Metformin in patients with non-alcoholic fatty liver disease: A randomized, controlled trial

Faculty Division, Department of Gastroenterology, Aker University Hospital, Trondheimsveien 235, Oslo, Norway.
Scandinavian Journal of Gastroenterology (Impact Factor: 2.36). 01/2009; 44(7):853-60. DOI: 10.1080/00365520902845268
Source: PubMed


The antidiabetic agent metformin is regularly discussed as a promising treatment for non-alcoholic fatty liver disease (NAFLD), which is characterized by insulin resistance. However, the evidence for its beneficial effects is limited, and conflicting reports have been published. The purpose of this study was to conduct a randomized, double-blind, placebo-controlled trial to test whether metformin improves liver histology in patients with non-alcoholic fatty liver disease.
Forty-eight patients with biopsy-proven NAFLD were randomized to treatment with metformin (n=24) or placebo (n=24) for 6 months. A second liver biopsy was obtained in all subjects who completed the trial (n=44). Data analyses are restricted to this group (per-protocol analyses). The primary outcome was changes in histologically assessed liver steatosis. Secondary outcomes were changes in NAFLD activity (NAS)-score, liver steatosis assessed by computed tomography (CT), liver transaminases, body-weight, metabolic variables and inflammatory markers.
No significant differences between treatment with metformin or placebo were observed for changes in liver steatosis, assessed either histologically or by CT, NAS-score, liver transaminases or on markers of insulin resistance or inflammation. In contrast, beneficial effects of metformin were observed on changes in body-weight (p<0.001), serum levels of cholesterol (p=0.004), LDL-cholesterol (p<0.001), glucose (p=0.032) and on HbA1c (p=0.020).
Treatment with metformin for 6 months was no better than placebo in terms of improvement in liver histology in patients with NAFLD. Nevertheless, the use of metformin could still be beneficial in this group as it is associated with a reduction in serum levels of lipids and glucose. ( number, NCT00303537).

