There has been concern that use of orlistat (Xenical®) may be associated with an increased risk of serious hepatic events. The European Medicines Agency reviewed the strength of evidence relating to this possible risk and concluded in February 2012 that there is no strong evidence to determine a causal association, and that there was no known mechanism by which orlistat was expected to cause liver disorders.
The authors of the current study discuss the limitations of the safety data currently available, noting that analysis of individual case reports is not usually able to give reliable conclusions about causality, and that population-based studies are required to help inform decisions about the likely risks and benefits of orlistat. This was the first study based on use of orlistat in the real-world setting, and it utilised a self-controlled case series design to avoid inherent biases (those using orlistat are likely to have different risks of liver injury to non-users, due to obesity and its co-morbidities).
The study included 94,695 patients who had received at least one prescription for orlistat who were registered in the UK Clinical Practice Research Datalink (formerly the General Practice Research Database) and linked with Hospital Episode Statistics data between 1999 (launch date of orlistat) and 2011. From these 988 eligible cases of acute liver injury were identified (335 definite and 653 probable). The incidence of liver injury during periods of exposure to orlistat was compared with that observed during non-use in the 988 identified cases.
The main finding of the study was that the risk of liver injury was increased in the periods immediately before (90 days) and after (30 days) the start of orlistat treatment, and the authors suggest that this may have reflected changes in health status associated with the decision to begin treatment rather than any causal effect of the drug. An analysis restricted to definite cases showed no evidence of an increased risk of liver injury during treatment. Most of the events were raised liver function test results (99% of those occurring during orlistat treatment) and serious liver events were rare. These results are likely to be generalisable to other populations receiving orlistat, as the database used is representative of the UK population.
Potential biases of the study included the use of prescription issue to determine use of orlistat (may have overestimated use), however the authors note that the median duration of use was over a year, and that people would be unlikely to obtain repeat prescriptions for this length of time for a drug that they were not using. Sensitivity analyses found that the results were robust to some other potential biases.
The authors comment on how studies based only on traditional epidemiological designs and spontaneous adverse event reports are likely to detect associations between starting orlistat and liver injury, and how they should not be interpreted as evidence for a causal association unless an increased risk in the period immediately before the start of treatment can be excluded.