Metformin in the Treatment of Non-Alcoholic Steatohepatitis
Metformin in the Treatment of Non-Alcoholic Steatohepatitis
Background: Increased insulin resistance is the major pathogenic mechanism in the development of non-alcoholic steatohepatitis.
Aim: To investigate the therapeutic effect of metformin, a well-known insulin-sensitizing agent, in the treatment of non-alcoholic steatohepatitis.
Methods: Thirty-six patients with non-alcoholic steatohepatitis were randomized into two groups. The first group was given lipid and calorie-restricted dietary treatment alone, and the second group was given metformin 850 mg b.d. plus dietary treatment, for 6 months. The changes in biochemical, sonographic and histological parameters were compared.
Results: The mean serum alanine/aspartate aminotransferase, insulin and C-peptide levels decreased and the index of insulin resistance improved significantly from baseline in the group given metformin. The mean changes in these parameters in the metformin group were significantly greater than those in the group given dietary treatment alone. Although more patients in the metformin group showed improvement in the necro-inflammatory activity, compared with the group given dietary treatment alone, no significant differences in necro-inflammatory activity or fibrosis were seen between the groups.
Conclusion: The data suggest that improvement of the insulin sensitivity with metformin may improve the liver disease in patients with non-alcoholic steatohepatitis.
Non-alcoholic steatohepatitis is a common disease that may progress to end-stage liver disease. It is now considered to be a widespread liver disease in Western countries. Despite its common occurrence, there is no proven pharmaceutical therapy for patients. Without doubt, weight loss is the therapy of choice for those who are overweight, but this requires a dramatic change in dietary habits and lifestyle. Therefore, it can be achieved or maintained by only a limited number of patients. Several drugs, such as clofibrate, gemfibrozil, ursodeoxycholic acid and some antioxidants, have been used in various studies for the treatment of non-alcoholic steatohepatitis.
Ongoing studies and current reports have focused on the role of hyperinsulinaemia and increased insulin resistance as major pathogenic factors in the development of non-alcoholic steatohepatitis. On the basis of these data, it has been suggested that a decrease in insulin resistance with drugs such as thiazolidinediones and metformin may be of therapeutic value. Troglitazone produced some improvement in non-alcoholic steatohepatitis in one study, but was withdrawn from clinical use because of its hepatotoxicity. Recently, Neuschwander-Tetri et al. reported their interim results demonstrating the effects of rosiglitazone in patients with non-alcoholic steatohepatitis. Rosiglitazone improved insulin sensitivity, reduced liver fat content and improved liver enzyme concentrations in that study. Lin et al. showed that metformin reduced significantly the hepatomegaly and hepatic steatosis associated with insulin resistance in ob/ob mice. Moreover, Marchesini et al. showed that metformin reduced serum transaminase concentrations and liver volume in a recent study performed on humans for the first time. However, these results attributed to metformin have not been confirmed by any randomized studies. Furthermore, the effect of metformin treatment on human liver affected by non-alcoholic steatohepatitis has not been shown histologically. Metformin, apart from being non-hepatotoxic, is also cheaper and therefore more suitable for long-term treatment. In this first randomized controlled study, we investigated the effect of metformin on the insulin resistance, liver enzyme concentrations and hepatic histology of patients with non-alcoholic steatohepatitis.
Background: Increased insulin resistance is the major pathogenic mechanism in the development of non-alcoholic steatohepatitis.
Aim: To investigate the therapeutic effect of metformin, a well-known insulin-sensitizing agent, in the treatment of non-alcoholic steatohepatitis.
Methods: Thirty-six patients with non-alcoholic steatohepatitis were randomized into two groups. The first group was given lipid and calorie-restricted dietary treatment alone, and the second group was given metformin 850 mg b.d. plus dietary treatment, for 6 months. The changes in biochemical, sonographic and histological parameters were compared.
Results: The mean serum alanine/aspartate aminotransferase, insulin and C-peptide levels decreased and the index of insulin resistance improved significantly from baseline in the group given metformin. The mean changes in these parameters in the metformin group were significantly greater than those in the group given dietary treatment alone. Although more patients in the metformin group showed improvement in the necro-inflammatory activity, compared with the group given dietary treatment alone, no significant differences in necro-inflammatory activity or fibrosis were seen between the groups.
Conclusion: The data suggest that improvement of the insulin sensitivity with metformin may improve the liver disease in patients with non-alcoholic steatohepatitis.
Non-alcoholic steatohepatitis is a common disease that may progress to end-stage liver disease. It is now considered to be a widespread liver disease in Western countries. Despite its common occurrence, there is no proven pharmaceutical therapy for patients. Without doubt, weight loss is the therapy of choice for those who are overweight, but this requires a dramatic change in dietary habits and lifestyle. Therefore, it can be achieved or maintained by only a limited number of patients. Several drugs, such as clofibrate, gemfibrozil, ursodeoxycholic acid and some antioxidants, have been used in various studies for the treatment of non-alcoholic steatohepatitis.
Ongoing studies and current reports have focused on the role of hyperinsulinaemia and increased insulin resistance as major pathogenic factors in the development of non-alcoholic steatohepatitis. On the basis of these data, it has been suggested that a decrease in insulin resistance with drugs such as thiazolidinediones and metformin may be of therapeutic value. Troglitazone produced some improvement in non-alcoholic steatohepatitis in one study, but was withdrawn from clinical use because of its hepatotoxicity. Recently, Neuschwander-Tetri et al. reported their interim results demonstrating the effects of rosiglitazone in patients with non-alcoholic steatohepatitis. Rosiglitazone improved insulin sensitivity, reduced liver fat content and improved liver enzyme concentrations in that study. Lin et al. showed that metformin reduced significantly the hepatomegaly and hepatic steatosis associated with insulin resistance in ob/ob mice. Moreover, Marchesini et al. showed that metformin reduced serum transaminase concentrations and liver volume in a recent study performed on humans for the first time. However, these results attributed to metformin have not been confirmed by any randomized studies. Furthermore, the effect of metformin treatment on human liver affected by non-alcoholic steatohepatitis has not been shown histologically. Metformin, apart from being non-hepatotoxic, is also cheaper and therefore more suitable for long-term treatment. In this first randomized controlled study, we investigated the effect of metformin on the insulin resistance, liver enzyme concentrations and hepatic histology of patients with non-alcoholic steatohepatitis.
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