Management of Rosiglitazone-Induced Edema: Two Case Reports and a Review of the Literature

Abstract

The thiazolidinediones are an important class of insulin-sensitizing agents used for the treatment of type 2 diabetes. Similar to other antidiabetic agents, use of the thiazolidinediones is limited by adverse drug reactions. Specifically, use of the thiazolidinediones is associated with a triad of fluid retention, edema, and weight gain. In premarketing clinical trials, edema was reported to occur infrequently with minimal severity. However, several published cases from postmarketing data demonstrate that thiazolidinedione-induced fluid retention, exhibited by the initial onset of peripheral edema and weight gain, can progress to a more severe form of pulmonary edema that is refractory to diuretic therapy with resolution of symptoms only through discontinuation of the offending thiazolidinedione. In clinical practice, the occurrence of edema secondary to a thiazolidinedione drug may occur more frequently than reported. Two cases presented in this report illustrate a different outpatient management approach that enables both desired glycemic control and minimal fluid retention while using the thiazolidinediones.

Mechanism and Implications of Brown Adipose Tissue Proliferation in Rats and Monkeys Treated with the Thiazolidinedione Darglitazone, a Potent Peroxisome Proliferator-Activated Receptor-γ Agonist

“…For example, fluid extravasation into tissue, in the form of peripheral and pleural edema, can be caused by several mechanisms. Troglitazone and rosiglitazone increase endothelial permeability (see review by Wang et al, 2002), whereas troglitazone, but not rosiglitazone, has vasodilatory properties by itself (Walker et al, 1998). Insulin has both vasodilatory (McNally et al, 1995) and hemodynamic (Baron, 1994) properties.…”

GI262570, a Peroxisome Proliferator-Activated Receptor γ Agonist, Changes Electrolytes and Water Reabsorption from the Distal Nephron in Rats

“…Ϫ symport) and thiazide or thiazide-like diuretics (inhibit Na ϩ -Cl Ϫ symport) are used (Niemeyer and Janney, 2002;Wang et al, 2002;Kermani and Garg, 2003;Mudaliar et al, 2003;Tang et al, 2003). In most cases, the edema appears to be refractory to diuretics until the TZD therapy is discontinued.…”

“…Although adipogenesis in the subcutaneous adipose tissue contributed to the weight gain, it has been documented that some patients also had increased plasma volume and fluid retention (Wang et al, 2002;Mudaliar et al, 2003). In some cases, patients even developed peripheral edema or congestive symptoms, which is reversible after drug withdrawal (Wang et al, 2002;Kermani and Garg, 2003;Tang et al, 2003). Both fluid retention and overt clinical edema typically developed within the first few months of drug administration (Niemeyer and Janney, 2002;Kermani and Garg, 2003).…”

Increased susceptibility of db/db mice to rosiglitazone-induced plasma volume expansion: role of dysregulation of renal water transporters

“…The severity of the side effect increases in patients treated with TZD in combination with insulin therapy (15). The fluid retention is often resistant to loop diuretics until the TZD therapy is discontinued (12,17,28).The mechanism of TZD-induced fluid retention has been extensively investigated. Abundant evidence supports increased renal tubular transport as a major contributor of TZDinduced fluid retention although extrarenal mechanisms also play a role.…”

“…The severity of the side effect increases in patients treated with TZD in combination with insulin therapy (15). The fluid retention is often resistant to loop diuretics until the TZD therapy is discontinued (12,17,28).…”