Management of nonalcoholic steatohepatitis: Pharmacotherapy

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Abbreviations

ALT

alanine aminotransferase

NASH

nonalcoholic steatohepatitis

PIVENS

Pioglitazone or Vitamin E for NASH Study

UDCA

ursodeoxycholic acid

Nonalcoholic steatohepatitis (NASH) is a common liver disease that increases liver‐related mortality and reduces survival; hence, optimal management is a priority for today's practicing hepatologist. Because NASH is linked to excess body weight and resulting insulin resistance, diet and lifestyle measures are the recommended first‐line therapy. Unfortunately, in many patients, these measures cannot be implemented efficiently or maintained in the long run. Besides, the liver injury can be advanced enough to justify a specific therapy; therefore, there is a need for pharmacological therapies aimed at improving NASH.

Insulin‐Sensitizing and Antidiabetic Agents

Thiazolidinediones (Glitazones)

Glitazones are peroxisome proliferator‐activated receptor gamma agonists with potent insulin‐sensitizing activity, and they are marketed for the treatment of type 2 diabetes. They promote the differentiation of adipocytes into small, insulin‐sensitive adipocytes. With long‐term treatment, fat storage is redirected from the liver and muscles and toward the adipose tissue, which alleviates hepatic and muscle insulin resistance. Glitazones also increase the levels of adiponectin, which is an antisteatogenic and anti‐inflammatory cytokine that is reduced in nonalcoholic fatty liver disease. There are several open‐label and controlled studies with pioglitazone or rosiglitazone as well as one pediatric trial with pioglitazone; they are fairly heterogeneous with respect to the daily doses, the duration of therapy, and the included populations (diabetics or nondiabetics).1 The largest trial so far compared pioglitazone (at a low dose of 30 mg/day), vitamin E (800 IU/day), and a placebo for 2 years in nondiabetic patients [Pioglitazone or Vitamin E for NASH Study (PIVENS)].2 Although the primary endpoint of histological improvement (which was defined as a reduction in the nonalcoholic fatty liver disease activity score without worsening of fibrosis) was not formally met, pioglitazone improved all individual histological features (except for fibrosis) and, in particular, significantly enhanced the resolution of steatohepatitis (another important primary endpoint in NASH clinical trials). Importantly, when the analysis was limited to patients with well‐defined steatohepatitis upon inclusion, the primary endpoint was reached with pioglitazone (P < 0.025). The histological benefit occurred together with an improvement in alanine aminotransferase (ALT) levels and a partial correction of insulin resistance.2 Similar results have been reported for two other randomized trials with durations of 6 months and 1 year.3 For reasons that are still unclear, rosiglitazone failed to show histological benefits even though there was a significant reduction in steatosis as well as biochemical (ALT) and metabolic responses [homeostasis model assessment (a surrogate marker of insulin sensitivity)]. Most of these effects occurred in the first year of therapy, and prolonged therapy for up to 3 years did not result in further improvements.

Unfortunately, the safety and tolerability of glitazones considerably limit their therapeutic potential.1 Weight gain is frequent and is not always reversible with discontinuation. Bone fractures in women seem to be due to an increased rate of bone loss with both glitazones. Congestive heart failure, although it is very rare, has warranted a black‐box warning for both glitazones. Recently, the demonstration of an increased risk of bladder cancer with pioglitazone justified its market withdrawal in some European countries. There seems to be an increased risk of cardiovascular events and especially myocardial infarction with rosiglitazone, and this drug has been withdrawn from many European countries. Recently published multisociety practice guidelines recommend that pioglitazone be used to treat steatohepatitis in patients with biopsy‐proven steatohepatitis, but they caution that its long‐term safety and efficacy in patients with NASH have not been established.4

Metformin

Metformin is a safe and inexpensive antidiabetic drug that reduces hepatic glucose production and can induce weight loss. Early open‐label studies suggested histological improvements, but this was not confirmed by more recent studies, randomized trials, and meta‐analyses. Presumably, higher weight loss in some patients could explain histological improvements. The antisteatogenic effect of metformin is weak and is consistent with its inability to restore serum adiponectin levels. Metformin is, therefore, not recommended for the treatment of NASH in either children or adults.4

Hepatoprotectants

Ursodeoxycholic Acid (UDCA)

UDCA is a natural hydrophilic bile acid with numerous in vitro cytoprotective activities. High doses (20‐30 mg/kg/day) significantly reduced ALT levels in comparison with a placebo, but two randomized trials did not show histological efficacy.5 Therefore, UDCA cannot be recommended for patients with NASH.

Vitamin E

Vitamin E (α‐tocopherol) is a naturally occurring antioxidant. A 2‐year treatment in the PIVENS trial (800 IU/day) reversed steatohepatitis and improved all histological features of NASH (except fibrosis) in comparison with a placebo.2 Interestingly, this beneficial effect of vitamin E was not associated with an improvement in insulin sensitivity. The 2‐year Treatment of Nonalcoholic Fatty Liver Disease in Children trial confirmed the clearance of NASH and improvements in ballooning degeneration.7 Notably, there was no effect on steatosis or inflammation, and despite prolonged therapy, there was still no effect on fibrosis. Moreover, the primary endpoint, a reduction in ALT, was not significant. A smaller pediatric Italian trial failed to show any histological or biochemical efficacy with the combination of vitamin E (600 IU/day) and vitamin C, although the trial might have been confounded by marked weight loss in both arms.8 Controversy over long‐term safety is ongoing, with recent studies and meta‐analyses having shown increased mortality, a risk of hemorrhagic stroke, and a risk of prostate cancer.

Pentoxifylline

A small randomized trial has shown some histological efficacy in patients with NASH (mainly reductions in steatosis and inflammation) but no changes in ballooning.9 A marginal effect on fibrosis has been reported. These promising but very preliminary results await further validation.

Weight‐Loss Agents

Orlistat, an enteric lipase inhibitor, was not better than a placebo for the improvement of liver histology and aminotransferases.10 It also failed to achieve weight loss in the two available randomized trials. It is not recommended for the treatment of NASH.

Conclusion

Current guidelines do not recommend the use of hepatic pharmacological therapy in patients with steatosis alone.4 Instead, patients with NASH and significant liver disease (bridging fibrosis) are good candidates for therapy. According to the clinical practice guidelines of the American Association for the Study of Liver Diseases, the first choice of therapy is vitamin E (preferably 800 IU/day in an α‐tocopherol formulation). The most data are available for glitazones, and pioglitazone is an alternative, evidence‐based choice for the treatment of NASH.4 The duration of therapy is unknown, and tolerability (especially weight gain) could be a limiting factor. Notably, almost all data have been generated from patients with NASH but without diabetes, so extrapolating the efficacy (and safety) data from the aforementioned trials to diabetic populations warrants caution. Because of the black‐box warnings for glitazones and their limited availability in many countries and because of the contrasting efficacy results for vitamin E, these drugs will probably not be the choice therapies for NASH in future years. The results of current phase 2b trials will most certainly set the stage for the future of pharmacological therapy in patients with NASH.