Glycerol Phenylbutyrate for Hepatic Encephalopathy?

The mainstay treatment of hepatic encephalopathy (HE) includes lactulose or enulose (poorly absorbed disaccharides) and rifaximin (an antibiotic). Whereas these agents likely act by reducing ammonia production and absorption in the intestine, glycerol phenylbutyrate (GPB) directly lowers ammonia by providing an alternate pathway to urea. Currently approved for the treatment of urea cycle disorders, GPB is now being studied for its potential in treating HE.

In the current industry-funded, double-blind phase II trial, investigators randomized 178 patients with cirrhosis and a history of HE (defined as ≥2 events in the previous 6 months) to receive 6 mL of GPB or placebo twice daily with food for 16 weeks. The primary endpoint was the proportion of patients with HE events.

Based on intention-to-treat analysis, 137 patients (77%) were taking lactulose at baseline and 59 (33%) were taking rifaximin; these percentages were similar between study groups. Compared with the placebo group, the GPB group had a lower rate of HE events (21% vs. 36%; P=0.02) and fewer hospitalizations (13 vs. 25; P=0.06). Among the 119 patients not receiving rifaximin, development of HE was lower in the GPB group than in the placebo group (10% vs. 32%; P<0.01). Plasma ammonia levels were significantly lower with GPB versus placebo and correlated strongly with HE events. Rates of adverse events were similar between the GPB and placebo groups (79% and 76%).