Clinical trial: pilot study of metformin for the treatment of non-alcoholic steatohepatitis

Abstract

Background: Non-alcoholic steatohepatitis (NASH) is a form of progressive fatty liver disease that is strongly associated with insulin resistance, which suggests that insulin sensitizing agents such as metformin may be beneficial for NASH.

Aim: To assess the effects of metformin on insulin sensitivity, body composition, serum alanine aminotransferase (ALT) levels and liver histology in patients with NASH.

Methods: Patients underwent liver biopsy, metabolic profiling and imaging studies before and at the end 48 weeks of metformin (2000 mg/day) therapy. The primary endpoint was a three-point improvement in the histological NASH activity index.

Results: Of 28 patients enrolled, 26 (13 females; average age 44 years) completed 48 weeks of treatment and underwent repeat metabolic studies, imaging and liver biopsy. Thirty per cent achieved a histological response. Most patients lost weight, the average being 6 kg. There was a marked association between weight loss and improvements in NASH activity index and ALT levels (both, P < 0.01). Insulin sensitivity also improved, but the degree of change did not correlate with histological improvement.

Conclusion: Metformin leads to improvements in liver histology and ALT levels in 30% of patients with NASH, probably by its effects in causing weight loss.

Trial registration: ClinicalTrials.gov NCT00063232.

Figures

Figure 1

Changes in body weight in 26 patients treated with metformin for 48 weeks.

Figure 2

Changes in average weight in eight responders and 18 nonresponders to a 48-week course of metformin. The diamonds represent the mean weights of the eight responders and the squares, the mean weights of the 18 nonresponders during therapy and then again when measured 6 months later (in eight responders and 16 nonresponders who were seen between 20 and 32 weeks after stopping therapy).

Figure 3

Changes in mean serum alanine aminotransferase (ALT) in eight responders and 18 nonresponders during a 48-week course of metformin. Squares represent the mean values of the 18 nonresponders, the diamonds, the mean values for the eight responders. While ALT levels did not change overall, there was a gradual fall into the normal range in the responders and by the end of therapy, the mean level was 30 U/L and levels were normal in seven of the eight patients. After stopping therapy, ALT levels rose in the eight nonresponders, but remained largely unchanged in the 16 nonresponders who were followed up (including four nonresponders who remained on metformin).

Figure 4

Changes in average homeostasis model assessment (HOMA) values in eight responders and 18 nonresponders to a 48-week course of metformin. The diamonds represent the mean HOMA values of the eight responders and the squares, those of the 18 nonresponders during therapy and then again when measured 4, 12 and 24 weeks later (in eight responders, only one remaining on metformin and 16 nonresponders, four remaining on metformin).

Figure 5

Correlation between per cent change in body weight and change in NASH activity index after 48 weeks of metformin. The eight squares represent responders and the 18 circles represent nonresponders. There was a positive significant correlation between decrease in NASH activity index score and decrease in body weight in kilograms (r = 0.78: P < 0.0001).