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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:

Background

Glucagon-like peptide-1 receptor agonists may be a treatment option in patients with non-alcoholic fatty liver disease (NAFLD).

Aims

To investigate the effects of semaglutide on liver stiffness and liver fat in subjects with NAFLD using non-invasive magnetic resonance imaging (MRI) methods.

Methods

This randomised, double-blind, placebo-controlled trial enrolled subjects with liver stiffness 2.50-4.63 kPa by magnetic resonance elastography (MRE) and liver steatosis ≥10% by MRI proton density fat fraction (MRI-PDFF). The primary endpoint was change from baseline to week 48 in liver stiffness assessed by MRE.

Results

Sixty-seven subjects were randomised to once-daily subcutaneous semaglutide 0.4 mg (n = 34) or placebo (n = 33). Change from baseline in liver stiffness was not significantly different between semaglutide and placebo at week 48 (estimated treatment ratio 0.96 (95% CI 0.89, 1.03; P = 0.2798); significant differences in liver stiffness were not observed at weeks 24 or 72. Reductions in liver steatosis were significantly greater with semaglutide (estimated treatment ratios: 0.70 [0.59, 0.84], P = 0.0002; 0.47 [0.36, 0.60], P < 0.0001; and 0.50 [0.39, 0.66], P < 0.0001) and more subjects achieved a ≥ 30% reduction in liver fat content with semaglutide at weeks 24, 48 and 72, (all P < 0.001). Decreases in liver enzymes, body weight and HbA_1c were also observed with semaglutide.

Conclusions

The change in liver stiffness in subjects with NAFLD was not significantly different between semaglutide and placebo. However, semaglutide significantly reduced liver steatosis compared with placebo which, together with improvements in liver enzymes and metabolic parameters, suggests a positive impact on disease activity and metabolic profile. ClinicalTrials.gov identifier: NCT03357380.

SUBMITTER: Flint A

PROVIDER: S-EPMC9292692 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectivesTo evaluate the relationship between biopsy-assessed hepatic steatosis, magnetic resonance imaging (MRI)-assessed proton density fat fraction (PDFF), and magnetic resonance elastography (MRE)-assessed liver stiffness measurement (LSM), in patients with or at risk for nonalcoholic fatty liver disease (NAFLD).MethodsA retrospective study was performed, encompassing 256 patients who had a liver biopsy and MRI/MRE examination performed within 1 year. Clinical and laboratory data were retrieved from the electronic medical record. Hepatic steatosis and fibrosis were assessed by histopathological grading/staging. First, we analyzed the diagnostic performance of PDFF for distinguishing hepatic steatosis with the receiver operating characteristic analyses. Second, variables influencing LSM were screened with univariant analyses, then identified with multivariable linear regression. Finally, the potential relationship between PDFF and LSM was assessed with linear regression after adjustment for other influencing factors, in patients with diagnosed steatosis (PDFF ≥ 5%).ResultsThe diagnostic accuracy of PDFF in distinguishing steatosis grades (S0-3) was above 0.82. No significant difference in LSM was found between patients with S1, S2, and S3 steatosis and between all steatosis grades after patients were grouped according to fibrosis stage. No statistically significant relationship was found between the LSM and PDFF (estimate = - 0.02, p = 0.065) after adjustment for fibrosis stage and age in patients with diagnosed steatosis (PDFF ≥ 5%).ConclusionsIn patients with NAFLD, the severity of hepatic steatosis has no significant influence on the liver stiffness measurement with magnetic resonance elastography.Key points• The MRI-based proton density fat fraction provides a quantitative assessment of hepatic steatosis with high accuracy. • No significant effect of hepatic steatosis on MRE-based liver stiffness measurement was found in patients with S1, S2, and S3 steatosis and between all steatosis grades after patients were grouped according to fibrosis stage. • After adjusting for fibrosis stage and age, there was no statistically significant relationship between liver stiffness and proton density fat fraction in patients with hepatic steatosis (p = 0.065).

Project description:BackgroundNon-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease, and among the non-invasive tests, controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) have shown better diagnostic performance in NAFLD. This meta-analysis aimed to evaluate the performance of CAP and LSM for assessing steatosis and fibrosis in NAFLD.MethodsWe searched the PubMed, Web of Science, Cochrane Library, and Embase databases for relevant articles published up to February 13th, 2022, and selected studies that met the inclusion and exclusion criteria, and evaluated the quality of evidence. Then we pooled sensitivity (SE), specificity (SP), and area under receiver operating characteristic (AUROC) curves. A random effect model was applied regardless of heterogeneity. Meta-regression analysis and subgroup analysis were performed to explore heterogeneity, and Fagan plot analysis was used to evaluate clinical utility. This meta-analysis was completed in Nanjing, Jiangsu and registered on PROSPERO (CRD42022309965).FindingsA total of 10537 patients from 61 studies were included in our meta-analysis. The AUROC of CAP were 0·924, 0·794 and 0·778 for steatosis grades ≥ S1, ≥ S2 and = S3, respectively, and the AUROC of LSM for detecting fibrosis stages ≥ F1, ≥ F2, ≥ F3, and = F4 were 0·851, 0·830, 0·897 and 0·925, respectively. Subgroup analysis revealed that BMI ≥ 30 kg/m² had lower accuracy for diagnosing S ≥ S1, ≥ S2 than BMI<30 kg/m². For the mean cut-off values, significant differences were found in CAP values among different body mass index (BMI) populations and LSM values among different regions. For diagnosing S ≥ S1, ≥ S2 and = S3, the mean CAP cut-off values for BMI ≥ 30 kg/m² were 30·7, 28·2, and 27·9 dB/m higher than for BMI < 30 kg/m² (P = 0·001, 0·001 and 0·018, respectively). For diagnosing F ≥ F2 and = F4, the mean cut-off values of Europe and America were 0·96 and 2·03 kPa higher than Asia (P = 0·027, P = 0·034), respectively. In addition, the results did not change significantly after sensitivity analysis and the trim and fill method to correct for publication bias, proving that the conclusions are robust.InterpretationThe good performance of CAP and LSM for the diagnosis of mild steatosis (S ≥ S1), advanced liver fibrosis (F ≥ F3), and cirrhosis (F = F4) can be used to screen for NAFLD in high-risk populations. Of note, the accuracy of CAP for the detection of steatosis in patients with obesity is reduced and requires specific diagnostic values. For LSM, the same diagnostic values can be used when the appropriate probes are selected based on BMI and the automated probe selection tool. The performance of CAP and LSM in assessing steatosis in patients with obesity, moderate to severe steatosis, and low-grade fibrosis should be further validated and improved in the future.FundingThe study was funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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