Randomised clinical trial: semaglutide versus placebo reduced liver steatosis but not liver stiffness in subjects with non‐alcoholic fatty liver disease assessed by magnetic resonance imaging

Flint, Anne; Andersen, Grit; Hockings, Paul; Johansson, Lars; Morsing, Anni; Palle, Mads Sundby; Vogl, Thomas J.; Loomba, Rohit; Plum‐Mörschel, Leona

doi:10.1111/apt.16608

Cited by 119 publications

(81 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on those results, semaglutide is expected to prove its benefit as a treatment for NASH through additional phase 3 clinical trials. Recently study suggested that semaglutide versus placebo reduced liver steatosis but not liver stiffness in subjects with non-alcoholic fatty liver disease assessed by MRI (69), which results of this study suggest that Semaglutide has no benefit in the improvement of fibrosis in NAFLD patients, which is consistent with previous studies. Collectively, significant improvement in biopsy-confirmed liver histology with GLP-1RAs treatment provides the most substantial evidence for the efficacy of GLP-1RAs in the management of NASH, although the role of GLP-1 RAs is still needed to be validated in large sample controlled trials with longterm follow-up.…”

Section: Discussionsupporting

confidence: 91%

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

Zhu

Zhang

et al. 2021

Front. Endocrinol.

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 91%

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

Zhu

Zhang

et al. 2021

Front. Endocrinol.

View full text Add to dashboard Cite

show abstract

“…While previous studies with investigational NASH agents that have reached clinical testing have reported body weight, liver weight, plasma lipids, AST, ALT, or histological findings 27 – 30 , only GLP-1 based approaches have been associated with significant weight loss in published trials to date. Significant improvement of NASH has been associated with greater than 5% weight loss, but resolution of fibrosis appears to require > 10% body weight loss for optimal effects 9 , 11 , 31 – 33 .…”

Section: Discussionmentioning

confidence: 99%

Effects of ALT-801, a GLP-1 and glucagon receptor dual agonist, in a translational mouse model of non-alcoholic steatohepatitis

Nestor

Parkes

Feigh

et al. 2022

Sci Rep

View full text Add to dashboard Cite

Body weight loss of ≥ 10% improves the metabolic derangements and liver disease in the majority of non-alcoholic steatohepatitis (NASH) patients, suggesting metabolic modulators may be effective in controlling disease. The pharmacodynamics of ALT-801, a GLP-1/glucagon receptor dual agonist optimized for NASH and weight loss, were compared to semaglutide (GLP-1 receptor agonist) and elafibranor (peroxisome proliferator-activated receptor, PPAR-α/δ, agonist) in a biopsy-confirmed, diet-induced obese (DIO) mouse model of NASH (DIO-NASH). Male C57BL/6J mice were fed Amylin Liver NASH (AMLN) diet for 32 weeks. Animals with biopsy-confirmed steatosis and fibrosis received ALT-801, semaglutide, elafibranor, or vehicle daily for 12 weeks while maintained on the AMLN diet. Study endpoints included body and liver weight, liver and plasma total cholesterol and triglycerides, plasma aminotransferases, histological analysis of liver steatosis, inflammation (galectin-3) and fibrosis (collagen type 1 alpha 1), and evaluation of individual animal changes in composite Non-alcoholic Fatty Liver Disease Activity Score (NAS), and fibrosis stage. ALT-801 demonstrated significant reductions in body weight (approx. 25%), plasma aminotransferases, plasma total cholesterol and liver triglycerides/total cholesterol in conjunction with improved liver steatosis, with greater reductions (p < 0.05) compared to semaglutide and elafibranor. ALT-801 significantly reduced the inflammation marker galectin-3 and the fibrosis marker collagen type 1 alpha 1 vs. vehicle (p < 0.05), with ALT-801 producing greater reductions in galectin-3 vs. elafibranor (p < 0.05). Importantly, all animals treated with ALT-801 significantly improved composite NAS compared to the active controls. This study provides evidence for a potential role for ALT-801 in the therapeutic treatment of NASH.

show abstract

“…An increase in liver stiffness on MRE is associated with fibrosis progression, 8 and MRE is increasingly being used as an end point in early stage NAFLD treatment trials. 9 , 10 Emerging data from recent studies have suggested that liver stiffness on MRE may be associated with liver-related outcomes. 11 – 14 Other NITs including the FIB-4 score (fibrosis index based on the 4 factor) and NAFLD Fibrosis Score (NFS) have demonstrated associations with liver-related events and death; 15 – 17 however, when used alone, they have only modest discriminatory ability.…”

Section: Introductionmentioning

confidence: 99%

Prognostic utility of magnetic resonance elastography and MEFIB index in predicting liver-related outcomes and mortality in individuals at risk of and with nonalcoholic fatty liver disease

Ajmera

Nguyen

Tamaki

et al. 2022

Therap Adv Gastroenterol

Self Cite

View full text Add to dashboard Cite

Background: Magnetic resonance elastography (MRE) is an accurate biomarker of liver fibrosis; however, limited data characterize its association with outcomes. We aimed to evaluate the association between liver stiffness (LS) on MRE and liver-related outcomes. Methods: This is a longitudinal, retrospective analysis of subjects at risk of NAFLD who had MRE assessment. LS was estimated using MRE, and liver fat was assessed using magnetic resonance imaging proton density fat fraction. Univariable and multivariable survival and regression analyses were used to assess the association between LS on MRE and liver-related outcomes including a cumulative primary outcome of hepatic decompensation, hepatocellular carcinoma (HCC), or death. Results: In all, 265 patients (68% women) with a mean age of 50 (±18) years and 44% Hispanic ethnicity and 45.3% with NAFLD were included. A total of 76 liver-related events or death occurred, and there was 453 person-years of follow-up time in 97 patients with available follow-up. Each 1-kPa increase in LS was associated with 2.20-fold (95% CI: 1.70–2.84, p < 0.001) increased odds of prevalent hepatic decompensation or HCC. A positive MEFIB index, a combination of MRE ⩾ 3.3 kPa and FIB-4 ⩾ 1.6, had a strong association with the primary outcome compared with those without, HR = 21.8 (95% CI: 4.28–111.4, p < 0.001). The MEFIB index had a sensitivity of 75% and specificity of 90%, and a negative score was associated with 98% negative predictive value for incident liver-related events or death. Conclusion: LS assessed by MRE is associated with hepatic decompensation and death, and the MEFIB combination of MRE with FIB-4 may have high negative predictive value for liver-related events.

show abstract

Randomised clinical trial: semaglutide versus placebo reduced liver steatosis but not liver stiffness in subjects with non‐alcoholic fatty liver disease assessed by magnetic resonance imaging

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 119 publications

References 43 publications

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

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

Effects of ALT-801, a GLP-1 and glucagon receptor dual agonist, in a translational mouse model of non-alcoholic steatohepatitis

Prognostic utility of magnetic resonance elastography and MEFIB index in predicting liver-related outcomes and mortality in individuals at risk of and with nonalcoholic fatty liver disease

Contact Info

Product

Resources

About