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    • "Additionally, metformin has been shown to improve hepatic necro-inflammatory activity, hepatic steatosis, hepatocyte ballooning, and acinar/portal inflammation to levels seen in patients who have undergone caloric restriction (Uygun et al. 2004). However, a randomized, placebo-controlled trial testing metformin effects in NAFLD showed limited improvement of liver histopathology (Haukeland et al. 2009). It is important to note, however, that most of these studies enrolled subjects with more advanced liver disease, including NASH, and there have been limited investigations to determine the effect of metformin on early-onset hepatic steatosis. "
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    ABSTRACT: Weight loss is recommended for patients with nonalcoholic fatty liver disease (NAFLD), while metformin may lower liver enzymes in type 2 diabetics. Yet, the efficacy of the combination of weight loss and metformin in the treatment of NAFLD is unclear. We assessed the effects of metformin, caloric restriction, and their combination on NAFLD in diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Male OLETF rats (age 20 weeks; n = 6-8 per group) were fed ad libitum (AL), given metformin (300 mg·kg(-1)·day(-1); Met), calorically restricted (70% of AL; CR), or calorically restricted and given metformin (CR+Met) for 12 weeks. Met lowered adiposity compared with AL but not to the same magnitude as CR or CR+Met (p < 0.05). Although only CR improved fasting insulin and glucose, the combination of CR+Met was needed to improve post-challenge glucose tolerance. All treatments lowered hepatic triglycerides, but further improvements were observed in the CR groups (p < 0.05, Met vs. CR or CR+Met) and a further reduction in serum alanine aminotransferases was observed in CR+Met rats. CR lowered markers of hepatic de novo lipogenesis (fatty acid synthase, acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase-1 (SCD-1)) and increased hepatic mitochondrial activity (palmitate oxidation and β-hydroxyacyl CoA dehydrogenase (β-HAD) activity). Changes were enhanced in the CR+Met group for ACC, SCD-1, β-HAD, and the mitophagy marker BNIP3. Met decreased total hepatic mTOR content and inhibited mTOR complex 1, which may have contributed to Met-induced reductions in de novo lipogenesis. These findings in the OLETF rat suggest that the combination of caloric restriction and metformin may provide a more optimal approach than either treatment alone in the management of type 2 diabetes and NAFLD.
    Applied Physiology Nutrition and Metabolism 06/2015; 40(10):150624143707005. DOI:10.1139/apnm-2015-0236 · 2.34 Impact Factor
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    • "Even though various approaches have been proposed including classical antidiabetic drugs such as insulin sensitizers, e.g. metformin or pioglitazone [5] [6], or others such as antioxidants, e.g. vitamin E [7], lipid-lowering drugs, e.g. "
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    ABSTRACT: There is an unmet medical need for novel NAFLD treatments. Here we have examined the effects of liver-selective NO donor (V-PYRRO/NO) as compared with metformin on hepatic steatosis and glucose tolerance in mice fed high fat diet. Effects of V-PYRRO/NO (5mgkg(-1)) or metformin (616mgkg(-1)) were examined in C57BL/6J mice fed high fat diet (HF, 60 kcal% fat). Quantitative determination of steatosis, liver fatty acid composition and western blot analysis of selected proteins involved in mitochondrial biogenesis, fatty acid de novo synthesis and oxidation, triacylglycerols and cholesterol transport from the liver were performed. Liver NOx and nitrate concentration and blood biochemistry were also analyzed. V-PYRRO/NO and metformin reduced liver steatosis with simultaneous reduction of total liver triacylglycerols, diacylglycerols and ceramides fraction and reversed HF-induced decrease in UFA/SFA ratio. V-PYRRO/NO substantially improved postprandial glucose tolerance, while the effect of metformin was modest and more pronounced on HOMA IR index. The anti-steatotic mechanism of V-PYRRO/NO was dependent on NO release, differed from that of metformin and involved improved glucose tolerance and inhibition of de novo fatty acid synthesis by Akt activation and ACC phosphorylation. In turn, major mechanism of metformin action involved increased expression of proteins implicated in mitochondrial biogenesis and metabolism (PGC-1α, PPARα, COX IV, cytochrome c, HADHSC). V-PYRRO/NO acts as a liver-specific NO donor pro-drug affording pronounced anti-steatotic effects and may represent an efficient, mechanistically novel approach to prevent liver steatosis and insulin resistance. Copyright © 2014. Published by Elsevier Inc.
    Biochemical Pharmacology 12/2014; 93(3). DOI:10.1016/j.bcp.2014.12.004 · 5.01 Impact Factor
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    • "g/day) alone or in association with vitamin E [94] or lifestyle intervention [75, 78, 84]. Only three open-label studies have found no benefits of metformin treatment on aminotransferase levels and IR markers [85–87]. However, only few studies shown an improvement in liver histology [77, 78, 81, 83]. "
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    ABSTRACT: Insulin resistance is a clinical condition shared by many diseases besides type 2 diabetes (T2DM) such as obesity, polycystic ovary syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD). Experimental evidence, produced over the years, suggests that metformin has many benefits in the treatment of these diseases. Metformin is a first-line drug in the treatment of overweight and obese type 2 diabetic patients, offering a selective pathophysiological approach by its effect on insulin resistance. Moreover, a number of studies have established the favorable effect of metformin on body weight, not only when evaluating BMI, but also if body mass composition is considered, through the reduction of fat mass. In addition, it reduces insulin resistance, hyperinsulinemia, lipid parameters, arterial hypertension and endothelial dysfunction. In particular, a new formulation of metformin extended-release (ER) is now available with different formulation in different countries. Metformin ER delivers the active drug through hydrated polymers which expand safe uptake of fluid, prolonging gastric transit and delaying drug absorption in the upper gastrointestinal tract. In addition, Metformin ER causes a small, but statistically significant decrease in BMI, when added to a lifestyle intervention program in obese adolescents. Because of the suggested benefits for the treatment of insulin resistance in many clinical conditions, besides type 2 diabetes, the prospective exists that more indications for metformin treatment are becoming a reality.
    Eating and weight disorders: EWD 07/2014; 19(3). DOI:10.1007/s40519-014-0139-y · 0.79 Impact Factor
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