The finding and conclusions of the recent article published by Boden et al. (1) need to be interpreted with caution in view of several factors.
The authors state that the combination of rosiglitazone (RGZ) and fenofibrate (FFB) “completely prevented the water retention and weight gain associated with RGZ.” FFB has significant peroxisome proliferator–activated receptor (PPAR)-α activity (2,3) and is widely used for the treatment of hyperlipidemia.
A small number of patients, n = 13, was studied. Of these, five patients, who were used as the RGZ control group, were taken from a separate previously published study (4). The study was not designed to test the hypothesis of prevention of fluid retention, and indeed the design was totally inadequate for this purpose.
RGZ alone, in the five patients from a different study treated for 2 months, did not affect free fatty acid (FFA) levels. In fact, FFA levels tended to increase. This finding is inconsistent with the published literature, which shows a highly significant FFA-lowering effect of PPAR-γ agonist therapy (5,6).
Table 1 reports data on total body water only. Changes in extracellular fluid volume compartment would be more relevant in the context of PPAR-γ–induced fluid retention. No separation between fat mass accumulation and fluid retention as contributors to weight gain is provided.
Because of the PPAR-α agonist properties of FFB, the combination of RGZ and FFB would be expected to act as a PPAR-γ/PPAR-α agonist. Current data suggest that dual PPAR agonists are significantly more likely to result in fluid retention and edema and possible adverse renal and cardiovascular outcomes, particularly congestive heart failure (7,8). These findings have resulted in two pharmaceutical companies halting their dual PPAR-γ and -α programs (9,10).
We believe that the use of FFB in combination with RGZ should not be advocated as a useful strategy to prevent PPAR-γ–induced fluid retention. Extrapolations from the results of this small, non–ad hoc designed study for the management of fluid retention with thiazolidinediones are unwarranted.
