Reply

Abstract

To the Editor: I have noted the comments made by Bays and Musliner in their assessment of the case of ezetimibe-induced hyperlipidaemia we described (1). In reply to their issues of lifestyle in this patient, no changes in drug therapy or lifestyle occurred over the periods of ezetimibe administration. This patient's lipid profile has shown a great deal of stability over the last decade except when she was prescribed ezetimibe. An immediate pre-treatment assessment was not performed as the patient was prescribed ezetimibe on a compassionate use protocol and so travelled specially to pick up her prescription. Little is known about the long-term actions of ezetimibe. The Niemann-Pick C1 Like 1 (NPC1L1) protein shows substantial expression outside the duodenum, including in the liver and in muscle (2). A prolonged action of ezetimibe cannot be excluded as there are few data on the effects of this drug on these tissues, and the plasma half-life of the drug may not be relevant to its actions. Ezetimibe is known to have a widely variable response profile and may be subject to pharmacogenetic variations in NPC1L1 (3). This case may illustrate an extreme variant of this. Lathosterol was measured in this individual to assess the source of her excess very low density lipoprotein (VLDL) and to exclude paradoxical increased intestinal cholesterol uptake. Ezetimibe does not have a generic action on all phytosterols; it reduces sitosterol levels but not sitostanol levels: these are handled differently by the intestinal enterocytes (4). Other cases where LDL-C was increased with ezetimibe therapy exist (Wierzbicki and Crook; unpublished data) as do reports of abnormal transaminases, pancreatitis, rhabdomyolysis and chronic myalgia induced by this agent 5-8). In this case, the patient did not have myalgia, had a minimal transaminase elevation and did have some minor abdominal pains but with no evidence of pancreatitis (normal amylase). It is possible that some of the reported case of ‘pancreatitis’ with ezetimibe may be homologues of this one as severe mixed hyperlipidaemia is often found in acute pancreatitis. The exact side-effect profile of ezetimibe will emerge in due course, and in most individuals ezetimibe is a welcome addition to the lipid-lowering formulary. However, the deficiencies of licensing trials in ascertaining rare, but significant, side-effects are well known and indeed such reports have formed the basis of later formal regulatory surveillance of new compounds once marketed. The purpose of such case reports is to describe such side-effects in detail for the benefit of other physicians who may be able to identify further cases of similar responses, and thus allow clarification of the mechanism by which these rare phenomena occur.