confirmed the aforementioned benefits of GLP-1R agonists on the management of MAFLD, based on significant improvement of liver function test, including AST (WMD: −3.29), ALT (WMD: −9.92), GGT (WMD: −12.38), and FIB-4 (WMD: −0.15), suggesting that DM patients who take GLP-1R agonists also have extraglycemic benefits on MAFLD. In theory, this class medication is linked to the suppression of dysfunctional endoplasmic reticulum stress response, sparing hepatocytes from damage by FFA; the blockage of the process of macroautophagy to injury hepatocytes, and inhibition of FGF 21 production to avoid obesity-related liver injury.…”