Glycerol Phenylbutyrate for Hepatic Encephalopathy?

March 12, 2014

Glycerol Phenylbutyrate for Hepatic Encephalopathy?

  1. Atif Zaman, MD, MPH

Results of a phase II trial show efficacy in patients with cirrhosis and recurrent HE.

  1. Atif Zaman, MD, MPH

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%).


This phase II study demonstrates that glycerol phenylbutyrate is effective in reducing hepatic encephalopathy events in patients with cirrhosis and recurrent HE. This was true even in patients on lactulose, rifaximin, or both. Once these results are validated in phase III trials, GPB will be another therapeutic option for hepatic encephalopathy.

Editor Disclosures at Time of Publication

  • Disclosures for Atif Zaman, MD, MPH at time of publication Speaker’s bureau Bristol-Myers Squibb; Genentech; Gilead; Kadmon; Merck; Salix; Vertex


Reader Comments (2)

javier Bori Physician, Gastroenterology, Hospital

How exactly is de glycerol GPB acting??.And its advers effects??
Thank you
Dr Bori

Marcia Ratner, PhD Other, Pharmacology/Pharmacy, BUSM

Many patients are non-compliant with their lactulose regime due to the diarrhea it causes and this noncompliance is what actually lands them in ER with encephalopathy. Therefore, the availability of a therapeutic option that facilitates conversion of ammonia to urea rather than promoting its excretion in the feces will be great news for these patients.

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