Unclear how orlistat's mechanism can lead to liver damage. Likely a non-issue.

Orlistat is designed to act peripherally in the GI tract and studies have demonstrated negligible systemic absorption of orlistat. Patients suffering from liver damage are either hypersensitive to orlistat or have taken too much of the drug. It is likely that these cases of liver injury are unrelated to orlistat, since obesity predisposes patients for liver damage. But overall cases of liver damage are small compared to the total number of patients who have taken the drug over the years.

Orlistat (Roche Pharmaceutical's Xenical, GSK's Alli) is widely perceived by physicians as being the safest obesity drug available on the market due to its peripheral mechanism of action. Although the drug's mechanism of action causes unpleasant gastrointestinal side effects, the fact that the drug does not exert its action via the central nervous system like other obesity drugs (sibutramine [Abbott's Meridia] and phentermine [UCB's Ionamin, GSK's Fastin]) has been an important driving force that has made orlistat the most widely prescribed obesity drug worldwide.

 

Reports that there have been 32 cases of serious liver injury over the ten-year period that orlistat has been available in the US market, including 27 cases requiring hospitalization and 6 cases of liver failure, come at a surprise and it is unclear how a peripherally-acting drug can cause such damage to the liver.

 

Studies utilizing 14C-labeled orlistat have demonstrated that negligible amounts of orlistat are absorbed into body if therapeutic levels of the drug are ingested (Zhi J, 1995). Thus it is possible that there are certain individuals that are hypersensitive to the small amount of absorbed orlistat, or else those patients who suffered liver injuy took substantially higher amounts of the standard 120 mg tid dose of the drug. However, until additional data become available, there is nothing to indicate that there is a direct link between orlistat and the cases of liver damage that have been noted because the obese patient population is already at elevated risk for liver abnormalities.

 

Given that the overall cases of liver damage are so low compared to the overall millions of patients who have been treated with orlistat over the ten-year period, the bottom line is that this will not likely be a significant issue that will impact prescribing of orlistat. If there was a strong causal link or a more common event, then these cases of liver damage would have been observed within the first two years of orlistat's launch when the drug experienced peak usage.