Letter: Combination Therapies With Vitamin E for Metabolic Dysfunction-Associated Steatotic Liver Disease

Abstract

In their randomised controlled trial (RCT), Alkhouri et al. reported that the combination of vitamin E (1000 mg/day) with docosahexaenoic acid (DHA; 1.89 g/day) did not improve liver fat content or liver function tests in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) [1].

We previously supported that a single medication may not be effective in all patients with MASLD, primarily due to the multifactorial pathogenesis of the disease [2]. Even in the most prominent RCTs, only a percentage of patients reached the primary outcomes. In the PIVENS trial [3], a 2-year, triple-arm RCT comparing vitamin E (800 IU/day) or pioglitazone (30 mg/day) with placebo in patients with metabolic dysfunction-associated steatohepatitis (MASH), the primary outcome was reached by 43%, 34% and 19% of patients, respectively. Similar findings were shown in other relevant RCTs, including the MAESTRO-NASH trial, a 1-year, triple-arm RCT, which led to the approval of resmetirom for patients with MASH and fibrosis stage 2 or 3 by the FDA [4]. These results indicate that most patients did not reach the predefined primary outcomes. Therefore, combinations of medications may be more effective by targeting multiple pathogenetic contributors of the disease [5]. However, the medications of the combinations should be complementary each other, thus targeting different mechanisms; for example, one medication of the combination may focus on improving hepatic steatosis, whereas another may focus on improving hepatic fibrosis.

Vitamin E has previously been evaluated in combination with ursodeoxycholic acid, pioglitazone, choline, vitamin D, vitamin C, silybin and phosphatidylcholine [5]. A 48-week RCT with a smaller sample size than that of Alkhouri et al. [1], having investigated the combination of vitamin E, DHA and choline versus placebo in children with MASH, reported improvement in severe hepatic steatosis and alanine aminotransferase in the treatment group, but no change in the placebo group [6]. However, all these combinations largely lack the aforementioned complementarity of the medications, as most of them primarily target hepatic steatosis and/or possibly inflammation, but not fibrosis.

We previously conducted a 1-year RCT evaluating the effect of the combination of vitamin E (400 IU/day) with spironolactone (25 mg/day) versus vitamin E monotherapy (400 IU/day) in patients with MASLD [7]. Our rationale for using the low-cost spironolactone was based on its beneficial effects on cardiac or vascular fibrosis [8]. The observed association between elevated aldosterone concentrations and the rates of MASLD further supports the potential use of the aldosterone antagonist, spironolactone, against MASLD [9]. Our RCT, however, showed a beneficial effect of the combination over vitamin E monotherapy on presumed hepatic steatosis, but not on fibrosis [7]. More recently, a post hoc lipidomic analysis revealed that the vitamin E/spironolactone combination resulted in higher circulating cholesteryl docosahexaenoate (cholesterol ester with DHA; 22:6) concentrations compared with vitamin E monotherapy [10], suggesting a potential connection of the combination with DHA metabolism; however, further mechanistic studies are required to elucidate whether this finding has any pathophysiological implications in MASLD.

In conclusion, future RCTs investigating combination therapies for MASLD should ideally target both hepatic steatosis and fibrosis, although the validity of this approach remains to be shown.

Stergios A. Polyzos: conceptualization, investigation, writing – original draft, writing – review and editing, methodology. Jannis Kountouras: conceptualization, methodology, writing – review and editing, validation.

The authors declare no conflicts of interest.

This article is linked to Alkhouri et al paper. To view this article, visit https://doi.org/10.1111/apt.18149.