Currently available but off label medications
Vitamin E, an antioxidant, administered at a daily dose of 800 IU/day improves steatosis, inflammation, and ballooning, but not fibrosis in nondiabetic adults with biopsy-proven NASH.44 Vitamin E for 96 weeks was associated with a significantly higher rate of improvement in NASH (43% vs. 19%, P less than .01), compared with placebo.44 In the Treatment of Nonalcoholic Fatty Liver Disease in Children trial (TONIC), which examined vitamin E (800 IU/day) or metformin (500 mg twice daily) against placebo in children with biopsy-proven NAFLD, resolution of NASH was significantly greater in children treated with vitamin E than in children treated with placebo (58% vs. 28%, P less than .01). Metformin did not significantly improve the NASH resolution rates, compared with placebo (41% vs. 28%, P = .23). Vitamin E could be recommended for nondiabetic adults or children if lifestyle modifications do not produce the expected results as a result of noncompliance or ineffectiveness. Since continued use of vitamin E has been suggested to be associated with a very small increase in the risk for prostate cancer (an absolute increase of 1.6 per 1,000 person-years of vitamin E use) in men, risks and benefits should be discussed with each patient before starting therapy. A meta-analysis of nine placebo-controlled trials including roughly 119,000 patients reported that vitamin E supplementation increases the risk of hemorrhagic stroke by 20% while reducing ischemic stroke by 10%. It was estimated that vitamin E supplementation would prevent one ischemic stroke per 476 treated patients while inducing one hemorrhagic stroke for every 1,250 patients. It is noteworthy that the combination of vitamin E with anticoagulant and/or antiplatelet therapy was not examined in this trial, so we could not determine how combination therapy might affect the risk of ischemic or hemorrhagic stroke.45
Thiazolidinediones drugs have been reported to be effective in improving NAFLD in many human studies. Evidence from RCTs suggests that pioglitazone could significantly improve glucose metabolism, alanine aminotransferase, and liver histology – such as hepatic steatosis, lobular inflammation, and ballooning degeneration – among patients with or without T2D. However, the beneficial effects on improving fibrosis remain to be verified.1,46 Because of safety concerns, the risk/benefit balance of using pioglitazone to treat NASH should be discussed with each patient.47-48 Pioglitazone has been associated with long-term risk of bladder cancer,49 congestive heart failure,50 and bone fractures.51 Data from the Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis (PIVENS) trial showed that pioglitazone was significantly associated with weight gain but with no other serious adverse events. However, this study was not powered to test any safety-related hypotheses.44
Glucagon-like peptide 1 analogs have been reported to induce weight loss and reduce insulin resistance, which may lead to improvements in NAFLD. Phase II RCTs of glucagon-like peptide 1 receptor agonists (liraglutide and semaglutide) for the treatment of biopsy-proven NASH showed significant improvements in serum liver enzymes, steatosis, and inflammation, as well as NASH resolution without worsening liver fibrosis, although no direct benefit was observed in reversing fibrosis.52-53 One of these studies explores the efficacy and safety of different doses of daily subcutaneous semaglutide vs. placebo on the rates of resolution of NASH with no worsening of fibrosis. The highest dose (0.4 mg) showed the greatest difference (59% vs. 17%, P less than .01), compared with the placebo arm. However, there was no difference in improvement in fibrosis stage between the two groups (43% in the 0.4-mg group vs. 33% in the placebo group, P = .48).53 Gastrointestinal adverse events were common in the semaglutide arm.
“Spontaneous” NASH resolution and fibrosis improvement are commonly seen in participants assigned to placebo arms in clinical trials. A recent meta-analysis of 43 RCTs including 2649 placebo-treated patients showed a pooled estimate of NASH resolution without worsening of fibrosis and 1 stage reduction or more in fibrosis of 12% and 19%, respectively. Relevant factors involved in “spontaneous” NASH improvement are unknown but could be related to changes in BMI resulting from lifestyle changes, race and ethnicity, age, and, likely, NAFLD-related genetic variations, although more data is needed to better understand the histologic response in placebo-treated patients.54
Semaglutide injections (2.4 mg once weekly) or (2.0 mg once weekly) have been recently approved by the FDA for chronic weight management in adults with obesity or overweight with at least one weight-related condition or glucose control of T2D, respectively. Of note, the semaglutide dose used in the NASH trial is not currently available for the treatment of patients who are overweight/obese or have T2D, but the beneficial effects on body weight reductions and glucose control are similar overall to the effects seen with currently available doses for management of obesity or diabetes. One may consider using semaglutide in patients who are overweight/obese or have T2D with NASH, but in the senior author’s experience, it has been quite challenging to receive the payer’s approval, as its use is not specifically approved to treat liver disease.1
