Role of Vitamin E for Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes: A Randomized Controlled Trial

Abstract

OBJECTIVE While vitamin E has shown to improve nonalcoholic steatohepatitis (NASH) in patients without diabetes, information on patients with type 2 diabetes mellitus (T2DM) is lacking. The aim of this study was to determine whether vitamin E, alone or combined with pioglitazone, improves histology in patients with T2DM and NASH. RESEARCH DESIGN AND METHODS This was a proof-of-concept, randomized, double-blind, placebo-controlled trial conducted from 2010 to 2016. Patients with T2DM and biopsy-proven NASH (n = 105) were randomized to vitamin E 400 IU b.i.d., vitamin E 400 IU b.i.d. plus pioglitazone 45 mg/day, or placebo. Eighty-six patients completed the 18-month study. The primary end point was a two-point reduction in the nonalcoholic fatty liver disease activity score from two different parameters, without worsening of fibrosis. Secondary outcomes were resolution of NASH without worsening of fibrosis, individual histological scores, and metabolic parameters. RESULTS More patients on combination therapy achieved the primary outcome versus placebo (54% vs. 19%, P = 0.003) but not with vitamin E alone (31% vs. 19%, P = 0.26). Both groups showed improvements in resolution of NASH compared with placebo (combination group: 43% vs. 12%, P = 0.005; vitamin E alone: 33% vs. 12%, P = 0.04). While steatosis assessed by histology improved with combination therapy (P < 0.001) and vitamin E alone (P = 0.018), inflammation (P = 0.018) and ballooning (P = 0.022) only improved with combination therapy. No improvement in fibrosis was observed in any group. CONCLUSIONS In this proof-of-concept study, combination therapy was better than placebo in improving liver histology in patients with NASH and T2DM. Vitamin E alone did not significantly change the primary histological outcome.

A diabetologist’s perspective of non‐alcoholic steatohepatitis (NASH): Knowledge gaps and future directions

“…Table summarizes the five pioglitazone RCTs that have treated a total of 498 patients for up to 3 years. More than 50% of patients (placebo‐subtracted difference of ~30 to 40%) showed a consistent response with either resolution of NASH or improvement in individual histological parameters (such as ballooning or inflammation) . However, improvement of fibrosis was only reported in some of the studies .…”

“…Vitamin E is effective in patients with biopsy-proven NASH without diabetes 27 and had a somewhat similar effect for the resolution of NASH in a recent small proof-of-concept study in patients with T2DM. 28 However, the main goal of the study was to examine the role of adding vitamin E to pioglitazone which did not result in an improvement in histological parameters compared to those with thiazolidinedione alone. 27,[29][30][31] A large multicenter study is needed to determine the efficacy and safety of vitamin E in patients with diabetes.…”

“…More than 50% of patients (placebo-subtracted difference of ~30 to 40%) showed a consistent response with either resolution of NASH or improvement in individual histological parameters (such as ballooning or inflammation). [27][28][29][30][31] However, improvement of fibrosis was only reported in some of the studies. 29,31 We refer readers to recent in-depth reviews on the overall safety and efficacy of pioglitazone in NASH.…”

Incretin‐Based Therapies for the Management of Nonalcoholic Fatty Liver Disease in Patients With Type 2 Diabetes

“…Given the magnitude of the problem, there is a real sense of urgency to identify the best pharmacological approach to treat both diabetes and nonalcoholic steatohepatitis (NASH) in this population. Vitamin E is recommended for patients with biopsy‐proven NASH without diabetes, but did not have similar efficacy in a recent proof‐of‐concept randomized placebo‐controlled trial (RCT) in patients with T2DM . Regarding antidiabetic agents, there is a significant amount of data for some agents, but much more limited information for others .…”

“…Vitamin E is recommended for patients with biopsy-proven NASH without diabetes, (2) but did not have similar efficacy in a recent proof-of-concept randomized placebo-controlled trial (RCT) in patients with T2DM. (3) Regarding antidiabetic agents, there is a significant amount of data for some agents, but much more limited information for others. (1,4) Among insulin sensitizers, whereas metformin has not shown significant benefit, pioglitazone has been incorporated into current treatment guidelines for patients with or without T2DM and biopsy-proven NASH.…”