Eschewing the Fat: What's on the Horizon for Treating NASH?

William F. Balistreri, MD


March 10, 2015

In This Article

FXR Agonists

Obeticholic acid (OCA). Bile acid signaling is a critical regulator of glucose and energy metabolism, mainly mediated by FXR and TGR.[13,14] Activation of FXR, a nuclear hormone receptor regulated by bile acids, may be an effective approach for the treatment of NASH.[15]

A promising agent is a semi-synthetic bile acid derivative, OCA, a first-in-class FXR agonist. OCA was shown to have antifibrotic properties in murine models.[16] Studies aimed at treating NASH with OCA in humans have shown promise, potential, and problems.[17,18,19]

In a multicenter double-blind clinical trial involving 283 individuals at eight centers, OCA was compared with placebo.[20] Patients with NASH who received OCA (25 mg/day for 72 weeks) had an improvement in histologic features of NASH (steatosis, inflammation, and liver-cell injury), a reduction in biochemical markers of hepatic damage (aminotransferase levels), and reduced body weight compared with placebo recipients. There was a mild, but significant, improvement in fibrosis; 35% of OCA-treated patients regressed by one stage or more vs 19% of placebo-treated patients.

OCA administration, however, was associated with unintended adverse effects. A higher percentage of patients in the OCA group developed highly troublesome pruritus compared with the control group (23% vs 6%, respectively).[20] It is not clear whether a lower dose of OCA would be associated with less itching. Furthermore, there was an unanticipated increase in total serum cholesterol levels in the OCA recipients—this included increased low-density lipoprotein (LDL) cholesterol and reduced high-density lipoprotein (HDL) cholesterol. These findings were of specific clinical concern given the fact that patients with NASH are at higher risk for cardiovascular disease.[21] These adverse effects on cholesterol levels were not sustained after OCA was discontinued. Unfortunately, the improvement in liver enzymes was also not sustained after OCA was stopped. Management of elevated cholesterol levels (for example, with statins) was not a standardized component of the study, and long-term assessment of cardiovascular outcomes will be required. However, these results may represent an important advance in the search for therapeutic options to halt the progression of NASH.

Fexaramine. Bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine was shown to alter bile acid composition. This agent works solely in the intestine and thus does not activate FXR target genes in the liver.

Fexaramine was shown to slow diet-induced weight gain, inflammation, and hepatic glucose production in mice, while enhancing thermogenesis and browning of white adipose tissue.[22] The net effect is similar to the postprandial state—with "burning" of calories. These pronounced metabolic improvements suggest that tissue-restricted FXR activation is a valid approach to the treatment of obesity and metabolic syndrome. Clinical trials in patients with NASH are eagerly awaited.

Semisynthetic bile acid analogs: dual FXR-TGR5 receptor agonists. Roda and colleagues[23] reported the relationship between the structure-pharmacokinetics, metabolism, and therapeutic activity of other semisynthetic bile acid analogs, including 6-alpha-ethyl-3-alpha,7-alpha-dihydroxy-5-beta-cholan-24-oic acid (another selective FXR agonist), 6-alpha-ethyl-23(S)-methyl-3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholan-24-oic acid (a specific TGR5 receptor agonist), and 6-alpha-ethyl-3-alpha,7-alpha-dihydroxy-24-nor-5-beta-cholan-23-sulfate (a dual FXR/TGR5 agonist).

Miyazaki-Anzai and colleagues[13] demonstrated that concurrent activation of FXR and TGR5 attenuated atherosclerosis by reducing both circulating lipids and inflammation, suggesting a potential for benefit in patients with NASH.


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