Randomized trial comparing the effects of gliclazide, liraglutide, and metformin on diabetes with non‐alcoholic fatty liver disease

Abstract

Background: The aim of the present study was to compare the effects of gliclazide, liraglutide, and metformin in type 2 diabetes mellitus (T2DM) patients with non-alcoholic fatty liver disease (NAFLD). Methods: Eighty-seven subjects were randomized to receive liraglutide, metformin, or gliclazide for 24 weeks. Primary outcomes included HbA1c levels, intrahepatic fat (IHF) content, and liver function. Results: Both HbA1c levels and IHF content were reduced after treatment in all three groups. However, HbA1c levels were lower in the liraglutide-and metformin-treated groups than in the gliclazide-treated group, and reductions in IHF content were greater with liraglutide than with gliclazide. Liraglutide and metformin treatments reduced weight and improved liver function. Changes in IHF content were positively correlated with reductions in serum alanine aminotransferase and triglyceride levels, as well as weight. At 24 weeks, reductions in IHF content were greater in subjects with weight loss ≥5%, changes in waistline ≤0 cm (including decreases in waistline), HbA1c reductions ≥2.5%, and HbA1c levels <6.5%. Conclusions: In T2DM patients with NAFLD, compared with liraglutide and metformin, gliclazide resulted in less improvement in liver function, reductions in IHF content and HbA1c levels, and less weight loss; in addition, slightly better improvements were achieved with liraglutide than with metformin.

Liraglutide improves hepatic steatosis and metabolic dysfunctions in a 3-week dietary mouse model of non-alcoholic steatohepatitis

“…Our present study revealed that once-daily injection of liraglutide for 2 weeks decreased caloric intake and body weight, improved glucose tolerance, and protected from HFCC-CDX-induced insulin resistance, which are well-known effects of liraglutide in humans [27,28]. In addition, we observed that liraglutide could resolve hypertriglyceridemia and reduce hepatic steatosis, oxidative stress, and systemic and hepatic inflammation but not fibrosis, results that are in general agreement with the effects of liraglutide documented in preclinical studies with mice [29][30][31] and clinical trials for NASH [32][33][34]. In NAFLD patients, plasma ALT and AST levels have been found to decrease gradually during liraglutide treatment [32][33][34].…”

“…In addition, we observed that liraglutide could resolve hypertriglyceridemia and reduce hepatic steatosis, oxidative stress, and systemic and hepatic inflammation but not fibrosis, results that are in general agreement with the effects of liraglutide documented in preclinical studies with mice [29][30][31] and clinical trials for NASH [32][33][34]. In NAFLD patients, plasma ALT and AST levels have been found to decrease gradually during liraglutide treatment [32][33][34]. In our experimental setting, liraglutide could indeed significantly decrease the total NAFLD activity score but could not counter the HFCC-CDX-induced increase in plasma ALT and AST, in agreement with results from another dietary mouse model of NASH [30].…”

Of mice and men: Is there a future for metformin in the treatment of hepatic steatosis?

“…It is also invasive, therefore, the use of non‐invasive methods is becoming more common, including ultrasonography, CT, MRI and magnetic resonance spectroscopy (MRS; reviewed in Green et al). Of these imaging methods, ultrasonography appears to be used most often and a reduction in IHTAG content has been reported in the majority of subjects after metformin treatment; however, ultrasonography has limited sensitivity in individuals with high body mass index (≥40 kg/m 2 ) and the current grading system is simplistic and therefore may not be suitable for evaluating patients with NAFLD after therapeutic interventions such as metformin. In contrast, MRI and MRS offer direct quantification of IHTAG content with higher accuracy; the only studies that used MRI reported no change in IHTAG content with metformin treatment …”

Metformin-Induced Changes of the Coding Transcriptome and Non-Coding RNAs in the Livers of Non-Alcoholic Fatty Liver Disease Mice

“…Metformin is a hypoglycaemic drug that has been clinically applied for half a century and not only improves insulin resistance and hyperinsulinaemia but can also directly influence insulin target cells, particularly by increasing insulin sensitivity via post-receptor mechanisms [10, 11]. Thus, metformin is recommended and effective for the treatment of NAFLD [12]. …”